Thyroid-stimulating Immunoglobulin Research Articles

The Early Changes in Thyroid-Stimulating Immunoglobulin Bioassay over Anti-Thyroid Drug Treatment Could Predict Prognosis of Graves' Disease.

To determine whether baseline thyroid-stimulating immunoglobulin (TSI) bioassay or its early response upon treatment with an anti-thyroid drug (ATD) can predict prognosis of Graves' disease (GD) in real-world practice. This retrospective study enrolled GD patients who had previous ATD treatment with TSI bioassay checked at baseline and at follow-up from April 2010 to November 2019 in one referral hospital. The study population were divided into two groups: patients who experienced relapse or continued ATD (relapse/persistence), and patients who experienced no relapse after ATD discontinuation (remission). The slope and area under the curve at 1st year (AUC1yr) of thyroid-stimulating hormone receptor antibodies including TSI bioassay and thyrotropin-binding inhibitory immunoglobulin (TBII) were calculated as differences between baseline and second values divided by time duration (year). Among enrolled 156 study subjects, 74 (47.4%) had relapse/persistence. Baseline TSI bioassay values did not show significant differences between the two groups. However, the relapse/persistence group showed less decremental TSI bioassay in response to ATD than the remission group (-84.7 [TSI slope, -198.2 to 8.2] vs. -120.1 [TSI slope, -204.4 to -45.9], P=0.026), whereas the TBII slope was not significantly different between the two groups. The relapse/persistence group showed higher AUC1yr of TSI bioassay and TBII in the 1st year during ATD treatment than the remission group (AUC1yr for TSI bioassay, P=0.0125; AUC1yr for TBII, P=0.001). Early changes in TSI bioassay can better predict prognosis of GD than TBII. Measurement of TSI bioassay at beginning and follow-up could help predict GD prognosis.

Short- and long-term outcomes of patients with hyper or hypothyroidism following COVID vaccine.

Since the beginning of the wide-scale anti-Coronavirus disease 2019 (COVID-19) vaccination program, sporadic cases of thyroid disease following vaccination have been reported. We describe 19 consecutive cases of COVID vaccine-related thyroid disease. Medical records were reviewed for 9 patients with Graves' disease (GD) and 10 with Thyroiditis, all of whom were diagnosed following COVID-19 vaccination. In the GD group, the median age was 45.5 years, female/male(F/M) ratio 5:4, thyroid-stimulating immunoglobulins were elevated in seven patients. The median time from vaccination to diagnosis was 3 months. Methimazole treatment was given to all but one patient. At a median follow-up of 8.5 months from vaccination, three patients were still on methimazole, five went into remission (data were missing for one). In the Thyroiditis group, the median age was 47 years, the F/M ratio 7:3. Thyroiditis was diagnosed after the first, second, and third doses in one, two, and seven patients, respectively. The median time from vaccination to diagnosis was 2 months. TPO antibodies were positive in three patients. All patients were euthyroid off medication at the last visit. Six patients were diagnosed in the hypothyroid phase at 2.5 months from vaccination. Four resolved spontaneously at 3, 6, 4, and 8 months; the other two were treated with thyroxine at 1.5 and 2 months from vaccination and remained on treatment at their last visit, at 11.5 and 8.5 months, respectively. Thyroid disease should be included among possible complications of COVID-19 vaccine and either a late onset or delayed diagnosis should be considered.

Abstract #1401671: Hashimoto’s Disease with Thyroid Eye Disease, Negative TRAB and Positive TPO Antibodies Treated with Teprotumumab

Thyroid Eye Disease (TED) is most commonly associated with hyperthyroidism secondary to Graves’ disease (GD). The disease activity of TED is positively correlated with the presence of thyrotropin receptor antibodies (TRAB). Some with TED are euthyroid at presentation but have positive TRAB. Less frequently, patients with Hashimoto’s disease have TED, the majority of which are TRAB positive. We present a unique case of euthyroid TED with negative TRAB but positive thyroid peroxidase antibodies (TPO Ab) treated with teprotumumab. A 65-year-old African-American male presented with a 9-day history of gradually worsening vision, ocular pain, and bilateral eye bulging. His best-corrected visual acuity at near was 20/200 right eye and 20/400 left eye with full peripheral vision by confrontation. Pupils were equal and reactive to light with normal intraocular pressure. There was bilateral upper eyelid retraction, diffuse conjunctival injection, proptosis, and diffuse external ophthalmoplegia. His clinical activity score was 7. The thyroid exam was normal. Computed Tomography (CT) scan of the orbits showed significant, tendon-sparing enlargement of all extraocular muscles along with bilateral orbital apex crowding. Bilateral compressive optic neuropathy from severe TED was suspected. TSH, free T4, and T3 were normal. TPO Ab was positive but TRAB was negative by both binding inhibitory and Thyroid Stimulating Immunoglobulin (TSI) assays. He was treated with high-dose intravenous methylprednisolone for 5 days followed by 2 weeks of oral prednisone. One month after presentation treatment was initiated with 8 infusions of teprotumumab with complete resolution of all ocular symptoms and restoration of normal vision. Six months after the last dose of teprotumumab he remains euthyroid with negative TRAB and positive TPO Ab. TED is uncommon in euthyroid individuals. Most have positive TRAB and many ultimately develop hyperthyroidism. Even less common are those with Hashimoto’s thyroiditis (HT) presenting with TED. Teprotumumab is the only Food and Drug Administration-approved medication to treat TED. Our patient with vision-threatening TED had a remarkable response to teprotumumab with the restoration of normal vision and resolution of TED. We could not identify any other reports of a patient with euthyroid HT with positive TPO Ab but negative TRAB treated with teprotumumab. Physicians should be mindful of this unusual presentation to detect cases early and institute appropriate treatment to prevent visual complications.

Abstract #1406483: Thyroid Hormone Resistance Diagnostic and Therapeutic Challenges

Resistance to thyroid hormone (RTH) is a clinical syndrome defined by impaired sensitivity to thyroid hormone (TH). We present the challenges in diagnosing and treating a 24-year-old male who presented with a mixed picture of hypothyroidism and hyperthyroidism with elevated TSH, upper normal free T4, and elevated free T3 and was found to have a mutation in the THRβ gene. A 24-year-old male was referred for a second opinion of post-ablative hypothyroidism with elevated TSH, elevated free T3, and suspicion of pituitary microadenoma. He complained of fatigue, weight gain, tremors heat cold intolerance. Family history is Graves’ disease in his mother's status post partial thyroidectomy due to a salivary tumor. Initially, in 2020, he was diagnosed with negative antibody Grave’s disease. Labs were TSH 0.86 mIU/L, free T4 1.99 ng/dl (0.89-1.76), and free T3 4.66 pg/ml (2.3-4.2). A thyroid ultrasound showed mild thyromegaly. A thyroid uptake scan showed 24-hour thyroid uptake of 36.7%. Thyroid antibodies including thyroglobulin, TPO, thyroid receptor, and thyroid stimulating immunoglobulin were negative. He was treated with radioactive iodine ablation (I-131). Afterward, His TSH increased gradually along with free T3. Free T4 was normal. The patient remained symptomatic, and he was not on any thyroid replacement therapy. A repeat thyroid uptake scan showed an increase uptake of 36% at 24 hrs. During our evaluation, a repeat TSH 54.05 mIU/l, free T4 1.3 ng/dl, free T3 4.3 pg/ml, and T3 by equilibrium dialysis 4.0. A repeat magnetic resonance imaging of the head showed no definitive focal enhancing lesion. Pituitary axis hormones were normal, and the alpha subunit was 0.73 (high); however, the alpha-glycoprotein subunit /TSH molar ratio 0.135 sex hormone binding globulin 5.8 nmol/l (low), macro TSH was not detected. These findings raised suspicion for THRB mutation; hence genetic studies were obtained. PCR amplification of THRB gene exons 10, 9, and 8, followed by gene sequencing, showed a heterozygous missense mutation C >G located at exon 10. The mutation caused a change in thyroid hormone receptor beta protein amino acid 453 proline to an alanine, P453A Initially, he was started on levothyroxine 25 mg PO daily but soon after, it was stopped due to palpitations; a beta blocker was started along with liothyronine 5 mg every other day and levothyroxine 50 mg every other day. The patient tolerated the regimen with significant improvement in his symptoms. RTH is rather uncommon; it is important to be able to recognize the syndrome to avoid unnecessary invasive treatment. There is no specific therapy currently available to fully correct the TRβ defect. The goal of treatment is based on the patient's symptoms and clinical picture instead of aiming to normalize thyroid hormone levels. Thyroidectomy and radioactive iodine ablation result in lifelong levothyroxine replacement therapy and RTHβ persistently high serum TSH. Levothyroxine therapy is challenging, and supraphysiologic doses are often needed to maintain serum TSH in the lowest tolerable level.

Abstract #1399287: New-Onset Thyroid Eye Disease After COVID-19 Infection in Patient with Graves’ Disease Post-Radioactive Iodine Treatment

Coronavirus disease 2019 (COVID-19) has been associated with dysregulation of the immune system and abnormal thyroid function. The aim of this novel case report is to inform physicians of the possibility that COVID-19 infection may precipitate thyroid eye disease (TED) in patients with Graves’ Disease (GD) even after treatment with radioactive iodine (RAI). In this report, we describe a patient with GD treated with RAI who developed TED after COVID-19 infection. The patient was initially diagnosed with GD in 2018. A thyroid uptake scan (I-123) was consistent with GD with moderately elevated uptake. She was initially managed with methimazole and atenolol and was eventually treated with RAI (16.32 millicurie I-131) in February 2021. She had post-ablative hypothyroidism managed with levothyroxine. The patient contracted COVID-19 in January 2022. In February 2022, the patient started experiencing eye irritation, dryness, protrusion of eyes, eyelid swelling, and visual disturbances. Thyroid stimulating hormone (TSH) receptor auto-antibodies (7.33 IU/L, normal < /=1.00 IU/L) and thyroid stimulating immunoglobulin (4.30 IU/L, normal < /=1.00 IU/L) were elevated. TSH was normal (2.180 mIU/L, normal 0.270 - 4.200 mIU/L) on levothyroxine 125 mcg daily. She was later diagnosed with TED. GD is an autoimmune thyroid disorder related to the presence of TSH receptor-stimulating antibodies and is often associated with ocular symptoms. Activation of an autoimmune response during COVID-19 infection, may induce onset or relapse of GD. A study using the national health insurance service database in South Korea noted an increase in the incidence of subacute thyroiditis in 2020 in association with the COVID-19 pandemic. TED is usually seen in patients with GD. Radioactive iodine is widely used in the treatment of GD and has been associated with development or worsening of TED. There are published cases of TED occurring in patients with GD after receiving COVID-19 vaccine. It is thought that the inflammatory syndrome induced by the adjuvants could induce molecular mimicry, which could trigger TED. In most cases this adverse effect was transient, lasting a few months after treatment. There have been case reports of TED occurring after 3 to 21 days of COVID-19 vaccination in patients with controlled GD. Symptoms improved in 4-8 months. Development of TED in patients with GD who have been treated with RAI typically occurs soon after RAI therapy. For TED to occur in a GD patient 11 months after receiving RAI therapy is unusual. COVID-19 infection appears to have been the trigger for this patient's eye disease. This is highly unusual and has not been published to our knowledge.

Abstract #1403045: Thyroiditis Post COVID-19 mRNA Booster Dose Vaccination

SARS-CoV-2 vaccines have been associated with thyroid dysfunction including thyroiditis and Graves' disease. We report a patient who developed thyrotoxicosis secondary to thyroiditis after COVID-19 mRNA booster dose vaccination. A 74-year-old man with no known personal or family history of thyroid disorders went to his primary care physician with symptoms of palpitations. Of note, he had the first booster (third dose) of the Pfizer/BioNTech vaccine about 1 week before. He did not recall any similar symptoms after the first two doses of the same vaccine. There were no other symptoms of thyrotoxicosis such as hand tremors, weight loss or mood change. There was no family history of thyroid disorders. He was not on any medications such as amiodarone and was not taking any herbal supplements. He did not have any symptoms of upper respiratory tract infection. There was no neck pain. Physical examination was unremarkable with no goiter or thyroid eye manifestations. Thyroid function: free T4 elevated at 46.7 pmol/L (11.5-22.7) and TSH suppressed at 0.01 mIU/L (0.5-4.5). Thyroid stimulating immunoglobulin was positive at 200% (50-179). He was initially started on carbimazole 15mg daily. However, the patient became rapidly hypothyroid despite dose reduction and subsequent discontinuation of carbimazole with free T4 of 8 pmol/L and TSH of 36.4 mIU/L. An ultrasound of the thyroid gland showed vascularity with no discrete nodules. No thyroid uptake scan was done. The diagnosis was revised to thyroiditis post vaccination. Hypothyroidism persisted despite discontinuation of carbimazole before recovery 8 months later. Patient was well and did not require any thyroxine supplementation. It is postulated that COVID-19 vaccines triggered thyroiditis via an autoimmune inflammatory syndrome caused by the vaccine adjuvants. A high index of suspicion is necessary and a thyroid uptake scan may be useful in making the diagnosis. Thyroiditis is a self-limiting condition and recognising it is important as no specific thyroid treatment is necessary in most patients. Patients should not be deterred from subsequent vaccination as COVID-19 infection has higher mortality risk than thyroiditis.

Abstract #1395500: Silent Thyroiditis as a Complication of Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine

Silent autoimmune thyroiditis, a type of chronic autoimmune thyroiditis, as an adverse effect of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is infrequently reported in the literature. We hereby describe a case of silent thyroiditis followed by Grave’s orbitopathy after vaccination against SARS-CoV2. An 84-year-old male presented to clinic with a 10-pound weight loss with no other symptoms of hyperthyroidism, no personal history of thyroid illnesses, or recent viral infections. He had normal thyroid function 3 months prior to presentation. He had received 3 doses of SARS-CoV2 Pfizer-BioNTech vaccine with the last dose 5 months prior to presentation. Thyroid exam was normal. Laboratory testing revealed thyroid stimulating hormone (TSH) level of 0.005 IU/ml (0.45-4.5 IU/ml), total T4 14.4 g/dl (4.5-12.1 g/dl), and total T3 1.22 nmol/l (0.6-1.81 nmol/l). Thyroid Ultrasound revealed a heterogeneous atrophic thyroid gland with no nodules or hypervascularity. He was started on Methimazole by primary care provider. Four months later, he was seen in the Endocrinology clinic and reported no hyperthyroidism symptoms. His TSH level at that time was 65.9 IU/ml, free T4 0.47 ng/dl (normal: 0.82-1.77 ng/dl), total T3 level 75 ng/dl (normal: 71-180 ng/dl), thyroid stimulating immunoglobulin 2.05 IU/l (0-0.55 IU/L), thyrotropin receptor antibody level 2.8 (0-1.75). Methimazole was discontinued. At 6 months after initial presentation laboratory testing showed TSH 5.010 IU/ml, free T4 1.2 ng/dl, thyroid peroxidase antibody of 148 IU/ml (normal 0-34 IU/ml), thyroglobulin antibody 131.6 IU/ml (normal 0.0-0.9 IU/ml). He was diagnosed with silent autoimmune thyroiditis. A few weeks later, the patient presented to an ophthalmologist with bilateral eye bulging and impaired vision. He was diagnosed with acute Graves’ orbitopathy and started on pulse-dose of intravenous Methylprednisolone 250 mg twice daily and urgently referred to a tertiary ophthalmology center for teprotumumab infusion. His thyroid function tests were normal at that time on no thyroid medications. The underlying mechanisms of thyroid impairment following SARS-CoV2 vaccination are not completely understood. There is a role of molecular mimicry between SARS-CoV2 antigens and thyroid antigens that may help to hasten the emergence of autoimmunity in vulnerable individuals. Our patient developed multiple thyroid-related antibodies following vaccination. Silent painless thyroiditis is a self-limiting condition, characterized by temporary thyrotoxicosis, followed by a brief period of hypothyroidism and then a complete return to normal thyroid function. A radioactive iodine uptake scan can help differentiate between the different causes of thyrotoxicosis in the acute thyrotoxic phase. Development of severe Graves orbitopathy following silent autoimmune thyroiditis after SARS COV2 vaccination has not been previously reported.

Abstract #1380270: Struma Ovarii: A Rare Cause of Hyperthyroidism That Can Be Missed

Struma ovarii is an extremely rare monodermal teratoma of the ovaries that produce thyroid hormone. We report a case of unexplained hyperthyroidism in a female patient that was found to have struma ovarii of the right ovary. A 59-year-old woman with a past medical history of hyperthyroidism was diagnosed 4 years ago. She started taking Methimazole approximately 2 years ago when she developed palpitations and was diagnosed with atrial fibrillation with rapid ventricular response. The patient was being evaluated for Graves' disease with a thyroid scintigraphy scan. The result showed decreased iodine uptake in the thyroid. She was also being evaluated for radioactive iodine ablation. The patient was admitted to the hospital due to atrial fibrillation with rapid ventricular response secondary to hyperthyroidism. Thyroid-stimulating hormone (TSH) was suppressed, free T4 and T3 were elevated. The thyroid ultrasound showed unremarkable findings and the nuclear medicine thyroid uptake scan showed decreased uptake in the thyroid. Thyroid peroxidase antibody (TPO-Ab), thyroid stimulating hormone receptor antibody (TSH-receptor Ab), thyroglobulin antibody, thyroid-stimulating immunoglobulin (TSI) were all negative. Due to unexplained hyperthyroidism, there was a concern about ectopic thyroid hormone production. The patient had pelvic ultrasound which showed a 4.5 x 4.1 x 3.4 cm right ovarian cyst. She underwent salpingo-oophorectomy of the right ovary. Pathology results confirmed struma ovarii. After the surgery, hyperthyroidism resolved, and she was taken off Methimazole. This patient presented with primary hyperthyroidism in the setting of normal thyroid ultrasound, thyroid uptake scan, and negative thyroid antibodies. The possibility of ectopic thyroid-producing tissue or tumor should be considered in the differential diagnosis. Struma ovarii is a specialized or monodermal teratoma predominantly composed of more than 50% of mature thyroid tissue or sufficient thyroid hormone production to cause hyperthyroidism. The most common presenting symptoms at the time of diagnosis was lower abdominal pain and palpable lower abdominal mass, but patients can be asymptomatic on presentation. Struma ovarii may mimic malignant ovarian tumors or sometimes can present with symptoms of hyperthyroidism. The treatment is surgical resection of the tumor. In rare cases, this tumor could be malignant and must be ruled out by histology.

Abstract #1405991: Graves’ Disease Presenting as Thymic Hyperplasia

Thymic hyperplasia associated with Graves' disease (GD) is well known to thyroidologist, and reported up to 38% of GD worldwide; however, it remains unrecognized in routine clinical practice. Here we report two cases of GD presenting as anterior mediastinum mass, consistent with thymic hyperplasia. I - A 41-year-old female presented with shortness of breath, chest pain, and nausea. She reported palpitations and unintentional weight loss over the last six months. There was no history of thyroid disease. Blood pressure was 162/86 mmHg, heart rate 94/minute, respiratory rate 26 breaths/minute, temperature 36.7 F, and body mass index 23.5 kg/m2. The thyroid was enlarged with mild tenderness. Laboratory showed TSH < 0.005 (0.358 to 3.74 mc IU/mL), free thyroxine 5.54 (0.76 to 1.46 ng/dL), thyroid-stimulating immunoglobulins 407% (0 to 140%). Computed tomography of the chest with contrast revealed an anterior mediastinal mass. GD was diagnosed, and she was started on standard therapy. II - A 54-year-old female presented with worsening shortness of breath, palpitations, and leg swelling for a several weeks. She reported progressive exertional shortness of breath for ten months, intermittent palpitations, fatigue, and weight loss for the last five months. She had a history of hypertension but no history of thyroid disease. At presentation blood pressure was 159/72 mm Hg, heart rate 102 beats/minute, respiratory rate 20/minute, temperature 37.1 F, and body mass index 32.7 kg/m2. She had atrial fibrillation with a rapid ventricular rate. Her examination showed mild bilateral proptosis and non-tender enlarged thyroid. Results showed TSH < 0.005 (0.358 to 3.74 mc IU/mL), free thyroxine 7.23 (0.76 to 1.46 ng/dL), free triiodothyronine 13.2 (2.18 to 3.98 pg/mL), anti-microsomal antibody (TPO) 315 (0 to 60 IU/mL), and thyroid-stimulating immunoglobulins (TSI) 429 (0 to 140%). Computed tomography of the chest with contrast revealed an anterior mediastinal mass. GD was diagnosed, and standard therapy was started. Discussion: Our two cases demonstrate GD-associated thymic hyperplasia later confirmed during hospitalization with MRI imaging. CT-imaging results were available at the same time or earlier than thyroid function tests but did not mention the differential diagnosis of GD or other autoimmune diseases which would help to avoid unnecessary interventions and guide therapy. Both patients were schedule to closely follow up with endocrinology and repeat imaging in about six months to one year is expected to show reduction in thymic size which would support the diagnosis of GD-associated hyperplasia.

Thyrotropin Receptor Autoantibody Assessment in Thyroid Eye Disease: Does the Assay Type Matter?

Thyroid receptor antibodies can quantify thyroid eye disease activity, predict outcomes and aid timing of interventions. The type and generation of assay is frequently unspecified, complicating meta-analyses. To determine the clinical and biochemical relationships between a second-generation thyrotropin receptor-binding inhibition antibody (TRAb) immunoassay, detecting stimulatory and blocking antibodies, with the thyroid stimulating immunoglobulin (TSI) bridging immunoassay detecting the stimulatory component only. Retrospective review of 100 consecutive patients attending a regional specialist service. For each patient and visit, both a TRAb and TSI were performed, and a clinical activity score (CAS) recorded. A significant positive correlation between TRAb and TSI (rho = 0.828, p < 0.01) but a weaker correlation between the assays and CAS (TRAb: rho = 0.439, p < 0.01; TSI: r = 0.357, p < 0.01) were found. In 10% of the episodic data, patients had a TRAb level that was disproportionately high (39.41 ± 52.84 IU/L), compared to their TSI levels (9.53 ± 12.10 IU/L) with a higher-than-average CAS (2.47 ± 1.78; range, 0-5). Within 12 months of diagnosis, a significant positive correlation between CAS and TRAb (rho = 0.503, p < 0.01) as well as between CAS and TSI (rho = 0.329, p < 0.01) were found. In patients with a diagnosis over 12 months, the correlation with CAS for both TSI and TRAb were Spearman rank correlation coefficient of 0.347 (p < 0.01) and 0.327 (p < 0.01), respectively. TRAb and TSI correlate strongly and to a lesser extent with the CAS. For most patients, TRAb can be replaced with the more economical TSI. TRAb also correlates better with newly diagnosed, more active patients than TSI. In a subset of patients, blocking antibodies may play a significant pathogenic role, requiring different treatment and monitoring. Further studies are required to investigate this relationship.

Evaluation of the diagnostic performance of thyroid-stimulating immunoglobulin and thyrotropin receptor antibodies for Graves' disease.

To evaluate thyroid-stimulating immunoglobulin (TSI) and thyrotropin receptor antibodies (TRAb) diagnostic performance for Graves' disease (GD) and determine clinical cut-off value for diagnosing GD. Of 1369 retrospectively enrolled subjects, 1364 had a definitive diagnosis of untreated GD (GD-UT, n = 87); treated GD (GD-T, n = 206); autoimmune thyroid disease (AIT, n = 241); thyroid nodules (TN, n = 677); subacute thyroiditis (ST, n = 28); healthy subjects (HS, n = 125); other diseases with serological hyperthyroidism (n = 5) and were grouped into the following: UT-GD and control groups (AIT, TN, ST, and HS); and UT-GD and non-GD hyperthyroidism groups. Diagnostic performance of TSI and TRAb was evaluated using area under the curve (AUC) of receiver-operating characteristic (ROC) curve, and optimal clinical cut-off value was determined using maximization of Youden index. TRAb AUC and clinical cut-off value for diagnosing GD were 0.981 and 1.245 IU/L (sensitivity, 96.6%; specificity, 97.1%; positive predictive value [PPV], 71.8%; negative predictive value [NPV], 99.9%; positive likelihood ratio [PLR], 33.31; negative likelihood ratio [NLR, 0.035), respectively, for the GD-UT and control groups. Those for TSI were 0.992 and 0.467 IU/L (sensitivity 98.8%; specificity, 96.4%; PPV, 68.8%; NPV, 99.9%; PLR, 27.472; NLR, 0.011). Those for TRAb in GD-UT and non-GD hyperthyroidism groups were 0.923 and 1.78 IU/L (sensitivity, 92.0%; specificity, 89.1%; PPV, 93%; NPV, 87.5%; PLR, 8.44; NLR, 0.089), respectively. For TSI, these were 0.92 and 0.545 IU/L (sensitivity, 97.7%; specificity, 83.6%; PPV, 90.4%; NPV, 95.8%; PLR27.472, NLR, 0.011), respectively. TSI diagnostic performance for GD was excellent and had better sensitivity than TRAb.

Application of an Interpretable Machine Learning for Estimating Severity of Graves’ Orbitopathy Based on Initial Finding

(1) Background: We constructed scores for moderate-to-severe and muscle-predominant types of Graves' orbitopathy (GO) risk prediction based on initial ophthalmic findings. (2) Methods: 400 patients diagnosed with GO and followed up at both endocrinology and ophthalmology clinics with at least 6 months of follow-up. The Score for Moderate-to-Severe type of GO risk Prediction (SMSGOP) and the Score for Muscle-predominant type of GO risk Prediction (SMGOP) were constructed using the machine learning-based automatic clinical score generation algorithm. (3) Results: 55.3% were classified as mild type and 44.8% were classified as moderate-to-severe type. In the moderate-to-severe type group, 32.3% and 12.5% were classified as fat-predominant and muscle-predominant type, respectively. SMSGOP included age, central diplopia, thyroid stimulating immunoglobulin, modified NOSPECS classification, clinical activity score and ratio of the inferior rectus muscle cross-sectional area to total orbit in initial examination. SMGOP included age, central diplopia, amount of eye deviation, serum FT4 level and the interval between diagnosis of GD and GO in initial examination. Scores ≥46 and ≥49 had predictive value, respectively. (4) Conclusions: This is the first study to analyze factors in initial findings that can predict the severity of GO and to construct scores for risk prediction for Korean. We set the predictive scores using initial findings.

Changes in Clinical Activity, Serum Autoantibody Levels, and Chorioretinal Vessels After Systemic Glucocorticoid Therapy in Thyroid Eye Disease.

The aim of this study was to investigate changes in the Clinical Activity Score, serum thyroid-stimulating hormone receptor antibody and thyroid-stimulating immunoglobulin levels, chorioretinal blood vessels, and extraocular muscle thickness in patients with thyroid eye disease following systemic steroid treatment. This prospective observational study enrolled 57 patients with active thyroid eye disease who received systemic intravenous glucocorticoids for 12weeks. Demographics, clinical activity scores, optical coherence tomography images, and serum thyroid-stimulating immunoglobulin and thyroid-stimulating hormone receptor antibody levels were assessed at baseline, at 6 and 12weeks after intravenous (IV) GC therapy initiation, and 2months after IV GC therapy termination. The extraocular muscle thickness, choroidal thickness, and choroidal vascularity index were measured. The clinical activity scores showed a significant decrease. Serum thyroid-stimulating immunoglobulin levels dropped continuously for 2months. The thyroid-stimulating hormone receptor antibody level decreased until 12weeks after treatment but returned to within the normal range in 75% of patients after 77 and 126days, respectively. The choroidal thickness decreased at all time points. The thickness of the medial and inferior rectus muscles decreased at 2months after treatment. The clinical activity score decreased to < 3 points in 50% of patients after 78days. Intravenous glucocorticoid therapy improved the clinical activity score, chorioretinal blood flow, and extraocular muscle thickness. The serum autoantibody levels were normalized in patients with active thyroid eye disease 2 months after IV GC termination. The serum thyroid-stimulating immunoglobulin and thyroid-stimulating hormone receptor antibody levels correlated with restoration of chorioretinal capillary perfusion and improved clinical symptoms and muscle thickness. Non-invasive optical coherence tomography findings and serologic factors predict the response to intravenous glucocorticoid therapy.

Comparison Between Thyroid Stimulating Immunoglobulin and TSH-Receptor Antibodies in the Management of Graves' Orbitopathy.

TSH-receptor antibodies (TRAb) targeting the TSH receptor (TSH-R) induce hyperthyroidism in Graves´ disease (GD). Graves´ orbitopathy (GO) is influenced by stimulation of the TSH-R in the orbita. GO has been, among other factors, linked to high TRAb levels. Thyroid stimulating immunoglobulins (TSI) is a relatively new method for assessing TSH-receptor antibodies. The aim of this study was to investigate the role of TSI in the management of GO. Patients with newly diagnosed GD (n=30, median age 55 years (range 35-72), 29 women) received pharmacological therapy (methimazole+++thyroxine) for up to 24 months. GO was identified by clinical signs and symptoms. Eleven patients had GO at diagnosis, and another six developed GO during treatment. Blood samples for TSI and other thyroidal biomarkers were obtained at baseline and on five occasions during the 24-month follow-up. Twenty-two subjects completed the drug regimen without surgery or radioiodine treatment. At baseline, TSI was highly correlated with TRAb (r s =0.64, p<0.001), and both assays similarly correlated to fT3 values. TSI and TRAb did not differ significantly between GO and non-GO patients for visit v1 (n=30, 17 GO during the whole study) or at follow-up (n=22, 12 GO during the whole study). During follow-up, levels of TSI and TRAb decreased and normalized in both groups. The present study does not support any added benefit of TSI compared to TRAb for the prediction and management of GO.

Factors related to steroid treatment responsiveness in thyroid eye disease patients and application of SHAP for feature analysis with XGBoost.

The primary treatment for active thyroid eye disease (TED) is immunosuppressive therapy with intravenous steroids. In this study, we attempted to predict responsiveness to steroid treatment in TED patients using eXtreme Gradient Boosting (XGBoost). Factors associated with steroid responsiveness were also statistically evaluated. Clinical characteristics and laboratory results of 89 patients with TED who received steroid treatment were retrospectively reviewed. XGBoost was used to explore responsiveness to steroid treatment, and the diagnostic performance was evaluated. Factors contributing to the model output were investigated using the SHapley Additive exPlanation (SHAP), and the treatment response was investigated statistically using SPSS software. The eXtra Gradient Boost model showed high performance, with an excellent accuracy of 0.861. Thyroid-stimulating hormone, thyroid-stimulating immunoglobulin (TSI), and low-density lipoprotein (LDL) cholesterol had the highest impact on the model. Multivariate logistic regression analysis showed that less extraocular muscle limitation and high TSI levels were associated with a high risk of poor intravenous methylprednisolone treatment response. As a result of analysis through SHAP, TSH, TSI, and LDL had the highest impact on the XGBoost model. TSI, extraocular muscle limitation, and LDL cholesterol levels may be useful in predicting steroid treatment response in patients with TED. In terms of machine learning, XGBoost showed relatively robust and reliable results for small datasets. The machine-learning model can assist in decision-making for further treatment of patients with TED.

Severe thrombocytopenia in a patient with diffuse toxic goitre

Abstract Introduction Diffuse toxic goitre is an autoimmune disorder with a marked prevalence in women. Thrombocytopenia may coexist with diffuse toxic goitre. Nevertheless, the mechanisms of decline in platelet count alongside with autoimmune thyroid disease have not been extensively investigated. Clinical Case A case of diffuse toxic goitre is reported in a 55-year-old man who has been receiving continuous treatment with methimazole for 7 years. The physical examination revealed an asthenic man, with an enlarged thyroid gland, inactive bilateral orbitopathy and multiple ecchymosis, but no lymphadenopathy or hepatosplenomegaly. Laboratory analysis revealed suppressed thyroid stimulating hormone (TSH) 0.01 mlU/ml, normal free T4 level 21.60 pmol/l, increased free T3 6.99 pmol/l and thyroid stimulating immunoglobulin (TSI) level of 23.60 IU/L. Complete blood count revealed severely decreased platelets 3×10^9 / l, decreased hemoglobin 110.00 g/l and hematocrit 21.90%, normal leucocytes 9.58×10^9/l, low prothrombin Index 11% and International normalized ratio (INR) 7.00. Additional serological investigations excluded HIV infection and C viral hepatitis. The bone marrow aspiration disclosed a rich cellular and polymorph marrow, an increased number of megakaryocytes suggesting that the thrombocytopenia is due to platelet destruction. The patient has recovered from viral pneumonia caused by SARS-COV-2, 1 month prior to the medical consultation. He received platelet transfusion and was started on 1 mg/kg oral prednisolone followed by a gradual taper and improvement of platelet count. Thrombocytopenia observed in diffuse toxic goitre may be mediated by both metabolic and immunological phenomena. In our case, the following causes may be considered: (1) an overlapping autoimmune process; (2) methimazole creating destructive antibodies; (3) COVID-19 disease. An autoimmune process is capable of triggering both conditions by activation of the reticuloendothelial system by thyroid hormones along with a cross-reaction between thyroid antibodies and platelet epitopes. Methimazole generates a drug-dependent immune response against platelets, involving platelet endothelial cell adhesion molecules and thus provoking thrombocytopenia. SARS-CoV-2 can induce thrombocytopenia by increasing the number of autoantibodies and immune complexes that destroy platelets. Lung damage by decreasing pulmonary capillary bed and platelet aggregation in the lungs indirectly leads to a reduced number of circulatory platelets. Conclusion Severe thrombocytopenia was detected in a patient with Grave's disease, in whom the number of platelets was 50 times below the lower limit of the reference range. Coexistence of thrombocytopenia may be explained by (1) an overlapping autoimmune process; (2) the effect of methimazole; (3) its occurrence or aggravation secondary to COVID-19.

Is there an association between endometriosis and thyroid autoimmunity?

It has been suggested that non-uterine endometrial implants can express thyroid-stimulating hormone receptors, thus inducing the formation of thyroid-stimulating immunoglobulin. We aimed to compare the autoantibody positivity in patients with and without endometriosis and to determine whether there is a difference in the incidence of thyroid diseases. This prospective observational study was conducted on 102 women who had been operated on for benign gynecological diseases. Cases enrolling in the study were divided into two groups: the study group with endometriosis (n=51) and the control group without endometriosis (n=51). The blood tests for thyroid-stimulating hormone, free thyroxine (fT4), thyroid-stimulating immunoglobulin, and anti-thyroid peroxidase antibody levels were checked. The mean thyroid-stimulating immunoglobulin level was found to be higher in the endometriosis group than in the control group. However, this difference was not statistically significant. No significant difference was detected between endometriosis and control groups in terms of anti-thyroid peroxidase antibody and thyroid-stimulating hormone levels. The mean fT4 value (0.97±0.13 ng/dL) of the endometriosis patients was found to be significantly lower than the control group (1.08±0.21 ng/dL) (p=0.002; p<0.05). The mean anti-thyroid peroxidase antibody value of cases with bilateral endometrioma (82.21±252.29 IU/mL) was significantly higher than cases with unilateral endometrioma (15.81±83.13 IU/mL) (p=0.028; p<0.05). There is a positive and significant relationship between the size of endometriosis and anti-thyroid peroxidase antibody values (p=0.011; p<0.05). This study points to an association between endometrioma diameter and anti-thyroid peroxidase antibody values which can be a stepping stone for new studies evaluating this hypothesis further.

Association of clinical course with thyroid-stimulating immunoglobulin in Graves' ophthalmopathy in Mongolians.

Graves' ophthalmopathy (GO) is a complex inflammatory condition affecting the orbit and is often associated with Graves' disease (GD). This study aims to determine the levels of thyroid-stimulating immunoglobulin (TSI) and thyroid-stimulating hormone receptor autoantibody (TSHR-ab) in the serum of patients with GO, compare it with the GD, and determine whether there is a correlation with the clinical course of GO. The cross-sectional study included 82 patients with GO, 81 patients with GD, and 75 healthy subjects. The ocular manifestations of GO were identified and evaluated by the clinical activity score (CAS) and severity of GO using the European Group of Graves' Orbitopathy (EUGOGO). TSI and TSHR-ab levels in the serum of participants were determined with ELISA kits and correlated with clinical findings. A total of 238 participant's data were analyzed. There were 14 patients (17%) with unilateral GO. The most common ocular signs were eyelid retraction 68 (82.3%) and proptosis 61 (74.4%). The mean CAS score was 2.65±1.64 in GO patients and was higher in men than women (P = 0.008). The mean of TSI was 37.95±35.41 in GO, 14.16±15.67 in GD, and 4.33±2.94 in healthy controls (P<0.0001). The TSI was significantly higher in patients with GO than in those with GD (P<0.0001). There were no correlations between TSI and TSHR-ab levels and CAS scores. However, we observed a correlation between the TSI level and the severity of GO (P = 0.023). The area under the ROC curve (AUC) of TSI was 0.933 and selected 14.1 IU/ml was the optimal cutoff value (98.78% of sensitivity, 83.97% of specificity). Our study showed that TSI is significantly related to GO and the severity of GO. Therefore, TSI can be used as a predictor of severe GO to help in prognostication, follow-up and treatment planning.

ODP518 Three Cases of Autoimmune Thyrotoxicosis after the BNT162b2 mRNA Covid-19 Vaccine

Abstract Background Various vaccines have been produced around the world in the battle against coronavirus disease 2019 (COVID-19) in the past year. Clinical trials and approvals of these vaccines were expedited at an unprecedented speed, with some of them approved under emergency use. Since March 2021, government coordinated vaccination program using two types of vaccines against COVID-19 were being undertaken in Hong Kong. BNT162b2 mRNA COVID-19 vaccine under the name of BioNTech was one. While it is a promising measure to control COVID-19, the new mRNA vaccine technology does cast some doubts, particularly its safety. In addition to the commonly reported injection site reactions and systemic upsets, less reported reactions after this new vaccine requires more clarifications. Here, we report 3 cases of autoimmune thyrotoxicosis all happened soon after the vaccination. Clinical Cases: Case1 A 40-year-old man with family history of thyroid cancer (mother had thyroid cancer with operation done) developed palpitations 17 days after receiving the first dose of BioNtech vaccine. Investigations confirms Graves’ thyrotoxicosis as evidenced by elevated fT4 and suppressed sTSH with positive thyroid stimulating immunoglobulin (TSI) and a diffuse vascular goiter on ultrasound (USG) thyroid. He was started on a course of anti-thyroid drug and had been advised to defer the second dose of vaccine until clinically stable. Case2 A 44-year old lady without personal/family history of thyroid disease developed progress neck swelling and palpitation with tremor 3 days after receiving the first dose of BioNtech vaccine. Investigations confirmed Graves’ thyrotoxicosis with elevated fT4 and suppressed sTSH with positive TSI, anti-TPO, and anti-ATG. USG thyroid showed diffuse vascular goiter. She was treated with a course of anti-thyroid drug and had been advised to defer the second dose of vaccine until stabilization of thyroid function. Case3 A 56-year-old man with positive family history of thyrotoxicosis (elder brother with history of thyrotoxicosis treated with radioactive iodine) developed progressive weight loss, increased appetite, insomnia, palpitation, and tremor around 7 days after the first dose of BioNtech vaccine. Patient only presented to an Endocrinologist for further workup 63 days after the first dose (42 days after second dose of BioNtech). Biochemically he had high fT4, suppressed sTSH, with positive anti-ATG, anti-TPO and TSI. USG thyroid revealed a small diffuse goiter. He was treated with a course of anti-thyroid drug with regular follow-up and monitoring. Conclusion This is the first case-series in Hong Kong demonstrating the possible triggering of Graves’ thyrotoxicosis after BioNTech vaccination. TSI and USG thyroid are invaluable tools to confirm the autoimmunity nature of the disease. Further studies are needed to clarify the prevalence, mechanisms, preventions, and treatments of this vaccine complication. Presentation: No date and time listed

ODP515 Severe thyrotoxicosis caused by subacute thyroiditis

Abstract Background Subacute thyroiditis, also named giant cell thyroiditis, painful thyroiditis, and de Quervain's thyroiditis, usually presents with neck pain or discomfort, a tender diffuse goiter and mild or moderate elevation of serum free T4 and T3 levels. Here we report a case of subacute thyroiditis patient presenting with severe thyrotoxicosis. Clinical case: A 27-year-old woman with no significant past medical history presents to the emergency room with palpitations and abnormal EKG with heart rate at 160 beats per minute. She developed a sore throat 3 days prior to the presentation, but she did not have neck pain or fever. She reports a 3-month history of hair loss, headaches and weight gain. Labs showed significantly elevated free T4 greater than 7.7 ng/dl (0.8-1.7) and free T3 level at 20.7 pg/ml (2. 0-4.8), and suppressed TSH less than 0. 01 uIU/ml (0.45-4.5) and normal ESR at 15 mm/hour. Her TPO antibody was greater than 1300 u/ml. Thyroid stimulating immunoglobulin (TSI) and TSH receptor antibody (TRab) were obtained but results were pending when she was discharged from the hospital. She has no typical clinical features of subacute thyroiditis with normal ESR and her free T3 and free T4 levels were significantly elevated. She was discharged on Methimazole and Propranolol and to do neck ultrasound as outpatient and follow-up TSI and TRab results and repeat free T4 and T3 in 1 week. Her neck ultrasound revealed mild hypervascularity but no Graves’ features. Her TSI and TRab were negative and free T4 level had no improvement even on significant dose of Methimazole. All the findings argue against Graves’ disease, but support subacute thyroiditis. Then Methimazole was discontinued and Prednisone was started at 20 mg daily and quickly taper to 5 mg daily in 2 weeks then stopped. After on Prednisone for 3 weeks, her free T4 was close to normal at 2. 0 ng/dl, T3 normal at 120 ng/dl, although TSH is suppressed. After stopped Prednisone for 2 weeks, her free T4, T3 and TSH were all back to normal. She is currently euthyroid without any medication at 5 months after her initial presentation. Conclusion Treatment of patients with subacute thyroiditis is pain relief with NSAID or Prednisone when NSAID is not effective. Anti-thyroid medications are rarely effective even in subacute thyroiditis patient with thyroid storm. Our case illustrated the role of corticosteroids in the treatment of subacute thyroiditis patient with severe thyrotoxicosis. Neck ultrasound and thyroid antibodies including TSI and TRab are critical to make a correct diagnosis in subacute thyroiditis patient with severe thyrotoxicosis. Presentation: No date and time listed