TSH Receptor Antibodies Research Articles

Stimulating thyrotropin receptor antibodies in early pregnancy.

Thyrotropin-receptor antibodies (TRAb) are used to diagnose Graves' hyperthyroidism in pregnant women. Bioassays provide a measure of thyrotropin-receptor stimulatory antibodies (TSI) specifically. The objective was to measure TSI in pregnant women for establishment of a pregnancy-specific cut-off and comparison with immunoassay measurements of TRAb. The retrospective Danish study was performed within the North Denmark Region Pregnancy Cohort (2011-2015) that includes stored biobank samples from early pregnancy (median week 10) with immunoassay measurements of thyroid function parameters and TRAb. TSI were measured in the same samples using the Turbo TSI bioassay (Quidel/Ortho-Clinical Diagnostics) with a recommended cut-off of 0.0241 IU/L in non-pregnant adults. A pregnancy-specific TSI cut-off (95-percentile) was established using Regression on Order Statistics. The established TSI cut-off was 0.0418 IU/L (95 % CI: 0.0417-0.0419). Among women with early pregnancy hyperthyroidism (n=438), 43 women (9.8 %) were TSI positive using the established cut-off, and these women had lower TSH (median 0.008 mIU/L) compared to women with TSI levels below 0.0241 (median TSH 0.040 mIU/L) or in the range from 0.0241 to 0.0418 (median TSH 0.033 mIU/L). Among the 438 women with early pregnancy hyperthyroidism, 22 women were positive for TSI and TRAb, 388 were negative for both, and 28 women were positive for either TSI or TRAb. This is the first study on TSI measurements in a large cohort of early pregnant women. A pregnancy-specific cut-off for TSI was established and agreement in the classification with immunoassay measurements of TRAb was seen in 94 % of cases.

The TSH receptor antibody reactome contributes to retro-orbital inflammation

Abstract The Thyroid Eye Disease (TED) of Graves’ disease is associated with high titers of stimulating TSH receptor antibodies, retro-orbital inflammation, fibroblast release of cytokines and chemokines and adipogenesis which in turn leads to proptosis, muscle fibrosis and dysfunction. Part of this scenario is the induction of fibroblast proliferation and autophagy secondary to synergism between the TSH receptor (TSHR) and the IGF-1 receptor (IGF-1R). While TED is well associated with thyroid stimulating antibodies to the TSHR which is also well expressed on fibroblasts, in fact the TSHR reactome has a variety of TSHR antibodies with varying biological activity. Therefore, we have now evaluated the possible role of neutral TSHR antibodies (N-TSHR-mAb), directed at the hinge region of the TSHR, which do not induce cell proliferation but are known to have effects on multiple proteins in thyroid cells including stress related signaling molecules. We examined the consequences of an N-TSHR-mAb acting on TSHR expressing fibroblasts and found marked cell stress which initiated signaling pathways involving inflammosome activation. This response ended in widespread cell death by pyroptosis through activation of caspase 8 and gasdermin D. Hence, not only can stimulating TSHR autoantibodies influence TED inflammation but the N-TSHR antibodies, representing more of the reactome, may also exaggerate the retro inflammatory response seen in TED.

Hypothyroidism Induced by a TSH Receptor Peptide-Implications for Thyroid Autoimmunity.

Background: The "neutral" thyrotropin receptor autoantibodies (N-TSHR-Ab) directed at the TSHR ectodomain's hinge region have been shown to induce thyroid cell damage in vitro. During these earlier studies, we developed a mouse monoclonal antibody (MC1) specific for a peptide (amino acid 322-340) in the region (MC1-Mab) which was able to induce thyroid cell stress and apoptosis when administered invivo. Methods: In order to examine the effect of invivo generated N-TSHR-Abs, rather than an acutely administered monoclonal antibody, we immunized Balb/c mice with the hinge region peptide over 18 weeks. Serum TSHR antibodies, specific TSHR hinge region antibodies, serum thyroglobulin (TG) and anti-TG as well as thyroxine and thyrotropin (TSH) levels were examined to evaluate the response to the immunization. Histological examination of the thyroid glands and flow cytometry of spleen T cells, B cells and macrophages were also performed to explore the underlying mechanisms. Results: We found that TSHR-peptide immunized mice developed N-TSHR-Abs against the peptide which resulted in thyroid damage shown by thyroid follicular destruction with follicular cell apoptosis, M1 macrophage infiltration, thyroglobulin release, and induction of thyroglobulin antibodies. This resulted in hypothyroidism with increased TSH levels. Conclusion: This study demonstrated that endogenous neutral antibodies to the TSHR could induce thyroid cell damage from apoptosis and M1 macrophage infiltration and resulted in hypothyroidism.

Long-Term Antithyroid Drug Therapy in Smoldering or Fluctuating-Type Graves' Hyperthyroidism with Potassium Iodide.

Graves' hyperthyroidism is characterized by stimulation of the thyroid gland by thyroid-stimulating hormone receptor antibodies (TRAbs). Antithyroid drug (ATD) continuation is recommended as long as the thyroid gland is stimulated. Goiter size, thyroidal 123I uptake, serum thyroglobulin level, and TRAb positivity are reliable markers of thyroid stimulation. Attention must also be paid to the responsiveness of the thyroid gland due to the high prevalence of painless thyroiditis and spontaneous hypothyroidism during treatment. TRAbs disappeared at <5 years entering remission in 36.6% of patients (smooth-type), while re-elevation of TRAb activity occurred in 37.7% (fluctuating-type) and remained positive for >5 years in 21.1% (smoldering-type). Seven percent of patients remained positive for TRAbs for >30 years, requiring life-long ATD treatment. Remission occurred after median 6.8 years (interquartile range, 4.0 to 10.9) of ATD treatment in 55% of patients. However, late relapse may occur after stressful events (dormant type). In apparently intractable Graves' disease (GD) with a large goiter (>40 g), 131I therapy should be considered. For initial and long-term ATD treatment, we must choose effective, safe, and economical drugs such as 100 mg potassium iodide (KI), although KI sensitivity varies in patients with GD. Thionamide, which has notorious side effects, is added only during the KI-resistant period.

The efficacy and safety of intravenous tocilizumab to treat Graves' ophthalmopathy: A systematic review and single-arm meta-analysis.

This study aims to evaluate the efficacy and safety of intravenous tocilizumab (TCZ) in the treatment of Graves' ophthalmopathy (GO). A comprehensive search was conducted across the Web of Science, PubMed, Embase, Cochrane Library, World Health Organization International Clinical Trials Registry Platform, and https://ClinicalTrials.gov databases from inception to April 2024. Randomized controlled trials (RCTs) and cohort studies that utilized intravenous TCZ for treating GO were included. Twelve studies encompassing 219 patients with active, steroid-resistant GO were analyzed. The meta-analysis demonstrated significant improvements in Clinical Activity Score (CAS) response (effect size [ES] = 0.98, 95% confidence interval [CI]: 0.93-1.00), proptosis response (ES = 0.50, 95% CI: 0.27-0.73), and diplopia response (ES = 0.48, 95% CI: 0.24-0.74). The ES for adverse events was 0.27 (95% CI: 0.22-0.33), with only three severe cases necessitating treatment discontinuation, and a low reactivation rate (ES = 0.01, 95% CI: 0.00-0.04). TCZ treatment led to a mean CAS reduction of 4.60 points (95% CI: 3.88-5.32) across 10 studies, a mean proptosis reduction of 2.04 mm (95% CI: 1.42-2.65) across 7 studies, and a mean decrease in thyroid-stimulating hormone receptor antibodies (TRAb) levels of 10.62 IU (95% CI: 4.67-10.62) across 5 studies. This meta-analysis provides robust evidence supporting the efficacy and safety of intravenous TCZ in patients with GO who are resistant to glucocorticoid therapy. The results highlight TCZ's comparable efficacy to glucocorticoids and suggest that TCZ could significantly expand clinical management options for GO. In the future, more high-quality, large-scale RCTs are still needed to confirm these findings.

Long-term outcome of Graves' orbitopathy following treatment with sirolimus.

Sirolimus was found to be associated with a better outcome of Graves' orbitopathy (GO) at 24weeks compared to methylprednisolone. We conducted a retrospective study to investigate its efficacy and safety over a longer period. Data from 40 consecutive patients with moderate-to-severe, active GO, 20 treated with sirolimus and 20 with methylprednisolone, were collected. overall outcome (composite evaluation) of GO at 48weeks. (1) GO outcome at 24weeks, and, at 24 and 48weeks: (2) outcome of single eye features; (3) quality of life (GO-QoL); (4) TSH-receptor antibodies; (5) GO relapse at 48weeks; (6) adverse events. The overall GO outcome at 48weeks did not differ between the two groups (responders: 55% vs 55%). At 24weeks, prevalence of responders was greater in sirolimus group (65% vs 25%; P = 0.01). A reduction ≥ 1 point in clinical activity score (CAS) was more frequent in sirolimus patients at 24 (85% vs 40%; P = 0.005) and 48weeks (75% vs 60%; P = 0.03). The proportion of GO-QoL responders (appearance subscale) at 24weeks was greater in sirolimus group (62.5% vs 26.3%; P = 0.03). No difference was observed for the remaining outcome measures. Treatment with sirolimus is followed by a greater overall response of GO compared with methylprednisolone at 24weeks, but not at 48weeks, when only CAS is affected. A more prolonged period of treatment may be required for a better outcome to be observed over a longer period.

12387 Late New-onset Graves' Orbitopathy: 14 Years Post-radioactive Iodine Treatment Of Graves' Disease: Case Report

Abstract Disclosure: F.F. Altaleb: None. K. Alaybaa: None. N. Aljohani: None. Introduction: Graves' orbitopathy (GO) is an autoimmune condition affecting the orbit and retro-ocular tissues, often accompanied by hyperthyroidism associated with Graves' disease, but it is rarely observed in euthyroid or hypothyroid individuals. Radioactive iodine (RAI) therapy for Graves' disease and smoking are recognized risk factors for GO development and progression. Individuals who smoke and undergo RAI treatment are significantly more likely to experience ocular lesions and worsening of GO compared to non-smokers. The exacerbation of GO post RAI therapy is attributed to elevated levels of TSH receptor antibodies, which may persist for up to a year post-treatment. Our case presents a rare occurrence of severe new-onset GO manifesting 14 years after achieving prolonged euthyroid status and successful RAI treatment for Graves' disease, accompanied by persistent TSH receptor antibody positivity that is unlikely to be suppressed by long term levothyroxine therapy. Clinical case: A 55-year-old male who’s a smoker and previously diagnosed with Grave’s hyperthyroidism, received treatment with RAI ablation therapy 14 years ago. At the time of diagnosis, there were no symptoms or signs of GO, and no history of thyroid eye disease was detected. Following the RAI treatment, he developed hypothyroidism and was promptly started on a daily dosage of 100 mcg of levothyroxine.Upon ocular examination: Visual acuity: 20/30 in both eyes. Significant restriction in extraocular muscle movements, with reported diplopia and pain. Bilateral lid retraction, proptosis, right conjunctival chemosis, and injection of the bulbar conjunctiva and caruncle, as well as lagophthalmos, were evident. No relative afferent pupillary defect observed. Color vision: 3/15 in the right eye, 15/15 in the left eye. Intraocular pressure: 22 mmHg (right eye), 16 mmHg (left eye). Optic discs unremarkable. Proptosis measurements: 26 mm (right eye), 23 mm (left eye). Ophthalmopathy clinical activity score: 7.Our laboratory analysis indicated normal thyroid function test However, the TSH receptor antibody and TPO antibody returned positive.We initiated treatment with IV methylprednisolone at a dosage of 500 Mg weekly for a duration of 4 weeks. Additionally, we introduced local measures, along with selenium supplementation. Within a week of initiating treatment, the conjunctival chemosis resolved, and there was improvement in ocular movement, resulting in mild to moderate restriction in all directions of gaze. Conclusion: This case illustrates the unexpected development of GO in a patient who had been euthyroid and effectively cured of Grave's disease for a span of 14 years following RAI treatment. The presence of TSH receptor antibodies, which are likely unresponsive to suppression by levothyroxine, as well as smoking cigarette might have contributed to the late new onset of the disease. Presentation: 6/3/2024

8806 A Case of Autoimmune Thyroid Switching

Abstract Disclosure: J. Case: None. R.V. Chemitiganti: None. D. Suravajjala: None. Autoimmune thyroid disease comprises both hyper- and hypothyroid states including Graves' disease and Hashimoto's thyroiditis, respectively. The predominant antibody activity, demonstrable by thyrotropin receptor antibody, predicts the clinical presentation and treatment; thyrotropin receptor antibodies may act as a stimulatory or inhibitory stimulus upon the thyroid gland recognized as thyroid stimulating antibody(TSAb) and thyroid blocking antibody(TBAb). Rarely patients may transition from a hyperthyroid to a hypothyroid state and vice versa if the predominant antibody activity shifts which may occur due to a variety of mechanisms and characteristics related to each individual patient and treatment course. A 29 year old female presented to establish care for autoimmune thyroiditis. She was diagnosed with Graves' disease at age 19 when pregnant and treated with propylthiouracil; she switched to methimazole for the next six years when her thyroid function normalized and therapy discontinued. Two years later she became concerned with weight gain and her thyroid function was reevaluated demonstrating hypothyroidism and she was treated with levothyroxine 25mcg daily until presentation. Further labwork revealed undetectable TSI, and TPO antibody elevated at 177 u/mL. She became clinically and biochemically euthyroid on levothyroxine 50mcg daily. Switching between hyper- and hypothyroid states is a rare occurrence among patients with may attributable factors. Both antithyroid drugs including methimazole as well as replacement therapy with levothyroxine may alter the antibody milieu and so the predominant ratio and activity among TSAb and TBAb thereby leading to a shift in clinical presentation and thyroid state. Pregnancy may lead to hemodilution contributing to lessening of autoimmune activity which may return following delivery leading typically to a shift from TSAb to TBAb. Uncontrolled hyper- and hypothyroidism may affect dendritic activity leading to altered presentation and increased immune reactivity. The unlikely occurrence of switching from a hyperthyroid to a hypothyroid state based upon autoimmunity as in this patient was likely affected these factors. Recognition of this potential transition and associated factors would lead to beneficial monitoring and possibly development of assays more attuned to this phenomenon with better capability in maintaining a euthyroid state and potentially predicting a transition. Presentation: 6/3/2024

6601 A Case of Recurrent Painless Thyroiditis and Discussion of Management

Abstract Disclosure: M.C. Slack: None. S. Grock: None. Introduction: Painless (silent) thyroiditis is characterized as a subacute and generally self-limited disease process in which patients develop transient thyrotoxicosis, which is often followed by a hypothyroid phase before entering the recovery euthyroid phase. Given high frequency of positive thyroid antibodies, it may be autoimmune-mediated; recurrence is rare. Here we present a case of recurrent painless thyroiditis and discuss management options. Clinical Case: A Korean woman was followed by endocrinology from age 38 to 60 and experienced at least seven episodes of painless thyroiditis over this time. The episodes occurred without an identifiable trigger and were not preceded by viral illness. During episodes she developed palpitations, hair loss, and dyspnea on exertion and biochemical evidence of thyrotoxicosis with TSH suppressed to &amp;lt;0.2 mIU/mL (normal 0.3-4.7) and elevated free T4 levels as high as 5.4 ng/dL (normal 0.8-1.7). TSI, TPO, and TSH receptor antibodies were checked during multiple episodes and resulted negative, though thyroglobulin antibody was significantly elevated. A radioactive iodine uptake scan was obtained during an active episode of thyroiditis and revealed diffusely low uptake. The patient’s episodes lasted approximately two to three months before normalization of her TSH and FT4. She had at least one instance of transient hypothyroidism after thyrotoxicosis with a TSH of 13.2 and FT4 of 0.6 which subsequently normalized 6 weeks later. The patient did not have known cardiovascular disease and DXA scans revealed mild osteopenia with the lowest T-score -1.3. RAI was considered for the patient based on the total number and increasing frequency of her episodes. She ultimately declined treatment with RAI and continues to follow with endocrinology. Clinical Lessons: While the deleterious effects of prolonged hyperthyroidism (e.g. osteoporosis, arrhythmia, cardiovascular disease) are well known, it is unclear what risk recurrent painless thyroiditis episodes pose. As there are no guidelines regarding treatment, clinical gestalt incorporating frequency and duration of episodes, as well as symptoms, is often used to determine if definitive management is indicated. There are case reports in the literature of treatment of recurrent thyroiditis with RAI ablation performed during a euthyroid state, which eliminated recurrence of episodes but did lead to permanent hypothyroidism necessitating hormone replacement. Surgical thyroidectomy may also be considered in select patients. This case highlights the challenges in treating rare cases of recurrent painless thyroiditis given the lack of research or established guidelines. It is reasonable to consider the frequency, severity, and total number of episodes, as well as patient risk factors, symptoms, and preferences when making recommendations regarding management. Presentation: 6/1/2024

6770 Graves’ disease induced by COVID-19 infection in a 49 year old male

Abstract Disclosure: N. Al-hosainat: None. A. Al Najada: None. T. Salar: None. S. Iqbal: None. K. Abdel Gadir: None. Introduction: Graves’ disease is an autoimmune disease causing hyperthyroidism, characterized by elevated thyrotropin-receptor antibodies. COVID-19 infection has been increasingly reported as a trigger of thyroid illness including Graves’ disease. We present a unique case of 49-year-old patient who was diagnosed with Graves’ disease after COVID-19 infection. Case description: A 49-year-old male patient with history of prediabetes presented with complaints of tremor, fatigue, generalized itching, and unintentional weight loss (30 Ibs in 6 months). He had COVID-19 infection 3 months prior. The remainder of review of systems was negative. No family history of thyroid disease. On exam, the patient had sinus tachycardia with otherwise normal vital signs. Diffuse thyromegaly was noted along with an intermittent fine tremor of the extremities. Blood work was notable for low TSH &amp;lt;0.01 uIU/mL, elevated free T4 (3.4 ng/dL), free T3 (17.6ng/dL), and TSH receptor antibody (12 IU/L). Thyroid ultrasound showed mild goiter with 2 nodules, one of which was TIRADS 4 and 1.5cm. This nodule was biopsied and found to be benign. Radioactive iodine uptake scan revealed homogeneous diffuse increased thyroid uptake. The diagnosis of Graves’ disease was made, and the patient was started on propranolol and methimazole with significant improvement of his symptoms and his laboratory tests normalizing. Discussion: Graves' disease is an autoimmune disease, characterized by hyperthyroidism, goiter, occasional orbitopathy and dermopathy. Caused by antibodies against thyroid-stimulating hormone receptors which stimulate thyroid hormone secretion and thyroid growth. Treatment is aimed to decrease thyroid hormone synthesis by either a Thionamide, radioiodine ablation, or surgery. Remission rates with antithyroid drugs average under 40 percent after one to two years of treatment and could exceed 80 percent after 5 to 10 years of treatment. COVID-19 is a multi-system disease, caused by SARS-CoV-2 virus, transmitted by large droplets and small particle aerosols, was declared a pandemic in 2020 and affected millions of people worldwide. There is emerging data showing the association of COVID-19 with various thyroid diseases including thyroiditis and relapse of known Graves' disease after the infection. We present a case of newly diagnosed Graves’ disease after COVID-19 infection in a patient with no personal or family history of such disease which raises the concern of autoimmune pathway activation induced by the infection. The onset of Graves’ disease after COVID-19 infection does not depend on the presence of pre-existing thyroid pathology and in this case responded well to antithyroid medication. Conclusion: COVID-19 can lead to the development of a range of medical illnesses. In patients who develop symptoms of thyrotoxicosis, Graves’ disease should be suspected, investigated, and treated appropriately Presentation: 6/3/2024

6771 New onset Graves’ Disease in a Patient with Hashimoto's Thyroiditis and Positive Thyroid Peroxidase Autoantibodies. Case Report

Abstract Disclosure: M.M. Eid: None. J.L. Zapater: None. Introduction: Hashimoto’s Thyroiditis (HT) and Graves’ Disease (GD) are the most common thyroid autoimmune disorders. Transition of GD to HT is common, but transition of HT to GD is rare. Case: A 55 year old, female with depression, HTN and fibromyalgia. She was referred for evaluation of chronic fatigue and reduction in functional capacity. Five years earlier, she had also been evaluated for fatigue. Labs at that time: TSH 3.80 µIU/ml (0.35-3.74 µIU/ml), free T4 0.8 ng/dl (0.76-1.46 ng/dl), thyroid peroxidase antibody (anti-TPO) 605.6 U/ml (0-60 U/ml), and anti-thyroglobulin antibody (anti-TG) 37.2 U/ml (0-60 U/ml). Subclinical hypothyroidism was diagnosed, but no levothyroxine was initiated. Her TSH was found to be normal in 2019 and 2021. At the current clinical encounter, other than fatigue she denies weight/voice change, tremor, palpitation, anxiety, recent flu like illness or radiation exposure, neck swelling/pain, heat intolerance, or difficulty swallowing. Her daily medications are amlodipine 10mg and duloxetine 20mg. She had menopause 2 years ago. She has no known allergy. She has a brother with rheumatoid arthritis. She denies smoking or alcohol consumption. On exam, vital signs are normal, and BMI is 28.1. There is diffuse, firm thyromegaly without a palpable nodule. There is no cervical lymphadenopathy, tremor, neck tenderness, exophthalmos, or lid lag. Creatinine, liver enzymes are normal but hemoglobin is 9gm/dl. Anti-tissue transglutaminase and anti-gliadin antibodies were negative. Her thyroid labs were: TSH &amp;lt;0.008 uIU/ml, free T4 1.06ng/dl, free T3 4.07 pg/ml (2.3-4.2 pg/ml), total T3 1.74 ng/ml (0.60-1.81 ng/ml), anti-TPO antibody 12,414 U/ml, anti-TG antibody 22 U/ml, thyrotropin receptor antibody (TRAB) 15.24 IU/L (0-1.75 IU/L), and thyroid stimulating immunoglobulin (TSI) 331% (&amp;lt;130%). Thyroid uptake scan showed 49% iodine-131 uptake in symmetric and homogenous uptake, and no hot or cold nodules. GD was diagnosed, methimazole 5mg daily was initiated. Conclusion: Our case had subclinical HT with positive anti-TPO antibodies 5 years preceding the onset of GD. Causes of autoimmune conversion are not well understood. Viral infection or radiation exposure in genetic susceptible patients have been assumed as triggers (1). The blocking and stimulating action of TRAB on TSH receptors is considered as a possible mechanism of switching between hypothyroidism and hyperthyroidism. Clinical and biochemical evaluation for possible conversion to GD in patients with HT is recommended (2).

7314 The Thyroid Tetralogy: Hypothyroidism, Graves' Disease, AFTN, and Thyroid Cancer in a Single Patient

Abstract Disclosure: F. Sajid: None. F. Mohammadrezaei: None. K. Tiwari: None. J. Shapiro: None. F. Mohsin: None. T. Lin: None. Introduction: In this case, we explore a rare and complex situation involving a patient's shift from hypothyroidism to hyperthyroidism. This transition led to the diagnosis of Marine Lenhart Syndrome (MLS), an uncommon condition characterized by the coexistence of Graves' disease and autonomously functioning thyroid nodules (AFTNs). Adding to the complexity of the case, the patient was also diagnosed with papillary thyroid carcinoma (PTC). Case Presentation: A 47-year-old woman with a history of hypothyroidism, treated with levothyroxine for 14 years, presented with palpitations, weight loss, and insomnia for a few months. Her levothyroxine dose was gradually reduced and eventually discontinued by her primary care physician due to low TSH and high free T4 levels. Post-discontinuation, her symptoms were improving. Laboratory tests showed TSH 0.01 mIU/mL (0.39-4.08), Thyroglobulin (TG) 72 ng/mL (3-40), Free T4 2.5 ng/dL (0.8-1.8), Free T3 11.5 ng/dL (0.2-0.5ng/dL). Furthermore, Thyrotropin Receptor Antibody (TRAb), and Thyroid Peroxidase Antibody (TPO Ab) were positive leading to a diagnosis of Graves' Disease and initiation of Methimazole. After three months on Methimazole, her TSH remained suppressed with normalized free T4 and T3 levels. A thyroid ultrasound revealed bilateral nodules, with a calcified well-circumscribed nodule in the right mid-pole. A Radioactive iodine uptake (RAIU) scan showed a hyperfunctioning right mid-pole thyroid nodule. Fine-needle aspiration biopsy was consistent with Bethesda V, suggestive of possible malignancy. Consequently, she underwent a total thyroidectomy, with pathology confirming multifocal classic PTC, stage pT1bN0. Post-surgery, she developed hypothyroidism and was started on levothyroxine. Four weeks later, her TSH remain suppressed, other thyroid function tests and calcium levels were within normal range: TSH 0.01 mIU/mL, Free T4 1.0 ng/dL, TG 4.6 ng/mL, Thyroglobulin antibodies 1 IU/mL (less than or equal to 1), PTH intact 43 pg/mL (16-77), and Calcium 8.9 mg/dL (8.6-10.2). Conclusion: This case represents a complex and unusual medical scenario where a patient transitioned from hypothyroidism to hyperthyroidism, ultimately leading to the diagnosis of MLS in conjunction with PTC. The exact mechanism behind this transition is not fully understood. In the management of hypothyroidism, adjustments in thyroxine dosage are common, but significant tapering of the dose should prompt further investigation. The presence of PTC in AFTNs is considered rare, as AFTNs are typically characterized as hot nodules, implying they are hyperfunctioning and generally considered to be less likely malignant compared to cold nodules. This case underscores the need for comprehensive evaluation and follow-up in patients with thyroid disorders, especially when there is a change in thyroid function or the presence of nodules. Presentation: 6/3/2024

9396 Deciphering The Enigma: A Case Report On New-onset Graves Disease Presenting As Thyroid Storm In The First Trimester Of Pregnancy, Managed In The Intensive Care Setting

Abstract Disclosure: M. Zeb: None. S.W. Salari: None. A. Tiwari: None. A. Vadher: None. A. Dabaja: None. S. Kambhatla: None. Graves' disease, an autoimmune disorder characterized by hyperthyroidism, presents unique challenges when manifesting as thyroid storm during pregnancy. We report a case of a 27-year-old African American woman at 9 weeks gestation who presented with palpitations, agitation, and fever. On examination, she exhibited fever, tachycardia, tremors in hands, and mild bilateral exophthalmos. Thyroid function tests revealed markedly elevated free thyroxine and suppressed thyroid-stimulating hormone levels. Thyroid ultrasound confirmed diffuse thyroid enlargement with increased vascularity, consistent with Graves' disease. Pelvic ultrasound estimated the gestational age at 9 weeks and 2 days, with a serum β-hCG level of 135,037 mIU/mL. An electrocardiogram revealed sinus tachycardia, and a complete metabolic panel indicated mild hypokalemia. The Thyroid Stimulation Immunoglobulin (TSI) and Thyrotropin receptor antibodies were tested positive. The Burch-Warsofsky point score of 45, supported the diagnosis of thyroid storm. The patient received intensive care treatment including intravenous fluids, hydrocortisone, beta-blockers, Lugol’s iodine, propylthiouracil, and potassium replacement. Following treatment, thyroid function stabilized within 48 hours, and her hyperthyroid symptoms resolved. The patient was discharged on oral labetalol and propylthiouracil. Thyroid storm, characterized by severe manifestations of hyperthyroidism, is a rare but potentially life-threatening condition, especially during pregnancy. Prompt recognition and intervention are crucial due to associated maternal and fetal morbidity and mortality. A multidisciplinary approach, involving endocrinology, obstetrics, and critical care, is essential to optimize outcomes. The unique physiologic changes of pregnancy, such as increased thyroid hormone production and altered thyroid hormone-binding globulin levels, can complicate the diagnosis and management of hyperthyroidism. Our case underscores the importance of vigilance for thyroid dysfunction in pregnant women, even in the absence of prior thyroid disease. Additionally, the potential impact of hyperthyroidism and thyroid storm on pregnancy outcomes highlights the need for early recognition and intervention. Long-term management of Graves' disease during pregnancy may also require adjustment of antithyroid medication dosage and monitoring of thyroid function to maintain euthyroidism while minimizing fetal exposure to medication. Further research is warranted to refine diagnostic criteria, treatment protocols, and long-term management strategies for thyroid storm in pregnancy. Increased awareness among healthcare providers about the risks and management strategies for this rare but serious complication is also necessary. Presentation: 6/3/2024

7786 Successful Use of Lithium in Hyperthyroidism Following a Carbimazole-Induced Agranulocytosis: A Case Report

Abstract Disclosure: J.G. Sazon: None. D.V. Bawal: None. J.V. Chua: None. J. Reyes: None. Graves' disease (GD) constitutes a significant proportion of global thyrotoxicosis cases. Carbimazole is an ATD with a notably and a rare yet severe complication of ATD with substantial adverse implications for health, is agranulocytosis. This condition is reversible if recognized early and treated accordingly. We report a case of successful use of lithium prior to radioiodine ablation (RAI) in management of thyrotoxicosis in the context of Carbimazole-induced agranulocytosis. This is a case of a 38-year-old female newly-diagnosed with Graves' Disease presenting with palpitations. Diagnostics showed FT4 &amp;gt;100 (11.9 – 21.6 pmol/L), TSH at &amp;lt;0.005 (0.270 – 4.200 mIU/L) and positive TSH receptor antibodies (TRAb) at 13.9 IU/L (normal value: &amp;lt;1.76 IU/L). Electrocardiogram revealed Atrial Fibrillation. She was initiated on Carbimazole 30 mg/tab OD, Apixaban 10 mg/tab OD, and Bisoprolol 10mg/tab OD. After 28 days of drug-intake, she developed fever (TMax 38.5°C) and work-up revealed severe neutropenia with an ANC of 0. Peripheral blood smear showed agranulocytosis. A seven-day course of piperacillin-tazobactam and moxifloxacin was administered, along with G-CSF at a dose of 300ug BID. Subsequently, was scheduled for Radioactive Iodine (RAI) therapy for definitive treatment. In the interim, with persistent tachycardia and elevated thyroid function tests (FT3 22.20 pmol/L, FT4 47.24 pmol/L) Lithium 450mg/tab BID and Prednisone 40mg/day was initiated, providing significant relief from hyperthyroid symptoms. RAI was administered with a dose of 24mci. Ten days post-RAI, thyroid hormone levels further improved. Four weeks after RAI, repeat tests revealed hypothyroidism. Levothyroxine was initiated at 12.5 mcg and gradually adjusted. Pre-RAI administration of lithium serves to mitigate alterations in serum thyroid hormone concentrations and augments the efficacy of RAI therapy. In this study, the utilization of lithium aimed to regulate thyrotoxicosis and preemptively curtail the elevation of FT4 levels. Lithium emerges as a particularly suitable therapeutic option for patients experiencing adverse effects related to ATDs prior to undergoing definitive therapies such as RAI or thyroidectomy. Furthermore, imperative to the prevention of agranulocytosis, an enhanced understanding of its deleterious effects through patient education is deemed vital. Presentation: 6/2/2024

6502 Comparing TBII vs TSI Assays at University Hospital; A Quality Improvement Project

Abstract Disclosure: L.E. Chozet: None. G. Le: None. M.A. Escobar Vasco: None. Radionuclide uptake and scan in the setting of thyrotoxicosis is considered the gold standard test to diagnose Graves' disease (GD). However, TSH-receptor antibodies (TRAB) tests are now being used as optional first-line tests given their widespread availability and cost-effectiveness. Thyrotropin-binding inhibitory immunoglobulin (TBII) and thyroid-stimulating immunoglobulin (TSI) assays are commonly obtained in patients admitted with thyrotoxicosis. Both assays are readily available at our institution. Our project aimed to further review and compare these two assays. To determine turnaround times of these assays at our institution, as well as cost-effectiveness of ordering both TBII and TSI assays vs only ordering one assay. We did a retrospective evaluation of 27 patients with lab evidence of thyrotoxicosis at University Hospital between April 2022, and May 2023 who were tested with both TBII, TSI assays simultaneously during their hospital stay to compare their concordance. We then compared turnaround times in days for laboratory results to be available. TBII, TSI assays are not done in-house. They are instead sent to an outside laboratory. Our hospital pathology services provided us with information regarding lab costs. We investigated which assay is more cost-effective. Based on our data, TBII and TSI were concordant in almost all patients evaluated (26 out of 27). Ordering TBII as the first initial test for GD is more cost-effective than ordering both TSI, TBII simultaneously. Our findings are consistent with previous studies, which suggest that ordering both assays (TBII and TSI) could be reserved for patients where the diagnosis of GD is not clear. Presentation: 6/3/2024

7527 Subacute Thyroiditis in First Trimester of Pregnancy: Rare Cause of Thyrotoxicosis

Abstract Disclosure: K. Wilcher: None. A. Gupta: None. Background: Subacute thyroiditis (SAT) is extremely rare in pregnancy with only 8 prior cases reported in the literature. SAT can result in maternal and fetal complications. In this case report, we describe a case of subacute thyroiditis presenting in the first trimester of pregnancy. Case Presentation: A 38-year-old female with past medical history of stillbirth presented with thyrotoxicosis in gestational week 10 of her pregnancy. The patient has a history of stillbirth in gestational week 38 of her first pregnancy requiring cesarean section one year prior to presentation. She was in the process of getting in vitro fertilization (IVF) and had an egg retrieval. During the process, she started on thyroxine 50 mcg daily for blood thyroid-stimulating hormone (TSH) 3.77 mcIU/mL. She became pregnant without the help of IVF and stopped thyroxine. One month later, labs showed low TSH 0.022 mcIU/mL (reference range: 0.4-4.5 mcIU/mL) and high blood free thyroxine (FT4) 1.87 ng/dL (reference range: 0.7-1.8 ng/dL). Repeat labs two weeks later showed low blood TSH 0.012 mcIU/mL, high FT4 2.08 ng/dL, and high blood free triiodothyronine (FT3) 5.2 pg/mL (reference range: 2.3-4.2 pg/mL). She was referred to endocrinology for evaluation. She reported mild intermittent right sided neck pain since diagnosis of pregnancy. She denied any history of viral infection, cough, or fever. She reported symptoms of severe nausea, mild constipation, and mild anxiety. She denied diarrhea, tremors, changes in voice, palpitations, or weight loss. Her family history is significant for hypothyroidism in her father. Physical exam demonstrated a non-tender, symmetric thyroid without enlargement or nodules. Ultrasound showed heterogenous thyroid with an ill-defined heterogenous area in the right lobe appearing pseudo-nodule, and increased vascularity. At this time, the patient was diagnosed with mild gestational hyperthyroidism with a plan to monitor thyroid hormone levels. Repeat labs two weeks later showed low blood TSH 0.005 mcIU/mL, high FT4 2.35 ng/dL, and high FT3 6.4 pg/mL. TSH-receptor antibodies, thyroid stimulating immunoglobulin, and thyroid peroxidase antibodies were normal on testing. In gestational week 16, labs showed normal TSH 2.76 mcIU/mL, low FT4 0.56 ng/dL, and low FT3 2.1 pg/mL. At that time, she started on levothyroxine 75 mcg daily and was diagnosed with subacute thyroiditis. Follow up labs in gestational weeks 18, 20, and 24 showed improvement in TSH and FT4 on thyroid hormone supplementation. Conclusion: This case report discusses the findings of SAT in first trimester pregnancy. Currently, she is in gestational week 28 and still requiring thyroid hormone supplementation. SAT in pregnancy is very rare. This case report significantly contributes to the literature and current knowledge of the prevalence, presentation, and disease process of subacute thyroiditis in first trimester pregnancy. Presentation: 6/2/2024

7342 Thyrotoxic Periodic Paralysis

Abstract Disclosure: G. Arora: None. Case presentation: A 40 year old male with no significant past medical history presented to the emergency department with diffuse body weakness for one day. On the night prior to admission, his thighs started getting sore which in a matter of a few hours, progressed to weakness involving his entire body. He was unable to flex his hips, shoulders, and neck. He was unable to get up or move without assistance. He was found to have an irregular heartbeat two weeks prior to admission and had undergone a thyroid ultrasound which showed inflammation of the thyroid gland. He was not started on any new medications. He endorsed fatigue, palpitations, neck swelling, and 45 lbs unintentional weight loss over 6 months. No fever, chills, vision changes, congestion, chest pain, shortness of breath, cough, tingling, numbness or weakness. He denied alcohol or drug use. Physical examination was notable for blood pressure 151/80 mm Hg, heart rate 120 bpm, enlarged thyroid gland tender to palpation, and muscle weakness (motor strength 3/5 in flexors and extensors of hips and knees). Labs were notable for K 2.3 (3.5 - 5.1 mmol/L), ALP 218 (32 - 91 U/L), TSH &amp;lt;0.010 (0.400 - 4.300 mcIU/mL), Free T4 3.5 (0.6 - 1.6 ng/dL), CK 608 (49 - 397 U/L). Urine toxicology was negative. MRI spine did not show any acute abnormality except for thyromegaly. He received potassium supplementation which led to symptomatic improvement and was admitted to medical floor. Further tests revealed: TSI 39.50 (&amp;lt;=0.54 IU/L), TSH receptor antibody 26 (&amp;lt;=1.75 IU/L), thyroid microsomal antibody 773.3 (0.0 - 9.0 IU/mL), anti-thyroglobulin antibody 4 (&amp;lt;4 IU/mL). Thyroid ultrasound showed an enlarged, heterogenous, hypervascular thyroid without any nodules. He was started on Propranolol and Propylthiouracil, which led to symptom resolution and he was discharged. Discussion: Thyrotoxic periodic paralysis (TPP) is a rare muscle disorder, belonging to the family of diseases called channelopathies. Thyroid hormone increases tissue responsiveness to beta-adrenergic stimulation, which increases Na-K ATPase activity on the skeletal muscle membrane driving potassium into cells. This leads to hyperpolarization of the muscle membrane and relative inexcitability of the muscle fibers, especially in the presence of a trigger such as provocation with exercise, fasting state or a high carbohydrate meal (insulin stimulates Na-K ATPase pump). Furthermore, more than 95% of TPP cases occur in males. This predominance is due to androgen-induced Na-K ATPase sensitization, more pronounced hyperinsulinemia, comparatively higher sympathetic and catecholamine-induced Na-K ATPase activity and higher muscle mass in males. Given the life-threatening association of severe hypokalemia, TPP should be considered in all patients presenting with acute painless muscle weakness. Presentation: 6/3/2024

8791 A Case of Hyperfunctioning Thyroid Nodules Evaluated for Thyroid Metastasis in the Setting of Oropharyngeal Squamous Cell Carcinoma

Abstract Disclosure: M. Alashoor: None. J. Gogineni: None. A. Bakar: None. Introduction: Identifying and evaluating hyperfunctioning thyroid nodules in the setting of metastatic head and neck cancers represents a diagnostic challenge that may result in inaccurate identification of perithyroidal lymph node metastasis as malignant or metastatic thyroid nodules with standard workup. Case presentation: A 72-year-old male with a history of stage IV metastatic oropharyngeal squamous cell carcinoma, metastasized to the lymph nodes, lungs, mediastinum, and bilateral iliac bones. He was diagnosed two years ago and received chemotherapy, maintenance immunotherapy with pembrolizumab, and targeted palliative radiation therapy, with good clinical response. Restaging PET-CT two years later revealed local progression. During his workup, he was noted to have persistently abnormal thyroid function test with low TSH (0.03​​µIU/mL, n 0.3-5.33), normal free T4 (0.97ng/dL, n 0.60 - 1.40), mildly elevated free T3 (3.91pg/mL, n 2.5-3.9), negative thyrotropin receptor antibodies levels, negative TSI, negative TPO antibody, noted evidence of subclinical hyperthyroidism consistent over the past year. Radioactive iodine uptake demonstrated multinodular gland, mildly elevated 24-hour uptake of 28% consistent with hyperthyroidism, with decreased activity in the left lobe. Thyroid ultrasound revealed multiple probable malignant thyroid nodules, a 1.8 cm TI-RADS 5 lesion of the deep margin of the lower pole of the right lobe, and a 1.6 cm TI-RADS 5 lesion of the upper pole on the right lobe. He was treated with methimazole 5 mg. Further workup with fine needle aspiration demonstrated the right upper lobe nodule sample was positive for squamous cell carcinoma, findings suspicious for metastasis. He subsequently proceeded with radical tonsillectomy, right neck dissection, and right hemithyroidectomy. Surgical pathology results noted, right neck metastatic HPV-associated squamous cell carcinoma involving the lymph nodes with extranodal extension, right oropharyngeal HPV-mediated squamous cell carcinoma. The thyroid gland biopsy was significant for incidental papillary microcarcinoma 2mm, thyroid follicular nodular disease, without evidence of squamous cell carcinoma or metastatic infiltration. Post-hemithyroidectomy, his thyroid function normalized, and methimazole was discontinued. Conclusion: Thyroid metastasis from head and neck cancers represent a rare entity. In patients with a history of malignancy, evaluation of new thyroid masses remains crucial. While FNA is a sensitive method for detecting thyroid metastases, inaccuracies may occur, impacting the identification of thyroid nodules in the presence of local metastatic lymphadenopathy. Identifying squamous cell carcinoma in the thyroid can significantly influence the treatment plan of patients with metastatic carcinomas, therefore careful consideration must be undertaken on evaluation. Presentation: 6/1/2024

Zirconium- 89 Labeled Antibody K1-70 for PET Imaging of Thyroid-stimulating Hormone Receptor Expression in Thyroid Cancer.

Thyroid-stimulating hormone receptor (TSHR) is a G-protein coupled receptor that is highly expressed on benign and malignant thyroid tissues. TSHR binding and activation has long been a component of thyroid cancer molecular imaging and radiotherapy, by promoting expression of the sodium-iodide symporter (NIS) and incorporation of I-131 into thyroid hormones. Here, we report the radiosynthesis and preclinical evaluation of a Zirconium-89 (89Zr) labeled TSHR antibody to serve as a positron emission tomography (PET) diagnostic correlate for therapeutic agents targeting TSHR without reliance on NIS. TSHR human monoclonal antibody K1-70 was conjugated to chelator desferrioxamine-p-benzyl-isothiocyanate, followed by labeling with Zr-89, yielding the radiotracer 89Zr-DFO-TSHR-Ab. The in vitro cellar uptake and binding affinity of 89Zr-DFO-TSHR-Ab were analyzed in three new TSHR stable overexpressing tumor cell lines and their corresponding wild types (WT) with low or no TSHR expression. 89Zr-DFO-TSHR-Ab PET/CT imaging of TSHR expression was evaluated in tumor mouse models bearing one TSHR-positive tumor and other negative control with or without the coinjection of antibody K1-70, and then verified by radiotracer biodistribution study and tumor immunohistochemistry (IHC). The conjugate DFO-TSHR-Ab was labeled with Zr-89 at 37°C for 60min and purified by PD-10 column in radiochemical yields of 68.8 ± 9.9%, radiochemical purities of 98.7 ± 0.8%, and specific activities of 19.1 ± 2.7mCi/mg (n = 5). In vitro cell studies showed 89Zr-DFO-TSHR-Ab had significantly high uptake on TSHR expressing tumor cells with nanomolar affinity and high potency. Preclinical PET/CT imaging revealed that 89Zr-DFO-TSHR-Ab selectively detected TSHR expressing thyroid tumors and displayed improved in vivo performance with the coinjection of unlabeled TSHR antibody K1-70 leading to higher uptake in TSHR expressing tumors than parental WT tumors and physiologic tissues; this observation was confirmed by the biodistribution and immunostaining analyses. We synthesized 89Zr-labeled antibody K1-70 as a new radiopharmaceutical for PET imaging of TSHR. 89Zr-DFO-TSHR-Ab has high radioactive uptake and retention in TSHR expressing tumors and cleared quickly from most background tissues in mouse models. Our study demonstrated that 89Zr-DFO-TSHR-Ab has the potential for PET imaging of TSHR-positive thyroid cancer and monitoring TSHR-targeted therapy.

Painless thyroiditis associated with SARS-CoV-2 and influenza infections in a patient with central hypothyroidism after pituitary surgery.

We present the case of a 50-year-old Japanese woman who was transferred to our hospital with a 2-day history of fever, sore throat, and malaise. She was diagnosed with acromegaly 9 months ago while being treated for diabetic ketoacidosis, for which she underwent pituitary surgery. She was diagnosed with hypopituitarism postoperatively and was prescribed hydrocortisone and levothyroxine. Her glycemic control was good on metformin. Tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza were positive in the emergency room. Other laboratory findings included thyrotoxicosis (free T3: 9.13 pg/mL; free T4: 3.64 ng/dL; and thyroid-stimulating hormone (TSH): <0.01 μIU/mL) and a high C-reactive protein (CRP) level (3.84 mg/dL). The test for the TSH receptor antibody was negative. She had no apparent goiter and reported no tenderness in response to thyroid palpation. 99m-Technetium scintigraphy revealed decreased tracer uptake. Ultrasonography showed no hypoechoic lesions. Her thyrotoxicosis spontaneously resolved after 6 weeks. Although both anti-thyroglobulin antibody (TgAb) and anti-thyroid peroxidase antibody (TPOAb) were negative 9 months ago, TgAb was positive at admission. The test for TPOAb became positive 6 weeks later. These findings were suggestive of painless thyroiditis. In this patient, painless thyroiditis was believed to be caused by SARS-CoV-2 and influenza infections. Screening tests of thyroid function in patients with viral infections such as SARS-CoV-2 or influenza are recommended, even when thyroid gland pain or tenderness is not observed. We describe a case of painless thyroiditis associated with SARS-CoV-2 and influenza infections. Although a few cases of painless thyroiditis associated with COVID-19 have been reported, no cases of painless thyroiditis associated with influenza have been reported. In this case, thyrotoxicosis developed immediately after the viral infection. In addition, tests for anti-thyroglobulin antibody and anti-thyroid peroxidase antibody were negative before the onset of symptoms. Tests for the former became positive at the time of onset of symptoms, whereas tests for the latter became positive several weeks after the onset of symptoms. Patients with viral infections such as SARS-CoV-2 and influenza, who had no goiter or thyroid tenderness, may develop painless thyroiditis; screening tests for thyroid function are recommended.