Graves' Disease Research Articles

Proangiogenic effect of thyrotropin receptor stimulating antibody in human umbilical vein endothelial cells.

This study aims to investigate the role of TRAb in the angiogenesis associated with Graves' disease (GD) and to elucidate its underlying mechanisms. Human thyroid follicular epithelial cells (Nthy-ori 3-1) and human umbilical vein endothelial cells (HUVECs) were treated with the monoclonal thyroid-stimulating antibody M22 and thyroid-stimulating hormone (TSH) at various concentrations. Cell viability, migration, and tube formation were evaluated using CCK-8, wound healing, and tube formation assays, respectively. Protein expressions of TSHR receptor (TSHR) and phosphorylated AKT (p-AKT) in M22-induced HUVECs were quantified via Western blotting. Proteomic analysis was employed to identify changes in protein expression profiles and relevant signaling pathways in GD specimens. Immunofluorescence assays were conducted to detect and localize the expressions of CD34 and PROX1 in GD specimens and normal thyroid tissues. M22 stimulated the proliferation of Nthy-ori 3-1 cells and HUVECs in a dose-dependent manner, while TSH exhibited an inverted U-shaped dose-response effect. M22 also dose-dependently promoted angiogenesis, and more effectively induced tube formation in HUVECs compared to TSH, although the difference was not statistically significant. A total of 16 proteins were significantly upregulated and 24 were downregulated in M22-induced HUVECs. Notably, PROX1, the most significantly upregulated protein, is closely associated with angiogenesis. Immunofluorescence confirmed that PROX1 was significantly more expressed in thyroid tissues from GD patients compared to normal tissues adjacent to papillary thyroid cancer (PTC), and it co-localized with CD34. TRAb enhances angiogenesis and upregulates PROX1 expression in HUVECs, suggesting a novel possible mechanism for goiter formation in GD.

Genetically mimicked effects of thyroid dysfunction on diabetic retinopathy risk: a 2-sample univariable and multivariable Mendelian randomization study

BackgroundThyroid dysfunction exhibits a heightened prevalence among people with diabetes compared to those without diabetes. Furthermore, TD emerges as a notable correlated risk factor for the onset of diabetic retinopathy.MethodsUsing data from the FinnGen database (R9), we investigated the causal relationship between thyroid dysfunction (TD) and four stages of diabetic retinopathy (DR). A two-sample univariable Mendelian randomization (UVMR) approach was employed to estimate the total causal effect of TD on four stages of DR, while multivariable Mendelian randomization (MVMR) was used to assess the direct causal effect. The meta-analysis was conducted to summarize the collective effect of TD on four stages of DR. The inverse variance weighted (IVW) method was the primary approach for Mendelian randomization analysis, with heterogeneity, horizontal pleiotropy, and leave-one-out sensitivity analyses performed to validate the robustness of the findings.ResultsIn UVMR analysis, thyrotoxicosis (TOS) was significantly associated with an increased risk of diabetic retinopathy across four stages (OR, 1.10–1.19; P<0.025). However, MVMR analysis, after adjusting for Graves’ disease (GD) and/or rheumatoid arthritis (RA), revealed no significant association between TOS and the four stages of diabetic retinopathy. The Meta-analysis demonstrated the collective effect of TOS on diabetic retinopathy across all stages [OR=1.11; 95% CI (1.08–1.15); P<0.01]. In UVMR analysis, the estimates for hypothyroidism (HPT) and GD were similar to those for TOS. In the MVMR analysis, after adjusting for RA, the significant effect of HPT on DR and non-proliferative diabetic retinopathy (NPDR) remained. Additionally, MVMR analysis suggested that the estimates for GD on DR were not affected by TOS, except for GD-proliferative diabetic retinopathy (PDR). However, no significant correlation persisted after adjusting for RA, including for GD-PDR.ConclusionOur study demonstrated a significant association between thyroid dysfunction TD and DR, with the relationship being particularly pronounced in HPT-DR.

Use of rituximab in the of immunoinflammatory rheumatic diseases combined with Graves' disease (autoimmune polyglandular syndrome in adults): case report and literature review

Rituximab (RTM) is a chimeric (murine and human) monoclonal antibody against B-lymphocytes (CD20). RTM is widely used in hematology for lymphoproliferative diseases and in rheumatology for rheumatoid arthritis, Sjögren's disease, some types of vasculitis and systemic connective tissue diseases. The administration of RTM is associated with a depletion of B-cells mediated by the regulation of apoptosis and cytotoxic effects via complement-dependent and antibody-dependent mechanisms. Considering the pathogenesis of autoimmune damage in Graves' disease (GD), an autoimmune thyroid disease associated with thyrotoxicosis, the use of RTM could be effective in this pathology. We present three patients with a combination of diffuse toxic goiter and rheumatic pathology treated with RTM; different outcomes of GD were observed.

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.

Comparison of Thyroid Size-Specific Radioiodine Dose and New Modified Dose Calculation in the Treatment of Graves' Disease.

Previous studies of fixed-dose radioiodine therapy (RIT) for Graves' disease (GD) have utilized a variety of techniques and reported differing success rates. This study sought to compare the efficacy of RIT using two fixed-dose protocols and to estimate the optimal radioiodine (RAI) activity for the treatment of GD. This retrospective trial enrolled 658 patients with GD who received RIT between January 2014 and December 2021. Participants were divided into two groups: protocol 1, which utilized a thyroid size-specific RAI dose, and protocol 2, which employed a modified dose calculation approach. The primary outcome assessed was the presence of euthyroidism or hypothyroidism at the 6-month follow-up. The success rates of RIT were compared between the two protocols. The RIT success rate was marginally lower for protocol 2 than for protocol 1 (63.6% vs. 67.2%); however, the risk of treatment failure did not differ considerably between the groups (relative risk, 1.1089; 95% confidence interval, 0.8937 to 1.3758; P=0.3477). The median RAI activity associated with protocol 2 was lower than that for protocol 1 (10.7 mCi vs. 15.0 mCi, P=0.0079), and the frequency of hypothyroidism was significantly lower in the protocol 2 group (39.0% vs. 48.9%, P=0.0117). The success rate of the modified dose calculation protocol was comparable to that of the thyroid size-specific RAI dose protocol. The former approach reduced RAI activity and the incidence of hypothyroidism following RIT without compromising the success rate.

New onset of Graves' disease after controlled ovarian stimulation: A case report and brief literature review.

De novo onset of Graves' disease (GD) after controlled ovarian stimulation (OS) is exceptional. Only one case of progression to GD after OS in a patient with pre-existing subclinical hyperthyroidism has been reported. We describe the case of a patient with neither previous thyroid disorders nor autoimmunity who developed GD after OS for primary infertility. A 40-year-old woman with primary infertility underwent four cycles of OS. Her thyroid function performed before the last cycle was unremarkable (thyroid stimulating hormone [TSH] 1.9 mU/L, fT4 1.3 ng/dL, fT3 2.4 pg/mL), and thyroid autoimmunity was negative (anti-thyroperoxidase antibodies and anti-thyroglobuline antibodies). Six weeks after the last cycle she developed overt thyrotoxicosis (TSH < 0.005 mU/L, fT4 4.79 ng/dL, fT3 15.6 pg/mL) with anti-thyrotropin receptor antibodies (TRAb) positivity (9.2 IU/L). She was diagnosed with GD and anti-thyroid therapy was instituted. After 1 year of treatment, thyroid function was still suboptimal (TSH 0.2 mU/L, fT4 1.04 ng/dL, fT3 2.2 pg/mL), and TRAb titer still elevated (8.75 IU/L). Despite her desire to achieve pregnancy, a further cycle of OS was postponed until complete remission of thyroid dysfunction and withdrawal of anti-thyroid therapy. Although TSH assay after OS is not recommended in euthyroid women without autoimmunity, in the presence of hyperthyroid symptoms throughout OS it is advisable to evaluate thyroid function and TRAb. It is advisable to carefully evaluate the course of GD before proceeding with further courses of OS that could lead to its exacerbation or recurrence. In cases where a strong desire for pregnancy persists, thyroidectomy may be proposed.

Surgical Outcomes in Thyroidectomy for Patients with Graves’ Disease: A Randomized Controlled Trial

Background: Thyroidectomy is a preferred protocol for patients with Graves’ disease. However, it may be a challenging option in post-surgical management of various factors. There, this study aims to compare the surgical outcomes of total thyroidectomy and subtotal thyroidectomy in patients with Graves’ disease to provide evidence-based surgical decision-making. Methods: This randomized controlled trial was conducted at Sheikh Zaid Hospital, Rahim Yar Khan, October 2023 to April 2024; enrolled 120 patients diagnosed with Graves’ disease using a simple random sampling technique were assigned to Group A (n=60) and B (n=60) who underwent total thyroidectomy, and subtotal thyroidectomy respectively. Preoperative assessments and surgeries were performed while postoperative outcomes, complications, and thyroid function tests were also monitored and represented using independent t-tests while a p&lt;0.05 was considered significant. Results: It was revealed that operative time was significantly higher for total thyroidectomy than subtotal thyroidectomy 125.60±14.56 and 97.54±12.56 respectively, suggesting significantly lower time consumption in subtotal thyroidectomy procedure (p=0.001). Patients who underwent subtotal thyroidectomy had a significantly shorter hospital stay compared to those who underwent total thyroidectomy (p=0.02). Moreover, levels of triiodothyronine (T3), thyroxine (T4), and thyroid-stimulating hormone (TSH) were significantly different between the two groups. Patients who underwent subtotal thyroidectomy had significantly lower T3 and T4 levels and higher TSH levels compared to those who underwent total thyroidectomy (p&lt;0.05). Conclusion: Subtotal thyroidectomy demonstrated favorable outcomes, including shorter operative time, lower rates of postoperative complications, and thyroid function tests compared to total thyroidectomy. These findings help and support the consideration of subtotal thyroidectomy as a viable surgical approach for patients with Graves' disease. Keywords: Grave Disease, Thyroidectomy, Thyroxine, Triiodothyronine.

Unveiling the Role of Gut Microbiota and Metabolites in Autoimmune Thyroid Diseases: Emerging Perspectives.

Autoimmune thyroid diseases (AITDs) are among the most prevalent organ-specific autoimmune disorders, with thyroid hormones playing a pivotal role in the gastrointestinal system's structure and function. Emerging evidence suggests a link between AITDs and the gut microbiome, which is a diverse community of organisms that are essential for digestion, absorption, intestinal homeostasis, and immune defense. Recent studies using 16S rRNA and metagenomic sequencing of fecal samples from AITD patients have revealed a significant correlation between a gut microbiota imbalance and the severity of AITDs. Progress in animal models of autoimmune diseases has shown that intervention in the gut microbiota can significantly alter the disease severity. The gut microbiota influences T cell subgroup differentiation and modulates the pathological immune response to AITDs through mechanisms involving short-chain fatty acids (SCFAs), lipopolysaccharides (LPSs), and mucosal immunity. Conversely, thyroid hormones also influence gut function and microbiota composition. Thus, there is a bidirectional relationship between the thyroid and the gut ecosystem. This review explores the pathogenic mechanisms of the gut microbiota and its metabolites in AITDs, characterizes the gut microbiota in Graves' disease (GD) and Hashimoto's thyroiditis (HT), and examines the interactions between the gut microbiota, thyroid hormones, T cell differentiation, and trace elements. The review aims to enhance understanding of the gut microbiota-thyroid axis and proposes novel approaches to mitigate AITD severity through gut microbiota modulation.

Evaluation of alpha Klotho and fibroblast growth factor-23 levels in Iraqi patients with Graves’ disease

Background &amp; Objective: Graves’ disease (GD) is an autoimmune condition that targets the thyroid gland, resulting in excessive stimulation and synthesis of thyroid hormones. Excessive synthesis of these hormones can lead to symptoms such as loss of body weight, accelerated heart rate, irritability, reduced tolerance to heat, and excessive perspiration. Alpha-Klotho (KL), a protein crucial for physiological processes, is also involved in GD. The defective immunological condition of GD patients may increase Klotho expression, and the enhanced expression of fibroblast growth factor-23 (FGF23) in GD may be linked to the disease pathophysiology. We investigated serum levels of KL and FGF23 in Iraqi patients with Graves’ disease, analyzing correlations with clinical status and evaluating their potential as biomarkers for disease activity. Methodology: We conducted this cross-sectional study at The National Diabetes Center, Mustansiriyah University, between December 2022 and April 2023. The study involved 103 patients diagnosed with GD, and 103 patients, aged 21-70 y, as a control group. Patients with multinodular goiter, single thyroid nodules, thyroiditis, pregnant women, and those on medications or oral contraceptives, were excluded. Result: clinical significance of FGF23 and Klotho (KL) levels in patients with Graves’ disease (GD) compared to a control group. Results indicate that the median of KL levels are significantly higher in GD patients (KL = 6.31) compared to the control group (KL = 2.40), with a highly significant difference (P &lt; 0.001). In contrast, differences in median of FGF23 levels between GD patients (149) and controls (86.05) were not statistically significant (P = 0.07). Furthermore, KL levels were significantly higher in hyperthyroid patients compared to other thyroid statuses (P = 0.023), while FGF23 levels did not significantly differ across thyroid statuses (P = 0.255). Additionally, the study found a strong correlation between TRAb levels and both KL (r = 0.291, P &lt; 0.001) and FGF23 (r = 0.211, P = 0.003), and between KL and FGF23 directly (r = 0.412, P &lt; 0.001). These findings suggest that while KL may be a significant biomarker in GD, FGF23 relevance appears limited in this context. Conclusion: In Graves’ Disease patients have significantly higher levels of KL and FGF23 compared to controls, suggesting a distinct pathophysiological role for these biomarkers in mineral homeostasis and thyroid hormone regulation. Abbreviations: AITD - Autoimmune thyroid diseases; KL - Alpha-Klotho; FGF23 - fibroblast growth factor-23; GD - Graves’ disease; HT - Hashimoto's thyroiditis; IGF-1R - Insulin-like Growth Factor-1 Receptor; Keywords: Autoimmune Thyroid Disorders, Hyperthyroidism, Graves’ disease, Alpha-Klotho Citation: Rashid MF, Alammar HAJ, Rahmah AM. Evaluation of alpha Klotho and fibroblast growth factor-23 levels in Iraqi patients with Graves’ disease. Anaesth. pain intensive care 2024;28(5):836−841. DOI: 10.35975/apic.v28i5.2567 Received: June 16, 2024; Reviewed: July 07, 2024; Accepted: July 18, 2024

6581 Case of Conversion from Hashimoto’s Thyroiditis to Graves’ Disease: An Unusual Sequence

Abstract Disclosure: A. Atri: None. C. Anastasopoulou: None. Introduction: The two most common autoimmune thyroid diseases are Hashimoto’s thyroiditis (HT) and Graves’ disease (GD). HT is a destructive thyroiditis, via autoantibodies most commonly against the thyroid peroxidase enzyme (anti-TPO), while GD results in hyperthyroidism, due to TSH-receptor stimulating antibodies (TSAb) and Thyroid Stimulating Immunoglobulin (TSI). Case Report: A 23-year-old male presented to the clinic with complaints of weight gain, dry skin and excessive hair loss. His physical examination was non-contributory and laboratory evaluation revealed a TSH of 130 uIU/ml (ref: 0.45-4.5), free T4 (fT4) 0.4 ng/dl (ref: 0.82-1.77), and positive anti-TPO antibodies, for which he was started on levothyroxine (LT4) supplementation for newly diagnosed HT. Over the first five months on treatment, his TSH and T4 progressively improved to 31.8 uIU/ml and 1.48 ng/dl, respectively. Six months later, his TSH rapidly decreased to 0.01 uIU/ml, with an fT4 elevation to 2.45 ng/dl, alongside developing hyperthyroid symptoms like weight loss, insomnia and palpitations. Due to persistently positive anti-TPO antibody titers, his hyperthyroidism was considered iatrogenic, and LT4 dose was gradually reduced, but eventually required to be discontinued. A thyroid ultrasound depicted generalized increase in vascularity, consistent with active thyroiditis. He continued to have a significantly suppressed TSH &amp;lt;0.005 uIU/ml and elevated fT4, off all medications, and was also found to have multiple positive antibody titers [TSI of 1.02 IU/L (ref: &amp;lt; 0.55), thyroglobulin antibody of 351 IU/ml (&amp;lt; 0.9) and anti-TPO Ab &amp;gt;600 IU/ml (ref&amp;lt; 34)]. He was then diagnosed with new GD, and thyroid suppression therapy with 10mg/day of methimazole was initiated, to which he rapidly responded, with a TSH of 0.059 uIU/ml and reduced fT4 of 1.37 ng/dl. His diagnosis of GD was confirmed via an I-123 thyroid uptake scan which revealed a homogenous increased tracer uptake of 57% at 24 hours (ref 15-35%), following which he received definitive therapy for GD, with radio-active iodine (RAI) ablation with 20.6 mCi of I-131. Discussion: As HT and GD have a common autoimmunity-based pathophysiology, conversions between the two clinical states have been described, though HT to GD, as seen in our patient is much less common than the reverse conversion. Some described mechanisms include an antibody switch from thyrotropin receptor blocking to stimulating action, HT-induced thyrotroph destruction resulting in GD antibody formation, and treatment with LT4. Simultaneously elevated levels of both TSI and anti-TPO can occur, and therefore treatment and diagnosis should be based on thyroid function tests and clinical presentation. Patients with autoimmune thyroid disease require close monitoring, due to the potential risk of conversion from one clinical end of the spectrum to the other, and early recognition is important. Presentation: 6/1/2024

7729 Autoimmune Thyroid Disease And Risk of Premature Ovarian Failure - A Comprehensive Analysis Combining Observational Studies, Two-sample Mendelian Randomization Study, And Targeted Drug Forecast

Abstract Disclosure: R. Wang: None. T. Dou: None. L. Guan: None. X. Qi: None. X. Wang: None. C. Yu: None. Q. Guan: None. Premature ovarian failure (POF), a condition impacting women's fertility and physical well-being. Specifically, autoimmune thyroid disease (TAI) is recognized as an organ-specific autoimmune condition that may co-occur with POF in clinical scenarios, yet the precise nature of their relationship remains uncertain. The objective of this study is to investigate the influence of TAI on ovarian function, identify shared pathogenic genes, predict potentially effective drugs, and establish a foundation for clinical interventions. Firstly, a case-controlled study was conducted using the Nationwide Readmissions Database (NRD) in the United States. This involved identifying patients with Hashimoto's thyroiditis (HT) and Graves' disease (GD) as the study group, and those without deficiency as the control group, to explore the correlation with POF. Additionally, an Asian population-based case group comprising 897 patients with POF and a control group of 897 healthy women were gathered to analyze the association of POF with TAI-related antibodies, namely TGAb and TPOAb. Furthermore, a two-sample Mendelian randomization(MR) study was undertaken in European populations to investigate the causal relationship between TAI and POF. Lastly, genes associated with HT, GD, and POF were compiled from the GEO, GeneCards, and DisGeNET databases, and common genes were identified through intersection. Subsequent gene ontology and pathway enrichment analyses, protein-protein interaction analyses, and candidate drug predictions were performed based on the shared genes. The findings revealed a significant association between TAI and POF in the NRD, with patients exhibiting TAI being notably more prone to POF compared to the control group (OR 1.78, 1.34-2.35, P&amp;lt;0.001). Subgroup analysis further demonstrated an increased risk of POF in patients with HT (OR 1.51, 1.02-2.22, P&amp;lt;0.05) and GD (OR 2.18, 1.45-3.29, P&amp;lt;0.05). In the Asian population, a retrospective analysis indicated a positive correlation between TPOAB positivity and POF (OR 1.76, 1.24-2.51, P&amp;lt;0.05). MR analysis unveiled a causal relationship between GD and POF. Through a comprehensive examination of multiple gene databases, 47 common genes were identified between HT and POF, and 20 common genes between GD and POF. Enrichment analysis demonstrated relative similarities in cytokines and signal transduction, apoptosis, inflammatory response, and other aspects between HT and POF. GD was found to potentially influence ovarian function through pathways such as the PI3K-Akt signaling pathway and adhesive plaques. Dexamethasone, rapamycin, and other drugs emerged as potential therapeutic options for both diseases. In summary, our study suggests that TAI, particularly GD, may elevate the risk of POF. Additionally, we predict potential therapeutic drugs, and shed light on the potential biological mechanisms linking HT/GD and POF. Presentation: 6/3/2024

8518 Prevalence of Hearing Dysfunction in Patients with Autoimmune Thyroid Disorders, Thyroid Eye Disease and the General US population: A Claims Database Analysis

Abstract Disclosure: T.J. Smith: Consulting Fee; Self; Amgen Inc, Viridian, Minghui, Lassen, Lundbeck. Other; Self; US patents covering the use of IGF-1 receptor inhibitors in TED which are held by UCLA and the Lundquist Institute. A. Meyers: Employee; Self; Amgen Inc. Stock Owner; Self; Amgen Inc. Q. Fu: Stock Owner; Self; Amgen Inc. Other; Self; Amgen Inc, former employee. R.J. Holt: Employee; Self; Amgen Inc. Stock Owner; Self; Amgen Inc. K. Zhu: Employee; Self; Amgen Inc. Stock Owner; Self; Amgen Inc. Background: Autoimmune thyroid conditions including Graves’ disease (GD) have been associated with hearing impairment.([1]-3) Approximately 90% of patients (pts) with thyroid eye disease (TED) have hyperthyroidism/GD. Teprotumumab, an insulin-like growth factor-I receptor inhibitor, significantly improves TED signs/symptoms and became the first FDA-approved treatment for TED in 2020. Hearing-related adverse events were identified in pivotal trials of teprotumumab in TED.4 This epidemiology study aims to describe the prevalence of hearing loss/ototoxicity via claims data in commercially insured pts with autoimmune thyroid conditions, TED, and those receiving teprotumumab, as well as the general population (gen pop). Methods: Five mutually exclusive cohorts were created using deidentified claims data (Merative MarketScan®): GD pts (index is first GD diagnosis [dx] code), TED pts (index is later of both GD dx or eye symptom codes within 1 yr), teprotumumab pts (index is first claim for teprotumumab), other Thyroid Disorders (TD) pts (index is TD dx), and gen pop pts. Pts with teprotumumab claim were excluded from other cohorts. Eligible pts were ≥18 years (yrs) of age, continuously enrolled for ≥6 months pre and post index, between 1/1/2020-12/21/2021. Demographics (age, sex) were described between the cohorts and the gen pop. Proportions of pts with inpatient and outpatient claims for hearing loss/ototoxicity claims and proportions with hearing loss/ototoxicity claims in the 3 yrs preceding index were calculated. Age-standardized prevalence was presented using gen pop as the reference. Results: Of 21,256,714 eligible pts, 82,629 GD, 4,455 TED, 2,758 teprotumumab, 1,261,250 TD and 4,857,408 gen pop pts were identified. 47% pts in the gen pop cohort were female vs 72.1-75.7% in the other cohorts. Gen pop cohort was younger (mean [SD] age: 53 [15.1] yrs) vs 58.0-61.5 [15.1-15.6] yrs in other cohorts. Age-standardized prevalence of hearing loss/ototoxicity claims on/after index date was 3.3% for GD, 5.2% for TED, 4.3% for teprotumumab, 3.9% for TD, and 3.9% for gen pop pts. Hearing loss/ototoxicity claims were prevalent in the 3 years prior to index among these patients: 30.8% GD, 36.6% TED, 35.4% teprotumumab, 31.5% TD, and 27.3%) gen pop pts had a hearing loss/ototoxicity claim. Conclusions: In this descriptive unadjusted analysis, we observed similar prevalence of hearing loss/ototoxicity claims across thyroid disorders, TED pts, teprotumumab pts, and the gen pop group. Between 27%-37% had claims prior to thyroid diagnosis or receiving teprotumumab. It is expected that future analyses could adjust the rates for potential confounders across cohorts.

8135 A Rare Case of Late Recurrence of Graves’ Disease Decades After Radioactive Iodine Therapy: Is it Really a Definitive Treatment?

Abstract Disclosure: K.S. Hill: None. R. Osman: None. Graves’ disease (GD) is the most common cause of hyperthyroidism in the US and worldwide. Radioactive iodine (RAI) therapy has excellent success rates in treatment of GD. Studies have demonstrated that RAI successfully treats GD with a single session in the majority of cases. Recurrence after RAI, if it occurs, is most commonly seen in the first year after RAI. However, this is rare particularly in patients who have developed evidence of successful treatment in the form of post-ablative hypothyroidism. Only a few case reports have demonstrated recurrence of GD more than 10 years after treatment of GD with RAI and development of post-ablative hypothyroidism. We report a case of GD recurrence approximately 30 years after ablation. A 69 y/o woman presented for evaluation of hyperthyroidism and newly discovered thyroid nodule. Her history was significant for GD with orbitopathy diagnosed in the early 1990s and treated with RAI. Following the ablation, she developed hypothyroidism and was managed for over 20 years on levothyroxine therapy. In recent years she began to develop symptoms of palpitations and heat intolerance with biochemical evidence of thyrotoxicosis despite reductions in her levothyroxine dose. She also developed recurrence of her orbitopathy, confirmed by ophthalmology. During this time, a neck CT incidentally described an atrophic thyroid gland with a 9 mm soft tissue nodule in the left thyroid bed. Follow up ultrasound showed a 1.1 cm nodule with increased vascularity in the left thyroid bed with an otherwise atrophic gland and no lymphadenopathy. Her levothyroxine was stopped for one month in preparation for a thyroid uptake scan, during which TSH increased to 15 mcU/mL. Scan showed overall severely decreased radioactive iodine uptake of the gland consistent with prior ablation although there was a faint uptake most focally conspicuous on the left side inferiorly. Thyroid stimulating immunoglobulin (TSI) was elevated at 1.35 IU/L (Ref 0.00-0.55). After discussion with the patient, the decision was made for surgical treatment with thyroidectomy. Pathology was benign. She was continued on her prior dose of levothyroxine 75 mcg daily however now with clinical and biochemical evidence of hypothyroidism requiring continued increase in levothyroxine dose to normalize TSH levels. GD is the most common cause of hyperthyroidism and RAI therapy is the most common definitive treatment for GD in the US. Recurrence of GD after ablative hypothyroidism is rare, particularly in the case of late recurrence decades after ablation. Only a few cases are reported in the literature, ours with the longest interval-to-relapse. Recurrence of orbitopathy may be the first clue. Our case highlights the need to continue to monitor clinically for recurrence of Graves’ disease long after RAI use. Presentation: 6/3/2024

8471 A Rare Case of Graves' Disease in a Three-Year-Old

Abstract Disclosure: A. Rajesh: None. A. Ravari: None. L.E. Kimball-Ravari: None. H. Roan: None. Graves’ Disease (GD) is an autoimmune disease that causes hyperfunctioning of the thyroid gland which may be triggered by environmental factors such as infection or stress. Though the leading cause of hyperthyroidism in both adult and pediatric populations is GD, it is extremely rare in children under the age of four years old. Some studies show the incidence to be 1 per 1,000,000 cases[1],2. Detecting GD in children early is very important as untreated GD poses a risk for failure to thrive. There have also been cases of young children suffering from psychomotor delays, craniosynostosis, and language delays because their suspected diagnosis of GD had not been detected for one to two years. In this article, we report the case of a previously healthy three-year-old Caucasian female who presented to the pediatric endocrinologist after collapsing from an episode of hypoglycemia; plasma glucose 47 mg/dL (71-180) . The patient was diagnosed with Graves’ Disease due to her significantly elevated free T3 and T4, decreased TSH, positive thyroid peroxidase (TPO) antibodies, and elevated TSIg. She was started on methimazole treatment; however, she did not respond after six months of ATD and underwent total thyroidectomy. Her hypoglycemia was attributed to abnormal proinsulin processing and glucose metabolism, which has been associated with hyperthyroidism; thyroid hormones can produce increased GLUT2 transporters3. This case report demonstrates the importance of recognizing the signs and symptoms of GD early, as well as discuss the importance of increasing the recognition of autoimmune diseases in the pediatric population.

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).

7854 Ablation Aberration: A Case of Thyroid Dermopathy Exacerbation in a Filipino Male Following Radioactive Iodine Ablation and Total Thyroidectomy Improved by Weekly Intradermal Long-Acting Glucocorticoid Injection

Abstract Disclosure: K.T. Lim: None. O.C. Dampil: None. Ablation Aberration: A Case of Thyroid Dermopathy Exacerbation in a Filipino Male Following Radioactive Iodine Ablation and Total Thyroidectomy Improved by Weekly Intradermal Long-Acting Glucocorticoid Injection Introduction: Thyroid dermopathy (TD) represents an unusual extrathyroidal presentation of Graves' disease (GD), impacting about 0.5–4% of patients. RAI treatment for hyperthyroidism is known to progress Graves' ophthalmopathy. RAI-induced TD exacerbation, however, is rare in literature. Here, we present a case of worsening TD and ophthalmopathy in a Filipino patient with GD who underwent definitive therapy for persistent hyperthyroidism. Clinical Case: A 44-year-old man with GD had bilateral lower extremity indurated, mildly erythematous plaques for 4 years. Hyperthyroidism persisted despite methimazole compliance, so he underwent RAI ablation two years earlier, total thyroidectomy a year later, and has been on levothyroxine since. Despite definitive treatment, his extrathyroidal symptoms worsened. A punch biopsy of the skin lesions revealed upper and mid-lower dermis mucin deposition, with occasional spindle-shaped and stellate fibroblasts, and mast cells. These histopathologic findings were consistent with pretibial myxedema. We assessed his thyroid function and found he was euthyroid with normal TSH (3.1 μIU/mL; reference range 0.27-4.20) and an elevated TRAb (35.73 IU/L; reference range &amp;lt;1.75). Physical examination revealed thickened skin, cobblestone-like plaques, and non-pitting edema on the pretibial, ankle, and pedal areas. A 3.5-cm-diameter, circumscribed, orange-peel-textured, indurated plaque covered his left ankle. Fluocinolone acetonide 0.025% w/w ointment was initiated. After 3 weeks, his cutaneous symptoms improved by 35%, albeit his left ankle circumscribed plaque improved marginally. Triamcinolone acetonide 40 mg/mL was injected into this and other nodular lesions at 4mg (0.1 mL) per 1-cm-diameter circular region. Each dose was equally dispersed by multipoint intradermal injections using a 1 mL syringe with a 0.5”x 25G needle. A week after intralesional triamcinolone injection and continuous topical steroid application on the non-nodular lesions, a 70% improvement in cutaneous manifestations was observed (from baseline) with the plaques becoming thinner and softer. After three weekly intradermal steroid injections, the circumscribed plaque had flattened (with residual hyperpigmentation), and the other plaques and nonpitting edema dissipated. Conclusion: Our experience with this patient highlights a paradoxical TD exacerbation following RAI ablation and definitive surgery for persistent hyperthyroidism in GD. It also reveals that weekly administration of multiple subcutaneous injections of a long-acting glucocorticoid alleviates lesions where topical ointment does not. Presentation: 6/1/2024

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

6537 Recurrent Graves Thyrotoxicosis After Prolonged Radioiodine-Induced Hypothyroidism

Abstract Disclosure: H.K. Deveaux: None. A. Gundeti: None. K. Mitrollari: None. A.P. Calimag: None. T. Yasmeen: None. Radioactive iodine (I-131) ablation (RAI) is one of the effective therapies for Graves’ disease (GD). Successful treatment is indicated by sustained, irreversible hypothyroidism requiring lifelong replacement for which recurrence of disease rarely develops. Recurrent hyperthyroidism is a rare development without apparent predisposition. Here, we describe a case of recurrent thyrotoxicosis after 36 years of RAI.70-year-old female PMH atrial fibrillation (AFib) on apixaban s/p cardioversion, HTN, HFpEF, Pulmonary HTN, and Graves’ Disease s/p RAI ablation 36 years ago with RAI-induced hypothyroidism. The patient was initially on levothyroxine for post-ablative hypothyroidism and stopped taking levothyroxine around 2019. NM scintigraphy done in 2019 showed an abnormal I-123 thyroid uptake and scan with the five-hour radioiodine thyroid uptake showed mildly hyperthyroid. On the thyroid scan, there is a note of a prominent pyramidal lobe with some thyroid gland asymmetry. In 2022, the patient was admitted for new-onset AFib and was noted to have subclinical hyperthyroidism with TSH 0.157, fT4 1.4, TrAb&amp;gt;40, and TSI 34.8. The patient was started on methimazole, which she stopped one month later. During this admission, the patient presented secondary to a mechanical fall and was found to be in AFib with a rapid ventricular rate. Her labs were significant for TSH&amp;lt;0.008 fT4 4.2, TrAb &amp;gt;40. Methimazole was restarted with maximal doses of diltiazem and metoprolol for rate control. Thyroid ultrasound demonstrated an enlarged, heterogeneous thyroid gland with increased vascularity and multiple bilateral TR3 thyroid nodules.Hyperthyroidism affects approximately 1.2% of the population. GD involves autoantibodies activating the thyrotropin receptor, increasing synthesis and release of thyroid hormone and is for 50-60% of cases with a 5-to-10-fold preference for females. RAI ablation is preferred, being inexpensive, with a cure rate approaching 100%. The incidence of transient hypothyroidism post-RAI varies from 9-17%. Retrospective studies have observed hyperthyroidism within the first 12 months post-RAI; however, some cases have seen a resurgence as late as 22 years later. Recurrent hyperthyroidism is an uncommon occurrence with various postulated aetiologies, such as inadequate dosing/incomplete ablation with residual cells remaining viable and regenerating in the setting of increased TSIiv, Marine-Lenhart syndrome (MLS), or an unclear mechanism associated with autoimmunity in the presence of TSI. Hyperthyroidism rarely recurs in GD after successful post-ablative treatment with RAI. Our case, while an uncommon presentation and underlying aetiology yet to be determined, illustrates the importance of continued surveillance, even after successful treatment.‌ Presentation: 6/3/2024

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

7824 Orbital Lymphoma masquerading as Thyroid Eye Disease

Abstract Disclosure: S. Ganawa: None. S. Joseph: None. C. Anshuman: None. D. Luciane L: None. A. Sajid: None. C. Anne: None. S. Dhage: None. Thyroid eye disease (TED) is the most common extrathyroidal manifestation in Graves’ disease (GD). In this case report, we present a case of a 64 years old lady, who was initially diagnosed with thyroid eye disease about 9 years ago. However, she was clinically and biochemically euthyroid. She was offered an orbital decompression surgery by local ophthalmology team. Patient wasn’t keen on the surgery at this stage.Recently she experienced increased swelling of her eyes, with conjunctival redness, oedema, and diplopia bilaterally, more evident on the left side. She was initiated on intravenous methylprednisolone (IVMP) weekly, by local ophthalmology team and was referred to our specialist thyroid eye clinic for further management.On presentation to us, her clinical activity score (CAS) was 5/7, but she was euthyroid clinically and biochemically. She was continued on weekly IVMP and oral mycophenolate mofetil (MMF) was added on as per the latest EUGOGO guidelines published in 2021. Her treatment was reviewed after the anti thyroperoxidase (TPO) and anti-Thyroid Stimulating Hormone receptor (TSH) antibodies were reported as negative and her eyes worsened despite the treatment with IVMP and MMF.Her repeat MR orbit at this stage showed possible orbital lymphoma. Her immunosuppressive medications were discontinued at this stage. After further discussions at regional thyroid eye MDT and radiology MDT, an orbital biopsy was arranged for, which confirmed Extra nodal Marginal Zone lymphoma, with no high-grade component. She has been referred to the oncology unit for further assessment and management.This case highlights the importance of considering alternative differential diagnosis in certain patients with atypical features or those who are non-responders to the first line immunosuppressive therapies for thyroid eye disease. Details of this case and relevant literature will be reviewed in this report. Presentation: 6/3/2024