bluuebunny/crossref_metadata_2025_split huggingface dataset:
FRI478 Pharmacometrics-based Computer Model Utilizing Heart Rate To Monitor Thyroid Function In Children With Graves' Disease
Authors: Steffens Britta , Koch Gilbert , Claude Fabien , Bachmann Freya , Schropp Johannes , Janner Marco , l'Allemand Dagmar , Konrad Daniel , Pfister Marc , Szinnai Gabor 
Published: October 2023

Abstract
Disclosure: B. Steffens: None. G. Koch: None. F. Claude: None. F. Bachmann: None. J. Schropp: None. M. Janner: None. D. l'Allemand: None. D. Konrad: None. M. Pfister: None. G. Szinnai: None.
Graves’ disease (GD) with onset in childhood or adolescence is a pediatric rare disease (ORPHA:525731) with a ten times lower incidence than in adults. Leading clinical signs of hyperthyroidism are sinus tachycardia, weight loss, tremor, and goiter. First-line treatment are anti-thyroid drugs in order to normalize thyroid function. However, dose finding in pediatric GD is complex due to a broad spectrum of disease severity at diagnosis, and highly variable disease activity during follow-up, especially during puberty. As thyroid hormones have a strong positive chronotropic effect, heart rate (HR) turns out to be a useful clinical marker to monitor thyroid activity under treatment. Our overall aim was to provide a practical pharmacometrics-based (PMX-based) computer model characterizing both, individual FT4 dynamics and the relation between FT4 and tachycardia in children with various disease severity of GD during the first 120 days of treatment. Development of the PMX computer model was based on the non-linear mixed effects approach (i) linking FT4 kinetics with HR dynamics, (ii) accounting for inter-individual variability, and (iii) incorporating individual patient characteristics. Retrospectively collected clinical (resting heart rate during consultation) and laboratory data (FT4) from 41 children and adolescents with GD at four pediatric hospitals in Switzerland (75% female, median age 11.2 [IQR 8.5, 13.5] years) with 187 FT4 measurements and 132 HR measurements, and 124 paired measurements, were available and used for model development. Pediatric patients showed median FT4 of 59.6 [IQR 44.5, 73.0] pmol/l and median HR of 112 [IQR 100, 128] bpm at diagnosis. GD severity groups were defined based on FT4 measurement at diagnosis, resulting in equal numbers of mild (13), moderate (14) and severe (14) GD. We observed a significant difference in HR at diagnosis (p &lt; 0.01) between the three GD severity groups based on FT4 at diagnosis. The final PMX computer model accounted for inter-individual variability and clinically relevant covariate effects such as age, gender, and GD severity, and was able to accurately predict FT4 and HR dynamics for each individual patient during the first 120 days of treatment. A PMX-based computer model that leverages individual HR dynamics can be applied to facilitate personalized pharmacotherapy in pediatric GD and mitigate the risk for under- or overdosing of anti-thyroid drugs in these patients. Prospective randomized validation trials are warranted to further validate and fine-tune such computer-supported personalized dosing in children with Graves’ disease.
Presentation: Friday, June 16, 2023
FRI489 The Interplay Between Thyroid Nodular Disease And Insulin Resistance Indices In Pregnant Women
Authors: Jerzy Nowak Andrzej , Trofimiuk-Muldner Malgorzata , Podlewski Jacek , Hubalewska-Dydejczyk Alicja 
Published: October 2023

Abstract
Disclosure: A.J. Nowak: None. M. Trofimiuk-Muldner: None. J. Podlewski: None. A. Hubalewska-Dydejczyk: None.
Thyroid cells proliferation and function is regulated by TSH. Other factor, such as insulin/insulin-like growth factors (IGF), through their mitogenic effects, may affect thyroid growth and nodules formation [1].This study evaluated the interplay between insulin resistance indices and thyroid structure in pregnant women. The study group was recruited from the Polish National Program for Elimination of Iodine Deficiency, conducted between 2007-2017. We assessed the fasting glucose, insulin levels, TSH in 1069 pregnant women (median age 29 years, IQR 6 years). Thyroid ultrasound was performed in each study participant. Based on calculated HOMA-IR, pregnant women were stratified into three subgroups HOMA1 (324 women with HOMA-IR &lt; 1), HOMA 2 (570 women with HOMA-IR ≥1& &lt;2.5) and HOMA3 (175 women with HOMA-IR ≥ 2.5). Results: Median (IQR) TSH concentrations were 1.42 (1.33) mIU/L, 1.65 (1.31) mIU/L, and 1.77 (1.29) mIU/L in HOMA1, HOMA2, and HOMA3 subgroups, respectively. The mean (±SD) thyroid volume was 12.36 (4.27) mL, 12.71 (5.37) mL, and 13.70 (4.92) mL in HOMA1, HOMA2, HOMA3 subgroups respectively.33 (10.2%) of women in HOMA1, 53 (9.3%) in HOMA2 and 11 (6.3%) in HOMA3 subgroup had at least one thyroid nodule - there was no significant difference between the subgroups (P = 0.4724)Fasting insulin &gt;10 mIU/mL was found in 27.53% of pregnant women (286 out of 1039) with thyroid volume &lt;25 mL, and in 36.67% women (11 out of 30) with thyroid volume ≥25mL (P=0.27).
Conclusions: We have not found any significant relationship between the thyroid volume or structure and insulin or insulin resistance indices in pregnant women.
1. Kimura T., Van Keymeulen A., Golstein J., Fusco A., Dumont J.E., Roger P.P. Regulation of thyroid cell proliferation by TSH and other factors: A critical evaluation of in vitro models. Endocr. Rev. 2001;22:631–656. doi: 10.1210/edrv.22.5.0444.
Presentation: Friday, June 16, 2023
FRI549 The See-Saw Theory - Hypothyroidism Due To Hashimoto's Thyroiditis Followed By Hyperthyroidism Due To Graves' Disease
Authors: Sharma Pranjali 
Published: October 2023

Abstract
Disclosure: P. Sharma: None.
Introduction: Hashimoto's thyroiditis is an autoimmune disorder characterized by chronic inflammation of the thyroid gland that leads to hypothyroidism due to formation of autoantibodies against thyroid antigens such as thyroid peroxidase (TPO Ab). Graves' disease is caused by stimulating TSH-receptor antibodies (TRAb) that cause hypertrophy of the thyroid gland leading to hyperthyroidism. While the transformation of Graves' disease to Hashimoto's thyroiditis has been reported, flipping from Hashimoto's thyroiditis to Graves' disease is uncommon. Case Report: A 62 year old female with 20 year history of hypothyroidism secondary to Hashimoto's thyroiditis presented to establish care. She had run out of levothyroxine refills one year prior during COVID-19 pandemic restrictions. She had tachycardia, diarrhea, fatigue, tremors, hair loss, dysphagia, and weight gain. Thyroid panel testing showed hyperthyroidism with an undetectable TSH (normal range 0.45-4.5uIU/ml) and elevated free T4 (2.84, normal 0.82-1.77ng/ml). Patient denied recent infections, iodine intake or iodine contrast exposure. Repeat labs confirmed hyperthyroidism with undetectable TSH with elevated free T4 (3.17ng/ml). Antibody testing comfirmed hyperthyroidism secondary to Graves disease (TRAb 20.7, normal &lt;1.75IU/L). Patient has been on methimazole with fluctuating response and is reviewing definitive therapy options. Discussion: We demonstrate the rare phenomenon of thyroid function transformation from long-standing inhibition to stimulation after 20 years. Hashimoto's thyroiditis is characterized by chronic inflammation due to autoantibodies against TPO, thyroglobulin and the TSH receptor with gradual gland destruction and hypothyroidism. Stimulating autoantibodies to the TSH receptor (thyroid stimulating immunoglobulin (TSIg), TRAb) in Graves' disease lead to hyperthyroidism from gland hypertrophy. The flip from underactivity to overactivity can be explained by recovery of the gland from Hashimoto's thyroiditis injury which gradually leads to an overt response to TSIg, causing a hyperfunctioning gland. An imbalance between the inhibitory and stimulating antibodies can also lead to this transformation. Age, pregnancy and immunomodulating drugs such as alemtuzumab are also thought to play a role. The recovery theory is unlikely in our patient with a 20 year history of Hashimoto's thyroiditis. We believe that she had a high inhibitory antibody titre initially and now has higher titre of stimulating antibodies later, leading to Graves' disease. Luckily, she ran out of levothyroxine otherwise the additive effect of levothyroxine and intrinsic gland activity could have led to worse symptoms. This case highlights that autoimmune hypothyroidism and hyperthyroidism are conditions in the same spectrum, rather than two distinct entities as previously thought.
Presentation: Friday, June 16, 2023
FRI553 ICI-induced Thyroid Ophthalmopathy With De Novo Graves’ Disease
Authors: Moctezuma Sananda I , Perlman Jordan , Sophie Mammen Jennifer 
Published: October 2023

Abstract
Disclosure: S.I. Moctezuma: None. J. Perlman: None. J.S. Mammen: None.
Background: Immune checkpoint inhibitors frequently target the thyroid gland. However, immune checkpoint inhibitor (ICI)-induced Graves’ disease (GD) is rare. To our knowledge, there are no reported cases of thyroid eye disease after immune checkpoint inhibitor therapy in patients with newly positive anti-thyroid antibodies. Clinical Case: An 81-year-old man developed thyroiditis within three weeks of a single dose of ipilimumab/nivolumab for the treatment of metastatic cholangiocarcinoma. ICI therapy was discontinued for cardiotoxicity. He presented one year later with onset of periorbital edema, pain with downgaze, redness, irritation and progressive proptosis with diplopia. He did not have a prior history of thyroid disease. Thyroid function tests before the start of ICI therapy revealed euthyroidism [TSH 2.982 uIU/mL (0.55 - 4.78)]. Symptoms of palpitations, weight loss, and hyper-defecation that characterized his initial presentation with thyroiditis were absent at the time of onset of eye disease. At presentation of thyrotoxicosis his TSH was &lt;0.01 uIU/mL, free T4 3.6 ng/dL (0.89 - 1.76) total T3 190 ng/dL (60-180) Thyroid-peroxidase autoantibodies (TPOAb) and thyroid-stimulating immunoglobulin (TSI) were negative. When his visual symptoms appeared, TPOAb remained negative while a repeat TSI antibody was positive [0.64 IU/L (0.00 - 0.55)]. Thyroid ultrasound at the time of thyroiditis revealed a heterogeneous gland without discrete nodules and a normal vascular flow. Most cases of ICI-induced GD have been reported at the start of therapy, particularly in the first 6 weeks, although thyrotoxicosis has been described to occur as late as 224 days after starting PD-1 inhibitor. GD is more frequently reported with combination anti-CTLA-4 and anti-PD-1 therapy. Patients with thyroid ICI-induced adverse events experience either isolated hypothyroidism or thyroiditis spontaneously evolving towards hypothyroidism. However, ICI-induced GD is more likely to have a relapsing-remitting disease. In 2021, Peiffert et al. described the antibody profile for 243 patients with ICI-induced thyrotoxicosis. In this case series, 5 patients developed thyrotoxicosis with positive thyrotropin-receptor antibodies (TRAb). Only 2 patients had a typical clinical presentation of GD. TSI antibodies were not reported. Furthermore, none of the patients with positive TRAb had Graves’ ophthalmopathy. Conclusion: Our case demonstrates the acquisition of auto-antibodies capable of mediating Graves’ disease, and raises the possibility that thyroid eye disease-like orbital inflammation may occur as a side effect of immune checkpoint inhibitor therapy. These symptoms developed as late as one year after initiation of therapy. As with sporadic cases, this can occur in the absence of clinically significant hyperthyroidism.
Presentation: Friday, June 16, 2023
OR14-01 Contact Between Thyroglobulin Opposite Domains Assists Its Upstream Regions In Intracellular Trafficking For Thyroid Hormonogenesis
Authors: Citterio Cintia E , Kim Kookjoo , Rajesh Bhavana , Pena Kevin , Clarke Oliver B , Arvan Peter 
Published: October 2023

Abstract
Disclosure: C.E. Citterio: None. K. Kim: None. B. Rajesh: None. K. Pena: None. O.B. Clarke: None. P. Arvan: None.
Thyroglobulin (Tg), must be released into the lumen of thyroid follicles to facilitate thyroid hormone synthesis. The Tg primary sequence (∼2,760 amino acids) includes regions I, II, III, as well as ∼570 residues of cholinesterase-like (ChEL) domain (which bears 47% similarity to acetylcholinesterase), folded as a globular protein with multiple contacts between different Tg regions. The ChEL domain is reported to function as an intramolecular chaperone assisting Tg region I. This function cannot be replaced by acetylcholinesterase or neuroligins, indicating a unique function of Tg ChEL. However, the specific amino acids of ChEL neighboring upstream Tg regions have only recently been identified, and the key functional residues for Tg folding remain unknown. Here, we’ve combined structural analyses with functional characterization of recombinant Tg expressed in cell culture. We’ve identified hTg-ChEL K2223 and W2222 as amino acids that exhibit the closest physical proximity with Tg region I. By cryo-EM of Tg (both human and bovine), Tg-K2223 and Tg-W2222 reside only ∼4.5Å from Tg-W1089 and Tg-P1098, respectively, both of which are located in the Tg 1-9 repeat within region I. We’ve employed site-directed mutagenesis to determine the impact of these contacts by studying both full length Tg as well as Tg expressed in a two-component system in cultured cells. We find that secretory ChEL-K2223E and ChEL-W2222A behave much like WT secretory ChEL; both mutants are reasonably well expressed and secreted efficiently. However, when secretory ChEL was co-expressed with Tg region I-II-III lacking its own ChEL domain, region I-II-III secretion could be rescued in the presence of WT secretory ChEL, but not by co-expression of either ChEL-K2223E or ChEL-W2222A. In context of a single contiguous full length Tg, both expression and secretion of Tg-K2223E and Tg-W2222A were significantly diminished. These results highlight two residues (K2223 and W2222) that are not needed for the independent folding (or endoplasmic reticulum export) of the Tg ChEL domain, but are key residues for contacting Tg region I, thereby offering the overall Tg structure a great increase in conformational stability, which is needed to satisfy endoplasmic reticulum quality control requirements for intracellular protein trafficking. These findings point to the possibility that mutations altering regional contacts within the Tg structure could contribute to the molecular pathogenesis of congenital hypothyroidism.
Presentation: Friday, June 16, 2023
SAT449 Clinical Characteristics Of Patients With Thyrotoxic Periodic Paralysis; An Experience From A Tertiary Care Hospital
Authors: Sun Park Tae , Goak Insun , Jin Heung-Yong , Ae Lee Kyung , Ji Kim Yu 
Published: October 2023

Abstract
Disclosure: T. Park: None. I. Goak: None. H. Jin: None. K. Lee: None. Y. Kim: None.
Backgrounds: Thyrotoxic periodic paralysis (TPP) is a life-threatening complication characterized recurrent episodes of hypokalemia and muscle weakness in the setting of thyrotoxicosis. The present study aimed to describe clinical manifestation and outcome of patients admitted for TPP in emergency department (ED). Methods: This retrospective study analyzed 42 patients with TPP who were admitted ED from January 2000 through December 2020 in a single tertiary referral hospital. Their clinical characteristics were reviewed retrospectively. Results: 42 patients with TPP were identified. The mean age of the patients was 35.0±12.4 years; all were males. The month in which the most patients occurred paralysis symptoms was February (16.7%), followed by October (14.3%). 5 patients had a history of severe exertion, 7 patients had ingested a heavy carbohydrate meal, one patient had an infection, 5 patients had ingested alcohol, but more than half of the patients (57.1%) were without a precipitating cause. TPP was the first presentation of thyrotoxicosis in 85.7% of patients. The most common cause of thyrotoxicosis in TPP patients was Graves' disease (88.1%). At the time of admission, the mean potassium level was 2.77±0.93 mmol/L (reference, 3.5-5.5), mean ionized calcium level was 1.17±0.15 mmol/L (1.13-1.32), mean Free T4 level was 43.36±16.92 pmol/L (11.5-22.7). About half of the patients (47.6%) suffered at least one further attack of TPP. 28 patients (66.7%) diagnosed with Graves’ disease had anti-thyroid drugs alone and 5 patients (11.9%) with thyrotoxic relapses eventually underwent radioactive iodine therapy. None of the patients underwent surgery. Conclusions: TPP can be the presenting feature of previously undiagnosed thyrotoxicosis and should be considered in the differential diagnosis in patients presenting with acute onset of motor paralysis. At the time of the TPP attack, a detailed interview and inquiry with a thorough physical examination usually provide clues to the diagnosis.
Presentation: Saturday, June 17, 2023
SAT454 Repetition Of Fine Needle Aspiration Cytology After An Initial Nondiagnostic Result: Does An Optimal Timing Exist?
Authors: Cosme Inês , Lacerda Nobre Ema , João Bugalho Maria 
Published: October 2023

Abstract
Disclosure: I. Cosme: None. E.L. Nobre: None. M.J. Bugalho: None.
Background: The optimal time to repeat a fine-needle aspiration cytology (FNAC) of a thyroid nodule, after a nondiagnostic (ND) result, is not established. It has been proposed to wait at least 3 months for a 2nd FNAC, in order to mitigate the possible inflammatory cytological changes induced by a previous FNAC. This study aimed to evaluate whether the time between 2 consecutive FNACs, influences the final cytological result. We analysed the occurrence of ND or atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) in the 2nd FNAC, in different repetition time intervals. Methods: Retrospective study (2017-2020) including thyroid nodules with a first ND FNAC, submitted to a 2nd FNAC. All FNACs were ultrasound-guided. Demographic data, time interval between FNACs and their results were collected. The 2nd FNAC results were analysed according to FNACs´ repetition interval. We considered 2 intervals: ≤ vs &gt; 3 months and ≤ vs &gt;6 months after the initial FNAC. The 2nd FNAC results were classified as ND, AUS/FLUS or diagnostic (including the other Bethesda FNAC categories). Results: Included 190 nodules (190 patients, 82.1% women, mean age 60±13.7 years) with a 1st ND FNAC submitted to a 2nd FNAC. The 2nd FNAC result remained ND in 63 cases, was AUS/FLUS in 9 and diagnostic in 118 (benign in 116 cases, follicular neoplasm/suspicious follicular neoplasm in 1 and malignant in 1 case). There were no statistical differences in 2nd FNAC result performed ≤3 months (13 ND, 2 AUS/FLUS, 19 diagnostic) vs &gt;3 months (50 ND, 7 AUS/FLUS, 99 diagnostic) - p=0.71. Considering a wider time interval between FNACs, there were also no statistical differences in the 2nd FNAC result: ≤ 6 months (32 ND, 3 AUS/FLUS, 59 diagnostic) vs &gt;6 months (31 ND, 6 AUS/FLUS, 59 diagnostic) - p=0.61. Conclusions: The time interval between FNACs was not relevant to the final cytological result. Early FNAC repetition did not increase the cases of ND or AUS/FLUS.
Presentation: Saturday, June 17, 2023
SAT493 Laser Ablation For Benign Thyroid Nodules: A Way To Treat And Still Preserve The Thyroid
Authors: Kalara Niketa , Maria Bignoli Daniela Laura , Acosta Crystal Maria , Manzano Alex 
Published: October 2023

Abstract
Disclosure: N. Kalara: None. D.L. Bignoli: None. C.M. Acosta: None. A. Manzano: None.
Introduction: Thyroid nodules in adults have a prevalence of 3-7% based on palpation and 20-76% based on ultrasound examination. The majority of which are benign but some increase in size causing compressive symptoms or cosmetic concerns, thus, needing treatment. Laser ablation (LA) is a safe, non-surgical approach for the management of benign thyroid nodules now approved in the US. Nodule reduction is achieved through laser induced cytoreduction and tissue coagulation. Two benign FNA biopsies 3-6 months apart and a nodule size of more than 2.5 cm are some of the inclusion criteria for LA. We present a case of a benign thyroid nodule causing compressive symptoms where LA was done since the patient declined surgery. Case description: 76-year-old female with a history of type 2 diabetes mellitus, hypertension, and multinodular goiter for many years presented with concerns of neck fullness and discomfort for the past 6 months. Thyroid ultrasound confirmed a large dominant right complex nodule of 2.8 x 1.13 x 3 cm with a volume of 5 ml. Thyroid function test showed Thyroid stimulating hormone (TSH) 1.2 mIU/mL (0.40-4.50) and free T4 1.24 ng/dl (0.9-1.7). Two FNA biopsies done 3 months apart in the past were Bethesda II. Given the compressive symptoms due to a multinodular gland thyroidectomy was discussed as a treatment option with the patient which she declined. Hence, LA was discussed as an option for the largest nodule. The procedure was performed without complications. The nodule received 1450 Joules at 6 watts using one Elesta laser fiber. At the end of 2 months post-LA, thyroid ultrasound showed a significant reduction of the nodule with a current size of 1.5 x 1 x 1.6 cm and 1.4ml volume. She continued to be clinically and biochemically euthyroid with a total volume reduction close to 70% and complete resolution in compressive symptoms. Conclusion: Percutaneous laser ablation is a non-surgical, minimally invasive procedure to treat benign thyroid nodules that is now accessible in the US with promising results and a good safety profile. It is covered by insurance in various states. In our case the patient refused surgical intervention, thus, laser ablation was done that resulted in the resolution of her compressive symptoms without any complications. More awareness regarding the laser ablation procedure and its availability for patients is needed, especially in cases where preservation of the thyroid gland is desired. Reference: 1. Gambelunghe G, Stefanetti E, Avenia N, De Feo P. Percutaneous Ultrasound-Guided Laser Ablation of Benign Thyroid Nodules: Results of 10-Year Follow-Up in 171 Patients. J Endocr Soc. 2021 May 5;5(7):bvab081. doi: 10.1210/jendso/bvab081. PMID: 34159286; PMCID: PMC8212682.
Presentation Date: Saturday, June 17, 2023