bluuebunny/crossref_metadata_2025 huggingface dataset:
6517 Cardiac Tamponade Secondary to Occult Primary Hypothyroidism
Authors: Javed Laraib , Al jumaili Hamsa , Mahaldar Anshinee , Goyal Itivrita , Shakir Nabeela , Punni Emma
Published: October 2024

Disclosure: L. Javed: None. H. Al jumaili: None. A. Mahaldar: None. I. Goyal: None. N. Shakir: None. E. Punni: None.

Introduction: The incidence of pericardial effusion in hypothyroidism seems to correlate with severity and duration of the condition and ranges from 3% to 37%. Cardiac tamponade resulting from hypothyroidism is exceptionally rare. We present a case of a patient presenting with this complication.Case Summary:A 38-year-old woman presented during a routine clinic visit with symptoms of fatigue and was found to have elevated liver functions enzymes with ALT 107 (N<48 U/L ) and AST 70 (N<47 U/L)Further evaluation through abdominal imaging revealed incidental finding of a partially imaged moderate pericardial effusion. A subsequent echocardiogram showed circumferential pericardial effusion with early tamponade physiology, necessitating immediate referral to the emergency room (ER) for further assessment and management.Upon admission to the ER, the patient reported progressive fatigue, increased sleep and menorrhagia over 8 months. There were no accompanying symptoms of weight gain or constipation. Family history was positive for thyroid disease in her grandmother. Initial vital signs on admission were Blood pressure: 119/86, Pulse: 55, Respiratory Rate: 13, Temp: 36.7 °C. Electrocardiogram showed sinus bradycardia. Laboratory findings were significant for: Hgb 8.7 (N>11.5), MCV 77.5 (N>80 fL), mildly elevated ALT 56, markedly elevated TSH 255 (N<5 IU/mL), low free T4 <0.1 (N ≥ 0.7 ng/dL), low free T3 <0.6 (N ≥2.0 pg/m), and elevated TPO 472 (N 35 IU/mL). Infectious and rheumatologic work-up were negative. Thyroid ultrasound showed heterogenous echogenicity consistent with thyroiditis.Patient underwent urgent pericardiocentesis draining 750 ml of clear yellowish pericardial fluid. Simultaneously, the patient was initiated on daily levothyroxine at a dose of 112 mcg.Stability in hemodynamics and repeat echocardiogram showcasing no pericardial effusion facilitated the patient’s discharge. Notable improvement with reduction in TSH from 260 to 20 was seen at the one-month follow-up in endocrinology clinic. Conclusion: Hypothyroidism should be considered in patients diagnosed with cardiac tamponade presenting with bradycardia, as in this case. It's been observed that hypothyroidism can affect LFTs which typically resolve with thyroid replacement. Treatment of cardiac tamponade depends on the patient's hemodynamic status. For early mildly affected cases of tamponade, a conservative approach involving close monitoring and limiting fluid intake may suffice, but drainage is often necessary. Since the pericardial effusion and tamponade stem from hypothyroidism, there's a high chance of effusion recurring after drainage. Hence, administering levothyroxine is essential, often leading to effusion resolution within 2-12 months without recurrence.

Presentation: 6/3/2024
6602 Classification of TSH Trajectories During Levothyroxine Treatment in the ELSA-Brasil Cohort
Authors: Ettleson Matthew D , Penna Gustavo C E , Wan Wen , Bensenor Isabela M , Laiteerapong Neda , Bianco Antonio C
Published: October 2024

Disclosure: M.D. Ettleson: None. G.C. Penna: Consulting Fee; Self; Ipsen, Bayer, Inc.. W. Wan: None. I.M. Bensenor: None. N. Laiteerapong: None. A.C. Bianco: Consulting Fee; Self; Abbvie.

Classification of TSH Trajectories During Levothyroxine Treatment in the ELSA-Brasil Cohort Introduction: Hypothyroidism is a common endocrine disorder for which levothyroxine (LT4) serves as the primary treatment. Periods during which thyroid stimulating hormone (TSH) levels are outside the normal range have been associated with adverse cardiovascular outcomes, including mortality. In practice, serial TSH levels are measured over time to ensure therapeutic LT4 treatment is maintained. However, there is no measure of the quality of treatment maintenance over time. TSH trajectory classification represents a novel approach to define the adequacy of LT4 treatment for hypothyroidism over time utilizing multiple observation points. Methods: With longitudinal clinical data, including thyroid function from a large prospective study, we aimed to define classes of TSH trajectories and examine changes in cardiovascular (CV) health markers over a 9 year study period with three observation points. Growth mixture modeling (GMM), including latent class growth analysis (LCGA), was used to classify LT4-treated individuals participating in the Longitudinal Study of Adult Health in Brazil (ELSA-Brasil) based on serial TSH levels. Repeated measure analyses were then utilized to measure within-class changes in blood pressure, lipid levels, hemoglobin A1c, and CV-related medication utilization. Results: From the 621 LT4-treated study participants, the best-fit GMM approach identified four TSH trajectory classes, as defined by their relationship to the normal TSH range: 1) High-high normal TSH, 2) Normal TSH, 3) Normal-to-low TSH, and 4) Low-to-normal TSH. Notably, the average baseline LT4 dose was lowest in the high-high normal TSH group (77.7 mcg, p <0.001). There were no significant differences in CV health markers between the classes at baseline. At least one significant difference in CV markers occurred in all classes, highlighted by the low-to-normal class, in which total and HDL cholesterol, triglycerides, and A1c all increased significantly (p = 0.049, p <0.001, p <0.001, and p = 0.001, respectively). Medication utilization increased in all classes over the study period. Conclusion: GMM/LCGA represents a viable approach to define and examine LT4 treatment by TSH trajectory. In the future, more comprehensive datasets will allow for more complex trajectory modeling and analysis of clinical outcome differences between trajectory classes. Defining the adequacy of LT4 treatment using a longitudinal scope could allow clinicians to more accurately communicate treatment progress and identify patients at risk for adverse CV outcomes.

Presentation: 6/3/2024
8368 Functional Evaluation Of Novel CYP21A2 Variants: Expanding The Genetic Basis Of Non-classic CAH
Authors: Matveeva Anna , Xu Yingtong , Tardy-Guidollet Véronique , Pandey Amit V
Published: October 2024

Disclosure: A. Matveeva: None. Y. Xu: None. V. Tardy-Guidollet: None. A.V. Pandey: None.

Introduction: Congenital adrenal hyperplasia (CAH) comprises a group of autosomal recessive genetic disorders affecting the production of glucocorticoids, mineralocorticoids, and gonadocorticoids. In approximately 95% of cases, CAH results from a deficiency in CYP21A2. A Non-Classic form of CAH (NC-CAH) arises when CYP21A2 activity decreases to 20-50% of the normal level, occurring at an estimated frequency of 1 in 200 - 1000 individuals. The clinical picture is characterized by the accumulation of androgen precursors, causing hirsutism, acne, metabolic syndrome, menstrual irregularities, infertility in females, and androgenic alopecia, oligospermia in males. Methods: We selected mutations from CYP21A2 sequence data of patients with NC-CAH symptoms admitted to CHU Lyon, France (L49V, A81T, R125G, I161T, L199F, L289H, L289F, V306D, L462P). Additional variants were selected from the SNP databases (dbSNP, gnomAD, ClinVar) based on a high frequency in humans (H393Q, P387L, T201A, S203G S274Y, S494N, R76K, Leu10del). All variants underwent in silico assessment considering evolutionary, structural, and functional aspects (ConSurf, Predict SNP2, CADD, DANN, FATHMM, FunSeq2, GWAVA, PANTHER, SNPs&GO, PhD-SNP, SIFT, SNAP, Meta-SNP, Polyphen2, HDIV, DUET). The CYP21A2 proteins carrying the mutations were overexpressed in HEK 293T cells. We evaluated CYP21A2 enzyme activities by measuring the conversion of 14C-Progesterone into 11-deoxycortisol by thin layer chromatography and autoradiography. Samples were tested in duplicates, using the activity of WT CYP21A2 as a control. Results: Computational analysis revealed that A81T, R125G, I161T, and L289H substitutions significantly impair protein structure, while other variants showed moderate effects. Except for L199F, all patient-derived variants exhibited reduced 21-hydroxylase (CYP21A2) activity associated with NC-CAH phenotypes. Variants from databases did not demonstrate a significant loss of function related to CAH. Conclusion: In this study we investigate the pathogenicity of uncharacterized CYP21A2 variants in relation to non-classic congenital adrenal hyperplasia (NC-CAH), contributing to a better understanding of associated phenotypes. The findings, particularly the identification of novel mutations and the assessment of their impact on CYP21A2 activity, hold promise for improving diagnosis and treatment strategies aimed at mitigating severe outcomes of NC-CAH, such as miscarriages or irreversible alopecia. It also raises awareness among heterozygous carriers, assisting in family planning and medical decisions.

Presentation: 6/1/2024
7812 Community Practice Setting Experience in Evaluation of Incidental Thyroid Nodules
Authors: Abate N , Rhodes H , Horlavadi M , Adams-Huet B , Chandalia M
Published: October 2024

Disclosure: N. Abate: None. H. Rhodes: None. M. Horlavadi: None. B. Adams-Huet: None. M. Chandalia: Advisory Board Member; Self; Boehringer Ingelheim. Speaker; Self; Boehringer Ingelheim, Eli Lilly & Company, Novo Nordisk.

Background: There is a significant increase in detection of incidental thyroid nodules due to increase in routine screening ultrasounds at church, workplace, and health fairs, increase in routine ultrasound in primary care clinics and incidental finding of thyroid nodule during carotid artery ultrasound. These patients are then referred for thyroid nodule fine needle aspiration biopsy. Aim of this study was to evaluate real world data in frequency of thyroid cancer in patients referred for incidental thyroid nodule to a nonacademic Endocrinology clinic utilizing centralized collection of cytology and molecular analysis. Method: Medical records were reviewed for consecutive FNA of incidental thyroid nodule in an Endocrinology clinic in greater Houston from 2021 to 2023. FNA was performed in patients selected based on ACR TI-RADS classification. Patients with Bethesda score of 3 or more had molecular testing with Thyroseq performed. Patients with intermediate or high probability of cancer on Thyroseq as well as Patients with Bethesda 4 and 5 on cytopathology were referred for surgery. Surgical pathology was obtained in patients who underwent surgery. Data was tabulated and analyzed using SAS. Results: A total of 304 subjects, 267 Female and 37 males, age 57 ± 13, nodule size 2.69 ± 1.4 (mean ± SD), had thyroid nodule FNA between 2021 and 2023. Of these FNA, 23 (7.5%) sample collections were insufficient, 233 (77.3%) were benign (Bethesda 2), 46 (15%) were Atypia of undetermined significance or Suspicious for malignancy. Of those subjects with Bethesda 3 or higher, 36 patients had molecular testing by Thyroseq Method. Fifteen patients had intermediate and high risk finding on Thyroseq. Thirty-four subjects had surgery and 8 patients had malignancy on surgical pathology. One patient was identified as Medullary Thyroid cancer on Thyroseq, confirmed by surgery. Frequency of malignancy in incidentally detected thyroid nodule in the whole group was 2.6%, those with Bethesda 3 and more was 17.4% and those with Thyroseq intermediate or high risk was 27%. Conclusion: Availability of centralized cytopathology and reflex molecular testing to Community practice settings helps reducing unnecessary thyroid surgeries in patients with incidental thyroid nodules.

Presentation: 6/1/2024
8534 Comorbid Autoimmune Thyroid Disease in a Parent-Child Pair with Resistance to Thyroid Hormone Beta
Authors: Smith A H , Grethen E
Published: October 2024

Disclosure: A.H. Smith: None. E. Grethen: None.

Resistance to Thyroid Hormone Beta (RTHβ) is an inherited disorder caused by mutations in the gene encoding the thyroid hormone receptor beta protein, resulting in decreased binding affinity to triiodothyronine in certain tissues. An asymptomatic individual with RTHβ may demonstrate abnormalities in serologic evaluation of thyroid hormone markers. When other thyroid pathologies present with RTHβ, however, the diagnosis and management can quickly become complex. Below we discuss two cases, a parent-child pair, with different presentations of presumably the same RTHβ gene. Patient 1 is a 61-year-old male with a history of autoimmune thyroiditis several years ago, presenting for continuation of care; he has had levothyroxine doses gradually uptitrated to over 3 mcg/kg to normalize TSH despite persistently high free T4 levels. He also has a family history notable for six out of seven siblings with autoimmune thyroid disease. Patient 2 is a 44-year-old male who was evaluated for hypothyroidism and difficulty with levothyroxine titration. Prior to consultation, he underwent radioactive iodine ablation for presumed Grave’s disease, followed by total thyroidectomy due to persistent symptoms. Post-operatively, he required high doses of levothyroxine to maintain normal TSH levels; however T4 and T3 levels remained high. Both patients confirmed proper levothyroxine supplementation. Further analysis of both patients demonstrated mildly elevated TBG and normal alpha subunit. Patient 2 pursued genetic testing while patient 1 declined, revealing a heterozygous R320S mutation in the TR-beta protein. Further testing and genetic counseling were offered to other family members. Propranolol and levothyroxine supplementation were titrated accordingly; triiodothyronine administration was attempted but did not alleviate symptoms. These two cases demonstrate the increased risk of autoimmune thyroid disorders in patients with RTHβ and the unique challenges they pose in accurate diagnosis. Autoimmune thyroiditis in RTHβ, with goiter, elevated T4 and elevated T3 levels, can be easily confused with Grave’s disease, especially when TSH is suppressed during active thyroiditis. Timely diagnosis can aid in targeted management of sequelae, prevent ineffective treatments for comorbid conditions which may mimic other diseases, and provide anticipatory/preventive guidance for family members to help with screening.

Presentation: 6/1/2024
6502 Comparing TBII vs TSI Assays at University Hospital; A Quality Improvement Project
Authors: Chozet Luis Edmundo , Le Guillaume , Vasco Maria Adelaida Escobar , Bruder Jan
Published: October 2024

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
6431 Comparison of Diagnostic Scoring Systems for Myxedema Coma
Authors: Wei K S , Joyo A , Lim A N , Angell T E
Published: October 2024

Disclosure: K.S. Wei: None. A. Joyo: None. A.N. Lim: None. T.E. Angell: None.

Introduction: Myxedema coma (MC) is a rare condition of severe hypothyroidism with high mortality. Diagnostic scoring systems exist, such as criteria by Popoveniuc et al. (2014) and Chiong et al. (2015), which both include categories of: “highly likely MC” (hlMC), “suggestive of MC” (sMC), and “unlikely MC” (uMC). Because few data support their clinical utility, we performed an analysis comparing these diagnostic criteria and associations with mortality and hospital measures. Methods: Patients with MC were included from a retrospective cohort of hospitalized adult patients with TSH greater than or equal to 10 mIU/L and free thyroxine (fT4) below the lower reference limit. Initial clinical diagnosis of MC was generally based on: hypothyroidism, precipitating illness, hypothermia, and altered mentation. Data collection included patient characteristics, mortality, ICU admission, and hospital length of stay (LOS). Patients were post-hoc categorized based on criteria of Popoveniuc and Chiong. Results: Of 386 initial patients, 25 patients had a clinical diagnosis of MC (median age = 60.1 years [IQR: 53.6-70.0]; 10/25 [40%] female). Median TSH was 58 mIU/L (IQR: 33.8-93.3) and median fT4 was 0.48 ng/dL (IQR: 0.16-0.68). All patients received IV levothyroxine and supportive care. Using Popoveniuc, 20/25 (80%) patients were hlMC and 5/25 (20%) were sMC. In contrast, using Chiong, 11/25 (44%) were hlMC, while 14/25 (56%) were sMC. No patient was considered uMC by either system. 10/25 (40%) patients were hlMC in both systems. 10/25 (40%) were hlMC in Popoveniuc but not Chiong, while only 1/25 (4%) was hlMC in Chiong but not Popoveniuc. Finally, 4/25 (16%) were not hlMC in either system. Mortality occurred in 3/25 (12%) patients, 2 of which were hlMC in Popoveniuc but not Chiong. There was a trend toward longer median hospital LOS in patients identified as hlMC vs not hlMC using Popoveniuc (11 days [IQR: 5.3-37.0] vs. 3.0 days [IQR: 2.0-17.5], p=0.07) but no statistically significant differences in hospital LOS were noted. There were no significant differences in ICU admission or LOS. Conclusion: Existing diagnostic scoring criteria of MC identified most patients but differed in their categorizations. Some cases of clinically diagnosed MC were not identified as hlMC by either scoring criteria. Criteria by Popoveniuc et al. appears to better capture patients most at risk for mortality and prolonged hospitalization.

Presentation: 6/2/2024
7876 Complex Complications of Thionamide Therapy in One Patient: Methimazole-Induced Agranulocytosis and PTU-Induced ANCA-Vasculitis
Authors: Zweibach Eugenia , Chang Amy
Published: October 2024

Disclosure: E. Zweibach: None. A. Chang: None.

Introduction: Thionamides, including methimazole and propylthiouracil (PTU), are essential for treating Graves' disease but can cause serious side effects such as agranulocytosis and ANCA-vasculitis. Although agranulocytosis itself is quite uncommon, the incidence of ANCA vasculitis is even more infrequent, making combination of conditions particularly exceptional. We present a unique case of a Graves' disease patient who suffered both complications: agranulocytosis due to methimazole and ANCA vasculitis from PTU, with successful resolution of both the clinical signs and laboratory findings following drug discontinuation. Case: 61-year-old female with a history of Graves' disease previously managed with methimazole but discontinued due to agranulocytosis, presented with lower extremity swelling, atrial fibrillation with RVR, and high output cardiac failure. Laboratory tests showed hyperthyroidism (TSH 0.008, Free T4 3.07), leading to a diagnosis of thyroid storm. Patient was started on PTU inpatient and discharged with this medication to home. Eight months later, the patient developed alarming signs including gross hematuria, oral ulcers, widespread muscle pain, found to have AKI with Cr of 2.79 and hospitalized for further eval. While hospitalized, the patient was found to have a range of complications including leukopenia with normal granulocyte count, anemia, AKI, proteinuria, and microscopic hematuria. Rheumatological evaluation showed +ANA and a high ANCA titer >1:1280, along with elevated levels of MPO and PR-3, and reduced complement levels. These symptoms and laboratory findings led to a diagnosis of ANCA vasculitis induced by PTU, resulting in the cessation of this medication. Following the discontinuation of PTU there was a notable improvement with normalization of serum Cr and resolution of proteinuria within 1.5 months. Concurrently, MPO and PR-3 levels began to decrease, and her hematological abnormalities resolved. During this period, her Free T4 levels gradually increased, leading to the administration of radioactive iodine for the treatment of her Graves' disease. Discussion: This case underscores the complexities in treating a patient with Graves' disease highlighting the unpredictable and severe side effects of antithyroid drugs like agranulocytosis and ANCA vasculitis. We report the first documented case of sequential thionamide-induced complications: agranulocytosis with methimazole, followed by ANCA vasculitis with propylthiouracil. Although both can arise from immune responses to these medications, they are distinct in their pathophysiology and are not associated with one another. The unpredictable nature of these side effects complicates prevention. Educating patients to promptly report any unusual symptoms and immediate medical intervention with drug discontinuation are key to managing these adverse reactions effectively.

Presentation: 6/1/2024
8588 Cribriform Thyroid Cancer with Novel STK11 and KEAP1 Mutations
Authors: Ruiz Dannel Diaz , Chemitiganti Ramachandra Rahul V , Suravajjala Devi , Eranki Madhuri , Case James
Published: October 2024

Disclosure: D. Diaz Ruiz: None. R.V. Chemitiganti: None. D. Suravajjala: None. J. Case: None.

Mrs. CS is a 69-year-old female with a medical history of Hashimoto thyroiditis evaluated for incidentally detected thyroid nodules. She was euthyroid and was found to have multiple nodules on thyroid sonography - Two TI-RADS 5 (TR5) nodules in the right mid pole(3cm) and inferior pole(1.8cm) and a third TR2 nodule in the in the inferior pole (<1 cm). She declined a biopsy and was lost to follow-up during the Covid pandemic. She returned for new pressure symptoms in the neck and now had a large palpable right thyroid mass. A repeat sonogram now showed a TR5 thyroid nodule (4.4 cm) of the right lower pole. The other two TR5 nodules were unchanged. Thyroid FNA biopsy indicated - malignant, poorly differentiated carcinoma of thyroid origin (Bethesda stage VI). The cytology and cell block preparations were cellular and showed sheets of epithelial cells with crowded round to ovoid nuclei. The nuclei showed rare intranuclear inclusions. Immunohistochemical stains were positive for both TTF-1 and PAX-8. BRAF p.V600E c.1799T>A were negative. RET/PTC1, RET/PTC3 were not detected. She underwent an uneventful total thyroidectomy; the surgical pathology report revealed a Cribriform Thyroid Cancer (CTC) with vascular invasion. Post Thyroidectomy I-131 whole body scan was positive for only focal uptake on the right thyroid bed extending into the right lower neck. Bone scan, Head and chest CT were negative for metastases. Cancer genome sequencing studies identified Serine/threonine kinase 11 (STK11) and Kelch-like ECH-associated protein 1 (KEAP1) mutations. Adenomatous polyposis coli (APC) and beta-catenin (CTNNB1) mutations were absent. Cribriform Thyroid Cancer is proposed as a distinct form of thyroid carcinoma unrelated to other neoplasms of thyroid follicular cells. It is an extremely uncommon malignancy that usually affects younger women (18-59 yrs; mean age 33). They were initially described as cribriform variant of papillary thyroid cancer associated with familial adenomatous polyposis (FAP) syndrome. Sporadic forms are known to occur due to somatic alterations in the Wnt/beta-catenin pathway. Germline or somatic mutations of Adenomatous polyposis coli (APC) gene and somatic mutations of the beta-catenin (CTNNB1) gene are usually present in CTC. Inherited mutations in the STK11 gene are associated with Peutz-Jeghers syndrome and an increased risk of developing other cancers. While KEAP1 somatic mutations disproportionately occur in non-small-cell lung, liver, endometrial, bladder and squamous cell cancers. Human germline mutations in KEAP1 are rare. One report in a five-generation multinodular goiter family identified the first KEAP1 mutation, none are yet to be reported in a sporadic form of CTC. This case showcases and adds to our knowledge of unique mutations associated with sporadic form of CTC.

Presentation: 6/3/2024
9176 Deep Learning Analysis with Gray Scale and Doppler Ultrasonography Images to Differentiate Graves’ Disease
Authors: Baek H S , Lim D
Published: October 2024

Disclosure: H. Baek: None. D. Lim: None.

Abstract Context: Thyrotoxicosis requires accurate and expeditious differentiation between Graves’ disease (GD) and thyroiditis to ensure effective treatment decisions. Objective: This study aimed to develop a machine learning algorithm using ultrasonography and Doppler images to differentiate thyrotoxicosis subtypes, with a focus on GD. Methods: This study included patients who initially presented with thyrotoxicosis and underwent thyroid ultrasonography at a single tertiary hospital. A total of 7,719 ultrasonography images from 351 patients with GD and 2,980 images from 136 patients with thyroiditis were used. Data augmentation techniques were applied to enhance the algorithm’s performance. Two deep learning models, Xception and EfficientNetB0_2, were employed. Performance metrics such as accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and F1 score were calculated for both models. Image pre-processing, neural network model generation, and neural network training results verification were performed using DEEP:PHI® platform. Results: The Xception model achieved 84.94% accuracy, 89.26% sensitivity, 73.17% specificity, 90.06% PPV, 71.43% NPV, and an F1 score of 89.66 for the diagnosis of GD. The EfficientNetB0_2 model exhibited 85.31% accuracy, 90.28% sensitivity, 71.78% specificity, 89.71% PPV, 73.05% NPV, and an F1 score of 89.99. Conclusion: Machine learning models based on ultrasound and Doppler images showed promising results with high accuracy and sensitivity in differentiating GD from thyroiditis.

Presentation: 6/1/2024
8465 Diagnostic Conundrum: The Mystery of Metastatic Papillary Thyroid Cancer with Persistently Elusive Thyroglobulin
Authors: Vemparala Pranathi , Bollineni Mohini Vijayalakshmi
Published: October 2024

Disclosure: P. Vemparala: None. M. Bollineni: None.

Introduction- Among endocrine malignancies, differentiated thyroid cancers account for the majority with most of them boasting a favorable prognosis. Thyroglobulin, a pivotal biochemical marker, aids in detecting recurrence or persistent disease when combined with neck ultrasound, I-131 scintigraphy, and FDG PET scans. Anti-thyroglobulin antibodies, found in a quarter of cases, can falsely lower serum thyroglobulin levels in immunometric assays. Our intriguing case features a patient with metastatic papillary thyroid cancer, yet thyroglobulin levels persistently eluded detection. CASE PRESENTATION- A 33-year-old female presented initially to an outside facility with neck swelling, leading to a diagnosis of a 4 x 3 cm papillary thyroid cancer (PTC) in the right lobe and a 0.5 x 0.5 cm focus of PTC in the left lobe, accompanied by capsular extension, malignant cells in the left lobe margin, and lymphovascular invasion. After total thyroidectomy and lymph node exploration, radioactive iodine scan detected disease in right-sided lymph nodes, treated subsequently with radioactive iodine ablation. Two years later, she presented to our clinic with neck swelling, voice changes, and fatigue. Thyroglobulin level was measured which returned at <0.1 ng/ml, however thyroglobulin antibodies were elevated at 292 IU/ml, albeit decreased from a value of 431.5 IU/ml at initial diagnosis. Elevated thyroglobulin antibodies complicated interpretation, prompting liquid chromatography-mass spectrometry (LC-MS) for accurate measurement of thyroglobulin, which returned at <0.5 ng/ml. Ultrasound indicated metastatic disease in right cervical lymph nodes, confirmed by fine needle aspiration. In-office ultrasound-guided FNA of additional nodes validated metastasis. Modified radical neck dissection revealed metastatic PTC in 7 out of 34 lymph nodes. Surprisingly, thyroglobulin levels remained <0.5 ng/ml, pre- and post-operatively. Referred for radioactive iodine ablation, her complex journey underscored the challenges in monitoring thyroid cancer recurrence or persistent disease with thyroglobulin levels even by methods such as mass spectrometry. Conclusion- Key learnings from this case highlight the importance of cognizance in utilizing thyroglobulin levels to guide adjuvant therapy decisions and for postoperative monitoring in high risk patients, as low levels do not rule out recurrence or persistence. Anti-thyroglobulin antibodies pose challenges, necessitating techniques like LC-MS. Finally, recognizing “nonsecretor” thyroid cancers, an aggressive subgroup with poorer prognosis, is vital as they often present with low or undetectable thyroglobulin levels.

Presentation: 6/2/2024
5143 Disulfide Bonds of Thyroid Peroxidase Are Critical Elements for Subcellular Localization, Proteasome-Dependent Degradation, and Enzyme Activity
Authors: Iwasaki Hajime , Suwanai Hirotsugu , Kanekura Kohsuke , Satoshi Narumi , Yakou Fumiyoshi , Sakai Hiroyuki , Ishii Keitaro , hara Natsuko , Suzuki Ryo
Published: October 2024

Disclosure: H. Iwasaki: None. H. Suwanai: None. K. Kanekura: None. N. Satoshi: None. F. Yakou: None. H. Sakai: None. K. Ishii: None. N. hara: None. R. Suzuki: None.

Background: Congenital hypothyroidism (CH) is caused by mutations in cysteine residues including Cys655 and Cys825 that form disulfide bonds in thyroid peroxidase (TPO). It is highly likely that disulfide bonds play an important role in TPO activity. However, no study has comprehensively analyzed cysteine mutations that form disulfide bonds in TPO. In this study, we induced mutations in cysteine residues involved in the formation of disulfide bonds and analyzed their effect on subcellular localization, degradation, and enzyme activities to evaluate the importance of disulfide bonds in TPO. Methods: Vector plasmid TPO mutants C655F and C825R in CH patients were transfected into HEK293 cells. TPO activity and protein expression levels were measured by Amplex red assay and western blotting. The same procedure was performed in the presence of proteasome inhibitor MG132. Subcellular localization was determined by immunocytochemistry and flow cytometry. The location of all disulfide bonds within TPO was predicted by in silico analysis. All TPO mutations associated with disulfide bonds were induced. TPO activity and protein expression levels were also measured in all TPO mutants associated with disulfide bonds using the Amplex red assay and western blotting. Results: C655F and C825R showed significantly decreased activity and protein expression compared to the wild-type (P < 0.05). In the presence of a proteasome inhibitor MG132, the protein expression level of TPO was increased to the level comparable with that of the wild-type but its activity did not. The degree of subcellular distribution of TPO to the cell surface in the mutant was lower than that in the wild-type TPO. Twenty-four cysteine residues were involved in the formation of 12 disulfide bonds in TPO, and all TPO mutants harboring an amino acid substitution in each cysteine showed significantly reduced TPO activity and protein expression levels. Furthermore, the differences in TPO activity depended on the position of the disulfide bond. Conclusions: All 12 disulfide bonds play an important role in the activity of TPO. Furthermore, the mutations lead to misfolding, degradation and membrane insertion.

Presentation: 6/2/2024
6556 Does Autoimmune Hashimoto’s Hypothyroidism Mask the Diagnosis of Ehlers-Danlos-Syndrome?
Authors: Azmat Shazia , Rafat Ummara , Gilden Janice L
Published: October 2024

Disclosure: S. Azmat: None. U. Rafat: None. J.L. Gilden: None.

Does Autoimmune Hashimoto’s Hypothyroidism Mask the Diagnosis of Ehlers-Danlos Syndrome? Background: Hypothyroidism is well-known to be associated with muscle weakness and fatigue. There are other etiologies for decreased muscle tone such as Ehlers-Danlos syndrome (EDS) which is group of connective tissue disorders characterized by joint hypermobility, skin hyperextensibility and tissue fragility. Other rheumatological and cardiac conditions associated with this syndrome can pose diagnostic challenges. We present case of 32-year-old female presenting with facial muscle weakness and newly diagnosed Hashimoto’s hypothyroidism. We highlight importance of keeping EDS as another differential in patients with muscle weakness allowing for accurate, prompt diagnosis and treatment to be done in timely manner. Case Description: A 32-year-old female professional musician was referred to Endocrine for mouth muscles weakness and decreasing ability to play her French Horn wind instrument with vocal dystonia and the question of whether these were symptoms of hypothyroidism. She was noted to have mild thyroid enlargement and abnormal thyroid function tests with positive thyroid antibodies. Initial TSH was 7.506 uIU/mL(0.55-4.78), free T4 0.9 ng/dL (0.76-1.46), peroxidase antibody = 96,061U/mL (0-60) and thyroglobulin of 134.9 U/mL (0-60). She also reported low energy, intermittent difficulty swallowing and decreased muscle strength. There was no prior personal and family history of hypo/hyperthyroidism or any other disorders. VS were normal, physical exam showe d no thyromegaly, reflexes revealed objective decrease but normal muscle strength. The skin was noted to be hyperextensible with passive hyperextension of fifth metacarpophalangeal joint beyond 90 degrees, thumb to flexor aspect of forearm and elbows bilaterally with positive Beighton criteria for EDS. She later admitted to intermittent palpitations and easy bruising. Subsequent lab tests were negative ANA, anti-mitochondrial, PCEL and striated muscles antibodies. Additionally she had normal IGA, PTH, AM cortisol- ACTH, vitamin B12 levels with negative 21 hydroxylases antibodies and celiac titers. She was started on levothyroxine 25 mcg and recommended for Cardiology evaluation and genetic testing. Physiotherapy was started. Upon six months follow-up she clinically felt better with improved muscle strength, swallowing and energy level. Repeat lab testing showed improved TSH of 2.67 uIU/mL(0.55-4.78) with free T4 of 1.0 ng/dL (0.76-1.46). Conclusion: This case demonstrates that although muscle weakness can be symptom of hypothyroidism one must evaluate all patients for other possible causes. We highlight importance of keeping EDS as a differential especially in female patients with muscle weakness. Though history and physical exam is crucial allowing for prompt diagnosis and treatment for other conditions.

Presentation: 6/1/2024
7315 Does Protein Energy Malnutrition Impact Outcomes in Hypothyroidism? A National Inpatient Sample Analysis
Authors: Karki Sunita , Neupane Binita , Neupane Shila , Bhandari Abhishek , Farooq Umer , Rajamani Krishnakumar
Published: October 2024

Disclosure: S. Karki: None. B. Neupane: None. S. Neupane: None. A. Bhandari: None. U. Farooq: None. K. Rajamani: None.

Introduction: Hypothyroidism poses a significant public health burden in the United States, affecting approximately 4.6 % of the population. Various nutritional deficiencies can adversely affect thyroid function, potentially leading to thyroid disorders. Despite this, there is limited literature exploring the influence of Protein Energy Malnutrition (PEM) on outcomes in hypothyroidism. Objective of our study:This investigation aims to assess the impact of PEM on the healthcare burden and costs associated with hospitalizations in patients with and without hypothyroidism. Methods: A retrospective study was conducted using the National Inpatient Sample (NIS) data from 2017 to 2020. Among the 14,418,310 patients aged 18 and above with a primary diagnosis of hypothyroidism, two groups were formed based on the presence or absence of PEM, determined by International Classification of Diseases (ICD-10) codes. Statistical analysis was performed using STATA, employing the student’s t-test and Fischer’s exact test for continuous variables and proportions, respectively. Adjusted odds ratio was calculated through multivariate regression analysis. The primary outcome was mortality, with secondary outcomes encompassing mean length of stay (LOS), total cost, and various medical complications. Trends in mortality, LOS and total cost were compared for both groups. Results: Out of 14,418,310 hypothyroid patients, 7.06% (1,1018,310) were diagnosed with PEM. Patients with PEM exhibited higher mortality (6.80 % vs. 2.39 %, p<0.001), extended mean length of hospital stay (8.88 days vs. 4.85 days, p<0.001), and higher increased total hospitalization costs ($96,443 vs. $58,262, p<0.001). Furthermore, patients with PEM had elevated rates of various complications, including acute coronary syndrome, septic shock, pulmonary edema, mechanical ventilation, acute respiratory failure, acute respiratory distress syndrome, acute kidney injury, and cerebrovascular accident. Increasing trends in mortality, length of stay, and total cost of hospitalization were observed in hypothyroid patients with PEM. A similar upward trend was noted in hypothyroid patients without PEM. Conclusion: Our study underscores that the presence of PEM in hypothyroid patients substantially increases the healthcare burden, which is reflected in elevated mortality rates, prolonged hospital stays, higher total costs, and a range of adverse outcomes. Screening of PEM in hypothyroid patients is recommended, and early nutritional interventions, possibly involving dieticians, may mitigate these adverse effects. Further research is warranted to explore the association between PEM and hypothyroidism, as well as strategies for early identification and intervention.

Presentation: 6/1/2024
6814 Durability of Teprotumumab for the Treatment of Thyroid Eye Disease (TED) in Clinical Trials
Authors: Kahaly George J , Subramanian Prem S , Conrad Elizabeth , Holt Robert J , Smith Terry J
Published: October 2024

Disclosure: G.J. Kahaly: Consulting Fee; Self; Amgen Inc. Research Investigator; Self; Amgen Inc. P.S. Subramanian: Consulting Fee; Self; Amgen Inc. Research Investigator; Self; Amgen Inc. E. Conrad: Employee; Self; Amgen Inc. Stock Owner; Self; Amgen Inc. R.J. Holt: Employee; Self; Amgen Inc. Stock Owner; Self; Amgen Inc. 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.

Introduction: Teprotumumab has demonstrated efficacy for the treatment of thyroid eye disease (TED). To assess durability of responses to teprotumumab over the longer term, pooled clinical trial data were assessed beyond the 24-week treatment period for patients in phase 2, OPTIC, and OPTIC-X studies who received a full course of teprotumumab. Methods: Observed rates for clinical activity score (CAS, ≥2 point improvement), EUGOGO-recommended composite response, diplopia (≥1 Gorman grade improvement), proptosis (≥2 mm improvement), and Overall responder status (≥2 mm improvement proptosis and ≥2 point improvement CAS) were assessed and pooled from study baseline to Week 24 (formal study) and up to Week 72 (51 weeks post-final teprotumumab infusion). Graves’ ophthalmopathy quality-of-life (GO-QOL) scores were also examined. Additional therapies for TED administered up to Week 120 (i.e., 99 weeks post-therapy) were assessed for evidence of persistent benefit from Week 24 through Week 120. Studies differed in the timing of follow-up visits. Data were not available at every time point for all patients. Results: Response rates among patients receiving a full (8-infusion) course of teprotumumab (N=112) were largely maintained 51 weeks after the final teprotumumab infusion at study Week 72: CAS 52/57 (91.2%); composite 51/57 (89.5%); diplopia 35/48 (72.9%); proptosis 38/56 (67.9%); and Overall 37/56 (66.1%). The mean reduction in proptosis was 2.68 (SD 1.92) mm (N=56), mean GO-QOL reduction was 15.22 (SE 2.82, N=56), and disease inactivation (CAS ≤1) was detected in 40/57 (70.2%). Post-teprotumumab treatment, 17.9% (19/106) of reporting patients received additional TED treatment (systemic steroids or teprotumumab) and/or remedial periocular surgery as of 99 weeks after the last dose (to study Week 120). Conclusions: At Week 72, nearly one-year posttherapy, responses to teprotumumab were similar to those at Week 24 formal study end. Both CAS and ophthalmic composite responses were observed in 90% of observed patients. Diplopia and proptosis responses were seen in almost 70%. Additionally, 82% of patients did not require additional treatment for TED nearly two years after therapy completion. Public

Presentation: 6/2/2024
6410 Effects of Immune Check Point Inhibitors on Thyroid Function
Authors: Kachroo Varsha , Wangnoo Subhash Kumar , Siddiqui Mohammad Asim
Published: October 2024

Disclosure: V. Kachroo: None. S.K. Wangnoo: None. M.A. Siddiqui: None.

Immune check point inhibitors (ICPIs) are the newest agents for the treatment of malignant tumors, showing promising effects and potential, and has immune related adverse events (IRAEs) as well. IRAEs involve various organs and tissues and also cause thyroid dysfunction. This is a non randomized prospective observational study done at a tertiary referral hospital in patients initiated on ICPIs for the underlying malignancies between March 2022 to September 2023. A total of 35 patients were taken after calculating the sample size using appropriate statistical formula. Thyroid function tests (T3, T4, TSH,) were done monthly for first six months and then every three-monthly till 12 months in patients not on any thyroid medication. In patients already getting treatment for hypothyroidism/hyperthyroidism,TSH was assayed monthly for 3 months, then every 3 months for 12 months. Anti TPO antibody levels were done at baseline and at 12 months in all the individuals. Overt and subclinical hyperthyroidism/ hypothyroidism was defined usinh standard criteria.The assay used for the determination of TSH, FT4, FT3 and anti-TPO Antibody was Chemiluminescent Immunoassay (CLIA). Normal reference ranges for TSH was 0.27-4.20 mU/ml, FT4 was 0.90-1.70 ng/dl and FT3 was 2.0- 4.4 pg/ml. Out of 35 patients, 24(68.5%) were males and 11 were females (31.4%). 25.71% already had history of thyroid dysfunction in the form of primary hypothyroidism and were on levothyroxine and no one had hyperthyroidism when they were initiated on ICPIs. Out of 9 patients, 6 patients had no change in dose (66.67%); 2 patients had increased dose requirement (22.22%) and 1 patient had decreased dose requirement (11.11%). Out of remaining 26 patients who didn’t have any thyroid function, 12(46.15%) had new onset thyroid dysfunction. All 26 had hypothyroidism (either overt or subclinical). Out of these 26 patients, 9(34.62%) had overt hypothyroidism and started on levothyroxine as per their age and body weight requirements, 3(11.54%) patients had subclinical hypothyroidism. Out of 12 patients, who developed new onset TDF after initiation of ICPIs, 2 patients became TPO positive and 10 patients had negative TPO Antibodies at the end of 12 months. Kaplan Meir analysis showed that thyroid dysfunction at the end of 3 months was in 13.33% of patients, in 53.85% each at the end of 6 months and 12 months. The mean time of onset of thyroid dysfunction was 3.083 months in (IQR=2.25-3.917 months; 95% CI; SE=0.379). We conclude that thyroid dysfunction in the form of new onset hypothyroidism (subclinical or overt) or increased thyroxine dose requirement in the patient who are already hypothyroid is seen in patients receiving ICPIs. Regular surveillance of thyroid function is warranted in patients receiving these drugs.

Presentation: 6/3/2024
7179 Efficacy of radioactive iodine for the treatment of thyrotoxicosis in a prospective cohort in Aotearoa/New Zealand
Authors: Tamatea J , Nottingham S , Boyle V , Elston M S
Published: October 2024

Disclosure: J. Tamatea: None. S. Nottingham: None. V. Boyle: None. M.S. Elston: None.

Background – The outcome following treatment of thyrotoxicosis with a single fixed-dose radioiodine (RAI) can be difficult to predict and has been shown to have a lower success rate in Māori vs. non-Māori (1).Aim – the aim of this prospective study was to compare RAI treatment outcomes between Māori and non-Māori, identify factors that are associated with RAI treatment failure in thyrotoxicosis and whether these factors affect the difference in ethnicity outcomes seen.Method – all patients over the age of 16 years referred to Waikato Hospital (Hamilton, New Zealand) for the treatment of thyrotoxicosis with RAI between March 2013 and February 2015 were invited to participate in this study. Demographic information was collected with a questionnaire prior to treatment. Aetiology and severity of thyrotoxicosis at time of diagnosis was retrospectively collected. Laboratory investigations, ultrasound thyroid volume and thyroid pertechnetate uptake were carried out prior to RAI treatment. Participants were followed up for12 months after RAI to assess outcome to treatment. Univariate analysis of variables were carried out for the full cohort and for Graves’ Disease (GD) cohort. Logistic regression analysis was carried out including ethnicity and additional variables of age, gender, diagnosis, thyroid volume, smoking status, and BMI.Results – a total of 162 participants were included: 71 identified as Māori and 91 as non-Māori. At 12 months follow up, 146 participants (90.1%) had a successful treatment outcome follow a single dose of RAI. Successful outcome was achieved in 85.9% of Māori vs 93.4% of non-Māori (p = .113), however when only looking at the GD cohort, Māori were less likely to have successful outcome than non-Māori (68.75% vs 89.4% p = .022). Following regression analysis ethnicity was no longer a variable associated with treatment failure. When controlling for other variables, factors found to increase the risk of failing RAI were diagnosis of TMNG/STA (OR 0.03; 95%CI 0.002-0.035), larger thyroid volumes (OR 1.04; 95%CI 1.01 - 1.07 per mL of thyroid volume) and smoking (OR 6.71; 95%CI 1.2 - 37.4 for current smokers).Conclusion - RAI is an effective definitive treatment option for thyrotoxicosis. Factors found to be associated with treatment outcome are aetiology of thyrotoxicosis, thyroid volume, and smoking status. These factors likely explain the ethnicity difference in treatment outcome following RAI in Māori vs non-Māori.References – 1. Tamatea JAU, Conaglen JV, Elston MS. Response to Radioiodine Therapy for Thyrotoxicosis: Disparate Outcomes for an Indigenous Population. International Journal of Endocrinology. 2016;2016:7863867.

Presentation: 6/2/2024