bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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 &lt; 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

Abstract
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

Abstract
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&lt;0.001), extended mean length of hospital stay (8.88 days vs. 4.85 days, p&lt;0.001), and higher increased total hospitalization costs ($96,443 vs. $58,262, p&lt;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

Abstract
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

Abstract
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

Abstract
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
7450 Geographic Hotspots Of Adrenocortical Carcinoma (ACC) In Colorado
Authors: Holmstoen Tessa B , Volino Lucy K , Molina Kuna Elizabeth , Banerjee Tapahsama , Fishbein Lauren , Kiseljak-Vassiliades Katja , Wierman Margaret E 
Published: October 2024

Abstract
Disclosure: T.B. Holmstoen: None. L.K. Volino: None. T. Banerjee: None. L. Fishbein: None. K. Kiseljak-Vassiliades: None. M.E. Wierman: None.
Background: Adrenocortical carcinoma (ACC) is an under-investigated endocrine malignancy, with a reported annual incidence in the United States of 0.5-2 cases per million. The genetic profiles of ACC patients exhibit great heterogeneity, and 40% of cases have an unknown driver. We have observed an increase of ACC cases originating from western Colorado – a place of lower population, greater elevation, and focus on farming as well as oil and mining-related activities. Given this observation, we hypothesized there may be environmental factors associated with higher ACC incidence in western CO. Methods: We employed a population-based retrospective cohort study to analyze the characteristics of consecutive patients with ACC from Colorado who were seen in our multidisciplinary Adrenal Tumor Program between 2012 and 2023. Data collection included patient’s sex, age, date of diagnosis, and ZIP code of residence. Colorado population data were collected from the 2020 CO Census records. To classify location as western or eastern CO, patient ZIP codes were grouped into their appropriate counties, 21 of which are defined as western CO by the state demography office. The remaining 43 counties were considered to be eastern CO. ZIP code data were also collected from consecutive patients with pheochromocytoma or paraganglioma (PPGL) from Colorado, and these cases were classified as western or eastern CO using the same methods as described above. Chi-square tests were performed for the statistical comparison of population proportions. Results: Between 2012 and 2023, there were 62 incident cases of ACC in the state of Colorado. Given that the state population is 5.7 million, this equates to an average annual incidence of about 0.81 cases per million. Out of the 62 Colorado cases, 38 (61.2%) were female and 24 (38.7%) were male. The average age of diagnosis was 48.9 years. Of interest, the average annual incidence of ACC was increased at 1.44 per million in western CO and only 0.76 per million in eastern CO (p=0.024). The same analysis for 163 PPGL cases yielded no such difference, with an annual incidence of 3.2 cases per million in western CO, and 3.57 cases per million in eastern CO (p=0.7884). Conclusion: The overall clinical demographics and annual incidence of ACC in our Colorado cohort are similar to reported literature. However, the incidence of ACC in western CO is about twice as high as in eastern CO. Since this geographic dichotomy is not also observed in PPGL cases, these data suggest that environmental or other factors may play a role in ACC development. These data warrant further investigation of risk factors that predispose to ACC.
Presentation: 6/3/2024
8771 Evolving Landscape of Thyroid Cancer Attributable to High Body Mass Index in 38 OECD Countries (1990-2019): A Comprehensive Global Assessment
Authors: Adedara V , Chinthapalli M , Parisapogu A , Potluri G , Markandu K , Maddineni K , Desai H 
Published: October 2024

Abstract
Disclosure: V. Adedara: None. M. Chinthapalli: None. A. Parisapogu: None. G. Potluri: None. K. Markandu: None. K. Maddineni: None. H. Desai: None.
Introduction: Thyroid cancer (TC) is an increasingly pressing health issue worldwide, particularly within the Organisation for Economic Co-operation and Development (OECD) countries, which account for 36.57% of all global TC cases. This study focuses on the impact of high Body Mass Index (h-BMI), paralleling rising obesity rates, on the burden of TC across 38 OECD countries. Method: Employing the Global Burden of Disease framework, we analyzed the trends in deaths, Disability Adjusted Life Years (DALYs), and Years Lived with Disabilities (YLDs) attributable to TC attributable to h-BMI, considering variables such as age, sex, year, and location over the past three decades. Results: Our findings show a significant increase in the total number of TC deaths attributable to h-BMI, rising from 873 (95%UI: 422-1471) in 1990 to 1646 (95%UI: 819-2703) in 2019. Similarly, DALYs escalated from 22041 (95%UI: 10576-37075) in 1990 to 39485 (95%UI: 19952-63534) in 2019, with YLDs increasing from 2360 (95%UI: 1082-4179) to 6170 (95%UI: 3036-10416). The age-standardized rate (ASR) showed an annual percentage change (APC) in the death rate of 5% (95%UI: -0.07-20%), and a 10% increase (95%UI: 2-10) in DALYs rate over three decades. The United States reported the highest number of deaths at 449 (95%UI: 233-703) in 2019. Regarding ASR, Iceland had the highest death rate of 0.16 per 100,000, followed by Mexico (0.13), Estonia (0.11), and Latvia (0.11). Males exhibited a higher APC in deaths (131% vs. 60%) and DALYs (112% vs. 52%) compared to females over the last three decades. Additionally, an increase in deaths was observed with advancing age, with the highest DALYs noted in the 75-79 year age group. Conclusion: To effectively address the rising thyroid cancer rates linked to high BMI, a unified approach is essential: public health policies must focus on obesity prevention, clinicians should integrate BMI management in thyroid cancer care, collaboration between policymakers and healthcare providers needs strengthening, and public awareness about the risks of high BMI must be increased to promote early screening and lifestyle changes.
Presentation: 6/3/2024