bluuebunny/crossref_metadata_2025 huggingface dataset:
THU581 Possible Markers For Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Developed In Long Covid: Utility Of Serum Ferritin And Insulin-like Growth Factor-I
Authors: Yamamoto Yukichika , Otsuka Yuki , Tokumasu Kazuki , Sunada Naruhiko , Nakano Yasuhiro , Honda Hiroyuki , Sakurada Yasue , Hasegawa Toru , Hagiya Hideharu , Otsuka Fumio
Published: October 2023

Disclosure: Y. Yamamoto: None. Y. Otsuka: None. K. Tokumasu: None. N. Sunada: None. Y. Nakano: None. H. Honda: None. Y. Sakurada: None. T. Hasegawa: None. H. Hagiya: None. F. Otsuka: None.

Almost three years have passed since coronavirus disease 2019 (COVID-19) pandemic broke out, and along with the number of acute COVID-19 patients, the number of patients suffering from chronic prolonged symptoms after COVID-19, long COVID, or post COVID-19 condition, has also increased. We establised an outpatient clinic specialized for COVID-19 after care (CAC) in Okayama University Hospital in Japan in February 2021. Our recent study has revealed that the most common symptom is “fatigue”, a part of which potentially may develop into myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). However, the pathogenesis and specific prognosticator have yet to be elucidated. The aim of this study was to elucidate the clinical characteristics of patients who developed ME/CFS after COVID-19. This retrospective observational study investigated the patients who visited our CAC outpatient clinic between February 2021 and March 2022. Of the 234 patients, 139 (59.4%) had fatigue symptoms, of whom 50 (21.4%) met the criteria for ME/CFS (ME/CFS group), while other 89 did not (non-ME/CFS group); 95 patients had no fatigue complaints (no-fatigue group). Although the patients’ backgrounds were not significantly different among the three groups, the ME/CFS group presented the highest scores on the self-rating symptom scales, including the Fatigue Assessment Scale (FAS), EuroQol, and Self-Rating Depression Scale (SDS). Of note, serum ferritin levels, which were correlated to FAS and SDS scores, were significantly higher in the ME/CFS group (193.0 μg/mL; interquartile range (IQR), 58.8-353.8) than those of non-ME/CFS (98.2 μg/mL; 40.4-251.5) and no-fatigue (86.7 μg/mL; 37.5-209.0) groups, and this trend was prominent in the female patients. Endocrine workup further showed that the ME/CFS group had higher thyrotropin levels but lower growth hormone levels in the serum, and that insulin-like growth factor (IGF)-I levels were inversely correlated with ferritin levels (R = -0.328, p < 0.05). Collectively, we revealed that serum ferritin levels could be a possible predictor for developing ME/CFS related to long COVID, especially in female patients. Earlier studies have suggested that hyperferritinemia is a clinical feature in the patients of long COVID, in which hepcidin-like effects could also be involved. Our present study also uncovered a relationship between hyperferrinemia and endocrine disorders among patients developing ME/CFS after COVID-19, although further investigations are necessary to understand the characteristics of ferritin metabolism.

Presentation: Thursday, June 15, 2023
OR0302 Regulation Of Human Melanocortin-5 Receptor By Isoforms Of Melanocortin-2 Receptor Accessory Proteins
Authors: Jiang Shanshan , Tao Ya-Xiong
Published: October 2023

Disclosure: S. Jiang: None. Y. Tao: None.

Melanocortin-5 receptor (MC5R) is ubiquitously expressed in central nervous system and peripheral tissues, has unique pharmacological properties, and physiological functions. Melanocortin-2 receptor accessory proteins (MRAPs) are regulators of melanocortin receptor family. To investigate the effects of MRAPs on trafficking, ligand binding and signaling properties of human (h) MC5R, HEK293T cells were transiently co-transfected with plasmids encoding MC5R and different isoforms of MRAPs (hMRAP1a, hMRAP1b, hMRAP2a, hMRAP2b, and hMRAP2c). The results showed that hMRAP1a and hMRAP2a increased the cell surface expression of hMC5R. All MRAPs have no effect on affinity to the superpotent analog of α-melanocyte stimulating hormone (α-MSH), NDP-MSH, while hMRAP2c significantly increased maximal binding. Additionally, α-MSH induced ERK1/2 activation. A higher basal level of ERK1/2 phosphorylation was observed when co-transfected with some MRAPs. All MRAPs had no effect on α-MSH-stimulated cAMP production (Gs-cAMP pathway). In summary, the two MRAP1s and three MRAP2s had differential effects on MC5R trafficking, binding, and signaling. These findings led to a better understanding of the regulation of MC5R by MRAP1s and MRAP2s.

Presentation: Thursday, June 15, 2023
SAT025 Characterization Of The Melatonin Type 1 Receptor / Cannabinoid Type 1 Receptor (MT1/CB1) Heteromers
Authors: Cui Yuanxu , Cherdoud Hakima , Marsicano Giovanni , Bellocchio Luigi , Jockers Ralf , Lahuna Olivier
Published: October 2023

Disclosure: Y. Cui: None. H. Cherdoud: None. G. Marsicano: None. L. Bellocchio: None. R. Jockers: None. O. Lahuna: None.

Membrane receptors belonging to the G proteins coupled receptors (GPCRs), the largest family of proteins in the human genome with more than 800 members. GPCR functions were initially thought to take place at the plasma membrane upon binding of single monomeric receptor unit by their cognate ligand. This scheme was complexified after identification of cross-talks between GPCRs upon heteromerization and identification of functional GPCRs within intracellular organelles as nucleus or endosomes. Among a few others receptors, functional melatonin receptor type 1 (MT1) and cannabinoid receptor type 1 (CB1) were found in neuronal mitochondria, suggesting a cross-talk between them. Here, we are identifying and characterizing MT1/CB1 heteromers as a new GPCR heteromer. Previously we showed that coexpression of the MT1 and CB1 receptors induced the constitutive formation of MT1/CB1 heteromers using coimmunoprecipitation experiments on transiently transfected HEK293 cells. Using simultaneous PLA (Proximity Ligation Assay) and immunofluorescence experiments, we described the existence of intracellular MT1/CB1 heteromers associated with the mitochondrial network. Since then, we have further characterized the properties of MT1/CB1 heteromers. Coimmunoprecipitation experiments performed on cerebellum from wild-type, MT1 or CB1 knock-out mice enabled us to identify MT1/CB1 heteromers in vivo. We established stable monoclonal HEK293 cell lines expressing both receptors. Transmission Electronic Microscopy (TEM) and PLA experiments showed the presence of MT1/CB1 complexes not only intracellularly but also at the cell surface. Using PLA experiments we identified a penetrating interfering peptide that specifically dissociate the MT1/CB1 complex and thus open the door to experiments targeting specifically the complex. We were able to follow the melatonin-dependent internalization and trafficking of the MT1/CB1 complex from the plasma membrane to the late endosomes using a combination of Nanoluciferase complementation experiments and bystander BRET (Bioluminescence Resonance Energy Transfer). Costimulation of HE293 cells expressing both receptors with melatonin and the selective CB1 agonist ACEA (Arachidonyl-2'-chloroethylamide), a derivative of the endocannabinoid AEA (Arachidonylethanolamide or anandamide) resulted in a potentiation of the melatonin-dependent cAMP inhibition. Use of the identified interfering peptide will enable us to identify actions on signaling pathways resulting from a direct cross-talk between MT1 or CB1 subunits.

Presentation: Saturday, June 17, 2023
THU138 The Association Between Irisin And Anthropometric And Metabolic Parameters In Obese Children And Adolescents
Authors: Kim Sung Eun , Kim Shin-Hee , Park Su Jin , Sim Soo Yeun , Kim Seulki , Ahn Moon Bae , Won-kyoung Cho , Soon Cho Kyoung , Jung Min-Ho , Suh Byung-Kyu
Published: October 2023

Disclosure: S. Kim: None. S. Kim: None. S. Park: None. S. Sim: None. S. Kim: None. M. Ahn: None. C. Won-kyoung: None. C. Kyoung Soon: None. M. Jung: None. B. Suh: None.

Background: Irisin is a myokine secreted from skeletal muscle that plays an important role in the regulation of adipokine secretion and the differentiation of osteoblast and osteoclasts. Irisin has been shown to increase browning of adipose tissue, thermogenesis, energy expenditure, and insulin sensitivity. The aim of this study was to evaluate the relation of serum irisin level with metabolic, anthropometric parameters and bone mineral density in children and adolescents. Methods: This study included 103 Korean children and adolescents in a single center: 49 (47.6 %) obese participants with a body mass index (BMI) ≥95th percentile and 54 (52.4%) healthy control with BMI 15-85th percentile. Fasting serum irisin was quantitatively assayed by ELISA. Lipid profile, fasting blood glucose, fasting insulin, the homeostasis model assessment of insulin resistance (HOMA-IR), Tryglyceride and glucose (TyG) index, osteocalcin and 25-hydroxyvitamin D3 were measured as metabolic parameters. Bone mineral density (BMD) was performed by dual energy X-ray absorptiometry (DXA) in 33 healthy subjects. Results: Serum irsin was significantly higher in obese group than in control group (mean 18.1 ± 3.5 vs 16.2 ± 2.0ng/mL; P = 0.002). There was no significant difference in serum irisin levels between prepubertal and pubertal subjects. In the all participants, irisin level was positively correlated with height SDS (r = 0.24; P = 0.02), BMI SDS (r = 0.37; P <0.001), HOMA-IR(r = 0.21; P = 0.04) and osteocalcin (r = 0.27; P = 0.006). Serum irisin level was negatively correlated with HDL cholesterol (r = -0.29; P = 0.005) and positively correlated with total body less head (TBLH) Z-score (r = 0.40, P = 0.03). Conclusions: This study showed the association between irisin levels with BMI standard deviation score, HOMA-IR and HDL cholesterol. Our data showed a positive correlation between irisin levels and BMD in healthy subjects. Further studies are needed to clarify the mechanisms by which irisin could affect glucose/lipid metabolism and bone metabolism.

Presentation: Thursday, June 15, 2023
THU222 Malignancy Risk In Nodules Classified As Atypia Of Undetermined Significance In A Predominantly Hispanic Free-standing Children’s Hospital
Authors: Baboun Daniela , Solano Natalia , Sanchez Andrea Martinez , Brathwaite Carole , Restrepo Ricardo , Alkhoury Fuad , Carrillo-Iregui Adriana
Published: October 2023

Disclosure: D. Baboun: None. N. Solano: None. A. Martinez Sanchez: None. C. Brathwaite: None. R. Restrepo: None. F. Alkhoury: None. A. Carrillo-Iregui: None.

Background: During the last 3 decades, there has been an increase in pediatric thyroid cancer. Ultrasound-guided fine needle aspiration (US-FNA) of thyroid nodules continues to be the main modality for histopathological evaluation. Thyroid nodules reported as atypia of undetermined significance (AUS) present a challenge to clinicians in deciding on surgical intervention versus observation (1). Objective: The purpose of this study is to determine the rate of malignancy in cases classified as AUS in the predominantly Hispanic population treated at a free-standing children’s hospital. Methods: Upon Institutional Review Board approval, we performed a retrospective chart review from 2012-2022 of 211 patients who underwent US-FNAs of thyroid nodules. We analyzed demographics and histopathological diagnoses. Results: The majority of our population identified as Hispanic (80.10%). There were 167 (79.10%) females and 44 (20.90%) males, and the age range was 4-21 years. Two hundred eleven patients underwent a total of 232 US-FNAs. The Bethesda distribution is as follows: 29 (12.50%) nondiagnostic, 98 (42.24%) benign, 45 (19.40%) AUS, 21 (9.05%) follicular neoplasm, 9 (3.88%) suspicious, and 30 (12.93%) malignant. Of the AUS group, 33 of the 43 patients underwent surgery. Of the surgical specimens, 16 (48.48%) were malignant, and 17 (51.52%) were benign. Of the 10 patients who did not undergo surgery, 2 underwent a repeat US-FNA with benign results, 5 were monitored, and 3 did not return for a follow-up. Conclusions: In our experience, patients with US-FNAs classified as AUS have a rate of malignancy of 48.48%, which is consistent with the published rate of higher incidence in the pediatric population than in the adult population. Thus, our results support the current recommendation of surgical intervention rather than observation in these pediatric patients. Molecular markers are a useful tool for determining management of thyroid nodules in adults; however, further research in the pediatric population is needed to have standardized recommendations.

Reference: (1) Rossi, E.D. et al., Cancer Cytopathology. 2017 Aug 125:594-603.

Presentation: Thursday, June 15, 2023
THU240 A Study Of 21 Cases Of Graves Disease In Childhood Presenting At Our Hospital For The First Time
Authors: Kashima Takemoto , Ujita Nagisa , Konno Hiroaki , Fujioka Akiko , Miyagi Hajime , Igarashi Mizuho , Doi Hibiki , Yoshii Keisuke , Naiki Yasuhiro , Horikawa Reiko , Noordin Mazidah
Published: October 2023

Disclosure: T. Kashima: None. N. Ujita: None. H. Konno: None. A. Fujioka: None. H. Miyagi: None. M. Igarashi: None. H. Doi: None. K. Yoshii: None. Y. Naiki: None. R. Horikawa: None. M. Noordin: None.

Although Graves disease is most common among women in their 20s and childhood-onset cases account for less than 5% of all cases of Graves disease, they account for the majority of hyperthyroidism in children. We report here a retrospective review of data on pediatric patients with Graves' disease who visited our hospital for the first time at the time of their initial examination. Methods We analyzed 21 pediatric patients with Graves disease who visited our hospital between November 2004 and January 2022. The electronic medical records of 21 patients were retrospectively reviewed for sex, age, height SD score, weight SD score, underlying disease, blood test results, and treatment initiation. Results There were 17 girls and 4 boys. The median age was 11 years and 5 months. Symptoms such as fever, feverishness, palpitations, weight loss, hyperactivity, and irritability were observed in 5 of the patients. Four patients had symptoms related to academic performance, such as low grades and poor concentration. Median physical findings were height SD score 0.62 (N=21), weight SD score 0.06 (N=21), and body mass index -4.4%. Two patients had bronchial asthma and atopic dermatitis, and one had myasthenia gravis and trisomy21 as underlying diseases. One patient was considered to have attention deficit hyperactivity disorder and was receiving antipsychotic medication. The median blood test values at the first visit were ALP 857 U/L (N=19), total cholesterol level 122 mg/dL (N=19), fT3 14.31 pg/mL (N=21), fT4 4.60 ng/dL (N=21), thyroid stimulating antibody 668 % (N=7), TSH receptor antibody 16.6 IU/L (N=20 TSH was less than sensitive in all cases. Nineteen patients received thiamazole. Fourteen patients received propranolol. Five patients received inorganic iodine. Five patients received inorganic iodine, starting at a median of 0.926 mg/kg/day of body weight. Discussion As with adults, females were more common. The symptoms were similar to those of attention deficit hyperactivity disorder, and thus warranted attention. Symptoms related to poor academic performance were also considered important. Anti-thyroglobulin antibodies and anti-TPO antibodies were also detected, suggesting that we should be careful about the possibility of the disease progressing to Hashimoto's disease.

Presentation: Thursday, June 15, 2023
FRI593 Ergocalciferol And Pancreatic β-Cell Function In New-onset Type 1 Diabetes: A Randomized Controlled Trial
Authors: Nwosu Benjamin Udoka , Parajuli Sadichchha , Sharma Rohit , Barton Bruce Alan , Lee Austin F
Published: October 2023

Disclosure: B.U. Nwosu: None. S. Parajuli: None. R. Sharma: None. B.A. Barton: None. A.F. Lee: None.

Background: The impact of high-dose vitamin D (ergocalciferol) on pancreatic β-cell function in youth with newly diagnosed type 1 diabetes (T1D) is unclear. Objective: To determine the effect of ergocalciferol on residual pancreatic β-cell function (RBCF) in youth with newly diagnosed T1D. Hypothesis: Ergocalciferol supplementation increases RBCF and prolongs the partial clinical remission (PR) phase of T1D. Design, Setting, and Participants: This 12-month randomized, double-blind, placebo-controlled trial of youth aged 10-21 years with newly diagnosed T1D of <3mo was conducted at a single center in the US between October 19, 2017 through April 20, 2021. Interventions: Participants were randomized 1:1 to once weekly dose of 50,000 IU of ergocalciferol for 2 months, and then once every 2 weeks for 10 months, versus placebo. Main outcomes and measures: The primary outcome was the percentage change from baseline in the area under the curve (AUC) of stimulated C-peptide over 12 months. Results: Thirty-six subjects were randomized to either the ergocalciferol arm: n=18, mean age 13.3±SD2.8 years, with 10 male and 8 female subjects; or to the placebo arm: n=18, mean age 14.3±2.9 years, with 14 male and 4 female subjects. Ergocalciferol significantly reduced the temporal trends in both the A1c (p=0.04) and the insulin-dose adjusted A1c (IDAA1c) (p=0.02), and the overall group means for IDAA1c versus placebo (p=0.02). A random intercept model, adjusted for age, sex, and race, showed that the percentage change in AUC C-peptide from baseline through the 12-month study period declined in both arms of the study. Specifically, by 28.4 ± 6.2 (p<.0001) in the ergocalciferol arm and by 41.5 ± 5.9 (p<.0001) in the placebo arm, with the decline in the ergocalciferol arm being significantly slower than that in the placebo arm, p=0.029 for the difference in the slopes of the trends between the two arms. There were no adverse events. Conclusion: High-dose ergocalciferol significantly slowed the rate of decline in C-peptide compared to placebo in children and adolescents with T1D.

Presentation: Friday, June 16, 2023
FRI594 Results Of A New Transition Of Care Process From Pediatric To Adult Diabetes Services
Authors: Cooper Felicia Ilyssa , Vyas Neha , Pierce Jessica , Kulasingham Alicia Yavani
Published: October 2023

Disclosure: F.I. Cooper: None. N. Vyas: None. J. Pierce: None. A. Kulasingham: None.

Adolescence is a challenging time in a child’s life and can be even more stressful for those living with diabetes. It has been shown that glycemic levels worsen in young adulthood due to factors such as increasing insulin resistance and gaps in care during the transitioning from pediatric to adult diabetes care. Data suggest that beginning transition preparation in early adolescence is associated with better outcomes. Our aim was to create a transition of care program for youth in our diabetes clinic following the Got Transition Core Elements and assess its effectiveness.

First, we established a clinic transition policy and corresponding informational letter, which we distributed to youth ages 12-16. Then, we adopted a Diabetes Summary Form to track and monitor transition progress. Next, we implemented transition readiness screening to youth ages 14-16 using the Readiness Assessment of Emerging Adults with Diabetes Diagnosed in Youth (READDY) tool. Last, we distributed GotTransition.org surveys to youth and their caregivers to assess satisfaction with our clinic’s transition process and perceived readiness to move to an adult provider. The transition letter distribution rate had a mean of 56% and the READDY completion rate had a mean of 40%. Although we did not achieve our distribution target goal of 80%, 90% of those who did complete the READDY indicated they were somewhat or very ready to transition to adult care. The satisfaction survey revealed that many youths still need assistance with insurance (32%) and finding an adult provider (45%). Overall, our initial efforts to establish a healthcare transition program were successful. We will continue our work on 1) improving letter distribution and readiness screening rates, 2) designing a curriculum centered around adolescent-specific issues, including insurance needs and 3) increasing our connections with adult endocrinologists to facilitate seamless transitions. We hope other pediatric diabetes clinics can learn from our experience, as well expanding to other subspecialty clinics in our children’s hospital.

Presentation: Friday, June 16, 2023
FRI166 Characterization of Aldosterone-producing Cell Cluster (APCC) At Single-cell Resolution
Authors: Iwahashi Norifusa , Umakoshi Hironobu , Seki Tsugio , Gomez-Sanchez Celso , Mukai Kuniaki , Suematsu Makoto , Umezawa Yuta , Oya Mototsugu , Kosaka Takeo , Seki Masahide , Suzuki Yutaka , Horiuchi Yutaka , Nishimoto Koshiro , Ogawa Yoshihiro
Published: October 2023

Disclosure: N. Iwahashi: None. H. Umakoshi: None. T. Seki: None. C. Gomez-Sanchez: None. K. Mukai: None. M. Suematsu: None. Y. Umezawa: None. M. Oya: None. T. Kosaka: None. M. Seki: None. Y. Suzuki: None. Y. Horiuchi: None. K. Nishimoto: None. Y. Ogawa: None.

Context: The adrenal cortex consists of zona glomerulosa (ZG), fasciculata (ZF), and reticularis. Aldosterone-producing cell clusters (APCCs) that express aldosterone synthase (CYP11B2) strongly can be frequently found in adult adrenals and harbor somatic mutations that are also present in aldosterone-producing adenomas (APAs). Primary aldosteronism is mainly caused by APAs or idiopathic hyperaldosteronism (IHA). We presume that APCCs are causing IHA and are precursors of APAs. However, the gene expression characteristics and especially the development of APCCs are not well understood. Objective: This study aimed to analyze the transcriptome of APCCs at single-cell resolution and infer the developmental trajectory. Methods: Single-cell RNA sequencing (scRNA-seq) was performed on two adult adrenals. Results: Immunohistochemical analyses confirmed the presence of APCCs in the two adrenals. scRNA-seq data of 6770 adrenal cells were obtained and 2928 high-quality cells were selected after quality control procedures. Unsupervised clustering and marker gene expressions such as CYP11A1 and NR5A1 identified 1765 adrenocortical cells, which were further divided into six clusters (B1-6). Using the list of APCC/ZG upregulated genes from our previously reported DNA microarray study, three clusters (B1, B3, and B6, totaling 923 cells) were identified as APCC/ZG cells. By further subclustering, the APCC/ZG cells were divided into 3 clusters (C1, C2, and C3). The APCC cluster (C3, 64 cells) and ZG cluster (C1, 447 cells) were identified. Cluster C2 seemed to be ZG-to-ZF transitional cells. RNA velocity analysis, which aimed to infer the direction of differentiation, inferred a direction of development from ZG cells to APCCs. Conclusion: Our results revealed the gene expression characteristics of APCC at single-cell resolution and show that some ZG cells remodel into APCCs.

Presentation: Friday, June 16, 2023
FRI171 Can 11-Dehydrodexamethasone Improve The Salivary Dexamethasone Suppression Test?
Authors: Marshall David , Issa Basil George , Keevil Brian George
Published: October 2023

Disclosure: D. Marshall: None. B.G. Issa: None. B.G. Keevil: None.

Background: The 1 mg overnight dexamethasone suppression test (ONDST) is recommended as a first-line test for the investigation of Cushing Syndrome. Measurement of dexamethasone alongside cortisol in a 9am serum sample has been credited with improving diagnostic sensitivity of the test. Previous studies have also looked at the utility of salivary dexamethasone and have observed poor correlation with serum dexamethasone. Herein we introduce the concept of measuring 11-dehydrodexamethasone: a dexamethasone metabolite produced in the salivary duct through metabolism with 11β-hydroxysteroid dehydrogenase type 2 (11Β-HSD2). Methods: Paired 9am serum and saliva samples (n=44) were collected post ONDST. The saliva samples were analysed utilising a novel in-house LC-MS/MS assay which measured cortisol, cortisone, dexamethasone and 11-dehydrodexamethasone. Serum cortisol and dexamethasone had previously been analysed separately by LC-MS/MS. Results were compared and correlations were assessed using Pearson regression. Results: Serum and salivary dexamethasone exhibited poor correlation (R-squared = 0.16), supporting what has been observed previously. Salivary dexamethasone and 11-dehydrodexamethasone also showed poor correlation (R-squared = 0.19). Serum dexamethasone and salivary 11-dehydrodexamethasone yielded a positive correlation with an R-squared of 0.65. However, at higher concentrations the correlation appeared non-linear. Conclusion: Correlation of serum dexamethasone with 11-dehydrodexamethasone is a novel finding, which to the author’s knowledge, has not been previously established/investigated. It is hypothesized that the non-linear correlation might be due to saturation kinetics of the enzyme 11Β-HSD2 in the salivary duct, a similar relationship was observed when comparison of salivary cortisol and cortisone was assessed. The development of this LC-MS/MS assay for salivary measurement of 11-dehydrodexamethasone opens the possibility for a fully remote DST, whereby patients could administer the drug and take a 9am saliva sample. Further sample comparisons are required to develop a 11-dehydrodexamethasone cut-off which equates to a serum dexamethasone concentration of 3.3 nmol/L.

Presentation: Friday, June 16, 2023
FRI174 Spectrum Of Presentation Of Adrenal Incidentalomas : Is The Distribution Changing? Experience From A Tertiary Care Centre Of Eastern India
Authors: Mishra Ipsita , Vivek Marrapu Venkata , Baliarsinha Anoj Kumar
Published: October 2023

Disclosure: I. Mishra: None. M.V. Vivek: None. A.K. Baliarsinha: None.

Spectrum of presentation of adrenal incidentalomas : Is the distribution changing? Experience from a tertiary care centre of Eastern India Abstract: Incidentally discovered adrenal masses have become a common clinical problem. An adrenal mass is uncovered in up to 4% -10% of patients imaged for non-adrenal disease. Incidentalomas are uncommon in patients younger than 30 years of age but increase in frequency with age; more frequently in females, especially in the sixth and seventh decades. Functioning tumors with a clear clinical phenotype (pheochromocytomas and those secreting cortisol, aldosterone, or sex steroids) and carcinomas account for around 28%- 32% of all adrenal incidentalomas. We reviewed last three year records of all the patients with the diagnosis of adrenal incidentaloma presenting to our institute and data regarding the clinical profile and outcomes of all the patients were analysed. The data obtained was entered into Microsoft Excel Worksheet and analysed using Statistical Package for Social Sciences (SPSS, IBM Corp. Released 2020.IBM SPSS Statistics for Windows, Version 20.0.Armonk,NY: IBM Corp.).Total 44 patients of adrenal incidentalomas were reviewed. In our case series, incidentalomas frequency were found to be increasing with age, most common in the 5th and 6th decades with equal frequency between male and females. Functioning tumours accounted for 54.5%(n=24), non functioning in 38.6%(n=17) and adrenal deficiciency in 6.8%(n=3)respectively. Most commonly encountered tumour was Pheochromocytoma(n=14,31.8%)followed by benign adenoma(n=10, 22.7%), adrenalcarcinoma (n=7,15.9%), myelolipoma(n=5,11.3%), aldosterone producing adenoma (n=3,6.8%), adrenal haemorrhage (n=1,2.2%), angiomyolipoma (n=1,2.2%), adrenal cyst (n=1,2.2%), and adrenal granuloma (n=2,4.5%) respectively. Amongst benign adenomas 40%(n=4) were functional( cortisol excess) and 60%(n=6) were non functional.Amongst adrenal carcinomas 42.8% (n=3) were functional and 57.2%(n=4) were non functional. Adrenal haemorrhage and adrenal granulomas had features of adrenal deficiency. The present work demonstrates that the distribution of adrenal incidentalomas is equal in both males and females, with functioning tumour Pheochromocytoma being more common than other variants. Hence the importance of complete biochemical investigation of adrenal incidentalomas is warranted. The probable changing pattern in the distribution of etiologies of adrenal incidentolomas can be further elucidated by analyzing data of a large cohort of patients with adrenal incidentolomas. Reference: Mansmann G, Lau J, Balk E, Rothberg M, Miyachi Y, Bornstein SR. The clinically inapparent adrenal mass: update in diagnosis and management. Endocr Rev. 2004 Apr;25(2):309-40. doi: 10.1210/er.2002-0031. PMID: 15082524.

Presentation: Friday, June 16, 2023
FRI425 BIUXX
Authors: Mendonça Macedo Daniel , Casanova João , Guerra Adalgisa , Francisco Rosário
Published: October 2023

Disclosure: D.M. Macedo: None. J. Casanova: None. A. Guerra: None. R. Francisco: None.

Title: Hyperandrogenism due to post-menopausal ovarian stromal hyperplasia. Introduction: Severe and rapidly progressive installation of hyperandrogenism in women after menopause should be carefully investigated. Stromal hyperplasia of the ovaries, which etiology is not completely understood, is a rare and benign cause of excess androgen production. In addition to hyperandrogenism, it is usually associated with hyperinsulinism, obesity, metabolic syndrome and acanthosis nigricans. Clinical case: A 60 year old overweight female patient with a history of type 2 diabetes mellitus, dyslipidemia, polycystic ovarian syndrome and menopause at 53 years old, reported the recent onset of hirsutism on the face and back, alopecia and increased libido. The laboratory evaluation revealed: total testosterone 89.6ng/dL (<35.9), free testosterone 5.13pg/mL (<4.2), sex hormone-binding globulin 22.9nmol/L (18-144), LH 21.3mIU/mL (14-52), FSH 27.4mIU/mL (26-135) and E2 <19.0pg/mL. The remaining androgens did not show alterations and hypercortisolism was excluded. Abdominal and pelvic ultrasound was performed and revealed enlarged ovaries with homogeneous echotexture and reduced echogenicity. A pelvic MRI was also performed and showed solid lesions in both ovaries, with moderate T1 and T2 hypointensity, suspicious of bilateral androgen-producing ovarian tumors. After multidisciplinary discussion, the patient underwent total hysterectomy with bilateral oophorectomy. Histopathology was compatible with bilateral stromal hyperplasia of the ovaries. Three months after surgery, the patient presented with a reduction of the facial and back hirsutism and slight improvement in alopecia. The laboratorial evaluation revealed a marked reduction in total testosterone (18.0ng/dL) and free testosterone (1.07pg/mL). Conclusions: New-onset hyperandrogenism in postmenopausal women is very uncommon and a diagnostic challenge. After excluding iatrogenic causes, hypercortisolism or adrenal tumor, the differential diagnosis between virilizing ovarian tumor and bilateral stromal hyperplasia is difficult to establish. Although the imaging distinction is possible, the definitive diagnosis is histopathologic and total hysterectomy with bilateral oophorectomy should be performed. In this case, although MRI was suspicious of bilateral ovarian tumors, the definitive diagnosis was stromal hyperplasia of the ovaries. Three months after surgery, the patient presented marked clinical and biochemical improvement.

Presentation Date: Friday, June 16, 2023
SAT004 A Novel Therapeutic Target Of Mitochondrial Protein To Prevent Steroid-induced Muscle Atrophy Through Regulation Of Proteolysis And Myogenesis
Authors: Kim Min-Ji , Singh Sinam Ibotombi , Kim Saehan , Siddique Zerwa , Hee Kwon So , Jeon Jae-Han , Lee In-Kyu
Published: October 2023

Disclosure: M. Kim: None. I.S. Sinam: None. S. Kim: None. Z. Siddique: None. S. Kwon: None. J. Jeon: None. I. Lee: None.

Objectives: Muscle atrophy, defined as a progressive loss of muscle mass and function induced by various etiology. Steroids is well-known muscle atrophy-inducible drug by enhancing of muscle catabolism and proteolysis. Pyruvate dehydrogenase kinase (PDK), a mitochondrial protein that inhibits the pyruvate dehydrogenase complex, is highly upregulated in metabolic diseases, especially pathologic muscle conditions associated with enhanced muscle proteolysis and aberrant myogenesis. Here, we investigated the role of PDK on proteolysis and myogenesis in steroid-induced muscle atrophy. Methods & Materials: Human skeletal (gluteus-maximus) muscles obtained from patients who underwent hip replacement surgery according to steroid administration were used for evaluated at the molecular level by expression of key genes and proteins involved in myogenesis. Steroid-induced muscle atrophy models were developed administered with glucocorticoid (GC) 25 mg/kg, intraperitoneally, for 10 days. Muscle dysfunction was studied in vivo in wild-type and PDK4 knockout mice treated with GC. We used C2C12 myotubes treated with GC for 24 h for in vitro study. Results: The expression of PDK4, as well as muscle-specific E3 ligases: muscle RING finger 1(MuRF1) and muscle atrophy F box (MAFbx), are significantly increased in skeletal muscle of steroid-user. In mouse model of steroid-induced muscle atrophy, expression of PDK4 and MAFbx are also upregulated, whereas knockdown of PDK4 reduces MAFbx expression and ameliorated steroid-induced muscle atrophy; increased muscle strength and muscle fibers. In C2C12 myotubes, knockdown of PDK4 was also associated with reduction of myogenin induction and MAFbx expression. To find out the mechanism, we used coimmunoprecipitation and liquid chromatography-mass spectrometry analysis and found that myogenin is novel substrate of PDK4. Mechanistically, this result suggests that PDK4 promotes MAFbx recruitment to catalyze muscle atrophy-induced MYOG ubiquitination and degradation. Conclusion: Taken together, the results suggest that PDK4-dependent activation of the ubiquitin degradation pathway appears to underly the promotion of muscle atrophy by directly targeting the muscle-specific MAFbx. Therefore, the inhibition of PDK4 represents as a novel therapeutic target to alleviate steroid-induced muscle atrophy.

Presentation: Saturday, June 17, 2023
OR33-05 Glucocorticoids Instigate Transcriptional Waves To Maintain Temporally Organized Fuel Production During Fasting
Authors: Goldberg Dana , Goldstein Ido
Published: October 2023

Disclosure: D. Goldberg: None. I. Goldstein: None.

Most animals are well equipped to endure prolonged fasting periods by converting energy stores into available biochemical fuel. This is achieved by the hepatic production of two fuel types supplying other tissues: glucose (originating from gluconeogenesis or glycogen breakdown) and ketone bodies (produced via ketogenesis). The adaptive response to fasting involves several hormones that together maintain homeostasis in the face of energy shortage. Glucocorticoids (GCs) are principal hormonal cues regulating the transcriptional response to fasting and were shown to augment both glucose and ketone production. We aimed to decipher how GCs control both the gluconeogenic and ketogenic programs. We profiled the transcriptional response and genome-wide enhancer dynamics of primary mouse hepatocytes to GC treatment. In addition to the induction of the expected fasting metabolism genes, we were surprised to find that GCs induced various genes encoding transcription factors (TFs). In fact, 13% of GC-induced genes were TFs, many of which were similarly induced in livers of fasted mice. Perturbation experiments and chromatin immunoprecipitation sequencing (ChIP-seq) showed that GCs induced these TFs via the glucocorticoid receptor (GR) which bound to DNA regulatory elements of the genes. We found that GCs induce two groups of TFs. The first group are TFs that maintain the early gluconeogenic fasting response. Indeed, knock-down of GC-induced TFs (C/EBPβ, MAFB or KLF15) reduced gluconeogenic gene expression. The second group are TFs which dictate a secondary transcriptional wave serving to produce fuel in prolonged fasting. Notably, GCs Initiate a TF cascade in which GR induces the expression of the Ppara gene, leading to increased PPARα protein. Upon subsequent ligand stimulation of PPARα, a ketogenic gene program is activated. We show that a dual treatment of GCs with a PPARα agonist leads to synergistic induction of ketogenic genes and that this induction is dependent on protein synthesis. We have analyzed the transcriptomic result of this TF cascade and found that dozens of ketogenic genes are synergistically induced. Genome-wide analysis of enhancer dynamics revealed numerous enhancers activated by the GR-PPARα cascade. These enhancers are proximal to ketogenic genes, are enriched for the PPARα binding motif and show increased PPARα binding as profiled by ChIP-seq. Taken together, our work reveals a GC-induced program whereby the expression of TFs increases during fasting, serving to rapidly support gluconeogenic capacity in short-term fasting and initiate a delayed ketogenic program brought about in prolonged fasting. These two regulatory modules may dictate the well-known temporal organization of the fasting response whereby gluconeogenesis predominates in early fasting but is gradually replaced by ketogenesis as fasting persists.

Presentation: Sunday, June 18, 2023
THU654 The Use Of Plasmapheresis In A Severe Case Of Amiodarone Induced Thyrotoxicosis
Authors: Moazezi Tina , Koh Chung-Kay
Published: October 2023

Disclosure: T. Moazezi: None. C. Koh: None.

Thyroid storm is an endocrine emergency that results in a hypermetabolic state due to excess levels of circulating thyroid hormone and carries a high mortality rate. Therapeutic plasma exchange (TPE) can be used in cases of thyrotoxicosis refractory to medical management to achieve hemodynamic and clinical stability. We present a case of a 74-year-old male with severe amiodarone-induced thyrotoxicosis who presented with altered mentation and ultimately required intubation and intensive care for management of thyroid storm. Standard medical therapy for treatment was initiated immediately with antithyroid drugs, beta blockers, glucocorticoids, potassium iodide solution, and cholestyramine. However, the patient remained unresponsive and intubated with worsening biochemical parameters with increased total T3 levels and sustained elevated levels of free T4 even after five days of maximal medical therapy. Due to the lack of a clinical and biochemical response to conventional medical therapy, the patient was started on plasmapheresis and underwent a total of seven cycles of plasmapheresis over a period of ten days. He significantly improved with TPE and was successfully bridged to a total thyroidectomy, which was completed without complications. Our case demonstrated a decrease in total T3 concentration of roughly 45% after one session of plasmapheresis and roughly 76% with seven sessions of plasmapheresis by the time of thyroidectomy. Free T4 levels remained elevated above reference range until the day after the fifth session of plasmapheresis. This case is important because the literature surrounding the use of TPE in thyroid storm is sparse, and there have only been case reports and retrospective studies published on the subject. Ultimately, while TPE is not conventionally used as part of routine treatment for thyroid storm, endocrinologists should keep this tool at the forefront of their management strategies to deliver quicker treatment to critically ill patients and prevent complications of thyroid storm. Nonetheless, more research is needed to delineate concrete guidelines and specific protocols for use of TPE in thyroid storm.

Presentation: Thursday, June 15, 2023
THU662 Poor Response To Medical Treatment In A Patient With Amiodarone-induced Hyperthyroidism: A Therapeutic Dilemma
Authors: Ahmed Asiri Alanood , Sulimani Riad , Alkhidady Wijdan
Published: October 2023

Disclosure: A.A. Asiri: None. R. Sulimani: None. W. Alkhidady: None.

Introduction: Hyperthyroidism is a well-known complication of amiodarone therapy. An incidence of 3% is reported in North America1, and even higher percentages in amiodarone deplete areas of about 10%.2 Treatment of amiodarone-induced hyperthyroidism (AIH) is challenging, it depends on various factors including the type of AIH, dependence of the patient’s cardiac condition on amiodarone therapy, other complications or comorbidities of the patient such as hepatic injury or dysfunction and the response of the patient to antithyroid therapy. Clinical Case: We present a case of a 32-year-old lady with a therapeutic dilemma in treating type I AIH, resistant to medical therapy. Our patient first had acquired COVID-19-induced myocarditis in 2020 and subsequently developed sustained ventricular tachycardia and was treated with amiodarone and placed on an implantable cardioverter-defibrillators (ICD) device. Two years later in 2022, the patient developed type I amiodarone-induced hyperthyroidism, with a free T4 reaching 100 pmol/L (Reference range 15-22 pmol/L) and complicated with transaminitis. She was unresponsive to medical therapy including: anti-thyroid medications, IV high-dose hydrocortisone, potassium iodide drops, and cholestyramine. She also developed adverse events with two of the antithyroid medications, Carbimazole and PTU; where she had elevated liver enzymes more than five time upper limit of normal and a generalized skin rash with PTU. Plasmapheresis was not an option as some of her cardiac medications drug levels could be affected. She underwent an emergent total thyroidectomy with dual beta blockade (Propranolol and Sotalol) successfully without any post op events. Her T4 level normalized within 8 days of her operation and her liver enzymes normalized within 2 weeks. Conclusion: We report the success and safety of surgical management in a patient with a cardiac arrhythmia and uncontrolled severe amiodarone-induced hyperthyroidism in the setting of adequate beta blockade. References: 1. Goldschlager N, Epstein AE, Naccarelli G, et al. Practical guidelines for clinicians who treat patients with amiodarone. Practice Guidelines Subcommittee, North American Society of Pacing and Electrophysiology. Arch Intern Med. 2000;160:1741–8. 2. Martino E, Aghini-Lombardi F, Mariotti S, et al. Environmental iodine intake and thyroid dysfunction during chronic amiodarone therapy. Ann Intern Med. 1984;101:28–34.

Presentation: Thursday, June 15, 2023
FRI186 Differences Of Body Composition And Comorbidities In Patients With Primary Aldosteronism According To Sex And Subtypes
Authors: Park Seung Shin , Ahn Chang Ho , Seo Sookkyeong , Kim Sang Wan , Yoon Ji Won , Kim Jung Hee
Published: October 2023

Disclosure: S. Park: None. C. Ahn: None. S. Seo: None. S. Kim: None. J. Yoon: None. J. Kim: None.

Background: Primary aldosteronism (PA) is associated with metabolic risks such as diabetes and obesity. However, controversy exists as to which subtype of PA has a higher metabolic risk between idiopathic hyperaldosteronism (IHA) and aldosterone-producing adenoma (APA). We aimed to assess the body composition of two PA subtypes according to sex and evaluate autonomous cortisol secretion (ACS) and its contribution to comorbidities. Methods: A total of 400 patients with PA and 1:10 age- and sex-matched healthy controls (n=4,000) were enrolled. Clinical and biochemical data were reveiwed. The skeletal muscle area (SMA), subcutaneous fat area, and visceral fat area (VFA) at the third lumbar spine were calculated using abdominal computed tomography-based body composition analysis. Results: In both sexes, a higher body mass index (BMI) was observed in patients with IHA than in those with APA (P<0.001 in men and P=0.049 in women). Hemoglobin A1c (HbA1c) level and the prevalence of diabetes were higher in female patients with IHA than in those with APA (6.0±0.9 vs. 5.6±0.5%, P=0.005 for HbA1c; 19.0% vs. 6.8%, P=0.016 for diabetes). The VFA/BMI ratio was significantly higher in patients with IHA than in patients with APA (5.77±2.69 vs. 4.56±2.35, P<0.001 in men; 4.03±2.58 vs. 2.53±2.05, P<0.001 in women). In subgroup analysis, decreased SMA was observed in PA patients with ACS compared with those without ACS. Compared with age- and sex-matched healthy controls, all patients with IHA and female patients with APA showed significantly higher VFA and VFA/BMI. Conclusion: Patients with IHA were more obese and had higher visercal adiposity than those with APA. This metabolically unfavorable body composition may contribute to a higher metabolic risk in patients with IHA. The role of adipose tissue in pathogenesis of IHA remains to be elucidated.

Presentation: Friday, June 16, 2023
SAT463 Hormonal Contraceptive Use and Hypothyroidism Risk
Authors: Gloe Shawna , Carroll Ty B
Published: October 2023

Disclosure: S. Gloe: None. T.B. Carroll: Consulting Fee; Self; Corcept Therapeutics. Research Investigator; Self; Corcept Therapeutics, Novartis Pharmaceuticals.

Introduction: Thyroid dysfunction is one of the most common endocrine disorders, with an estimated 4.3% of the US affected by subclinical hypothyroidism and 0.3% affected by overt hypothyroidism. Chronic autoimmune thyroiditis is the most common cause of hypothyroidism in the US and is estimated to affect 5-10x more women than men. Given this higher incidence in women, it is possible that hormonal difference or hormonal medications may play a role in thyroid dysfunction. Nearly 15% of women aged 15-49 use oral contraceptive pills (OCP) and 10.4% use other long-acting reversible hormonal contraceptives. A recent study showed a 25% increased prevalence of hypothyroidism in women with prior OCP use and in women with more than 10 years of OCP use the risk of developing hypothyroidism was nearly 4 times as high. Methods: Using the TriNetX database, four distinct groups of women aged 18-45 were identified using data from 1/1/2010 -1/1/2020. The four groups were EPC (n=5849), POC (n=5052), IUD (n=1000), and controls without prior hormonal contraception use (n = 6677). Demographic data, date of diagnosis of hypothyroidism, alcohol use, tobacco use, and BMI was obtained for each subject. Exclusion criteria included thyroidectomy (partial or total), lack of sufficient medication data, and a hypothyroidism diagnosis prior to or within 90 days of the first contraceptive medication order. A logistic model was then created accounting for known risk factors for the development of hypothyroidism (race/ethnicity, alcohol use, smoking, and BMI).Results: Initial comparison of treatment groups to controls demonstrated an no difference in risk of developing hypothyroidism for the EPC group (OR=1.18, p=0.2), but the POC and IUD groups had decreased risk of hypothyroidism (OR=0.39, p=<0.001 and OR=0.45, p=0.029, respectively). Using the logistic model, all groups demonstrated a decreased risk of hypothyroidism as compared to the control group (EPC: OR=0.3, p=<0.001, POC: OR=0.14, p=<0.001, IUD: OR=0.12, p=<0.001). Additionally, individuals identifying as Black/African Americans were less likely to develop hypothyroidism when compared to white/Caucasian subjects (OR=0.25, p=<0.001). Finally, BMI showed a fairly weak but significant association with development of hypothyroidism (OR=1.04, p=< 0.0001). Conclusion: Contrary to prior research, our data suggests a potential protective effect against the development of hypothyroidism for EPC, POC, and IUD use. The data also confirms prior studies showing a lower incidence of hypothyroidism in individuals who identify as Black/African American and perhaps those with lower BMI.

Presentation Date: Saturday, June 17, 2023