bluuebunny/crossref_metadata_2025 huggingface dataset:
PSUN246 Pilot Study: Impact of discharge follow up care at endocrine clinic on glycemic control and re-admission rate in a community hospital
Authors: Gangavarapu Praveen , Mon Sann Y
Published: November 2022

Introduction

The burden of diabetes among hospitalized patients is growing and 30-day readmission rates for those with DM are reported to be 5.9 to 9.2% higher than the rate for all hospitalized patients. We offered follow-up care at a community hospital-based endocrine clinic within 30 days after discharge for those with uncontrolled DM and analyzed its impact on glycemic control and 30 days re-admission rate.

Methods

This is a single-centered, retrospective study of 29 patients with DM who were hospitalized in our community hospital and were offered a follow-up Endocrine clinic appointment.

Results

We analyzed a total of 29 discharged patients’ chart with predominantly male (65.51%), T2DM (93%), mean age 58.9±15.7 yrs, BMI 31.35±-9.5 kg/m2, 72.4% on insulin therapy, 79.3% with at least one microvascular complication, and 37.9% with at least once macrovascular complication. A1C 3 8% on admission was observed in 27 patients (93.1%). Although all patients were offered a follow-up appointment, only 23 patients (79.3%) showed up for their follow-up appointments (G1) and 6 patients did not show up (G2).In G1, 4 out of 16 patients (25%) who were on insulin therapy were able to discontinue insulin therapy after endocrine clinic follow-up appointments.In G1, 15 patients (65.21%) achieved A1C < 8% at 3 months. In G1, mean A1C on admission was 11.8 ± 2.8% and improved to 7.7±2.5% whereas mean A1C remained the same for G2. (P= 0.6)The 30 days readmission rate was 21.73% in G1 although reasons for readmission were not directly related to diabetes, whereas no readmission was observed in G2.

Conclusion

Although our study failed to prove a reduction in 30 days of hospitalization by offering endocrine outpatient care, it has shown improvement in glycemic control.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN263 Diagnosis of Latent Autoimmune Diabetes of Adulthood Unveiled After Initiation of an SGLT2 Inhibitor
Authors: Patel Goonja , Kaur Komaldeep , Gandikota Praveena
Published: November 2022

SGLT2-inhibitors have revolutionized treatment for Type II diabetes (T2DM) due to their numerous benefits including improved glycemic control, cardioprotective properties, reduction of high blood pressure, and mitigation of disease progression in CKD.ew studies have investigated the benefits of this medication class on patients with Type 1 DM (T1DM). Herein we describe a case in which the diagnosis of latent autoimmune diabetes of adulthood (LADA) was unmasked following the use of an SGLT2-inhibitor.

A 56-year-old female with a history of T2DM diagnosed 10 years ago presented to the endocrine clinic for management of her poorly controlled diabetes. Her medications then included insulin detemir, insulin lispro, metformin, and repaglinide, but she still had an HbA1c of 11.3% (n<5.7%). She was tried on glipizide early in her disease course but it was discontinued due to fluid retention. She had a sedentary lifestyle with a BMI of 31.27 kg/m2. She was requiring increased doses of insulin over time with minimal improvement in her HbA1c. Two years later she was started on liraglutide with increasing dosages. Her HbA1c continued to decrease down to 8.7% and her BMI had decreased to 26.83 kg/m2. Over the next year, her HbA1c began to again increase up to 9.8%. At this time canagliflozin was added to her medication regimen. She responded very well to this medication initially with a drop in her HbA1c to 7.5% and a decrease in her BMI to 24.01 kg/m2. Unfortunately, one year after initiation of the SGLT2-inhibitor she was hospitalized for DKA and pancreatitis. At this time all her medications, except for insulin and metformin, were discontinued. A GAD65 antibody (>250 IU/mL; n<5.0 IU/mL) and c-peptide (<0.1 ng/mL; n = 1.1-4.4 ng/mL) levels were checked at this time which revealed the diagnosis of LADA approximately 16 years after her initial diagnosis of T2DM. She was transitioned to an insulin pump and managed according to protocol.

SGLT2 inhibitors have been studied as an adjuvant treatment with insulin for T1DM due to their ability to increase urinary glucose excretion but are currently not approved for T1DM. Despite their recorded benefits, they have also been shown to significantly increase the risk of DKA when used in patients with T1DM. Our patient, who was mistakenly treated as T2DM for almost two decades, was diagnosed with LADA after initiation of an SGLT2 inhibitor led to hospitalization for DKA. Further research is needed to assess the safety of SGLT2 inhibitors in T1DM, and caution must be taken when prescribing this medication to patients who may have underlying LADA.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
PSUN274 Chlorthalidone-Induced Diabetic Ketoacidosis.
Authors: Zafar Rafia , Syeda Javeria , Saber Suzan
Published: November 2022

Introduction

A variety of pharmacological agents affect glucose homeostasis resulting in hypo- or hyperglycemia. Several antihypertensives, including thiazide diuretics, are implicated in hyperglycemia.

Clinical Case

A 56 years old African American male with a history of type 2 diabetes mellitus, hypertension, and hyperlipidemia presented to the emergency department with diabetic ketoacidosis 3 weeks after initiation of chlorthalidone. His HbA1c at the time of chlorthalidone initiation was 6.8%. On presentation, his serum glucose was 870 mg/dL, beta-hydroxybutyrate was 34.70 (0.02–0.27), and HbA1c was 15.5%. The patient received aggressive IV fluid resuscitation and insulin infusion. Twenty hours later, DKA resolved and subcutaneous insulin was started. He was discharged home on MDI of insulin and chlorthalidone was discontinued. Metformin was restarted while insulin was tapered and stopped. Of note, the patient was diagnosed with diabetes mellitus 7 years before this presentation after an episode of DKA. After his first DKA, LADA was ruled out. His C-peptide level was intact and he was switched from MDI of insulin to metformin. The patient was maintained on metformin 1000 mg twice daily for 7 years with his HbA1c ranging from 6.1% to 6.4%. One year after his second DKA episode, he was still on metformin monotherapy with HbA1c of 6.8%. This is a case of DKA-prone diabetes and we believe that the use of thiazides precipitated his second episode due to the temporal relation and the lack of other contributing factors. There are several suggested mechanisms for thiazide diuretic-related hyperglycemia and other metabolic adverse effects. Genome Wide Association Study (GWAS) identifies the HMGCS2 locus to be associated with chlorthalidone induced glucose increase in hypertensive patients. Thiazide diuretics, especially chlorthalidone-associated DKA is not well documented and this entity may need further research. We found only one case report in the literature search.

Conclusion

Thiazide diuretics can worsen diabetes control in diabetic patients and may even lead to hyperglycemic emergencies, such as DKA in susceptible individuals. Patients should be closely monitored for some time after initiation of such medications to avoid hyperglycemia and related complications.

References

Qiao, X., & Moses, L. (2018). AN INTERESTING CAUSE OF DIABETIC KETOACIDOSIS: CASE REPORT, REVIEW OF LITERATURE AND POSSIBLE PATHOPHYSIOLOGY OF THIAZIDE DIURETICS-INDUCED DKA. Chest, 154(4), 265A.)

Singh, S., McDonough, C. W., Gong, Y., Alghamdi, W. A., Arwood, M. J., Bargal, S. A., … & Johnson, J. A. (2018). Genome wide association study identifies the HMGCS2 locus to be associated with chlorthalidone induced glucose increase in hypertensive patients. Journal of the American Heart Association, 7(6), e007339.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
RF04 | PSUN297 Genetic Knockout of Intestinal Hexokinase Domain Containing Protein-1 Affects Enterocyte Glucose Transport in Mice Fed High Fat Diet
Authors: Zapater Joseph , Wicksteed Barton , Layden Brian
Published: November 2022

Hexokinase domain containing protein-1, or HKDC1, is a widely expressed novel hexokinase that is genetically associated with elevated 2-hour gestational blood glucose levels during an oral glucose tolerance test, suggesting a role for HKDC1 in postprandial glucose regulation during pregnancy. Our earlier studies utilizing transgenic mice containing whole-body HKDC1 knockdown, or mice in which hepatic HKDC1 was overexpressed or knocked out, indicated that HKDC1 is important for whole-body glucose homeostasis in aging and pregnancy, through modulation of glucose tolerance, peripheral tissue glucose utilization, and hepatic energy storage. However, our knowledge of the precise mechanisms by which HKDC1 regulates postprandial glucose homeostasis under normal and diabetic conditions is lacking. As the intestine is the main entry portal for dietary glucose, and since HKDC1 is highly expressed within the intestine, in this study we assessed and characterized the in vivo significance of intestine-specific HKDC1 in regulating glucose homeostasis under normal and obesogenic conditions. We developed an intestine-specific HKDC1 knockout mouse model, HKDC1Int-/-, utilizing Cre-mediated recombination of HKDC1 in which Cre was expressed under the control of the villin gene promoter, leading to genetic knockout of HKDC1 solely within the intestinal epithelium. Mice were maintained until 28 weeks of age on either a normal chow diet or a high fat diet to develop obesity, hyperglycemia, and insulin resistance. While no overt glycemic phenotype was observed, 28-week-old HKDC1Int-/- mice fed a high fat diet exhibited an increased glucose excursion following an oral glucose load compared to mice expressing intestinal HKDC1. This finding was not due to differences in insulin levels, whole-body insulin tolerance, or gluconeogenesis, nor was it a result of alterations in enterocyte glucose utilization or a reduction in peripheral skeletal muscle glucose uptake. Furthermore, the enhanced glucose excursion was related to transport of glucose through the intestinal epithelium, as mice administered an intraperitoneal glucose load did not exhibit alterations in post-load glycemic excursion. Assessment of intestinal glucose transporters in high fat diet-fed HKDC1Int-/- mice indicated an increased expression of GLUT2 in the enterocyte apical membrane in the fasting state. Taken together, our results indicate that intestine-specific HKDC1 contributes to postprandial glycemic regulation by modulating dietary glucose transport across the intestinal epithelium under conditions of enhanced metabolic stress, such as obesity, hyperglycemia, and diabetes.

Presentation: Saturday, June 11, 2022 1:24 p.m. - 1:29 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
ODP272 ROUNDUP IS AN IMPORTANT DISRUPTOR THAT CAUSES PROLIFERATIVE EFFECTS ON NORMAL AND ON CANCER THYROID CELLS
Authors: Ward Laura Sterian , Rabi Larissa Teodoro , de Souza Teixeira Elisângela , de Oliveira Sarah Domingos , dos Santos da Silva Juliana Gabrielle , Peres Karina Colombera , Nascimento Matheus , Bufalo Natassia Elena , Bó Cruz Izabela Fernanda Dal’
Published: November 2022

Glyphosate has long be suspected to promote endocrine disruptive and even carcinogenic effects, but little is known about its effect at different concentrations on normal and on cancer thyroid cells. Since the endocrine system responds to low chemical concentrations and abnormal cells may have different sensitivity, it is essential to determine the effects of this compound at different levels, including the Acceptable Occupational Exposure Level (AOEL) and the Acceptable Daily Intake (IDA) doses. We used two human thyroid-derived cell lines strains, Nthy-ori 3-1 (from thyroid normal follicular cells) and TPC-1 (from papillary carcinoma) to test 15 different concentrations of Roundup® Original DI, ranging from 6.5 µg/L to 6.500 µg/L, including AOEL and IDA according to the Technical Note Process No. 25351. 056754/2013-17 of the National Health Surveillance Agency (ANVISA) in Brazil. Trypan blue assay and Cell Counting Kit – 8 (CCK-8) were employed to evaluate cell viability and cytotoxicity. Exposures were made for 24 and 48 hours in technical and biological triplicates. We observed a decrease in the number of viable cells at the 24h exposure compared to 48h in both strains. Exposure of Nthy-ori 3-1 and TPC-1 cells for 24h at the AOEL concentration (160µg/L) caused death of 52% and 58% of the cells, respectively, whereas IDA (830µg/L) resulted in 43% e 58% cell death. These data evidence an important disruptive effect of Roundup Original DI® at the acceptable concentrations. After 48h of exposure, AOEL and IDA concentrations caused a lower number of Nthy-ori 3-1 (19% e 15%) and TPC-1 (29% e 23%) dead cells, respectively, suggesting both thyroid strains have compensatory mechanisms that protect them from longer exposures to the herbicide. The CCK-8 assay, on the contrary, showed a proliferative effect on small concentrations: 6.5 µg/L increased the number of viable Nthy-ori 3-1 and TPC-1 cells to 113% and 118%, respectively, at 24h, and this stimulatory effect persisted after 48h of exposure. In contrast, AOEL and IDA concentrations produced a reduction in the number of both strains cells, likewise observed with the Trypan blue assay. Our data demonstrate that thyroid cells exposed to Roundup Original DI® present a non-monotone dose-response curve, which is a well-known characteristic of an endocrine disruptor. The proliferative effect produced on thyroid cells, especially TPC-1 mutant cells, by very low concentrations of this glyphosate-based herbicide widely used around the world, suggests that it may play a role in the increasing incidence rate of thyroid nodules and/or cancer that have been observed worldwide.

Presentation: No date and time listed
ODP577 A Qualitative Exploration of Internal Medicine Resident Experiences with Telemedicine During the COVID-19 Pandemic
Authors: Dolmans Diana , Saeed Omar , Yu Catherine , Wang Yiqiao (Daniel)
Published: November 2022

Telemedicine has become the cornerstone of health care delivery in the COVID-19 pandemic, as it allows patients to be cared for at a distance. This descriptive qualitative study sought to (1) explore internal medicine resident experiences with telehealth patient encounters during the COVID-19 pandemic, and (2) understand resident experiences with virtually reviewing cases with their supervisors. From November 2020 to March 2021, the authors conducted 20 semi-structured interviews with internal medicine residents who have completed ambulatory rotations such as endocrinology. Perceived benefits in patient encounters included increased efficiency. Challenges included a deficiency of nonverbal cues to use for building rapport with patients and confirming their understanding, inability to confidently form an impression of a patient and their disease severity, the lack of physical examination, and technical audio-visual challenges. While most residents preferred in-person to virtual review with their supervisors, the benefits of the virtual review included a supportive learning environment, and a high level of autonomy for senior residents. However, residents felt that feedback over a virtual platform was generic and not constructive, and junior trainees did not have opportunities to observe staff demonstrate essential skills needed for telemedicine care.

Presentation: No date and time listed
ODP648 MEN1 vs MEN4: when we cannot find a mutation
Authors: Correa Ricardo , Sheth Grishma
Published: November 2022

MEN1 is an autosomal dominant syndrome characterized by involvement of several endocrine and non-endocrine organs. The most common endocrine organs that are affected include pituitary, parathyroid, and/or pancreas. In 10-30% of patients, no germline mutations in the menin gene are identified, presenting a diagnostic challenge. This case raises the question of possible MEN4 syndrome, which shares a similar phenotype to MEN 1 with germline mutation in CDKN1B. Clinical case 59 y/o female with PMH HTN, obesity, hypothyroidism initially presented to our clinic in 2018 for evaluation of hypercalcemia. She prior was seen in 2005 for evaluation of prolactinoma by outside endocrinologist but was lost to follow up. Per history, she had a pituitary MRI in 1991 for work up of amenorrhea and found to have prolactinoma. She was placed on bromocriptine at that time; after repeat pituitary MRI and prolactin levels were found to be normal, bromocriptine was discontinued in 2019 but then restarted a few months later due to uptrending prolactin level. During the visit with us, work up for her hypercalcemia included calcium of 11. 0 mg/dL and PTH level of 93 pg/mL with normal albumin, vitamin D, and renal function. Patient had a negative sestamibi scan but was found to have a 10 mm×5 mm×12 mm enhancing nodule along the left thyroid gland and along left lateral margin of esophagus, suggesting parathyroid adenoma. She subsequently underwent successful left inferior parathyroidectomy in July 2019 with normalization of calcium and PTH levels. No other parathyroid was found to be enlarged. Given her pituitary and parathyroid adenoma, she was sent for genetic testing; she was evaluated for 7 gene variants and all were found negative including MEN1, CDKN1B, GNA11, AP2S1, CASR, CDC73, and RET. Of note, she has no family history of MEN1 or any endocrine tumors. However, further testing was still performed to evaluate for a pancreatic neuroendocrine tumor including CT abdomen, gastrin, C peptide, chromogranin-A, glucagon, VIP, and 5-HIAA. Her initial testing came back normal including normal CT abdomen in 2020. However, her most recently lab results in 2021 revealed an elevated gastrin level of 124 pg/mL and uptrending chromogranin A of 262 ng/mL (<=93), the diagnosis of gastrinoma was confirmed and PPIs were started.

Discussion

This case highlights the importance of continued surveillance in patients with multiple endocrine organ involvement or neoplasia despite negative genetic testing; it also supports the likelihood of unidentified mutations given the improbable chance this patient has 3 independent endocrine tumors. Possibilities including missed germline mutations on testing or phenocopies. This patient likely has an upstream mutation that was not identified and could represent either MEN1 vs MEN4

Presentation: No date and time listed
PSAT181 Amyloidosis as a Possible Cause of Hypoparathyroidism
Authors: Anderson Thea Lee , Bendaram Snigdha Reddy , Madhavan Parvathy
Published: November 2022

Background

Hypoparathyroidism is a relatively uncommon metabolic disorder with an estimated prevalence of 37 per 100,000 person-years in the United States. Postsurgical hypoparathyroidism is the most common etiology and accounts for 75% of the cases. Nonsurgical cases are frequently the result of autoimmune or genetic disorders. Rarely parathyroid gland infiltration, external radiation treatment is also known cause hypoparathyroidism. We present a rare case of hypoparathyroidism associated with amyloidosis.

Case

61-year-old female presented for evaluation of hypothyroidism and hypoparathyroidism and significant fatigue. Patient was already treated with levothyroxine as well as calcitriol at the time of presentation for management of these issues without improvement in her fatigue. Further review of prior records showed progressive decline in kidney function and albumin, hypothyroidism in addition to worsening hypocalcemia evidenced on ionized calcium levels over a two year period. This also coincided with the duration of the onset of fatigue. Past medical history was also significant for parathyroid surgery for primary hyperparathyroidism 12 years prior to the onset of symptoms. Patient did not develop hypoparathyroidism after surgery but maintained normal calcium levels until onset of symptoms 2 years ago.Physical exam did not reveal any abnormalities. Labs (when patient was receiving calcitriol) revealed a calcium of 9.5mg/dL (8.4-10.2mg/dL), with albumin 2.3g/dL(3.8-5.3g/dL), ionized calcium 1.27mmol/L(1.14-1.33mmol/L), 25-hydroxy Vitamin D 14ng/mL(>/=30ng/mL), PTH 7pg/mL(15-88pg/mL), Phosphorus 3.4mg/dL(2.4-4.8 mg/dL), Magnesium 2.6mg/dL(1.8-3.0 mg/dL), Creatinine 2.45mg/dL(0.40-0.99 mg/dL), eGFR 21 mL/min/1.73m2. She was trialled off calcitriol to assess for improvement of her PTH, however was noted to have inappropriately normal PTH despite hypocalcemia and was restarted on calcitriol. TPO antibody and 21 hydroxylase antibody levels were not elevated. Due to CKD, She underwent kidney biopsy that revealed lambda light chain amyloidosis. Patient is currently receiving daratumumab and Cyclophosphamide-Bortezomib-Dexamethasone and plans to undergo stem cell transplant in future.

Conclusion

Notably, the occurrence of amyloidosis with hypothyroidism and infiltrative amyloid goiter is well documented. Although prior case studies have detailed the co-occurrence of hyperparathyroidism and amyloidosis, little is known about the relationship of parathyroid disease and amyloidosis. Due to the temporal association of amyloidosis, hypoparathyroidism, and hypothyroidism, we hypothesize that infiltration of these endocrine glands by amyloid has contributed to the dysfunction. The patient will be monitored for improvement in her parathyroid function as the amyloidosis is treated. Further studies are needed to assess the interplay between the parathyroid and amyloidosis.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
PSUN160 Transfusion Related Endocrinopathies and Thalassemia (TREAT) Study
Authors: Erkin-Cakmak Ayca , Ahmad Tariq , Rishon Anne , Weyhmiller Marcela , Fung Ellen , Lodish Maya , Lal Ashutosh
Published: November 2022

Thalassemia (Thal), the most common form of inherited anemia worldwide, may require regular blood transfusions and life-long medical care. The introduction of oral chelators and imaging methods to monitor iron overload transformed Thal from a rapidly fatal disease of childhood to a chronic illness compatible with prolonged life expectancy. Regular blood transfusions resulting in tissue iron overload and oxidative stress may lead to liver disease and polyendocrinopathy. In this observational descriptive study, we described the patient characteristics and prevalence of endocrinopathies (growth failure, hypothyroidism, hypogonadism, low bone mass, and impaired glucose intolerance) in a contemporary group of transfusion dependent Thal patients cared for our tertiary care center since 2000. A total of 253 transfusion dependent Thal patients were identified. Of those patients, 51.8% were female; 22% (n=56) were adopted, mainly from China. The following ethnicities were represented: Chinese 19.9%, Indian 12.6%, Laotian 7.8%, Asian 7.8%, Italian 7.8%, Vietnamese 3.9%, Afgani 3.4%, Pakistani 3.4%, Thai 2.9%, Greek 2.4%, Cambodian 2.4%, Filipino, Caucasian, Iranian 1.9% each. Majority of the diagnoses were Beta Thal Major (69.9%), followed by E Beta 0 Thal (14.6%). The median age at first visit was 10.6 years (IQR1-IQR3: 2.2-25), last visit was 27 years (IQR1-IQR3: 12.1–39.4) with 33.5% of the patients ≤18 years of age. Median follow-up time was 10 years. Median final adult height (height z-score) for females was 159.5 cm (-0.53) (IQR1-IQR3: 152.4,160.3cm; height z-score: -1.68, -0.47) and for males 167.5cm (-1.3) (IQR1-IQR3: 161.5, 171cm; height z-score: -2.13, -0.81). Only, 16.5% (n=14) of children were on growth hormone treatment due to low-normal growth hormone surrogates or peak growth hormone <10ng/ml in growth hormone stimulation test. Hypothyroidism was diagnosed in 9.9% (n=25) of the patients and 5 patients had central hypothyroidism. Hypogonadism was diagnosed in 32.4% of adult female (n=24), and 44.6% of adult male (n=29) patients who were subsequently prescribed sex steroid replacement. Low bone mass in those with z-scores ≤2.0 was noted in 22.9% (n=43) female and 26% (n=49) males. The mean bone mineral density z-score for spine was -2.1±1.1 for females and -2.5±1.3 for males. Either impaired glucose tolerance or insulin-dependent DM was observed in 29% of the patients (n=54). Endocrinopathies are common and continue to be a significant morbidity in transfusion dependent Thal patients despite improved chelation agent availability and tissue iron monitoring. Future long-term longitudinal and intervention studies elucidating and mitigating potential effects of iron overload on developing children's developing endocrine organs are needed.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
RF22 | PMON09 BPA and BPF, but not BPS, alter pro- and anti-apoptotic transcript levels in granulosa cells, affecting cell viability.
Authors: Favetta Laura , Kourmaeva Emilia , Sabry Reem
Published: November 2022

Endocrine-disrupting compounds (EDCs) elicit adverse responses in the body, including the disruption of female reproductive functions. A common EDC is Bisphenol A (BPA), which is a frequently used plasticizer. Due to the negative effects of BPA on human health, production of BPA-free products using analogs, such as BPS and BPF, has increased; yet their effects are still largely unknown. Adequate oocyte maturation requires proper functioning of the surrounding environment, consisting of granulosa cells that impact oocyte competency. Granulosa cells are also susceptible to BPA disruption, affecting oocyte maturation and, ultimately, fertility.

In our lab, we showed that BPA and BPS significantly increased apoptosis in bovine embryos through increased DNA fragmentation (Saleh et al., 2021). However, the apoptotic pathway used is not fully characterized. Thus, the aim of this study is to investigate how bisphenols affect granulosa cell viability and through which apoptotic pathway. In vitro cultured granulosa cells were exposed for 12 or 48 hrs to six treatment groups: control, vehicle, estradiol, BPA, BPS and BPF at a low dose (0.005 mg/mL) and at the BPA Lowest Observed Adverse Effect Level (LOAEL-0.05 mg/mL). Live cells were counted using trypan exclusion. A significant decrease in the number of live cells after BPA treatment at the LOAEL dose for 12 hrs was observed (P=0.02, n=9).

mRNA expression of three proapoptotic (BAX, BAD, Casp9) and two antiapoptotic (HSP70 and BCl-2) genes was quantified by qPCR. A significant increase in BAX transcript levels after 12 hrs of exposure to BPA and BPF at the LOAEL dose (P=0.046, P= 0.033, n=6) as well as in BAD (P= 0.049, n=3) and Casp9 (P=0.049, n=4) levels after BPA exposure at the LOAEL dose was detected. Interestingly, at the 48 hr timepoint, a significant increase in BAD (P= 0.018, n= 9), BAX (P=0.002, n=10), and Casp9 (P=0.015, n=5) transcript levels was observed only following BPF treatment at the LOAEL dose. Despite expecting a decrease, both anti-apoptotic transcripts, at 12 and 48 hrs, showed increased levels following exposure to BPA and/or BPF at the LOAEL dose. This suggests an early first line of defense or shock response. Future protein analysis will help in further understanding these unexpected findings.

To quantify apoptosis levels, flow cytometry together with Annexin V/PI staining was used. Results indicate that after 48 hrs of treatment, BPA at the LOAEL dose significantly increases late apoptosis (P=0.004, n=5) and necrosis (P=0.0014, n=5), while showing a significant decrease in the number of healthy cells (P=0.0007, n=5). Preliminary data also show a similar pattern after BPA treatment for 12 hrs. This research aims to further our knowledge of the mechanisms by which bisphenols affect oocyte competency and suggests that BPF might have equivalent potency and effects to BPA.

Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
ODP282 Liver Dysfunction Monitoring in Patients With Turner Syndrome Followed at The Endocrinology Unit of a Tertiary Hospital in The Federal District (Brazil)
Authors: Siqueira Hiloma , Faria Erika , Furtado Adriana , Oliveira Pedro Philippo , Neto Nicãcio , Oliveira Alana , Cunha Jessica , Milward Marina , Rosa Isabella , Lima Cristiane , Carvalho-Louro Daniela Marino
Published: November 2022

Introduction

Liver involvement is common in patients with Turner syndrome. Most patients are asymptomatic and the pathogenesis of these findings remains unclear.

Objectives

The aim of this study is to correlate the main clinical, anthropometric and laboratory characteristics with the findings of hepatic elastography in patients with Turner syndrome.

Methods

We performed an observational cross-sectional study of adult patients diagnosed with Turner syndrome, confirmed by karyotype, without signs/symptoms of acute or chronic liver disease. Anthropometric and laboratory tests were done, including liver enzymes, lipid, and glycemic profile. Patients underwent liver health assessment using transient liver elastography at a tertiary hospital. Continuous variables were compared by Student's t-test and Mann-Whitney test as appropriate, while categorical variables were compared by Chi-square and Fisher exact test as appropriate.

Results

Twenty-three patients were enrolled and completed the study, with valid results from parameters of hepatic elastography. Patients who presented hepatic fibrosis risk on elastography, showed a higher concentration of triglycerides (p=0,046) and ALT/TGP (p=0. 028). The group with fatty liver showed higher concentrations of triglycerides (p=0. 033) and GGT (p=0. 046). Nine patients (34,8%) demonstrated intermediate risk of fibrosis and only one patient (4,8%) had a value suggestive of advanced fibrosis on liver elastography by kPa measurement. On the other hand, the CAP (Controlled Attenuation Parameter) identified steatosis grade I (S1) in 1/23 patients (4.3%), grade II (S2) in 1/23 patients (4.3%), and grade III (S3) in 7/23 patients (30.4%). Hepatic fibrosis and steatosis were not associated with the use of rhGH in childhood (p=0.190), neither with karyotype (p=0.675).

Conclusions

Our data showed a mild relationship among findings of elastography and comorbidities/kariotype. We demonstrate the importance of elastography as a non-invasive method for assessing liver involvement in Turner's syndrome, identifying degrees of fibrosis and steatosis in this population. Thus, fibroscan, with the measures of LSM (liver stiffness measurement) and CAP, emerges as a promising technique in the routine assessment of liver health in patients with Turner syndrome.

Presentation: No date and time listed
OR08-6 A Novel Nonsense Mutation in Delta-Like Non-Canonical Notch Ligand 1 Gene (DLK1) in a French Girl With Central Precocious Puberty
Authors: Latronico Ana Claudia , McElreavey Ken , Brito Nahime Vinicius , Pinheiro Machado Canton Ana , Raja Brauner , Rezende Tinano Flavia , Ribeiro Piovesan Maiara , Montenegro Luciana
Published: November 2022

Background

Central precocious puberty (CPP) results from early reactivation of the hypothalamic-pituitary-gonadal (HPG) axis. Four monogenic causes of CPP have been described (KISS, KISS1R MKRN3 and DLK1). Rare loss-of-function mutations of DLK1, a maternally imprinted gene located on chromosome 14q32.2, were identified in families with CPP. Both inherited or de novo DLK1 mutations were described in these affected families.

Objective

To investigate genetic abnormalities in the DLK1 in a French cohort of patients with idiopathic CPP.

Patients: Genomic DNA was obtained from 122 patients (99 girls and 23 boys) with sporadic or familial CPP. Automatic sequencing of the coding regions of DLK1 gene (5 exons, using Sanger method) was performed in all cases, including 91 familial and 31 sporadic cases.

Results

A pathogenic heterozygous variant in the DLK1 gene (c.372C>A p.Cys124Ter (rs749564412) was identified in a girl with sporadic CPP associated with overweight. This nonsense mutation was considered rare (gnomAD total population 1/251,082) and it was located in the third EGF-like repeat domain in the extracellular region. The affected girl had progressive breast development at 4.5 years and accelerated growth velocity. She had breast development Tanner stage 4 at 5.5 years and bone age (BA) was 6 yr. Her height was 114.5 cm and BMI 18.16 (BMI Z-score = 2.48). Basal LH and FSH was 0.6 IU/L and 5.7 IU/L, respectively. GnRH-stimulated LH and FSH peaks were 14 IU/L and 18 IU/L, respectively, with LH: FSH ratio of 0.77. Other hormonal results were normal (estradiol: 11 pg/mL; ACTH: 11 pg/mL; IGF-1: 235 ng/mL; cortisol: 77 ng/mL). Brain MRI was normal. Pelvic ultrasound revealed uterus length: 49 mm, mucosal thickness of 4 mm, ovaries 20 and 25 mm with follicles less than 10 mm. She was treated with a depot GnRH analog (triptorelin). The DLK1 variant was inherited from her asymptomatic father who had a height of 181 cm. Familial history of CPP history was denied.

Conclusion

DLK1 loss-of-function are rare genetic cause of familial or sporadic CPP. Novel genetic findings in this factor reinforce its role in the physiopathology of the premature HPG axis reactivation and precocious sexual development in humans.

Presentation: Saturday, June 11, 2022 12:45 p.m. - 1:00 p.m.
OR16-3 Analysis of Testis-Enriched Genes in Estrogen-Dependent Genome Regulation in Breast Cancer
Authors: Choudhari Ramesh , Diva Kimberly , Ramos Enrique , Sedano Melina , Yang Barbara , Gadad Shrikanth
Published: November 2022

Emerging studies show that testis-enriched genes play critical roles in several biological processes. The expression of these genes is tightly regulated and limited to immune-privileged organs; however, many of them escape regulation and are aberrantly expressed in several diseases such as cancer. Intriguingly, our genomic analysis revealed that many of them are transcribed from previously considered gene deserts. We also found that a significant number of them are robustly regulated by estrogen and other peptide hormones such as Tumor Necrosis Factor-alpha (TNF alpha). However, their direct role in estrogen-dependent transcriptional regulation and biological outcomes remains unstudied. In this regard, our integrated genomic approach, including RNA with 4-thiouridine (4sU) coupled with RNA-sequencing and CRISPR-based genetic screening, has identified key estrogen-regulated testis-enriched genes that may modulate estrogen-signaling. Through a series of molecular and phenotypic assays, we selected a potential but understudied transcript, which is predominantly localized to the nucleus. Furthermore, in the current study, we have interrogated the functional mechanisms by which selected transcript controls estrogen-dependent gene regulation in estrogen receptor-positive (ER+) breast cancer. We found that the transcript controls estrogen-dependent cell and tumor growth. Additionally, we have manipulated the levels of the transcript in estrogen-receptor-positive (ER+) breast cancer cells employing gain- and loss-of-function studies and performed 4sU-RNA-seq. Interestingly, the transcript modulates the expression of estrogen-driven transcripts that are transcribed from ER-alpha (ERa) binding sites. Mechanistically, the transcript is localized in the nucleus and interacts with chromatin-associated proteins. In addition, our integrated genomic analyses comprising 'Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq)' and 'chromatin immunoprecipitation (ChIP) with massively parallel DNA sequencing ChIP-seq' (H3K27ac, H3K27me3) identified a critical role for the transcript in controlling the epigenetic landscape at target gene promoters and enhancers in ER+ breast cancer. Collectively, our data support a functional role for testis-enriched genes in enhancer transcription and chromatin organization. This study sheds light on the molecular functions of testis-enriched genes and presents an opportunity to identify new diagnostic and develop treatment strategies in ER+ breast cancer.

S.S.G. is supported by a grant from the Cancer Prevention and Research Institute of Texas (CPRIT; RR170020). S.S.G. is also supported by a grant from Lizanell and Colbert Coldwell foundation.

Presentation: Sunday, June 12, 2022 11:30 a.m. - 11:45 a.m.
OR16-4 Genomic Interrogation of the Phytoestrogen Genistein in Ovarian Cancer Cells
Authors: Kraus W Lee , Hou Tim
Published: November 2022

Although studies have shown beneficial effects of the phytoestrogen genistein on reducing ovarian cancer risk, little is known at the molecular level regarding how genistein inhibits ovarian cancer growth, with estrogen receptor beta (ERb), a hormone-regulated transcription factor, receiving the bulk of the attention. When endogenous and exogenous ligands engage ERb, the receptor binds to regulatory regions in the genome known as enhancers, where it associates with coregulatory proteins, increases histone modifications associated with active enhancers, promotes chromatin looping, stimulates enhancer transcription and the production of enhancer RNAs, and ultimately regulates target gene transcription. Since signaling pathways converge at the transcriptome level, an unbiased approach is needed to examine how genistein acts to suppress ovarian cancer growth beyond ERb. We have previously used global run-on sequencing (GRO-seq), a high-throughput method that identifies the location and orientation of all transcriptionally active RNA polymerases across the genome, to identify active enhancers based on enhancer transcription and enrichment of the aforementioned genomic features. To determine the genomic responses upon genistein treatment in ovarian cancer cells, we have used PRO-seq to characterize the enhancer landscape in OVCAR3 and OVCAR4 ovarian cancer cell lines treated with genistein. The advantage of this method is the lack of a priori assumptions needed to determine which signaling pathways are regulated by genistein, since PRO-seq allows pathway determination based on the universe of active enhancers. Ultimately, this approach will allow us to uncover signaling pathways beyond ERb and determine how genistein acts as a signaling ligand to change the transcriptome in ovarian cancer cells.

Presentation: Sunday, June 12, 2022 11:45 a.m. - 12:00 p.m.
OR22-2 Ghrelin Receptor (GHSR1a) Functional Selectivity As A Novel Pharmacotherapeutic Strategy To Normalize Dysfunctional Metabolic Homeostasis
Authors: Gross Joshua
Published: November 2022

The growth hormone secretagogue receptor-1a (GHSR1a) is the cognate G protein-coupled receptor (GPCR) for the orexigenic agonist ghrelin and the anorexigenic antagonist liver-expressed antimicrobial peptide-2 (LEAP2). The ghrelinergic system is activated under conditions of caloric restriction and/or environmental stress, and it acts pleiotropically to restore physiological homeostasis by modulating both central and peripheral metabolic processes, including food-seeking behavior, glycemia, energy utilization/nutrient partitioning, and cardiovascular function. Consequently, ghrelin/GHSR1a signaling provides an accessible and desirable pharmacological target. GHSR1a-mediated physiological responses rely upon distinct G protein- and β-arrestin (βarr)-dependent signaling pathways, a property referred to as 'functional selectivity' or 'biased signaling.' Thus, when treating disorders of metabolic dysfunction (e.g., obesity, type II diabetes, neurodegenerative disease), a pharmacotherapeutic strategy that modulates 'biased' GHSR1a signaling may uncouple desired therapeutic outcomes from unwanted side effects. For example, animal models bearing G protein- or βarr-biasing GHSR1a mutations may express differences in orexigenic and glucoregulatory effects that are signaling pathway-dependent, and our group has demonstrated that GHSR1a antagonism blunts cocaine-induced neuroadaptive behaviors via a mechanism requiring βarr2 in dopaminergic neurons (Toth et al., 2016, Synapse). Based on these findings and the principle of ligand functional selectivity, we sought to identify new GHSR1a drug candidates that could distinguish between G protein and βarr pathways. We discovered a GHSR1a-selective, G protein-biased agonist — N8279 (NCATS-SM8864) — based on a novel chemotype. Comprehensive pharmacological analysis revealed that N8279 elicits potent and biased Gαq activity at both the apo- and ghrelin-bound GHSR1a. Molecular modeling coupled with mutagenesis and medical chemistry supports that N8279 signals through the GHSR1a via a unique extended binding mode requiring the extracellular loop 2 and thereby, enables preferential signaling through the Gαq pathway over alternative G proteins (Gαi∕o, Gα12∕13) and βarr2. Critically, N8279 is readily brain penetrant in mice, exhibits advantageous pharmacokinetics, and attenuates aberrant dopaminergic behaviors in both genetic and pharmacological mouse models of hyperdopaminergia. Our findings together provide important insights into mechanisms governing GPCR signaling and illustrate how functional selectivity might be leveraged to develop GHSR1a pharmacotherapeutics to normalize pathological disruptions of metabolic homeostasis.

Presentation: Monday, June 13, 2022 11:15 a.m. - 11:30 a.m.
RF17 | PMON23 Argentinian multicentric genetic study of pituitary hormonal deficiencies using a custom panel based on single molecule molecular inversion probes
Authors: Alonso Guillermo , Cau Carolina Arias , Belgorosky Alicia , Benzrihen G , Bergada Ignacio , Braslavsky Debora , Camper Sally , Ciaccio Marta , D'Amato S , Palma Isabel D , Figueroa Veronica , Forclaz Veronica , Keselman Ana , Kitzman Jacob , Gil Susana Mallea , Central Hospital Militar , Argentina Buenos Aires , Marino Roxana , Marti Marcelo , Miras Mirta , Garrido Natalia Perez , Ramirez Pablo , Vishnopolska Sebastian , Camilletti Maria Andrea , Mayer Julian Martinez , Murriello Augusto Chaves , Felker Gonzalo Chirino , Perez-Millan Maria
Published: November 2022

Hypopituitarism with deficiency of one or more pituitary hormones (combined pituitary hormone deficiency or CPHD) can vary in severity and age at presentation. Additionally, the hormone abnormalities may evolve with time necessitating frequent evaluation. These hormonal deficits can also be present as part of a syndrome, with patients showing extrapituitary abnormalities such as eye or forebrain malformations. Over the past decade, there has been an explosion in the knowledge of the genetic cascade that orchestrates hypothalamic and pituitary development. Several transcription factors and signaling molecules are critical for cell differentiation and proliferation at a very early stage of gestation. However, more genes remain to be identified in order to provide patients with a definitive aetiology. We studied 95 children with congenital hypopituitarism from seven pediatric hospitals from Argentina. Children with non-endocrine, non-familial idiopathic short stature served as a control group (n=100). A custom exon capture panel based on single-molecule molecular inversion probes sequencing (MIPS) was performed in probands and parents. This panel tests 104 genes: including a selection of reported and candidate genes chosen from our knowledge of pituitary development in mice and PROP1 interacting proteins. We found at least 1 variant in 50 probands. The prevalence of known variants in the pituitary transcription factor genes PROP1 and PIT1 (frequently mutated in CPHD) was low in our cohort. A significant number of disease-causing variants were found in LHX3, LHX4, GLI2 and OTX2. An important advance of our study is the identification of pathogenic variants in recently discovered and novel genes. We found an heterozygous variant in the Roundabout (ROBO) receptor homolog 1 gene: ROBO1;p.Arg1504* in a patient with CPHD and septo-optic dysplasia (SOD); two variants in Steroid Receptor SRA1: p. Ile179Thr and p.Val110delinsArgLeu in a patient with CPHD and hypogonadism hypogonadotropic and a missense variant in Semaphorin 3A SEMA3A: p.Val588Leu in a case of CPHD and aortic coarctation. Our findings support evidence that the etiology of congenital hypopituitarism is highly heterogeneous and may be infrequently monogenic with full penetrance, underlying a more complex pathogenesis.

Presentation: Sunday, June 12, 2022 12:36 p.m. - 12:41 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
RF17 | PMON27 Genetic Subtype Differences in Relation to Health Problems Among Adults With Prader-Willi Syndrome
Authors: Pellikaan Karlijn , Rosenberg Anna , Wellink Charlotte , Garcia Juan Tellez , van Abswoude Denise , van Zutven Laura , Brüggenwirth Hennie , Resnick James , van der Lely Aart Jan , de Graaff Laura
Published: November 2022

Background

Prader-Willi syndrome (PWS) is a complex rare genetic disorder associated with hypothalamic dysfunction, pituitary hormone deficiencies, hyperphagia and (morbid) obesity. PWS is caused by loss of expression of paternally expressed genes on chromosome 15q11.2-q13. The most common genetic mechanisms leading to PWS are paternal deletion (DEL) and maternal uniparental disomy (mUPD). DELs can be subdivided in type 1 and (smaller) type 2 deletions (DEL-1, DEL-2). Most research has focused on behavioral, cognitive and psychological differences between patients with a DEL-1, DEL-2 or mUPD. However, little is known about the genetic subtype differences in relation to physical health problems.

Methods

We reviewed the medical files of all adults with genetically confirmed PWS who visited the outpatient clinic of the Center for Adults with Complex Rare Genetic Syndromes at the Erasmus University Medical Center, Rotterdam, the Netherlands, between January 2015 and June 2021. All patients underwent a systematic health screening, including a structured interview, a medical questionnaire, a complete physical examination, biochemical measurements, and a review of the medical records. Health problems, physical complaints, symptoms of disease and behavioral challenges were compared between adults with an mUPD and DEL and between adults with a DEL-1 and DEL-2.

Results

Twenty-eight adults had an mUPD and 65 a DEL (13 DEL-1, 27 DEL-2, 25 unspecified). Gender, age and BMI did not differ between the genetic subgroups. Although psychiatric problems (psychotic episodes) were significantly more often present in adults with an mUPD (P < 0.001) and scoliosis was more prevalent among patients with DEL (P = 0.04), there was only a slight difference in prevalence of other medical problems like hypertension, cold intolerance, edema, hyperphagia, skin picking, abdominal pain and fatigue. There were no significant differences between DEL-1 and DEL-2. However, fatigue, cold intolerance, edema and hyperphagia were slightly more prevalent among adults with a DEL-1, whereas osteopenia, constipation and skin picking were more prevalent among adults with a DEL-2.

Conclusion

The differences in health problems between PWS adults with DEL-1, DEL-2 and mUPD are mostly present in the psychological domain. Especially psychotic episodes were more frequent in adults with an mUPD. Apart from scoliosis, there were no significant differences in physical health outcomes between the genetic subtypes.

Presentation: Sunday, June 12, 2022 1:00 p.m. - 1:05 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.