bluuebunny/crossref_metadata_2025 huggingface dataset:
SUN-LB1 Atypical Presentation Of Myocardial Infarction In A Young Patient With Polycystic Ovarian Syndrome
Authors: Mandal Shobha , Pradhan Ravi Ranjan , Avetisova Mariam , Kowalczewski Barbara Lidia Mols
Published: May 2020

Background: Polycystic ovarian syndrome (PCOS) is a very common and complex endocrine problem in women of childbearing age, with a prevalence of 4 to 12% globally. Myocardial infarction (MI) is the leading cause of death in women worldwide. PCOS increases the risk of MI because of chronic inflammation, endothelial dysfunction, impaired pulse wave velocity and its association with metabolic syndrome, and hormonal imbalance.

Clinical Case: A 36-year-old female with a history of PCOS, hirsutism, severe acne on spironolactone, presented to ER with a chief complaint of lower back pain for 10 days that started after lifting a 60-pounds printer. The pain was attributed to musculoskeletal type, one dose of ketorolac intramuscularly was given and she was discharged on cyclobenzaprine. The next morning, she presented with worsening back pain and new-onset vomiting. Physical exam was normal except for BMI 34.6kg/m2; vitals were stable. Lab work showed elevated troponin of 1.43 which rose to 10.6 ng/ml (normal 0.00-0.034), cholesterol 125 mg/dL (less than 200), HDL 33 mg/dL (normal 40-59), LDL 164 mg/dL (normal 100-129). Electrocardiogram showed sinus tachycardia with Q wave changes in leads III and V1 to V3. Echocardiogram showed hypokinesia of left ventricular wall in the mid to apical anterior septum. Computed tomography (CT) scan of the thoracic spine was negative for abscess or fracture. CT of abdomen and pelvis as well as CT angiography chest were negative. Urine drug screening was also negative.

As her presentation was attributed to MI, patient was started on heparin drip, aspirin, atorvastatin, and metoprolol. She underwent cardiac catheterization that showed 99% ostial left anterior descending artery stenosis; a drug-eluting stent was successfully placed. After intervention her back pain resolved. She was discharged on dual antiplatelet therapy (aspirin and Prasugrel) along with atorvastatin, metoprolol and nitroglycerin.

Conclusion: This case suggests an association of PCOS with MI. A meta-analysis has shown a two-fold increase in risk of coronary artery disease in patients with PCOS (1). Future studies are need to examine opportunities for cardiovascular disease risk reduction in PCOS patients.

Reference:1. de Groot PCM, Dekkers OM, Romijn JA, Dieben SWM, Helmerhorst FM. PCOS, coronary heart disease, stroke and the influence of obesity: a systematic review and meta-analysis. Human Reproduction Update 2011. 17 495-500.
SAT-LB91 Asparaginase Induced Severe Hypertriglyceridemia Requiring Multiple Plasmapheresis Sessions
Authors: Aftab Hassaan , Kantorovich Vitaly
Published: May 2020

Background: Asparaginase (ASP) is an essential component of chemotherapy for acute T-cell lymphoblastic lymphoma (T-ALL). Hypertriglyceridemia (HTG) is a known side effect of ASP therapy in children and adults (incidence up to 67 and 12.5%, respectively). The mechanism of HTG is multifactorial and involves lipoprotein lipase (LPL) suppression. Acute pancreatitis can occur in 13% of patients. There are no treatment guidelines currently available for ASP-induced HTG.

Clinical Case: A 33 year old male with history of prediabetes, HTG and T-ALL being treated with CALGB 10403 chemotherapy protocol (vincristine, methotrexate, cytarabine and pegylated-ASP) presented to the ED with acute onset abdominal pain radiating to the back with associated nausea. He denied alcohol use. Home medications included fenofibrate, metformin and atorvastatin. His TG level prior to initiating chemotherapy was 454 mg/dL (ref range < 150) with an HbA1C of 6.5%. Upon presentation; TG level was 11,650 mg/dL, lipase was 563 U/L (13-60) with CT abdomen findings suggestive of mild pancreatitis. He was treated in the ICU with insulin drip at 0.05 - 0.1 unit/kg/hr with repeat TG level 6,490 mg/dL after 48 hours. He eventually required 5 serial plasmapheresis sessions over a 10 day hospital course in order to achieve a goal TG level under 500 mg/dL.

Conclusion: ASP is part of standard multiagent chemotherapy for patients with ALL however poses the risk of developing severe HTG. This side effect may be explained by multiple mechanisms including increased synthesis of very low-density lipoprotein (VLDL), decreased LPL activity as a result of an increase in the apoCIII/apoCII ratio, and increase in serum chylomicrons. Studies have shown patients who had extreme HTG had a higher frequency of ApoE3/4 phenotype, suggesting that screening for ApoE polymorphism may identify patients at high risk for developing this. HTG secondary to ASP is often asymptomatic, with severe elevations in TG levels observed around 10 days after the 3rd administration of ASP and resolving 2-3 weeks after drug discontinuation. There are no treatment guidelines for ASP-associated HTG as there is no single typical clinical course. Management for severe HTG includes insulin infusion and plasmapheresis. Insulin rapidly activates LPL leading to mean TG reduction of 50% within the first 24 hours as compared to 66% reduction after single plasmapheresis therapy. However, there is paucity of data regarding the appropriate insulin dose and whether there is a linear dose-response in TG level reduction. Further studies are required to develop standard treatment guidelines for ASP-induced HTG which may help alleviate serious complications such as acute pancreatitis.

Reference: Tozuka et al “Characterization of hypertriglyceridemia induced by L-asparaginase therapy for acute lymphoblastic leukemia and malignant lymphoma.” Annals of Clinical & Laboratory Science 1997
MON-LB303 Behavioral Genotypes Associated With Adults With Obesity
Authors: James Kathy Shadle , Matsangas Panagiotis
Published: May 2020

The use of genetic testing to assist patients with weight loss is still relatively new. Genetic testing offers increased understanding of obesity risk, behaviors that can contribute to weight and much more. Research shows that patients are favorable to learning about how genetics influences their weight. As part of a larger project, this study aimed to identify the frequency of genotypes that influenced eating behavior traits of overweight and obese patients attending a medical weight loss clinic in southern California. All study procedures were approved by appropriate institutional review boards and administrators prior to initiation of the study. We used a quantitative retrospective design to identify participants with atypical eating behavior traits, i.e., (eating disinhibition, food desire, hunger, satiety, snacking, sweet taste, and the FTO obesity gene. The data were extracted from 75 genetic reports of patients who had completed a saliva sample with Pathway Genomics, San Diego, CA between 2017-2018. Analysis showed that 56 (75.7%) patients screened positive for eating disinhibition and 37 (50%) for food desire, whereas 29 (39.2%) were identified with the FTO gene. Also, 20 (27.0%) patients were positive for sweet taste, 13 (17.6%) satiety, 13 (17.6%) snacking, and 7 (9.46%) hunger. On average, patients screened positive for 2 (median value) eating behavior traits. Four (5.41%) patients screened positive for five eating behavior traits, the maximum observed in our sample. Biserial correlation analysis showed that satiety was correlated with the FTO gene (Pearson’s r=0.502, p<0.001) and eating disinhibition was negatively correlated with hunger (Pearson’s r=-0.450, p=0.034). Overall, overweight and obese patients had a disproportionally high incidence of eating disinhibition, food desire, and the FTO obese gene. These atypical behaviors can contribute to their difficulty in losing weight. Specific strategies can be discussed with patients around their atypical behaviors with regular follow up appointments by the clinician. Genetic testing can provide important patient education to improve outcomes related to weight management and health outcomes.
SUN-LB17 The Association of Growth Hormone Treatment in Children With Short Stature With Idiopathic Scoliosis
Authors: Nam Hyo-Kyoung , Rhie Young-Jun , Lee Kee-Hyoung
Published: May 2020

Objectives: Adolescent idiopathic scoliosis (AIS) is the most common form of scoliosis, which occurs usually in the periods of growth spurts and puberty changes. The spinal curve progression in AIS is related to growth, skeletal maturity and sexual maturity. Growth hormone treatment has been used to improve final adult height by increasing growth velocity in children with short stature. Therefore, AIS is expected to occur more frequently in children treated with growth hormone. The aim of this study was to investigate the relationship between AIS and growth hormone treatment in short children. Methods: A total 115 subjects aged 2.1 to 16.9 years who had been treated with growth hormone because of growth hormone deficiency (n=83), idiopathic short stature (n=16) and small for gestational age (n=16) were included. Their medical records were reviewed retrospectively. The scoliosis angle of each subject was measured on the standing frontal radiograph according to the Cobb method. A curve with a Cobb angle of 10 degrees or more is defined scoliosis. Follow up Cobb angle were measured after 1-year of growth hormone treatment. Results: Cobb angle has been increased after 1-year growth hormone treatment (6.1±3.1 vs. 6.9±3.4, P=0.024). The change of Cobb angle was correlated with serum insulin like growth factor-1 level at baseline (r=0.274, P=0.003) and after 1-year of growth hormone treatment (r=0.220, P=0.020). There was no significant correlation between the change of Cobb angle and growth velocity. The prevalence of AIS has been increased after 1-yrear of growth hormone treatment (11.3% vs. 19.1%, P=0.009). Conclusion: Growth hormone treatment in children with short stature seems to be associated with occurring and worsening of AIS.
SUN-LB101 NRF2 Represses Obesity-Associated Adipose Tissue Inflammation in Mice
Authors: Yagishita Yoko , Uruno Akira , Kensler Thomas W , Yamamoto Masayuki
Published: May 2020

Obesity is associated with type 2 diabetes, cardiovascular disease and increased incidence of cancer. Chronic inflammation, mainly emanating from adipose tissue, has been proposed to be one of the links between obesity and these pathologies. Thus, identification of new targets against obesity and especially obesity-induced inflammation is needed urgently. Transcription factor Nrf2 (NF-E2-related-factor-2) plays a central role in cytoprotective responses to oxidative and electrophilic stresses and also exerts anti-inflammatory effects in rodent models of inflammation. However, whether activation of Nrf2 signaling pathway influences obesity-associated inflammation in adipose tissue is not well established. To this end, we generated mice with systemic activation of the Nrf2 pathway (Keap1flox/–), as well as mouse models with tissue-specific Nrf2 pathway activation: adipocyte-specific (Fabp4Cre::Keap1flox/ flox) and myeloid cell-specific (LymCre::Keap1flox/ flox). These mice were exposed to a high-fat diet (HFD) 60% kcal fat regimen for 6-weeks or crossed into the db/db background. Keap1flox/– mice showed a dramatic decrease of the numbers of F4/80-positive macrophages in white adipose tissue (WAT). Interestingly, both Fabp4Cre::Keap1flox/ flox and LymCre::Keap1flox/ flox mice showed suppression of F4/80-positive macrophages in WAT as well, suggesting enhanced Nrf2 signaling in either adipocytes or myeloid cells might contribute to anti-inflammatory effects in WAT under the stress of HFD. Transcript levels of inflammatory markers, especially macrophage F4/80 and Cd68 and the chemokine Ccl2 were decreased in the WAT from Keap1flox/– mice on the standard diet and also in the WAT of Keap1flox/– mice in the db/db background. Pharmacological activation of the Nrf2 pathway by treatment with CDDO-Im also suppressed Ccl2 expression in WAT of HFD fed mice and db/db mice. As CCL2 is a key mediator of macrophage accumulation in adipose tissue, we further studied the potential effect of Nrf2 on the transcriptional regulation of Ccl2 using 3T3-L1 preadipocyte and RAW264.7 macrophage cell lines. Treatment of both lines with the small molecule inducer of Nrf2, diethyl maleate significantly suppressed LPS-induced expression of Ccl2. Analysis using luciferase reporter assay revealed that a Nrf2 binding site in the Ccl2 5’ flanking region from -235 to +85 contributed to gene silencing of Ccl2 by activation of Nrf2. Our findings suggest that the druggable Nrf2 pathway may be an effective target to combat obesity-associated inflammation in adipose tissue and its’ concomitant metabolic disorders. Supported by AMED BINDS JP19am0101001 (MY), 19H05649 (MY), 16KK0195 (AU), NIH R35 CA197222 (TWK), JSPS OT 290125 (YY).
SUN-LB2 Undescended Testicle and Short Stature as Manifestation of Pituitary Stalk Interruption Syndrome a Report From Saudi Arabia
Authors: Ahmed Rania , robert Asirvatham Alwin
Published: May 2020

Background

Pituitary stalk interruption syndrome (PSIS) is a congenital disease with isolated growth hormone deficiency or multiple anterior pituitary hormone deficiencies. Here, the authors report a case of PSIS from Saudi Arabia.

Clinical Case

A 16 year old Saudi boy presented to the endocrine clinic with short stature and undescended testis, status post bilateral orchidopexy. He was delivered by caesarean section because of breech presentation and birth asphyxia. Investigation revealed underdeveloped secondary sexual characteristics with decreased facial and pubic hair growth. The patient height was 134 cm whereas the bone age was 9 - 11 years. Pelvis examination showed a scrotum with bilateral 1 mL testes and the stretch penile length was 3 cm.

The patient laboratory investigations showed hemoglobin level of 13 g/dL, serum sodium 140 mmol/L, serum potassium 4.1 mmol/L, serum chloride 102 mmol/L, calcium 9.1 mg/dL, random blood sugar 110 mg/dL and albumin 3.8 mg/dL. A pituitary hormone profile showed hypopituitarism with thyroid, and adrenal sparing. The patient free T4 was 17.3 pmol/L (9-25 pmol/L) and synacthen test revealed a morning baseline cortisol level of 6.5 µg/dL (normal = 4.3-22.4 ug/dL) with adrenocorticotrophic hormone of 9.8 pmol/L (1.1 - 13.2 pmol/L). Insulin-like growth factor 1 level 50 ng/dL (normal = 193.0 - 731.0 ug/L), follicle-stimulating hormone 0.35 µIU/mL (normal, 0.0-10.0), and leutinizing hormone 0.4 µIU/mL (normal = 1.2-7.8). The patient’s morning testosterone level showed 8 ng/dL (normal = 280-800 ng/dL) and prolactin 116 mIU/L (normal = 86 - 324 mIU/L). There were no symptom suggestive of posterior pituitary involvement like polyuria and polydipsia as urine and serum osmolality. The MRI examination showed no pituitary gland identified in the sella turcica and no clear pituitary stalk. A T1 hyperintense focus with post-contrast enhancement was identified posterior to the optic chiasma representing an ectopic posterior pituitary gland. The growth hormone and testosterone therapy were added to medical therapy of the patients and no thyroid or hydrocortisone replacement therapy was given.

Conclusion: Despite the fact that this is a rare disorder, it should always be kept in the differential diagnosis of a patient presenting with short stature. Patients with this disease have an excellent opportunity to reach normal height if they present before the joining of epiphyses.
SUN-LB125 Violet Sensitive Preoptic Area Neurons That Express Opsin 5 Regulate Thermogenesis and Energy Metabolism
Authors: Zhang Kevin X
Published: May 2020

The thermogenic potential of brown adipose tissue (BAT) is a promising therapeutic target in the treatment of obesity and metabolic disorders. The preoptic area (POA) is a region in the anterior hypothalamus responsible for autonomic thermoregulation by means of modulating BAT activity through sympathetic nerve activity (SNA). Neurons in the POA express opsin-5 (OPN5), an atypical opsin found in various extraretinal tissues and known to respond to violet wavelengths with a lambda-max of 380 nm. OPN5 has previously been shown to regulate seasonal breeding behavior in birds. Loss of OPN5 in mice have been demonstrated to impair circadian photoentrainment. We have also shown OPN5 to be required in retinal ganglion cells for in vivo entrainment of a retina circadian clock independent of the suprachiasmatic nucleus. To date, no other physiological role for mammalian OPN5 has been proposed. The same POA neurons that express OPN5 also engage the central thermoregulatory circuit that modulates BAT activity. We show that POA OPN5 neurons polysynaptically project to the BAT using a retrograde PRV-mRFP1 pseudorabies virus. Also via a genetically targeted glycoprotein-deleted rabies virus injected into the POA, we identified labeled neurons in the rostral raphe pallidus (rRPa), the lateral parabrachial nucleus (LPB), and the dorsomedial hypothalamus (DMH), all nuclei known to participate in central BAT thermoregulation. Opn5-/- mice better defend their core body temperature during acute 4°C challenge. Our results indicate this effect to be due to increased BAT thermogenesis and not heat retention or pyrexia. Furthermore, BAT thermogenesis target gene transcripts (Ucp-1, Prdm16, Pgc-1a) were elevated in these cold stressed Opn5-/- animals. To demonstrate the importance of OPN5’s violet light sensing function in cold defense, C57BL/6J mice reared from E16.5 without 380 nm light largely phenocopy Opn5-/- animals when acutely cold challenged. Furthermore, chemogenetic inhibition of POA OPN5 neurons further augments cold exposure defense and BAT activation. Indirect calorimetry studies reveal Opn5-/- mice to be hypermetabolic, consuming more food and having a higher energy expenditure than controls. Paradoxically, this increased turnover does not translate to weight-gain resistance under high fat challenge. Our results suggest a mechanism where near-UV sensitive hypothalamic OPN5 neurons regulate BAT thermogenesis directly, proposing that the mammalian autonomic thermoregulatory apparatus is light responsive.
SAT-LB47 Tension Pneumothorax Following Cabergoline Initiation for Macroprolactinoma
Authors: Go Muriel Tania , Ganesh Malini , Mascarell Susana
Published: May 2020

Background Pneumocephalus is a rare and life-threatening complication of dopamine agonists (DA) for the treatment of invasive giant prolactinomas. Here we present a catastrophic case of pneumocephalus following cabergoline therapy for invasive macroprolactinoma. Clinical Case A 49-year-old man presented with transient left-sided facial weakness for one day. MRI Brain showed no acute infarcts but revealed a 3.7cm pituitary macroadenoma extending into the sphenoid sinus and left cavernous sinus, encasing the left internal carotid artery with scattered hemorrhagic foci. He was discharged on cabergoline 0.25mg twice weekly for hyperprolactinemia of 7640 ng/mL (N 2.64-13.13 ng/mL). Four weeks later, he was readmitted for altered sensorium, clear rhinorrhea and positional headache. Work-up showed a prolactin of 204 ng/mL confirmed on dilution testing, and a random cortisol of 8.3 mcg/dL. MRI Brain revealed mass involution measuring 2.8cm with the central component replaced by air, and extensive pneumocephalus overlying bilateral cerebral hemispheres, within lateral ventricles and basal cisterns. Further DA therapy was held, and the patient was started on stress dose steroids. He underwent emergent surgical repair of the CSF leak, partial tumor resection and lumbar drain placement. Pathology confirmed pituitary adenoma staining positive for prolactin. Two weeks later, prolactin was 7157 ng/mL. Subsequent attempts to restart DA therapy was complicated by recurrent CSF leaks requiring two additional surgical repairs. After a complicated hospital course requiring prolonged intubation, tracheostomy and PEG tube placement, he was discharged to an acute rehabilitation center on low dose bromocriptine 2.5mg daily as well as maintenance hydrocortisone 10mg twice daily. Discussion CSF leak with pneumocephalus is a rare complication of DA therapy for invasive macroprolactinomas. It occurs due to disruption of the dura with an osseous defect of the skull base. Rapid volume reduction by DA leads to exposure of previously created pathologic opening in the skull base originally plugged by tumor itself until then. Out of 60 patients from 1980 to 2017 who developed DA therapy-induced CSF leak, more than half (57%) were on bromocriptine. Median initial prolactin was 5460 ng/ml and median time from therapy initiation to presence of rhinorrhea was 6 weeks, although it can occur as late as 2 years. The recommended definitive management of DA-induced rhinorrhea is surgical repair. Subsequently, there is no consensus on how to restart DA post-repair. Conclusion This case illustrates the importance of watchful monitoring of response after DA therapy initiation in invasive macroprolactinomas. Although data is sparse, there may be benefit in lower and less frequent dosing initially. Patient education regarding the risk of complications and signs/symptoms to watch out for with DA therapy is also crucial.
MON-LB113 Insulin Resistance in Type 1 Diabetes Managed With Metformin (INTIMET): Rationale and Study Design of a Randomised Placebo-Controlled Trial
Authors: Snaith Jennifer R , Samocha-Bonet Dorit , Holmes-Walker Deborah J , Greenfield Jerry R
Published: May 2020

Background: Insulin resistance is an under-recognised cardiovascular risk factor in type 1 diabetes (T1D). Individuals with T1D exhibit insulin resistance relative to those without diabetes. In T1D, tissue-specific insulin resistance (muscle, hepatic, adipose) is likely to partly drive increased cardiovascular risk. Adjunctive metformin improves muscle insulin sensitivity in T1D adolescents, but factors that predict responsiveness remain unknown.Objective: To report the rationale and design of the INTIMET study, a double-blind randomised, placebo-controlled trial of metformin in T1D.Methods: Forty adults aged 20-50 years with T1D, and 20 age- gender- and BMI- matched non-diabetic controls will be studied. T1D inclusion criteria are diagnosis > 10 years, HbA1c 9.5% and fasting C-peptide < 0.3nmol/L. Liver and muscle insulin sensitivity will be determined by the 2-stage hyperinsulinemic (20 and 60 mUm2)-euglycemic (5.5 mmol/L) clamp method with deuterated glucose. Subjects with T1D will be randomised to metformin extended-release 1500mg/d or matched placebo for 26 weeks. The primary endpoint is the change in hepatic insulin sensitivity, measured by suppression of endogenous glucose production (EGP) with the low-dose insulin clamp. Secondary endpoints include change in muscle and adipose tissue insulin sensitivity, arterial stiffness, HbA1c, glucose variability, frequency of hypoglycemia, insulin dose, anthropometry, body composition, lipid profile, liver fat and stiffness. Conclusion: The INTIMET study will quantify muscle, liver and adipose insulin-resistance in T1D, determine whether metformin is effective in improving insulin resistance in T1D and identify factors that predict metformin-responsiveness.

The trial is registered (Australian New Zealand Clinical Trial Registry, ACTRN12619001440112) and is actively recruiting in Sydney, Australia.
SUN-LB68 Advanced Glycation Endproducts Are Associated With Worse Bone Material Strength in Older Adults With and Without Type 2 Diabetes
Authors: Samakkarnthai Parinya , Sfeir Jad G , Atkinson Elizabeth J , Achenbach Sara J , Tweed Amanda J , Volkman Tammie L , Drake Matthew T , Farr Joshua N , Khosla Sundeep
Published: May 2020

Patients with Type 2 Diabetes (T2D) are at increased fracture risk despite having relatively normal or even increased BMD by DXA. The critical aspect of bone quality deterioration in T2D patients could explain this clinically important discrepancy. Material composition is a component of bone quality that has emerged as a potential factor contributing to fragility fractures in T2D patients. However, there is sparse evidence regarding whether T2D patients have decreased bone material properties compared with non-diabetic controls. We hypothesized that increased production of advanced glycation endproducts (AGEs) has an important role in reducing bone material strength in patients with and without diabetes. Thus, we used the OsteoProbe®, a bone microindentation device that provides an index of cortical bone material properties (Bone Material Strength index – BMSi) in men with T2D age ≥ 50 yrs or postmenopausal women with T2D and nondiabetic controls. We also utilized a non-invasive measure of skin AGEs (AGE Reader®) to evaluate AGEs accumulation through skin autofluorescence. Linear regression models were used to assess group differences with and without adjusting for age, Body Mass Index (BMI), and sex. Relationships between variables were assessed using adjusted Pearson correlations. A total of 152 T2D patients (mean age 68.5 ±7.6 yrs.; 59.2% men; HbA1C=7.7 ±1.0%; mean diabetes duration 15.5 yrs.) and 105 non-diabetic controls (mean age 67.2±8.8 yrs.; 41.0% men; HbA1C =5.4 ±0.3%) were recruited to the study. Overall, there was no difference in BMSi between T2DM and control subjects: unadjusted (p= 0.636); adjusted (p= 0.695). However, skin AGEs were negatively correlated with BMSi (r= -0.23, p <0.001). In subgroup analyses, skin AGEs were also negatively associated with BMSi in both T2DM (r= -0.23, p=0.004) and control (r= -0.21, p=0.033) subjects. In conclusion, these findings demonstrate that a higher burden of AGEs is associated with worse bone quality. Our findings may explain the conflicting findings regarding reductions in BMSi in T2D because only T2D patients with a high level of AGEs accumulation have impaired BMSi. Moreover, the association of skin AGEs with BMSi in non-diabetic subjects emphasizes the important role of AGEs in decreasing bone quality and potentially contributing to fracture risk. Collectively, our data indicate that non-invasive skin AGEs measurement could be used as a tool to evaluate bone quality in patients with T2D as well as in the non-diabetic population.
MON-LB73 Incidence Rate of Post-Thyroidectomy Immediate Hypocalcemia and Its Relation to Pre-Operative Vitamin D and Parathyroid Hormone Levels
Authors: Sirajuddin Khadeeja , Asirvatham Alwin Robert , Alharbi Eman , Sirajuddin Fatima , Al Khahtani Nasir , Al-Gahmdi Abdullah , Al-KharashI Eyad , Alsaeed Abdulghani Habib
Published: May 2020

Aim: To find out the incidence rate of post-thyroidectomy immediate hypocalcemia within 48 hours and explore the association of pre-operative vitamin D and parathyroid hormone (PTH) levels.Methods: This retrospective study was conducted among 122 patients who underwent total thyroidectomy over one year (from January 2018 to December 2018) in Prince Sultan Military Medical City, Riyadh, Saudi Arabia. After thyroidectomy, all patients were admitted and observed for at least 24-48 hours. The postoperative hypocalcemia, alkaline phosphatase (ALP), phosphate (PO4), parathyroid hormone (PTH), and vitamin D level were collected.Results: During 2018 a total of 122 (mean age 41.6±1.2 years; females 90.2%) patients underwent total thyroidectomy. The mean calcium level in the first two days was 2.07 mmol/L and 2.01 mmol/L. Most of the cases of hypocalcemia occurred on day 1 postoperatively. Hypocalcemia mainly occurs in patients with benign pathology. The level of vitamin D in those patients with benign pathology was significantly lower as compared to those with malignant pathology (49±23 vs 62±25; P=0.009). The overall mean level of vitamin D was 54.6±25 (50-150 nmol/L). Interestingly, there were no correlation between pre-operative vitamin D, PTH level and postoperative hypocalcemia. There were no statistically significant differences between postoperative hypocalcemia with other parameters except for pre-operative alkaline phosphatase which was barely positive (P=0.052).Conclusion: The outcomes of this study manifestly illustrated that a significant decline in calcium level after the surgery. In contrast to previous studies, our findings did not show a significant correlation between vitamin D level and hypocalcemia. This could be due to small sample size. Furthermore, the mean level of vitamin D in our cohort was 54 which was within the normal range. Further, well-designed randomized controlled trials with greater sample sizes are necessary to validate our findings.
SAT-LB95 Low Density Lipoprotein Receptor and Proprotein Convertase Subtilisin/Kexin Type 9 Kinetics Using Heavy Water (2H2O) Labeling and Mass Spectrometry
Authors: Dandan Mohamad , Hellerstein Marc
Published: May 2020

Abnormally high blood cholesterol levels in low density lipoprotein (LDL) increases the risk of heart disease. Cell surface receptors such as LDL-receptors (LDLr) regulate the clearance of LDL from blood circulation. As cholesterol levels decrease, cells promote cholesterol synthesis and cholesterol uptake by increasing LDLr expression. Another regulatory protein of plasma cholesterol clearance is proprotein convertase subtilisin/kexin type 9 (PCSK9). It is secreted from the liver into circulation where it can bind to and target LDLr to the lysosome for subsequent degradation. The current model of cholesterol regulation describes how increased cholesterol content down-regulates the number of LDLr promoted by PCSK9 mediated degradation, however minimal knowledge is not known about LDLr and PCSK9 kinetics using heavy water labeling, and how cholesterol enriched diet affects LDLr and PCSK9 kinetics in vivo. Therefore, our objective(s) were to establish a method 1) to measure the kinetics of LDLr and PCSK9 via stable isotopic metabolic labeling with heavy water (2H2O) in vivo 2) to further test established models of cholesterol metabolic regulation on LDLr and PCSK9 turnover after feeding mice a cholesterol enriched diet. We hypothesize that a cholesterol enriched diet will decrease both LDLr and PCSK9 synthesis rates. In order to test this, mice were fed a cholesterol enrich diet for 1 week and metabolically labeled with heavy water (2H2O) up to 36 hours. LDLr and PCSK9 were immunoprecipitated from liver and deuterium incorporation into LDLr and PCSK9 were measured via mass spectrometry. Our results revealed high cholesterol feeding down-regulated cholesterol synthesis and LDLr fractional synthesis rate decreased from 10.0% to 6% per hour. PCSK9 concentration also decreased from 1 to 0.2 (ng/ml / total mg protein), but the synthesis rate increased from 9.0%/day in control mice to 19.5%/day in high cholesterol diet. These results suggest high cholesterol feeding increases PCSK9 synthesis that potentially depletes the intracellular pool to target LDLr to the lysosome thus decreasing LDLr turnover. This research provides a flux-based approach to measure the kinetics of LDLr and PCSK9 for a molecular based kinetic insight of their functions in physiology, disease and therapy.
OR28-07 Increased BMI Is Associated With Anti PD-1/PD-L1-Induced Thyroid Immune-Related Adverse Events
Authors: Pollack Rena , Ashash Amit , Cahn Avivit , Dresner-Pollak Rivka
Published: May 2020

Background: Immune checkpoint inhibitors have revolutionized cancer therapy, however, are associated with immune related adverse events (irAEs). Obesity is a pro-inflammatory metabolic state that may play a role in the development of irAEs. Hypothesis: We hypothesized that likelihood of developing thyroid irAEs following anti-PD-1/L1 therapy increases with increasing body mass index (BMI). Methods: We retrospectively analyzed data of 187 cancer patients who initiated anti-PD-1/L1 at our institution between 01/2014-12/2018, had normal thyroid function tests at baseline and had baseline BMI data available. Results: Overall, 97 (52.2%) patients were with low-normal BMI (<25 kg/m2), 52 (28.0%) overweight (≥25-30 kg/m2) and 37 (19.9%) obese (≥30 kg/m2). Thyroid dysfunction (hyper or hypo, overt or subclinical) developed in 72/187 (38.7%) patients, of whom 29/97 (29.9%) had low-normal BMI, 22/52 (42.3%) were overweight and 21/37 (56.8%) obese (p=0.14). With every 1 kg/m2 increase in BMI, the likelihood of thyroid dysfunction increased by 8.8% (p=0.004). Overt hyperthyroidism occurred in 32/186 (9.1%) of the patients - in 4.1% of patients with low-normal BMI, 11.5% of overweight patients and 18.9% of obese (p=0.006). Overt hypothyroidism occurred in 32/186 (17.2%) of the patients and was not significantly associated with BMI. Hyperthyroidism followed by overt hypothyroidism, consistent with thyroiditis, occurred in 13/186 (7.0%) of patients and was significantly associated with increasing BMI category (p=0.03). Conclusions: Increased BMI was associated with increased thyroid irAEs in patients treated with PD-1/L1 inhibitors. Further exploration of the interaction between obesity and immunotherapy may provide insight into the role of inflammation in mediating immune response.
SUN-LB26 Radioligand Theranostics of Endocrine-Related Cancers; A New, Revolutionary Approach
Authors: Harris Alan G , O’Dorisio Sue M
Published: May 2020

The successful clinical development of octreotide targeting somatostatin receptors (SSRs) revolutionized treatment of Neuro Endocrine Tumors (NETs)and pituitary adenomas. Recently, clinical applications of peptide bioconjugates including octreotide have taken a giant leap forward into a new diagnostic and therapeutic arena of additional endocrine-related cancers including prostate, breast, and small cell lung cancers. Molecularly targeted radionuclide therapy (RT) opens new horizons for otherwise resistant or widely dispersed malignancies and has far-reaching implications as a personalized therapeutic approach. Cancer-type specific, radiolabeled diagnostic imaging agents have been developed to select patients who then receive precise radioligand therapy targeting the identified cancer cells. This RT using alpha or beta radiation is cytotoxic to targeted cancer cells, while nearby healthy cells are unharmed—minimizing side effects and improving patient quality of life. Thus, theranostics represent a groundbreaking approach to bring radionuclide endocrine cancer therapy to patients via a multidisciplinary team consisting of endocrinologists, surgeons, oncologists and nuclear medicine physicians. In recognition of this exploding new field, the US FDA approved 68Ga-DOTATOC and -DOTATATE for use in PET/CT and 177Lu-DOTATATE for the treatment of SSR-positive NETs. Clinical trials with new theranostic compounds are ongoing for prostate cancer (PSMA), breast cancer (bombesin receptor), and small cell lung cancer (cytokine receptor CXCR4). Exciting future developments will undoubtedly involve development of radionuclide agents targeting additional cell surface receptors, enzymatic pathways, and clonal variations as well as combinations of alpha- and beta-emitters. Health care facilities worldwideare in the process of adding RT to their armamentarium for cancer patients; this requires a multidisciplinary team approach to optimize access to and delivery of care. To advance the science and enable translation of theranostics worldwide, the Gordon Research Conferences (GRC) organization [www.grc.org] has selected the authors to organize a 5-day inaugural meeting on Radionuclide Theranostics for the Management of Cancer in June 2020 [https://www.grc.org/radionuclide-theranostics-for-the-management-of-cancer-conference/2020/]that brings together cancer biologists, radiation physicists, receptor pharmacologists, nuclear medicine physicians, and industry representatives to 1) Identify new molecular targets and targeting vectors for specific malignancies; 2) Explore development of novel radionuclides and molecularly targeted radiopharmaceuticals; and 3) Optimize therapeutic benefits based on an understanding of radionuclide risks to normal tissues. This presentation will review the key topics discussed during this GRC meeting

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SUN-LB15 A Case of Familial Male-Limited Precocious Puberty With a Novel Mutation
Authors: Owens Lindsey L , Carakushansky Mauri , Gurnurkar Shilpa
Published: May 2020

Introduction:

Familial Male-Limited Precocious Puberty (FMPP), also known as testotoxicosis, is a rare cause of precocious puberty in males. It is caused by a mutation in the luteinizing hormone/chorionic gonadotropin receptor (LHCGR) gene, resulting in the receptor to be constitutively activated. This results in precocious puberty in males with rapid skeletal maturation and compromised final adult height if not treated. A combination on anti-androgens and aromatase inhibitors are the mainstay of treatment.

Case:

A 16-month-old male presented to our clinic due to concerns of precocious puberty. Pubic hair was noted at 6 months of age along with rapid growth acceleration. There was no known exposure to testosterone and no family history of early puberty or subnormal adult height. Upon presentation, his height was over the 99th percentile while his target height is at the 50th percentile. Physical examination revealed prepubertal testes with pubic hair at Tanner stage II. A bone age was reported as 12-18 months at a chronologic age of 12 months. Initial lab evaluation revealed normal serum levels of 17 OHP, androstenedione and DHEA-S with a slightly elevated serum LH (0.7mIU/ml), and very elevated serum testosterone level (289ng/dl). Leuprolide and ACTH stimulation tests as well as MRI of the abdomen and pelvis were normal. Serum levels of AFP, β-hCG and IGF-1 were also normal. Bone age advanced to 6 years at a chronological age of 21 months and to 8 years by 26 months of age. At 26 months of age, his stretched penile length measured 11cm. LH receptor testing was obtained, which revealed a novel heterozygous missense mutation in the LHCGR gene (c.1733A>C; p.Asp.578Ala). The mutation was reported to be a variant of unknown significance though likely in the pathological end of the spectrum by variant analysis with SIFT and PolyPhen. He was started on treatment with anastrozole 1 mg daily and bicalutamide 25 mg daily at 2 and 9/12 years of age. Pubertal progression, linear growth and skeletal maturation slowed down with treatment. His bone age remained stable at 13 years from the age of 2 and 10/12 years to 4 years old. Pubertal stage and stretched penile length have also remained stable on treatment. He is tolerating treatment well.

Conclusion:

We report a novel mutation in the LHCGR gene causing FMPP in a 6-month-old male who is responding very well to a combination of bicalutamide and anastrazole with marked decrease in growth velocity, pubertal progression and skeletal advancement.
SUN-LB91 The Arg16/Gln27 Polymorphism of the Beta2-Adrenergic Receptor Impacts Blood Pressure Levels in a Transgenic Mouse Model via Sex-Specific Mechanisms
Authors: Treesaranuwattana Thitinan , Williams Gordon H , Pojoga Luminita
Published: May 2020

Background : The β2-adrenergic receptor (β2-AR) has been implicated in blood pressure (BP) homeostasis via its effects on the sympathetic nervous system, cardiac function, peripheral vascular resistance, and renin release. We also have documented that a β2-AR diplotype (Arg16/Gln27), carried by 15% of hypertensives, have salt sensitive hypertension (SSBP) and increased aldosterone (ALDO).

Gap in knowledge: it has been reported that hypertensive men and women respond differently to beta blockers. However, information regarding sex differences in carriers of the β2-AR risk diplotype is limited.

Hypothesis : In mice, the phenotype in female carriers of the mutant β2-AR risk diplotype will differ from male carriers.

Methods: The CRISPR/Cas9 approach was used to generate transgenic mice carrying 0, 1 or 2 Arg16/Gln27 variant alleles (i.e. wild-type (WT), heterozygous (Het) or mutant (Mut)). The experimental design included twelve weeks old mice divided into 6 genotype/gender groups (male and female; WT, Het and Mut) maintained on low (0.03% Na+, LS) and high sodium diets (1.6% Na+, HS) for a week each.

Results: 1) Both male and female mice displayed significantly increased BP on LS and HS with increasing number of mutated alleles.

2) Only Mut females displayed SSBP (P<0.05).

3) As compared to WT, urine and plasma ALDO levels were lower in male (but not female) carriers of the mutated allele (P<0.05).

4) As anticipated, urine K+ excretion was significantly lower in the Mut male (but not female) mice (P<0.05).

5) Doppler ultrasound measurements of renovascular function shows that the resistive index was significantly lower in Mut vs WT males (P<0.05), consistent with an appropriate increase in renal blood flow (RBF) in the face of an elevated BP. However, in the Mut females the RBF was inappropriately decreased compared to the WT (P<0.05).

6) β2-AR expression was significantly lower in female vs. male WT mice; however, this difference was lost in the carriers of the mutated allele, as B2-AR expression levels were significantly higher in female carriers of the mutated allele, as compared to WT (P<0.05). Interestingly, the B2-AR genotype had no effect on the receptor expression levels in males.

Conclusion: Both male and female Mut animals have increased BP compared to WT mice, but the mechanisms underlying their increased BP differ by sex. Female Mut mice have SSBP, inappropriately non-suppressed ALDO and decreased RBF. Male Mut mice do not have SSBP and have appropriate ALDO and RBF response to the salt load.
SAT-LB99 Inflammation May Mediate Coronary Artery Disease in Women With Hypothalamic Hypoestrogenemia: Findings From the NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation (WISE)
Authors: Torbati Tina , Suppogu Nissi , Cook-Wiens Galen , Berga Sarah , Braunstein Glenn , Johnson Delia , Stanczyk Frank , Noel Bairey Merz C , Shufelt Chrisandra L
Published: May 2020

Background: Among premenopausal women presenting with ischemia, hypothalamic hypoestrogenemia (HHE) has been associated with angiographic coronary artery disease (CAD). Further, serum amyloid-alpha (SAA), a marker of systemic inflammation strongly predicts future adverse cardiovascular events. We sought to relate inflammatory markers to HHE and understand if inflammation mediates relations between HHE and CAD.

Methods: We assessed premenopausal women not on exogenous hormones undergoing coronary angiography for suspected ischemia. HHE was defined as estradiol<50 pg/ml, luteinizing hormone<10 IU/l and follicle stimulating hormone<10 IU/l. Serum inflammatory markers, reproductive hormones, and angiographic CAD were measured.

Results: Overall, 40 (31%) of the 127 women had HHE with similar age and body mass index compared to no HHE (p=0.48 and p=0.77, respectively). Women with HHE had lower estradiol compared to no HHE (30.4+11.7 vs 112.5+62.4 pg/ml, p<0.0001). There were no significant differences between high sensitivity C-reactive protein (hsCRP) (0.86 ± 1.45 vs 0.65 ± 1.17, p=0.5211) and interleukin 6 (IL-6) (4.95 ± 6.06 vs 3.90 ± 3.90, p=0.2358). However, HHE women had significantly higher SAA compared to no HHE (4.44+13.5 vs 0.94+2.37, p=0.0495).

Conclusion: Among premenopausal women undergoing coronary angiography for suspected myocardial ischemia, SAA levels were significantly elevated in women with HHE, suggesting that inflammation may serve as a mediator between HHE and CAD. Further investigation relative to inflammation as a treatment target in this cohort may be warranted.
SAT-LB302 From Urolithiasis to Genetic Testing: An Unusual Presentation of MEN-4 Syndrome
Authors: Alamri Bader Nasser , Palma Laura , Andonian Sero , Foulkes William D , Rivera Juan Andres
Published: May 2020

Background:Germline mutations in the CDKN1B gene are responsible for Multiple Endocrine Neoplasia Type 4 (MEN 4) syndrome (Alrezk et al. 2017). Around 20 cases have been reported to date. Here, we report on a new MEN4 family which possibly extends the phenotypic spectrum attributable to germline mutations in CDKN1B.

Clinical Case: A 56-year-old female presented with urolithiasis & was found to have hypercalcemia (serum calcium of 2.76 mmol/l ref. 2.12-2.62 mmol/l). Workup was in keeping with primary hyperparathyroidism (PHPT) (PTH 28.7 pmol/l ref. 1.50-9.30 pmol/l; phosphorus 0.89 mmol/l ref. 0.80-1.45 mmol/l). Sestamibi & US of the neck revealed no clear parathyroid adenoma. Two incidental thyroid nodules were benign on FNA cytology.

The patient underwent neck exploration & a single enlarged parathyroid gland was removed. Pathology showed an enlarged hypercellular gland. Her calcium & PTH normalized after surgery but recurrence was documented a year later. Her family history was significant for PHPT in two brothers & a history of kidney stones in a third brother. Multi-gene panel testing (CASR, CDC73, CDKN1B, MEN1, RET, Invitae Corp.) revealed a pathogenic variant (PV) in CDKN1B (c.215delG). The patient underwent a 2 ½ parathyroidectomy with subsequent normalization of her calcium & PTH. Further work-up showed a 4.5mm non-secreting pituitary adenoma. Plasma metanephrines & NE were intermittently elevated. Serum gastrin was also mildly elevated 83 pmol/l (<53 pmol/l). A Ga68-DOTATATE PET scan was negative. Her 23-year-old daughter tested positive for the familial PV. She is asymptomatic & has normal calcium & PTH; pituitary function is normal except for an elevated IGF-1 at 63.9 nmol/l (ref 13.3- 42.6 nmol/l) with borderline growth hormone during OGTT (0.40 ug/l). Her pituitary MRI was normal. One brother with history of prostate cancer, PHPT & partial parathyroidectomy has tested positive for the familial CDKN1B variant. A second brother was also found to carry the familial variant & was clinically asymptomatic.Endocrinological workup has revealed he has PHPT, elevated chromogranin A at 196.2 ng/ml (ref <=82), calcitonin at 25 ng/l (normal <=9 ng/l), IFG1 (35.3 nmol/L ref. 13-21) but normal plasma metanephrines. An MRI of the sella shows an 8mm hypoenhancing lesion. On CT, a retroperitoneal hyperenhancing 4cm mass adjacent to the left ilio-psoas was seen, in keeping with a paraganglioma; additionally, he has a congenital left atrophic kidney & ureter. Two additional brothers; one with history of non-Hodgkin’s lymphoma, PHPT & partial parathyroidectomy & a second brother, also with prostate cancer & recurrent renal stones, have yet to be tested.

Conclusions: A new MEN4 family is described here which expands the spectrum of clinical manifestations of this syndrome. Of great interest in our cases is the presence of paraganglioma, urological malformation, & pre-clinical GH/IGF1 elevation.