bluuebunny/crossref_metadata_2025 huggingface dataset:
MON-LB87 Recombinant Human TSH vs Thyroid Hormone Withdrawal Preparation for Radioiodine Ablation in Pediatric Differentiated Thyroid Cancer
Authors: Schumm Max A , Pyo Howard Q , Yeh Michael W , Kim Jiyoon , Tseng Chi-Hong , Leung Angela M , Chiu Harvey K
Published: May 2020

Introduction: Recombinant human TSH (rhTSH) is commonly used to prepare patients with differentiated thyroid cancer (DTC) for radioiodine (I-131) ablation after total thyroidectomy (TT). In adults, rhTSH is associated with equivalent oncologic efficacy and improved health-related quality of life in comparison to thyroid hormone withdrawal (THW). In this study, we aimed to measure disease-free survival after rhTSH stimulation vs. THW in pediatric patients with DTC. Methods: A prospective database was analyzed for pediatric patients under the age of 21 with DTC who underwent TT and I-131 ablation with rhTSH preparation at a single tertiary institution from 2012 through 2018. These patients were compared against historical controls prepared with THW. Tumor stage, I-131 treatment details, disease-free survival, structural recurrence, biochemical recurrence (defined as serum Tg > 2 at one year), and postoperative serum TSH, thyroglobulin (Tg) and Tg antibody levels were recorded. The log-rank test was used to compare groups, and time to recurrence was estimated by Kaplan-Meier analysis. Results: Seventeen patients who received rhTSH (mean age, 16.6±3.2 [SD] years) were compared to 28 historical controls prepared with THW. No differences were observed in RAI dose (mean 2.3±0.7 mCi/kg), tumor stage, or follow-up time (median [IQR] 2.6 [1.1-3.1] years) between groups. The THW group exhibited a nonsignificantly greater recurrence rate (14 [50%], 7 with biochemical recurrence and 7 with structural recurrence) than the rhTSH group (three [18%], 2 with biochemical recurrence and 1 with structural recurrence, p=0.2). A trend toward improved disease-free survival was identified in those treated with rhTSH compared to THW. Conclusion: In this cohort of pediatric patients with DTC, we observed a trend toward improved disease-free survival among those prepared with rhTSH compared to historical controls prepared with THW. Long-term follow up is needed to better characterize outcomes associated with rhTSH stimulation prior to I-131 ablation in the pediatric population.
MON-LB127 Pulmonary Embolism in the Setting of Diabetic Ketoacidosis. an Under-Recognized Complication
Authors: Ahmed Adeel Jabran , Ahmed Taha , Amir Maryam , Khabbaza Deena
Published: May 2020

The relation between Diabetic Ketoacidosis and Venous Thromboembolism is important to appreciate for early recognition and management. 90 year old female with Type 2 DM was brought to the ER after a syncopal episode. Family reported the patient to be lethargic with a decreased appetite for one week. On arrival, patient had a blood pressure of 84/44 mmHg. Oxygen saturation was 89% at room air and improved to 93% on supplemental O2. Patient was afebrile with a respiratory rate of 16 and heart rate 89/minute. On exam, she was dehydrated with decreased skin turgor, dry oral mucosa. Labs revealed blood glucose of 621 mg/dL, Bicarbonate 16 mmol/L, B-Hydroxybutyrate 5.00 mmol/L, Anion Gap 21, pH of 7.26 on ABG. Urinalysis was suggestive of a urinary tract infection. After initiation of IV antibiotics and insulin, she was transferred to the intensive care unit. In the ICU, her blood pressure failed to improve with fluid resuscitation, ultimately requiring vasopressors. Due to hypotension with hypoxia, CT Chest was performed which revealed extensive bilateral PE. She was started on IV heparin infusion. Pro-Brain Natriuretic Peptide was elevated at 4,716 pg/mL. Echocardiogram confirmed right heart strain with severely dilated right ventricle, positive McConnell’s sign, systolic and diastolic septal flattening and an estimated RSVP 67mmHg consistent with moderately severe pulmonary hypertension. Tissue plasminogen activator was recommended however given the patient’s age and functional status; family decided against systemic thrombolysis. Duplex ultrasound of her lower extremities also showed bilateral acute deep venous thrombosis. She was continued on intravenous anticoagulation and eventually was able to come off vasopressors. As the patient’s blood glucose levels improved and her anion gap closed, she was transitioned to basal/bolus insulin and transferred to the general medical floor. She was started on Apixaban and discharged home per family’s request after her code status was changed to DNR-Comfort Care Arrest.Pulmonary embolism is a serious venous thromboembolic event that is rarely reported in association with DKA. Proposed mechanisms include some of the same mechanisms implicated in arterial thrombosis, namely abnormalities in coagulation factors, increased platelet aggregation, impaired fibrinolysis and endothelial injury due to hypertonicity. Also, severe dehydration associated with DKA may contribute by virtue of increased red blood cell rigidity and increased blood viscosity establishing DKA as an underlying cause or contributing factor of pulmonary thromboembolism2.1 Langevin C et al Presumed paradoxical embolus in a patient with diabetic ketoacidosis Int J Gen Med 2015;8:297–301 2015 Sep 18

2 Scordi Bello I et al Fatal Pulmonary Thromboembolism in Patients with Diabetic Ketoacidosis A Seven-Case Series and Review of the Literature Acad Forensic Pathol 2016;6(2):198–205
SUN-LB84 Riedel’s Thyroiditis: A Diagnostic and Therapeutic Challenge
Authors: Sliwinska Aleksandra , Jalil Fatima , Millar Danielle , Malchoff Carl D
Published: May 2020

Background: Riedel’s thyroiditis is a rare thyroid pathology which presents a challenge for clinicians to diagnose and treat. Etiology remains largely unknown, although data suggests an association with Hashimoto thyroiditis, systemic fibrosis, and IgG-4 related systemic disease. Presentation of Riedel’s thyroiditis can mimic malignant thyroid neoplasm, lymphoma, or a fibrous variant of Hashimoto thyroiditis. Due to its rarity, there is no consensus on the treatment. Clinical case: A 36-year old woman presented with a two-month history of gradually progressing neck swelling. She developed associated neck pain, decreased range of motion, hoarseness, and dysphagia, without difficulty breathing. One year prior to presentation, she had been diagnosed with hypothyroidism. She did not have a family or personal history of thyroid malignancy, however, she lived near Chernobyl during her childhood. On exam, the anterior and lateral neck was hard and enlarged, but nontender. The neck range of motion was diminished. The initial ultrasound of the thyroid demonstrated asymmetrically enlarged heterogenous diffusely nodular right thyroid and isthmus measuring 1.9cm. A CT of the chest with contrast showed diffusely enlarged thyroid extending superiorly beyond the image with mild tracheal displacement. Initial laboratory results included TSH of 17.40 uU/ml (ref: 0.35-4.94 uU/ml), free T4 of 1.06 ng/dl (ref: 0.61-1.82 ng/dl). She had a significantly increased thyroid autoantibodies (Anti-TPO >700 IU/ml with ref: 0.0-9.0 IU/ml, Anti-TG >2000 IU/ml with ref: 0.0-4.0 IU/ml). PTH and calcium were normal, and calcitonin was low. In the interim, the patient was evaluated by ENT without evidence of airway compromise. She underwent a core biopsy of the right thyroid lobe which demonstrated dense fibrous connective tissue mixed with mature lymphocytes. Pathology and immunostaining results were suggestive of Riedel’s thyroiditis. The patient was started on prednisone 60mg daily, which she tolerated for 6 weeks. Due to side effects, prednisone dose was titrated down and tamoxifen was added. Over the following 6 months, compressive symptoms resolved, and the ultrasound showed a significant decrease in the thyroid size. TSH normalized with thyroid hormone replacement. To date, she is asymptomatic and continues on tamoxifen and low dose prednisone without evidence of progression. Conclusion: Riedel’s thyroiditis is a rare condition that can progress into a medical emergency and should be suspected in patients presenting with a thyroid mass. Clinical awareness of Riedel’s symptomatology and laboratory findings should enhance our ability to distinguish and make the diagnosis. Instituting effective treatment that results in the improvement of symptoms and reduction in thyroid size can be challenging due to possible poor response or development of side effects.
SUN-LB54 Nutritionally-Induced Alteration in KNDy Neuronal Expression in the Arcuate Nucleus of Ewes
Authors: Prezotto Ligia D , Lents Clay A , Redmer Dale A , Grazul-Bilska Anna T , Thorson Jennifer F
Published: May 2020

Kisspeptin, neurokinin B, and dynorphin are imperative for GnRH/LH pulsatility and reproductive cyclicity. Neurons co-expressing these neuropeptides, KNDy neurons, within the arcuate nucleus of the hypothalamus (ARC) are positioned to integrate energy balance signals from neuronal and glial cells. Energy balance mediates neurokinin B expression in the ARC and LH pulse amplitude. Dynorphin mediates progesterone negative feedback on GnRH neurons. The hypothesis that the number of KNDy-expressing neurons in the ARC of ewes during the luteal phase of the estrous cycle is influenced by energy balance was tested using ovary-intact, mature ewes fed to lose, maintain, or gain body weight. Fluorescent multiplex immunohistochemistry was employed to identify and quantify neurons expressing a single neuropeptide and co-expressing kisspeptin, neurokinin B, and dynorphin in the ARC. Kaminski et al. (1) reported previously that concentrations of insulin and leptin differed between ewes fed to achieve different body weights and that ewes fed to gain body weight had increased concentrations of progesterone in the luteal phase of the estrous cycle. Moreover, tanycyte density and cellular penetration into the ARC are increased in ewes fed to gain body weight (2). Number of neurons in the ARC expressing kisspeptin (14.9 ± 2.7 neurons, 20.9 ± 3.6 neurons, and 51.5 ± 3.3 neurons in ewes fed to lose, maintain, and gain body weight, respectively), neurokinin B (21.5 ± 3.2 neurons, 31.3 ± 4.3 neurons, and 56.0 ± 3.9 neurons in ewes fed to lose, maintain, and gain body weight, respectively), and dynorphin (10.1 ± 2.4 neurons, 14.9 ± 3.2 neurons, and 33.1 ± 2.9 neurons in ewes fed to lose, maintain, and gain body weight, respectively) protein was increased (P < 0.0001) in ewes fed to gain body weight. Number of KNDy neurons in the ARC expressing kisspeptin, neurokinin B, and dynorphin protein was decreased in ewes fed to lose body weight (1.0 ± 0.5 neurons; P = 0.01) and increased in ewes fed to gain body weight (6.7 ± 0.6 neurons; P = 0.0005) when compared to ewes fed to maintain body weight (3.3 ± 0.7 neurons). These findings suggest that expression of kisspeptin, neurokinin B, and dynorphin protein in the ARC during the luteal phase of the estrous cycle may be influenced by nutritionally-induced alterations in circulating concentrations of progesterone that drive changes in morphology and density of tanycytes. Moreover, these results demonstrate that changes in KNDy neurons within the ARC occur as an adaptation to energy balance, potentially regulated divergently by metabolic milieu.

References: (1) Kaminski et al., Theriogenology. 2015 83:808-16. (2) Prezotto et al., Domestic Animal Endocrinology. 2020 Accepted.
SUN-LB9 Pharmacokinetics of Sublingual Versus Oral Estradiol in Transgender Women
Authors: Doll Elizabeth E , Gunsolus Ian , Lamberton Nathan , Tangpricha Vin , Sarvaideo Jenna Lynne
Published: May 2020

Sublingual administration of estradiol (E2) may be a safer and more effective hormone replacement therapy (HRT) route than oral estradiol, the most commonly used formulation, but it has yet to be investigated in transgender women. Unlike oral E2, sublingual E2 is thought to bypass the first pass effect by the liver, making it less likely to impact hepatic clotting factor synthesis, and thus decreasing the risk of thromboembolic events posed by oral administration, such as VTE and ischemic stroke (1). Additionally, studies in cisgender women have demonstrated a 13-fold higher peak serum concentration and a decreased estrone (E1) to estradiol ratio with sublingual administration, suggesting that sublingual E2 is more a physiologically potent route (2). To advance the understanding of sublingual E2 as an alternative method of administration in transgender HRT, we investigated the pharmacokinetics of estradiol when administered orally versus sublingually in transgender women. Ten transgender women naïve to estrogen were provided 1.0 mg of oral estradiol. Blood samples were collected via percutaneous intravenous catheter at baseline and at T=1,2,3,4,6, and 8 hours post-dosing. After a 7-day washout period, 1.0 mg of sublingual estradiol was dosed with identical sampling over time. Analysis of serum samples was performed using LC-MS/MS and estradiol immunoassay. Initial results demonstrate a higher peak serum concentration within 8 hours with sublingual dosing in both LC-MS/MS and immunoassay quantification (178±47 and 150±31 pg/mL, respectively) compared to oral administration (36±5 and 35±4 pg/mL, respectively; N=5). Peak concentration was reached at T=1 hour for sublingual E2 in both LC-MS/MS and immunoassay analysis, whereas oral E2 reached peak serum concentration at T=8 hours in LC-MS/MS analysis and T=6 hours in immunoassay analysis. Sublingual E2 still maintained higher overall mean concentrations of estradiol across the 8 hours compared to oral E2. Importantly, subjects reported high satisfaction with sublingual administration due to rapid dissolution (<2 minutes) and minimal taste; as a result, subjects predicted high ease of adherence in future HRT, which indicates the feasibility of sublingual E2 as an alternative to oral E2. Additional analysis of half-life and oral clearance will be performed at the completion of the study, in order to further establish pharmacokinetic differences and potency between the two routes. This pharmacokinetic data will allow future studies on optimal dosing, safety, and efficacy compared to oral estradiol in hormone replacement therapy. (1) Hembree et al. J Clin Endocrinol Metab. 2017;102(11):3869-3903. (2) Price et al., Obstet Gynecol. 1997.
SUN-LB36 Primary Aldosteronism Due Tosimultaneous Occurrence of Aldosteronoma in the Left Adrenal Gland and Ectopicaldosteronoma in the Liver: A Case Report
Authors: He Xiaoying , Huang Zhimin , Ke Weijian , Li Yanbing
Published: May 2020

Rationale: Ectopic adrenal tissue is the adrenal rests along the path from gonads to adrenal glands during embryogenesis. Ectopic aldosteronoma is a rare disease presented with over-production of aldosterone by the ectopic adrenocortical tissue. Diagnosis is a clinical challenge with simultaneous occurrence of ectopic aldosteronoma. To our knowledge this is the first reported case of simultaneous occurrence of aldosteronoma in the adrenal gland and ectopic aldosteronoma in the liver based on literatures. Patient concerns: A 33-year-old woman presented with resistant hypertension and severe hypokalemea for 3 years. 5 months ago, the patient was diagnosed as aldosteronoma in left adrenal gland and underwent right adrenalectomy. The histopathological examination of the resected sample suggested adrenal cortical adenoma. The patient still had symptoms of hypertension and hypokalemia after operation, but the blood potassium level was higher than that before operation (minimum blood potassium level rose from 1.8 mmol/L to 2.6 mmol/L). Diagnosis: The saline load test, captopril test, and plasma aldosterone/renin ratio were indicative of primary aldosteronism (PA). The computed tomographic scan (CT) was suggestive of a low-density mass (2.9×2.2 cm) in the liver which was very near to the right adrenal area. Magnetic resonance imaging (MRI) further confirmed that the lesion was located in the liver. PET-CT eliminated the possibility of metastasis to other parts of the body. Ultrasound guided biopsy confirmed that the tumor was ectopic adrenal tissue in the liver. Interventions: Ultrasound-guided percutaneous radiofrequency ablation was performed to the tumor in the liver.Outcomes: The patient’s blood potassium level was 3.8 mmol/L on the third day after the ablation without any potassium supplementation treatments. On follow-up of 2-weeks duration, the patient has g good control over her blood pressure of around 126/74 mmHg and blood potassium of 4.55 mmol/L, without taking any medications. Lessons: The patient was diagnosed with PA due to simultaneous occurrence of aldosteronoma in the left adrenal gland and ectopic aldosteronoma in the liver, which is very rare. Ultrasound-Guided Percutaneous Radiofrequency Ablation is a safe and effective treatment for ectopic aldosteronoma in liver.
MON-LB123 Diagnosis and Management of Euglycemic DKA in the Setting of SGLT2 Inhibitor Use and Prostate Abscess
Authors: Rameshkumar Naveen Sundar
Published: May 2020

Introduction: SGLT2i has been associated with euglycemic DKA by increasing lipid oxidation and glucagon synthesis. In the event of an underlying infection, increased ketogenesis could lead to the presentation of DKA. Clinical case: A 35 year old male patient who was recently diagnosed with type 2 Diabetes mellitus after he presented to his primary care physician with increased urinary frequency, frothy urine. He was found to have a hemoglobin A1c of 12.5% and blood glucose 408 mg/dl. Urinalysis was negative for nitrites and leukocyte esterase. Patient endorsed to have one sexual partner and safe sexual practices. Urinary gonorrhea and chlamydia antigens were negative. He was diagnosed with diabetes mellitus and was started on ertugliflozin, exenatide and bactrim for possible UTI. Three days later, the patient presented to the ED with dysuria, polyuria, rectal pain, nausea and fatigue. Patient appeared to be in distress with tachypnea and tachycardia. Physical exam showed signs of dehydration. Laboratory evaluation revealed blood glucose at 185 mg/dL. Given the history of recent diagnosis of diabetes mellitus and SGLT2 inhibitor use, euglycemic DKA was suspected. ABG revealed metabolic acidosis (arterial blood gas pH 7.32, pCo2 20, pO2 130) with elevated anion gap of 24, HCO3 level of 10 mmol/L (reference range 22 - 28 mmol/L) and beta-hydroxybutyrate of 5.7 mmol/L (reference range 0 - 0.3 mmol/L). The lactate levels were normal. Wbc count 20,100. Urinalysis showed glucose 4+, ketones 4+, WBC 4, negative for infection. Computed tomography scan of his abdomen and pelvis with contrast showed 3.7 x 2.7 cm prostate abscess and acute cystitis. Patient was treated for euglycemic DKA with infusion of insulin and dextrose 10% with 0.45% NS. Careful monitoring of his blood sugar was required as it dropped with slight increase in infusion rate. He was started on ciprofloxacin for prostate abscess. Patient’s metabolic acidosis resolved and he showed clinical improvement. Endocrinologist was on consult. Patient was switched to insulin regimen for glycemic control. Conclusion: SGLT2i class of drugs has been increasingly used in the treatment of diabetes due to improved cardiovascular outcomes and renal protective effects. However, diagnosing DKA can be a concern while treating patients with this drug. While the SGLT2i is responsible for his euglycemic presentation, DKA was likely triggered by his prostate abscess. They can be used safely with extensive education to the physicians about euglycemic DKA presentation. Management requires starting D10 infusion along with insulin drip to avoid the risk of hypoglycemia.
SAT-LB82 Myxedema as Presenting Feature of Profound Primary Hypothyroidism in a Toddler
Authors: Alradadi Rasha , Eugster Erica A
Published: May 2020

Background: Myxedema is a rare presenting feature of profound primary hypothyroidism that results from disordered accumulation of glycosaminoglycan in the skin and soft tissue. Very few cases of myxedema have been reported in children during the first few years of life.

Clinical Case: A 2-year-old boy with a history of lissencephaly and developmental delay was sent to the emergency room by his primary care physician for worsening of edema. It was noticed by his mother six weeks previously and involved his face, arms, feet and legs. He had no history of cold intolerance, dry skin, hair loss, constipation, or excessive sleep. On exam, he had normal vital signs with no bradycardia and normal blood pressure. Physical exam was remarkable for a sallow complexion, coarse facial features, abdominal distention and non-pitting edema of the face, limbs, hands and feet. A cardiac echo revealed mild pericardial effusion and borderline QT prolongation was noted on EKG. Chest x-ray and abdominal x-ray were unremarkable. Metabolic profile showed normal electrolytes, a mildly low albumin of 2.8 gm/dl and normal renal and liver function. Thyroid function tests were remarkable for an elevated TSH of 562 mcu/ml and a low FT4 of 0.3 ng/dl. TPO and anti-thyroglobulin antibodies were negative. Thyroid ultrasound demonstrated a small thyroid gland in the normal location. Growth data revealed a normal linear growth velocity and weight persistently above the 25th percentile. The child’s newborn screen for congenital hypothyroidism had been normal. He was started on levothyroxine 50 mcg PO per day.

Conclusion: We report an extremely atypical presentation of primary hypothyroidism in a two-year-old boy. He presented with myxedema, pericardial effusions, severe biochemical hypothyroidism and negative thyroid antibodies. The precise etiology and duration of his hypothyroidism, as well as its role in his developmental delay, remain enigmatic. Awareness of unusual presenting features in very young children with hypothyroidism is essential in order to achieve expedient treatment and optimal neurocognitive outcomes.
SUN-LB55 Connect-seq to Superimpose Molecular on Anatomical Neural Circuit Maps
Authors: Hanchate Naresh , Lee Eun Jeong , Ellis Andria , Kondoh Kunio , Kuang Donghui , Basom Ryan , Trapnell Cole , Buck Linda
Published: May 2020

Animals exhibit instinctive behavioral and physiological responses to a variety of stressors to overcome danger and restore homeostasis. The physiological response to stress is governed by hypothalamic corticotropin-releasing hormone (CRH) neurons which regulate the hypothalamic-pituitary-adrenal axis to control blood levels of stress hormones. At present, the neural circuits and signaling mechanisms through which different stress signals are transmitted to CRH neurons are poorly understood. Here, we devised a new method, termed “Connect-Seq,” which couples single-cell transcriptomics and retrograde viral tracing to define the molecular identities of individual neurons in neural circuits. As a proof of concept, using Connect-Seq, we profiled single-cell transcriptomes of 124 brain neurons upstream of CRH neurons and identified subpopulations that are likely to communicate stress-related signals to CRH neurons. Analyses of single-cell transcriptomes for ‘fast-acting’ neurotransmitters revealed subsets of upstream neurons that expressed markers of inhibitory GABAergic neurons or excitatory glutamatergic neurons. Further analyses showed a number of other neuromodulators/neurotransmitters in upstream neurons, including acetylcholine, dopamine, histamine, and 43 different neuropeptides, each expressed in individual neurons or subsets of neurons. These findings reveal extreme molecular heterogeneity among upstream neurons and suggest the upstream neurons use diverse neurochemical messengers to transmit signals to CRH neurons. Many neurons coexpressed different neurotransmitters/neuromodulators, suggesting the co-release of neurochemical messengers. Dual labeling of brain sections verified expression of specific neuromodulators in virus-infected neurons upstream of CRH neurons in selected brain areas. Our results indicate that Connect-Seq can be applied to genetically dissect neural circuits and uncover molecular identities of neurons upstream of specific neuronal types of known function. Molecular markers identified in those neurons lay a foundation for the application of cell-specific genetic tools to investigate the functions and physiological significance of diverse neuronal subsets within complex neural circuits.
SUN-LB57 Assessing the Requirement of Arcuate Nucleus Kisspeptin Neurons in Puberty Onset and Adult LH Secretion
Authors: Coutinho Eulalia A , Esparza Lourdes A , Bolleddu Shreyana , Kauffman Alexander S
Published: May 2020

Puberty is a critical developmental period marking the transition to adulthood and attainment of reproductive capability. A hallmark of puberty is increased pulsatile secretion of pituitary luteinizing hormone (LH) which is itself driven by increased gonadotropin-releasing hormone (GnRH) from the forebrain. The mechanisms governing GnRH neuron activation at puberty still remain unclear, but likely include enhanced stimulation from upstream reproductive neural circuits, including kisspeptin neurons. Kisspeptin is a potent stimulator of GnRH and is required for proper puberty onset. However, the specific brain site(s) from where kisspeptin signaling arises to trigger puberty remain unclarified. Kisspeptin is expressed in two primary nuclei in the hypothalamus, the arcuate nucleus (ARC) and anteroventral periventricular (AVPV) region. Studies suggest that, in adulthood, ARC Kiss1 neurons are involved in driving pulsatile secretion of GnRH (and hence, LH) in both sexes whereas AVPV Kiss1 neurons participate in the preovulatory GnRH/LH surge in females. However, the specific role of either kisspeptin neuron population in puberty onset still remains unknown. We previously showed that both kisspeptin populations show increased Kiss1 gene expression across the pubertal period, yet whether just one or both (or neither) population is needed for puberty to occur has not been determined. Here, we sought to tease out the role—if any—of ARC and AVPV Kiss1 neurons in the pubertal onset process. Since ARC Kiss1 neurons are abundant in both sexes and drive pulsatile GnRH secretion in adulthood, we hypothesized that ARC Kiss1 neurons are necessary for normal puberty onset and, conversely, that AVPV Kiss1 neurons are not sufficient on their own to induce normal puberty. To test this hypothesis, we used a Cre-specific diphtheria toxin approach to ablate just ARC Kiss1 neurons in juvenile mice (~ 2 weeks old) while leaving AVPV Kiss1 neurons intact. Preliminary data thus far indicates that site specific ablation of just ARC Kiss1 neurons during the juvenile period significantly delays puberty onset in both sexes, as measured by vaginal opening, first estrous, and preputial separation. In addition, selective ARC Kiss1 neuron ablation in juvenile life diminishes pulsatile LH secretion levels measured in adulthood, but does not alter LH surge generation in adult females. These preliminary findings empirically demonstrate that, in mice, ARC Kiss1 neurons are required for proper activation of the reproductive axis during puberty but not the LH surge in adulthood, and AVPV Kiss1 neurons are not sufficient to trigger normal pubertal onset.
SAT-LB50 Fahr’s Syndrome: A Rare Neurological Disorder Unmasked by a Psychiatric Illness
Authors: Figueroa Arnaldo Rojas , Garcia Michelle Marie Mangual , Torres Marina Torres
Published: May 2020

Fahr’s syndrome is a rare familial disorder characterized by abnormal accumulation of calcium deposits bilaterally at basal ganglia. It commonly affects middle-aged adults and presents with a range of neuropsychiatric symptoms. The exact prevalence of Fahr’s syndrome is uncertain; however, intracranial calcifications suggestive of this disorder are detected incidentally in approximately 0.3 % to 1.2 % of CT imaging of the brain with a prevalence of 1/1,000,000. It may be idiopathic or secondary to numerous causes dominated by phosphorous and calcium disorders, with the most common etiology being hypoparathyroidism. We report the case of a 27 years old female patient with a medical history of insulin-dependent Diabetes Mellitus type 1, Bipolar disorder, Autoimmune Polyglandular Syndrome Type 1, Thalassemia major, Primary Hypoparathyroidism and Bronchial Asthma who was admitted to the hospital after presenting an episode of dizziness, slurred speech and involuntary movements associated to hypoglycemia. The patient had a medical history of recurrent episodes of conscious self-induced hypoglycemia with double doses of insulin therapy and noncompliance with home medications. Upon evaluation, patient presents aggressive and defiant behavior. Physical and neurological examination was difficult to assess since she refused to be examined. Laboratories were remarkable for serum calcium of 6.2mg/dl, albumin of 3.5g/dl, with corrected calcium levels of 6.5mg/dl, suggestive of severe hypercalcemia. Head CT scan showed bilateral subcortical, basal ganglia clouded, thalamic, and cerebellar calcifications with preserved gray and white matter differentiation. Treatment was tailored to symptoms control and correction of underlying abnormalities. These case present the most critical features of the diagnostic criteria of Fahr’s syndrome. Pathologically, calcifications occur in the vascular walls and in the perivascular spaces of arterioles, capillaries, and veins. Clinical findings of Fahr’s syndrome vary from neurological disorder to those mimicking Bipolar disorder. In this case, there were no neurological symptoms, and this patient only presented with psychiatric manifestations suggestive of bipolar disorder. For any psychiatric condition, it is essential to rule out organic brain disorders before labeling a patient, especially one who is young and has multiple endocrinopathies which could be associated with this rare condition.
SAT-LB61 METTL3 Promotes Sparsely Granulated GH-Secreting Pituitary Adenomas to Behavior as Densely Granulated Adenomas
Authors: Jiang Xiaobing , bian piaopiao , zhang weiyu
Published: May 2020

Background: Growth hormone (GH)-secreting pituitary adenomas can be divided into densely and sparsely granulated subtypes, based on electron microscopic studies. The latter are frequently associated with more invasive behavior, and respond worse to somatostatin analogues. The underlining mechanisms are largely unknown. Increasing evidence showed that N6-methyladenosine (m6A) of messenger RNAs (mRNAs) participated in the development of various tumors. We aimed to investigate the role of RNA m6A modification in the classification of GH-secreting pituitary adenomas. Methods: The main components of m6A methyltransferase complex, demethylase, and RNA m6A levels were compared between sparsely and densely GH-secreting tumors. The role of METTL3 was functionally studied. Results: The level of m6A methyltransferases (METTL3, WTAP and METTL14) and demethylase (FTO and ALKBH5) were significantly downregulated in GH adenomas, comparing to the normal pituitary tissues. However, only METTL3 and METTL14 were shown to significantly higher in densely granulated tumors than those in sparsely ones. Consistently, the level of RNA m6A was markedly increased in densely granulated GH adenomas. In addition, the expression of METTL3 was positively correlated with the level of RNA m6A among tumor samples, and METTL3 silencing decreased RNA m6A of GH3 cells. METTL3 was demonstrated to function as a tumor suppressor based on in vivo and in vitro evidence, using patient-derived and GH3 cells. Moreover, the sensitivity of GH3 cells to pasireotide was increased with METTL3 overexpression, but decreased when METTL3 was silenced. Consistently, METTL3 silencing inhibited GH secretory, and decreased the expression of SSTR2 and SSTR5. Conclusions: METTL3 functions as a tumor suppressor in GH secreting adenomas, and enhance tumor cells sensitivity to medical treatment. Our work uncovers the critical roles of METTL3 in the pathogenesis of GH adenomas, since it potentially promotes the transition from sparsely to densely granulated subtypes.
SAT-LB23 Paraneoplastic Hypercalcemia in a PTH Producing Adrenocortical Carcinoma - a Rare and Deadly Condition
Authors: Gruber Sven , Tang Cong , Berber Mesut , Fischli Stefan , Penton-Ribas David , Mihic-Probst Daniela , Beuschlein Felix
Published: May 2020

Background: Hypercalcemia is a commonly encountered paraneoplastic manifestation of certain cancers with or without endocrine differentiation. However, the association between adrenocortical carcinoma (ACC) with paraneoplastic hypercalcemia is very rare, and therefore little is known about the cause and its relevance in the disease. Clinical Case: A 40-year-old woman presented in the hospital with a 5-month history of progressive flank pain with unintentional weight loss of 6 kg. MRI revealed a mass of 9x8.1x4.8 cm of the right adrenal gland with inhomogeneous contrast enhancement. Biochemical investigations provided evidence of endogenous hypercortisolism (24-hour urinary cortisol excretion [490 µg, n<236 µg/l], 1mg dexamethasone suppression test [199 nmol/l, n<50 nmol/l], ACTH [28 ng/l, n<61 ng/l]) although the patient did not show any specific clinical sign of overt hypercortisolism. In addition, laboratory testing revealed an exceptionally high plasma level of calcium [max 3.67 mmol/l (albumin-corrected)] and low phosphate [min 0.26 mmol/l] in the setting of low PTH [6.4 ng/l, n>15 ng/l] and PTHrP levels [<0.50 pmol/l]. However, subsequent dilution unmasked a highly elevated PTH concentration of 2171.5 ng/l with persistent low PTHrP levels, indicating false low values due to a hook effect in the initial measurement. Levels of 1,25-dihydroxy vitamin D and 25-hydroxy vitamin D were in the normal range. A PET-CT provided no indications of metabolically active (osseous) metastases. After correction of the serum calcium towards tolerable values, the tumor was removed by open en bloc adrenalectomy. Histologic evaluation confirmed an ACC (TNM pT4 pN1 (2/3), L1, V1, high grade) despite missing immunohistochemically expression of classical adrenal markers (diagnosis of exclusion). Supplemental quantitative RT-PCR studies support the diagnosis of ACC by detecting significant SF-1 and CYP11B2 expression in the tumor cells. Further analyses provided evidence that the mRNA expression of PTH, but not PTHrP, was moderately increased in the ACC sample compared to NCI H295R cells. Upon tumor resection, serum calcium levels swiftly normalized indicating the tumor as the sole source of PTH secretion. Despite initiation of adjuvant mitotane- and salvage chemo-therapy, the patient died 3 months later upon of a massive tumor relapse with a recurrence of severe hypercalcemia. Conclusion: This case demonstrates paraneoplastic hypercalcemia in a PTH producing ACC. PTH may induce hypercalcemia, impair adrenal steroid synthesis and act as an autocrine growth factor in ACC, as described in few individual cases for PTHrp producing ACC [1]. This suggests a poor prognosis for this rare entity.

1. Rizk-Rabin, M., et al., Differential Expression of Parathyroid Hormone-Related Protein in Adrenocortical Tumors: Autocrine/Paracrine Effects on the Growth and Signaling Pathways in H295R Cells. 2008.
MON-LB51 Stimulation for Bilateral Inferior Petrosal Sinus Sampling May Be Unnecessary for Diagnosis of ACTH Dependent Cushing Syndrome
Authors: Builes-barrera Carlos Alfonso , Roman-Gonzalez Alejandro , Villada Oscar A , Escudero Pablo
Published: May 2020

Introduction: Bilateral inferior petrosal sinus sampling (BIPSS) is the gold standard test to differentiate Cushing’s disease (CD) and ectopic ACTH syndrome (EAS). Stimulation test for diagnosis may be unnecessary in some cases and the diagnostic yield of the stimulation test may be similar to the basal measurement. Methods: 34 adult patients referred for diagnosis of ACTH dependent Cushing syndrome. Basal simples for prolactin and ACTH were taken from bilateral inferior petrosal sinus and from peripheral vein. Stimulation test with desmopressin (32 subject) or CRH (2 subjects) was performed. Samples were taken at 0, 3, 5 and 10 minutes. To compare the percentage of diagnosis with each measurement the MacNemar test was done. Results: Right basal ACTH was 465 pg./ml (ICR 62-1250), ACTH at 3 minutes was 647 (ICR 227-2610), ACTH at 5 minutes was 1250 (ICR 245-1965), ACTH at 10 minutes was 230 (71-550). Left basal ACTH was 230 (71-550), at 3 minutes was 453 (ICR 116-1250), at 5 minutes was 431 (91-1250), at 10 minutes was 534 (140-1250). Median basal ACTH ratio was 13.8 (ICR 5.1-26), at 3 minutes was 34.5 (ICR 13-82), at 5 minutes was 30.6 (11.4-49.8), at 10 minutes was 18.5 (8.2-48.2). The higher ratio was at 3 minutes. Basal ACTH ratio was <2 in only 4 cases. 2 out of 4 cases had ratio >3 after stimulation test. CD was diagnosed with basal ratio in 88.6% of cases, and at 3, 5 and 10 minutes in 94.3% of cases. There was no difference in percentage of CD diagnosis at 3, 5 or 10 minutes (p=1.0). Discussion: Basal ACTH ratio was able to differentiate CD from ECS in most cases (88.6%). At least one additional sample with CRH or desmopressin stimuli identify 94.3% of CD cases with the higher increases at 3 minutes. Additional stimuli do not improve overall diagnosis, therefore, a basal ratio and additional stimulation test at 3 minutes is enough for CD diagnosis. This may decrease the cost of BIPSS and total duration of the procedure.
SAT-LB57 The Spectrum of Genomic and Transcriptomic Alterations in ACTH-Producing and ACTH-Silent Corticotroph Adenomas
Authors: Lerario Antonio Marcondes , Meredith David , Castlen Joseph , Johnson Lauren M , Catalino Michael , Carroll Rona S , Pallais J Carl , Kaiser Ursula B , Bi Wenya Linda , Laws Edward Raymond , Abreu Ana Paula
Published: May 2020

Corticotroph adenomas (CA) are rare pituitary tumors that impose several challenges in clinical management - CA are difficult to diagnose, often recur, and are associated with high morbidity and mortality. CA are characteristically Tpit-positive and PIT1-negative and comprise ACTH-producing (Cushing’s disease (CD)) and ACTH-silent (AS) classes. The molecular programs contributing to disease pathogenesis in CA are still poorly characterized, largely restricted to the identification of somatic mutations in USP8 in 40-60% of CD adenomas. To more fully characterize the mutational and transcriptional landscape driving both classes of CA, we performed whole-exome sequencing and RNA-seq in 19 CD and 16 AS adenomas. We identified USP8 mutations in 53% of CD (10/19) and 6% of AS (1/16) samples. Strikingly, in 19% of AS tumors (3/16), all exhibiting an unusually aggressive disease course, including two cases with brain metastases, we identified recurrent somatic pathogenic mutations in TP53 and novel loss-of-function mutations in telomere maintenance genes DAXX and ATRX. Furthermore, while all tumors with USP8 mutations (regardless of CD/AS status) exhibited no chromosomal abnormalities as measured by copy-number variation (CNV) and loss of heterozygosity (LOH) analysis, 33% of CD (4/12, including 1 tumor with a DAXX mutation) and 36% of AS (4/11, including all DAXX/ATRX-mutated cases) samples exhibited profound chromosomal instability, characterized by hyperdiploidy, widespread whole-chromosome LOH events, and arm-level breakpoints. Using transcriptome analysis (n=22), we identified three classes of tumors (C1-C3), reflecting these distinct somatic alteration profiles. C1 tumors (n=6) are characterized by chromosomal stability, includes exclusively USP8-mutated CD, and exhibits upregulation of genes involved in metabolic processes and protein acetylation. C2 tumors (n=10) are comprised exclusively of AS (including all TP53- and/or DAXX/ATRX-mutated cases), are characterized by chromosomal instability, and exhibits concordant upregulation of cell cycle programs. Finally, C3 (n=6) contains a mixture of AS and CD cases (including CD without mutations in USP8) and features an expression profile that partly overlap with C1 tumors, but also exhibit higher expression of inflammatory genes. Taken together, our data suggest that CD and AS are distinct molecular subtypes of CA, highlighting the dominant role of USP8 mutations in driving a unique transcriptional program and illustrate for the first time that unlike most cases of CD, AS cases are characterized by profound genomic instability and cell cycle activation, features associated with a more aggressive disease course.
SUN-LB67 Revisit Serum Calcium Correction
Authors: Li Yulong , Zhu JunJia , Blau Jenny , Simonds William F
Published: May 2020

Context: The serum calcium level is one of most routinely ordered tests in clinical practice. Many factors can affect calcium level and its interpretation. There are challenges and barriers in applying calcium correction formulas to every-day practice. Objective: Revisit correlation between total and ionized calcium levels, and dependence of serum calcium on albumin, pH and creatinine levels. Methods: This study included 1537 subjects enrolled in a parathyroid disease clinical protocol. We examined calcium and relevant biochemistry tests collected simultaneously and repetitively over consecutive years. Histograms, repeated measures correlation, correlation plots, and liner regression plots were used to analyze and visualize the data. Results: We found that: 1) directly measured total serum calcium and ionized calcium had excellent correlation and dependence with p-value=2.2e-16, repeated measures correlation coefficient (rmcorr)=0.919, and 95% interval (CI) = 0.916 to 0.922; 2) there was a low dependence between total serum calcium and albumin levels (rmcorr=0.454, 95% CI=0.433 to 0.474), a low dependence between ionized calcium and pH levels (rmcorr=-0.309, 95% CI= -0.326 to -0.292), and no dependence between total calcium and creatinine levels (rmcorr=0.026 95% CI=0.012 to 0.040); 3) using the commonly applied correction formulas, to either adjust total calcium based on albumin levels or else adjust ionized calcium based on pH levels, did not improve dependence among them. Conclusions: We therefore suggest using directly measured total serum calcium and/or ionized calcium level to assess clinical calcium status in general patients tested for parathyroid related disorders.
SAT-LB48 Novel Genetic Variant of Carney Complex With Acromegaly
Authors: Cristiano Elizabeth , Miles John M , Bhattacharya Rajib
Published: May 2020

Objective: To describe an uncommon case of Carney complex with acromegaly secondary to pituitary microadenoma with a novel genetic variant. Background: Carney complex (CNC) is a rare autosomal dominant syndrome characterized by myxomas, pigmented skin and mucosal lesions, as well as multiple endocrine tumors. The etiology is an inactivating mutation of the regulatory subunit type 1A of the cAMP-dependent protein kinase (PRKAR1A). Recently, additional CNC pathologic variants in PRKACA and PRKACB have been identified.[1] Elevated growth hormone (GH) and IGF-1 levels are sometimes seen in patients with CNC, thought to be secondary to somatotroph hyperplasia. However, less than one fifth of patients with CNC have clinical acromegaly. [2] Case: Here we describe a 35-year-old female diagnosed with atrial myxoma after presenting with fatigue in her 20s. After her fatigue failed to resolve following surgical excision, further investigation revealed an ovarian tumor. The patient sought care in Mexico where she underwent radiation for presumed ovarian malignancy. Review of the ovarian lesion biopsy at a university hospital later revealed benign melanocyte proliferation. She subsequently developed amenorrhea and hirsutism which prompted referral to endocrinology. Evaluation revealed coarse facial features, large hands, elevated IGF-1, and positive GH suppression test leading to a diagnosis of acromegaly. Gene sequencing revealed a novel pathologic variant of PRKAR1A consistent with CNC. MRI brain was originally negative for pituitary lesions; however follow up imaging after our visit with the patient showed a hypoenhancing lesion concerning for a pituitary microadenoma. Neurosurgical evaluation is underway. Discussion: Acromegaly with a pituitary adenoma is uncommon in patients with CNC. However, clinicians should have high suspicion for the disease in patients with CNC and other endocrine neoplasia disorders. The diagnosis has many deleterious consequences if not treated early. Additionally, this case represents a novel pathologic variant of PRKAR1A that has not previously been identified in Carney complex. References: 1. Correa, R., P. Salpea, and C.A. Stratakis, Carney complex: an update. Eur J Endocrinol, 2015. 173(4): p. M85-97. 2. Pack, S.D., et al., Genetic and histologic studies of somatomammotropic pituitary tumors in patients with the “complex of spotty skin pigmentation, myxomas, endocrine overactivity and schwannomas” (Carney complex). J Clin Endocrinol Metab, 2000. 85(10): p. 3860-5.
SAT-LB125 Broad Spectrum Effects of a Ketogenic Diet Delivered by Remote Continuous Care on Inflammation and Immune Modulators in Type 2 Diabetes and Prediabetes
Authors: Phinney Stephen , Adams Rebecca , Athinarayanan Shaminie , McKenzie Amy , Volek Jeff
Published: May 2020

Type 2 diabetes (T2D) is associated with, and often preceded by, increased levels of circulating c-reactive protein (CRP) and WBC count that mediate the body’s inflammatory and immune responses (inflammatory mediators [IMs]). This relationship between inflammation and diabetes is complex, as statins have anti-inflammatory properties but paradoxically promote or exacerbate T2D. Recently it has been reported that beta-hydroxybutyrate levels characteristic of nutritional ketosis enhance cellular defenses against oxidative stress and block the assembly of the NLRP3 inflammasome. As part of an ongoing study of the effects of a well-formulated ketogenic diet (WFKD) delivered via a web-based continuous care intervention (CCI) on 262 patients with T2D1 and 116 with prediabetes (PreD), we determined plasma levels of 16 IMs at baseline, 1 yr, and 2 yrs. These same IMs were concurrently monitored in 87 patients with T2D recruited as usual care controls (UC). At baseline, a statin was prescribed for 50% of the T2D/CCI patients, 27% of PreD/CCI patients, and 59% of the T2D/UC patients; at which time statin use was associated with reduced plasma CRP (P=7 x 10-5) compared to non-statin users in the T2D/CCI group only. There were no other significant baseline differences between statin users and non-users for any IMs (WBC, TNFa, IL-1b, IL-6, IL-8, IL-18, IFN-g, E- L-, and P-selectins, EGF, VEGF-A, MCP-1, ICAM-1 and VCAM-1). After 1 yr and 2 yrs of the CCI, mean weight losses in T2D were 12% and 10%, HbA1c reductions were 1.3% and 0.9%, and diabetes medication use was reduced by 51% and 53%, respectively. Linear mixed effects models were used to assess change in IMs over the 2 yrs, facilitating intent-to-treat analyses. Fourteen of the 16 IMs (excluding ICAM-1 and VCAM-1) were reduced compared to baseline in T2D/CCI (P<0.001), with none showing significant increases between yrs 1 and 2. A similar pattern albeit at lower magnitudes was seen in patients with PreD/CCI. Despite lower CRP values at baseline, T2D/CCI patients prescribed a statin experienced further reductions with the WFKD over the 2 years (P=3 x 10-5). In the T2D/UC group, no significant changes in any of the IMs were observed at 1 yr or 2 yrs. These observations suggest that a WFKD delivered via the CCI has broad-spectrum anti-inflammatory and immune modulatory effects in patients with T2D and PreD. Consistent with prior reports, statin use was associated with reduced CRP at baseline in the T2D/CCI group, but this effect was not significant in PreD/CCI and T2D/UC groups. CRP reductions were nonetheless significant in T2D/CCI statin users, suggesting added benefit of the WFKD. We conclude that improvements in IMs induced by a combination of nutritional ketosis and weight loss contribute to the beneficial effects of the CCI in the management of T2D.

1. Athinarayanan SJ, et al. Front Endocrinol. 2019. 5;10:348