bluuebunny/crossref_metadata_2025 huggingface dataset:
MON-211 Prevalence, Characteristics and Outcomes of Primary Aldosteronism in Newly Diagnosed Hypertensives in China (Pa China)
Authors: Xu Zhixin , Yang Jun , Hu Jinbo , Song Ying , Luo Ting , He Wenwen , Cheng Qingfeng , Ma Linqiang , Luo Rong , Fuller Peter J , Cai Jun , Yang Shumin , Li Qifu
Published: May 2020

Abstract

Background 44.7% adults in China have hypertension but the prevalence of primary aldosteronism (PA) in Chinese hypertensives is unknown. Objective We prospectively investigated the prevalence of PA in newly diagnosed hypertensives and tested the hypothesis that these PA patients have less severe cardiovascular complications and better outcomes when compared to those diagnosed after established (or prolonged) hypertension. Method In a community health center, consecutive hypertensive patients with an aldosterone-renin ratio≥2 (ng∙dL−1/mIU∙L−1) and plasma aldosterone concentration >10ng/dL underwent captopril challenge test and/or saline infusion test for confirmation. Adrenal CT scan and adrenal vein sampling were used for subtyping. PA patients were followed up for one year and clinical outcomes were compared with PA patients from an established hypertensive cohort. Results 1020 newly diagnosed hypertensive patients were screened over 16 months. Forty were diagnosed with PA, 948 with non-PA, resulting in a prevalence of 4.0%. Thirty-two patients were diagnosed as “possible PA” due to positive screening but failure to complete the confirmatory test. Compared to non-PA, PA patients more frequently displayed microalbuminuria (P=0.031), but the incidence of cardiovascular events was not different (P=0.927). For patients treated with surgery, complete clinical success rate was 85.7%, 28% higher than that of PA patients diagnosed after prolonged hypertension. For patients treated with medication, blood pressure control rate was 79.3%, 30% higher than that of PA patients diagnosed after prolonged hypertension. Conclusions The prevalence of PA in patients with newly diagnosed hypertension in China was at least 4.0%. PA screening in newly diagnosed hypertensive patients can lead to better clinical outcomes.
SAT-229 Bilateral Pheochromocytoma as Incidental Finding in a Patient with Neurofibromatosis Type 1
Authors: Herrera Raul A , Jimenez Camilo
Published: May 2020

Background.

In contrast to other genetic syndromes associated with Pheochromocytoma and Paraganglioma (PPGL) in which yearly biochemical screening is recommended, in neurofibromatosis due to the low penetrance of these tumors, screening is only recommended when there is clinical suspicion1. Given that signs and symptoms of catecholamine excess are vague and non-specific, clinicians should keep a low threshold for biochemical testing in these patients.

Clinical Case.

70 year old female with Neurofibromatosis type 1 (NF-1) diagnosed at age 24, hypertension and atrial fibrillation, was referred to our institution after being found incidentally with bilateral adrenal nodules. She had a 2 year history of poorly controlled, labile hypertension. Treatment at the time of presentation included doxazosin, metoprolol, valsartan and hydralazine. She denied other symptoms of catecholamine excess.

Further workup revealed elevated 24 hour urine normetanephrine at 2,530 mcg (ULN 500 mcg) and metanephrine at 1,325 mcg (ULN 290 mcg). Serum metanephrines were also elevated with free metanephrine of 1.6 nmol/L (ULN 0.5 nmol/L) and free normetanephrine of 4.1 nmol/L (ULN 0.9 nmol/L). Her biochemical metanephrine profile was consistent with pheochromocytomas in NF-1. MIBG uptake confirmed the presence of bilateral pheochromocytomas. She underwent a complete right adrenalectomy and a left cortical sparing adrenalectomy. Her adrenocortical function remains adequate. Post operatively while her blood pressures were no longer labile, she continued to require anti-hypertensive therapy.

Conclusion.

Patients who are at risk of developing pheochromocytomas and paragangliomas due to genetic syndromes or known germline mutations need ongoing clinical follow and biochemical testing for timely case detection. While in NF-1 pheochromocytomas are usually unilateral and present during early adulthood, they can present with bilateral disease and later in life2. During surgical treatment, even with unilateral disease, adrenocortical function should be preserved when possible3. Hypertension may persist despite complete surgical resection.

References

1. Lenders JWM, Duh Q-Y, Eisenhofer G, et al. Pheochromocytoma and Paraganglioma: An Endocrine Society Clinical Practice Guideline. The Journal of Clinical Endocrinology & Metabolism. 2014;99(6):1915-1942.

2. Moramarco J, El Ghorayeb N, Dumas N, et al. Pheochromocytomas are diagnosed incidentally and at older age in neurofibromatosis type 1. Clinical endocrinology. 2017;86(3):332-339.

3. Neumann HPH, Tsoy U, Bancos I, et al. Comparison of Pheochromocytoma-Specific Morbidity and Mortality Among Adults With Bilateral Pheochromocytomas Undergoing Total Adrenalectomy vs Cortical-Sparing Adrenalectomy. JAMA network open. 2019;2(8):e198898.
SUN-608 Juvenile Toxicity Study of Livoletide: A Peptide Analogue of Unacylated Ghrelin for the Treatment of Hyperphagia in Prader-Willi Syndrome
Authors: Xu Howard , Spencer Andrew , Milano Stephane
Published: May 2020

Background: Prader-Willi syndrome (PWS) is a rare endocrine disorder characterized by hyperphagia and abnormal food-related behaviors that contribute to severe morbidity, early mortality, and significant burdens for patients and caregivers. Dysregulation of acylated ghrelin (AG) and unacylated ghrelin (UAG) in people with PWS and hyperphagia has led to the hypothesis that replacing the relative deficit of UAG observed in this population will reduce hyperphagia. Livoletide is a cyclic, 8 amino acid analogue of UAG being developed as a potential treatment for hyperphagia and food-related behaviors associated with PWS. In a previous Phase 2a study (n=47) in people with PWS, livoletide improved food-related behaviors and hyperphagia scores relative to placebo. An extensive nonclinical safety program to support clinical development of livoletide has been conducted. Here we report the results of study of livoletide in juvenile rats.

Methods: Male and female juvenile Wistar rats were administered livoletide (10, 25, or 75 mg/kg/day, subcutaneous) once daily from the age of weaning (postnatal day 21) until 12 weeks of age (n=32/sex/group). Subgroups were sacrificed at the end of the dosing period or after a recovery period. Toxicity was assessed based on local tolerance, clinical observations, body weights, food consumption, tibia length, bone densitometry, behavioral tests, IGF1 (insulin-like growth factor-1), LH (luteinizing hormone), and other endpoints. Macroscopic (necropsy), microscopic/histopathological, and caesarean examinations were also performed. Toxicokinetic (TK) evaluations were performed at various time-points after dosing to assess exposure.

Results: Livoletide was not associated with treatment-related clinical signs or any relevant changes in hematological, coagulation, clinical chemistry parameters or urine analysis. Body weight and food consumption were unaffected. Livoletide did not affect systemic concentrations of IGF-1 or LH. No adverse effects of livoletide on bone growth, mating performance, or fertility were observed. Pups delivered by caesarian section did not exhibit abnormalities. Results were consistent with a lack of effect of livoletide on growth hormone signaling. Histological changes were limited to minimal local reversible reactions at injection sites that were non-adverse and observed at low incidence and severity.

Conclusions: Livoletide was well-tolerated and not associated with evidence of overt systemic toxicity. The no observed adverse effect level (NOAEL) of 75 mg/kg/day was associated with Cmax and AUC0-24h values of 72.6/83.2 μg/mL and 169/144 μg.h/mL (males/females), respectively. These exposures are >100-fold above the anticipated clinical exposures in the Phase 2b/3 ZEPHYR study, which is enrolling people ages 4 to 65 with PWS.
SAT-203 Misleading Diagnosis of Cushing’s Syndrome on Pramipexole
Authors: Pahomov Elizabeth , Dhital Subarna Mani
Published: May 2020

We present an intriguing case of a patient incorrectly diagnosed with Cushing’s disease secondary to pramipexole use for restless leg syndrome (RLS). 61-year-old male with symptoms of 55 lb weight gain, progressive fatigue, and subjective muscle weakness presented to endocrinology office for work-up of possible Cushing’s syndrome. Physical exam was significant for mild facial plethora, purple striae, and central obesity. Patient’s history includes diagnosis of prolactin-producing pituitary microadenoma 30 years ago treated with bromocriptine with normalization of prolactin and resolution of adenoma. Patient notes ten years ago, he was started on pramipexole 1 mg TID for severe RLS. Given patient’s clinical symptoms he underwent hormonal testing which was notable for an abnormal 1 mg ONDST with morning cortisol 2.44 mcg/dL (normal < 1.8 mg/dL) and two abnormal late night salivary cortisol 0.177 mcg/dL and 0.199 mcg/dL (normal < 0.122). Repeat MRI showed a 0.4 cm hypoenhancing lesion in the left side of the anterior pituitary gland. Patient was referred for IPSS. His central-to-peripheral plasma ACTH ratio was as follows: before CRH administration: left 5.8, right 1.2; after CRH administration: left 16.4, right 2.7. These results demonstrated positive IPSS indicating centralization or a pituitary source of ACTH excess. Patient was going to be referred to neurosurgery for left pituitary adenoma resection, but literature search revealed a study showing pramipexole causing an increase in cortisol levels in physiologic studies involving healthy subjects. Due to these findings, labs were repeated while holding pramipexole. His morning cortisol and ACTH levels were normal. Late night salivary cortisol x3 were normal: 0.038, 0.071, and 0.024 mcg/dL (normal < 0.090 mcg/dL). The 24 hour urine free cortisol x2 was also normal. These negative biochemical findings showed no evidence of hypercortisolism off of pramipexole. This further complicated the case as the patient had positive IPSS. In order to help exclude the diagnosis of an ACTH secreting pituitary tumor, a DDAVP stimulation test was performed showing a normal response. Based on these tests it was concluded he does not have Cushing’s and that his hypercortisolism was related to pramipexole use. Repeat brain MRI showed no structural evidence of any pituitary lesion. We report a very rare case of pramipexole use leading to a false diagnosis of Cushing’s syndrome. This was fortunately identified prior to patient undergoing unnecessary surgery. We recommend awareness of pramipexole use associated with hypercortisolism to prevent incorrect diagnosis of Cushing’s syndrome.

Schilling, J. C., Adamus, W. S., & Palluk, R. (1992). Neuroendocrine and side effect profile of pramipexole, a new dopamine receptor agonist, in humans. Clinical Pharmacology & Therapeutics, 51(5), 541-548.
SUN-383 Potential Impact of Using Male vs Female T-Scores for BMD Classification in Men
Authors: Fatoki Raleigh A , Ettinger Bruce , Chandra Malini , Horiuchi Kate M , Lo Joan Chia-Mei
Published: May 2020

BACKGROUND: Osteoporosis is traditionally associated with post-menopausal women, but up to up to one-third of osteoporosis-related fractures occur in elderly men. The International Society for Clinical Densitometry (ISCD), the World Health Organization, and the Fracture Risk Assessment Tool (FRAX) all recommend using a white female reference for BMD T-score for men. However, in clinical practice and previous clinical trials, a sex-specific white male reference T-score is used. This report examines the implications of using a female versus male reference for T-score calculation in men.

METHODS: We reviewed BMD findings in 703 men (age 70-85y) who experienced a proximal femur, humerus, or distal radius/ulna fracture. For this cohort, femoral neck BMD was used to calculate a BMD T-score using either the young adult male and young adult female peak values (mean BMD 0.930 ± 0.136 and 0.849 ± 0.111 g/cm2, respectively). Osteoporosis was defined by BMD T-score ≤ -2.5, and osteopenia by BMD T-score < -1.0 and > -2.5. We also calculated FRAX-estimated fracture risk for hypothetical men ages 60-85y, with and without prior fracture. We used the National Osteoporosis Foundation (NOF) recommendations for treatment based on BMD (osteoporosis by BMD, or osteopenia by BMD with a 10-year risk of hip fracture ≥ 3% or 10-year risk of major osteoporotic fracture ≥ 20%).

RESULTS: The mean BMD for this cohort was 0.670 g/cm2 and the median T scores were -2.0 (male reference) and -1.7 (female reference). Using the male T-score, 29% of men were classified as having osteoporosis, while using the female T-score, only 21% were so classified. 36% of men age 70-79y and 19% of men age 80-85y with osteoporosis (using the male T-score) would be reclassified from osteoporosis to osteopenia when a female T-score is used. Hypothetical cases of men age 60-85y (height 170 cm, weight 70 kg, BMD 0.590 g/cm2 equivalent to a male T -2.5 or female T -2.2) were used to calculate 10-year hip fracture risk using FRAX. For these hypothetical cases, the calculated 10-year risk of hip fracture exceeded the NOF treatment threshold of 3% (10-year hip fracture risk) for all cases, with or without prior fracture.

CONCLUSION: For elderly men with fracture with male-T osteoporosis and female-T osteopenia, the T-score reference population used does not alter treatment recommendations because the calculated hip fracture risk is already above the treatment threshold of 3%. This is also true for men age ≥70 without a prior fracture. Hence the debate pertaining to the appropriate T-score reference population for men has limited relevance for men age ≥ 70 years who are being screened for osteoporosis.
SAT-051 Effects of Testosterone Replacement on Glycemic Control and Other Cardiovascular Risk Factors in Hypogonadal Men with Uncontrolled Type 2 Diabetes (Stride Study): Design, Implementation and Baseline Data
Authors: Rao Preethi Mohan , Mumdzic Enis , Kelly Daniel Marcus , Jones Thomas Hugh
Published: May 2020

Up to 40% of men with type II diabetes are testosterone deficient. There is growing evidence that testosterone therapy has a beneficial effect on glycemic control, insulin resistance and may have a cardioprotective effect, contrary to the traditional view that testosterone is detrimental to the heart. Our study aims to evaluate the effect of testosterone therapy on glycaemic control other cardiovascular risk factors, symptomatic benefit and quality of life in a randomised double-blind placebo controlled add-on of testosterone therapy to their normal hypoglycemic medication in hypogonadal men with uncontrolled type 2 diabetes. The study population includes 65 eligible men (140 screened) with poorly controlled diabetes (HbA1c between 53 and 80 mmol/mol) and confirmed hypogonadism by early morning [0800−1200h] total testosterone [TT] ≤12 nmol/L or calculated free testosterone ≤255 pmol/L on two occasions ≥1 week apart, with at least two symptoms of hypogonadism. The trial is divided into 2 phases. Phase 1: patients are randomly assigned to either treatment (depot testosterone undecanoate) arm or the placebo arm for 6 months. Phase 2: open label phase for 6 months with subjects on placebo on placebo initiated on to testosterone therapy while subjects in the treatment group continue to receive treatment for the 12 month duration. No change to anti- glycaemic therapy was made during the first phase of the study. The primary endpoint is HbA1c. Secondary endpoints include body composition (bioelectrical impedence DEXA scan), HOMA-IR, lipid profile, blood pressure (24 hr BP monitor), carotid media intima thickness, monocyte mRNA cytokine expression, Questionnaires include AMS (Aging Male Symptom Score), IIEF-5(International Index of Erectile Dysfunction), SF36-Quality of life, Mini mental score, New questionnaire for hypogonadism in diabetes (to be validated), NERI (New England Research Institute) hypogonadal screener. Baseline data indicate the mean age 59 (42-77) years. Mean Duration of diabetes was 8.6(0-21) years. 18 men were on Insulin. The remaining 47 men were either diet controlled or on oral hypoglycaemic medications. 9 men had pre-existing history of MI and 4 had history of angina. Mean HbA1c at baseline was 65(53-80) mmol/mol. Mean total testosterone level was 8.9(2.1-16.9) nmol/l. Mean weight and BMI at baseline were 107(71-187) kg and 34.5(24-52) respectively. Mean waist circumference was 115.7(46-160) cm The primary aim of this is to determine if testosterone therapy improves glycemic control in men with uncontrolled diabetes. Secondly to assess beneficial effects on specific cardiovascular parameters as well as QOL. This could have a major clinical implication on how we treat patients with hypogonadism and type 2 diabetes.
MON-175 Structural Instability as an Underlying Pathomechanism in Congenital Adrenal Hyperplasia
Authors: Meese Nicolas , Paul Pallabi Sil , Haslbeck Martin , Huebner Angela , Reisch Nicole
Published: May 2020

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders affecting key enzymes of cortisol biosynthesis. In the majority of cases the underlying cause are detrimental mutations in the steroidogenic cytochrome P450 enzyme 21-hydroxylase (CYP21A2). Early diagnosis via newborn screening programs in most Western countries and lifelong oral cortisol replacement therapy enable survival, however quality of life often is reduced and co-morbidities are substantially increased. Treatment is a major challenge as disease control can only be achieved with supraphysiological glucocorticoid doses. In addition, the currently available drugs cannot ideally mimic the circadian rhythm and stress adaption of cortisol secretion. Currently, disease severity is classified by residual enzyme activity. The goal of our research is to better understand the specific biophysico-chemical pathomechanism of 21-hydroxylase deficiency in order to enable causative therapeutic approaches. To this end, we investigated the structural and stability properties of six clinically relevant mutant variants of CYP21A2 (V282G/L, P31L, D323G, R484Q/W). Difficulty in purification of these CYP21A2 variants and various biophysical studies suggest that the proteins were less stable than wild-type (WT). Structural and thermal stability assessment by circular dichroism (CD) spectroscopy of recombinant, purified CYP21A2 mutant variants revealed high α-helical content for the WT (65% α-helix) and the mutants at the position 282 (V282G: 60.6 %, V282L: 57.6%). Other mutations (P31L, D323G, R484Q/W) disrupt the α-helical organization of CYP21A2 in exchange for a slight increase in ß-sheet content but mainly for random coil. Temperature dependent CD spectroscopy showed that all mutant variants have reduced thermal stability (Tm: 41.3 - 45,6°C) compared to the WT (Tm: 47.1°C). Tryptophane fluorescence showed that mutant variants of the protein were more prone to local unfolding at the hydrophobic core compared to WT using urea as denaturant. Furthermore, in UV/Vis spectroscopy at 280 nm and 418 nm we could demonstrate that all mutant variants had a reduced heme incorporation (A418/A280: 0.20 - 0.63) compared to WT (A418/A280: 0.88). Our results show that correct structural folding and stability pose a major problem in specific mutations involved in CAH. Therefore we propose that structural protein instability, play a key role in the pathophysiology of CAH and thus might constitute a novel tailored therapeutic target for the treatment of affected patients.
SUN-120 Regional Hyperthermia Enhances Selective Mesenchymal Stem Cell Migration Towards the Tumor Stroma
Authors: Tutter Mariella , Schug Christina , Schmohl Kathrin Alexandra , Schwenk Nathalie , Petrini Matteo , Lindner Lars H , Nelson Peter J , Spitzweg Christine
Published: May 2020

The tumor homing characteristics of mesenchymal stem cells (MSCs) make them attractive vehicles for the tumor-specific delivery of therapeutic agents, such as the sodium iodide symporter (NIS). NIS is a theranostic protein that allows non-invasive monitoring of the in vivo biodistribution of functional NIS expression by radioiodine imaging as well as the therapeutic application of 131I. To enhance the actively recruitment of MSCs to growing tumor stroma and thereby trigger targeted delivery of the NIS gene to the tumor, we examined the combination with regional hyperthermia, as heat induces the secretion of immunomodulatory chemokines, cytokines and growth factors, well-known attractants of MSCs.

Human hepatocellular carcinoma cells (HuH7) were heat-treated in a water bath at 41 °C for 1h, followed by incubation at 37 °C for 0-48h. mRNA and protein levels of chemokines involved in MSC migration was analyzed by RT-PCR and ELISA. Chemotaxis of MSCs in relation to a gradient of supernatants was tested in a 3D live cell tracking migration assay. In a subcutaneous HuH7 mouse xenograft tumor model, a single systemic injection of CMV-NIS-MSCs was applied 6h, 24h, 48h after or 24h, 48h before hyperthermia treatment and tumoral 123I accumulation was assessed by 123I-scintigraphy. Ex vivo NIS analysis of tumor sections was performed by RT-PCR and immunohistochemistry. The optimal imaging regime was then used for a 131I therapy study.

Chemokine mRNA and protein analysis indicated a substantial increase in expression levels of chemokines and growth factors, involved in MSC tumor homing, after heat exposure. In addition, MSCs showed directed migration towards the supernatant of thermo-stimulated cancer cells. In vivo, with the optimal regime, we observed a significantly increased uptake of 123I in tumors of heat-treated animals (41 °C) when thermostimulated 24h after CMV-NIS-MSC injection compared to control animals (37 °C). Immunohistochemical staining of tumor sections showed strong tumoral NIS-specific immunoreactivity and RT-PCR an increased NIS mRNA expression in heat-treated tumors, thereby confirming tumor-selective, temperature-dependent MSC migration. CMV-NIS-MSC-mediated 131I therapy combined with regional hyperthermia resulted in a reduced tumor growth that was associated with prolonged survival of regional heat-treated animals compared to normothermic mice and to the saline control group.

In summary, we have demonstrated a significantly increased, selective MSC migration towards the tumor stroma after regional hyperthermia in the 123I imaging study. The combination of MSC-mediated NIS gene therapy with mild regional hyperthermia resulting in stimulated therapeutic efficacy of NIS-mediated 131I therapy.
SAT-269 A Rare Case of Functioning Gonadotroph Producing Pituitary Macroadenoma in Teenage Male
Authors: Dejhansathit Siroj , Thavaraputta Subhanudh , LaPointe Genevieve , Mejia Ana Marcella Rivas
Published: May 2020

Background: Unlike nonfunctioning gonadotroph pituitary adenomas, functioning gonadotroph pituitary adenomas (FGA) are an uncommon type of pituitary tumors that secrete biologically active gonadotropins (LH, FSH, or both).

Clinical Case: A 23-year-old man with no previous medical history presented to the emergency department with three months history of progressive decreased vision and decreased libido. He denied headache, seizure, erectile dysfunction, or weakness. On physical examination, his visual acuity was significantly reduced on the right eye and was only able to perceive light. He had a visual field narrowing on the left eye. Gynecomastia was noted bilaterally and testicles were found to be enlarged (Orchidometer >25 mL). Complete blood count was significant for hemoglobin of 19.2 g/dL (N, 13.7-17.5 g/dL), and hematocrit of 57.0% (N, 40.1-51.0%). Pituitary function tests were as follow: FSH >200.0 mIU/mL (N, 1.5-12.4 mIU/mL), LH 17.0 mIU/mL (N, 1.7-8.6 mIU/mL), total testosterone 41.3 nmol/L (N, 8.6-29.0 nmol/L), free testosterone 1.263 nmol/L (N, 0.148-0.718 nmol/L), and bioavailable testosterone 29.609 (N, 2.110-8.920 nmol/L). Prolactin, TSH, GH, and ACTH were all within the normal range. Magnetic resonance imaging (MRI) showed a sellar mass involving the planum sphenoidal measuring 5.8 x 5.2 x 5.6 cm with optic chiasm displaced superiorly, in addition, subfalcine herniation with mild hydrocephalus was also noted. The patient underwent orbitozygomatic approach resection of the pituitary tumor. Histological examination was consistent with a pituitary adenoma. Cells stained positive for transcription factor steroidogenic factor 1 (SF 1), FSH, LH, and alpha-subunit consistent with a gonadotroph adenoma. They were negative for transcription factor Pit 1 stain and the remaining pituitary hormones including ACTH, GH, prolactin, and TSH stain. Postsurgical hormone assessment showed a significant decline in FSH and LH to 2.3 and 0.4 mIU/mL, respectively and testosterone level decreased to < 0.087 nmol/L on postoperative day 18. The patient’s vision improved postoperatively prior to discharge but he lost follow up thereafter.

Conclusion: Most patients with functioning gonadotroph pituitary adenoma present with large tumors that are detected based on the occurrence of symptoms of compression that result from the enlarging sellar mass. Most patients, particularly men and postmenopausal women, do not develop symptoms of hormone excess and the lack of symptomatology results in delay in diagnosis. Our patients presented with significant polycythemia which resulted from excess testosterone and could have prompted earlier tumor detection if he had presented in an earlier stage. The incidence of polycythemia in male patients with functioning gonadotroph pituitary adenoma has previously been described in the literature in a few case reports.
SUN-343 Prevalence and Incidence of Hypomagnesemia and Hypermagnesemia in Medical Settings
Authors: Catalano Antonino , Bellone Federica , Morabito Nunziata , Chila Diego , Loddo Saverio , Corica Francesco , Benvenga Salvatore
Published: May 2020

Electrolytes disturbances are commonly observed in clinical practice. However, magnesium (Mg) disorders are often poorly considered. Our primary aim was to update the prevalence and the incidence of hypomagnesemia and hypermagnesemia in a real-life scenario. The secondary aim was to investigate the association of Mg disturbances with age and gender. Data from patients whose Mg serum levels were measured between January 2015 and December 2017 at our University Hospital were recorded. Hypomagnesemia was defined by Mg levels <1.5 mg/dL and hypermagnesemia by levels> 3.8 mg/dL. Hypo and hypermagnesemia cases were considered according to age, gender, year of observation and setting of subjects including outpatients and inpatients. In particular, inpatients were recruited from a total of 25 Hospital Divisions (i.e. Cardiology, Endocrinology, Geriatrics, Hematology, Intensive Care, Internal Medicine, Infectious Disease, Nephrology, Neonatal Intensive Care, Neurology, Neuropsychiatry, Neuroradiology, Oncology, Pulmonology, Pediatrics, Psychiatry, Rheumatology and Surgical Area that included 8 Units). Over the observation period, we recognized 12,696 patients whose Mg levels were checked. Prevalences of hypomagnesemia and hypermagnesemia were 8.43% (n=1071) and 1.78% (n=226) respectively. Hypomagnesemia was encountered more frequently in female [53.3% (n=560)] rather than in male patients [47.7 % (n=511)] (χ2= 4.03, p<0.045) and was significantly influenced by age: the higher prevalence of hypomagnesemia was found in patients over 65 yr. [59.01% (n=632)], whereas a lower prevalence was detected in the other age groups, specifically in 9.52 % (n=102) of patients aged 0-18 yr. and in 31.46 % (n=337) of patients between 19 and 65 yr. (χ2= 592.64; p<0.0001). Incidence of hypomagnesemia decreased over time with a borderline significance only in subjects over 65 yr. (r=-0.99; p=0.07). Geriatrics, Oncology and Intensive Care Division showed the highest incidences of hypomagnesemia. The hypermagnesemia prevalence was observed higher in outpatients in comparison with inpatients from any other Hospital Division and the hypermagnesemia incidence did not significantly change over time (r=0.96; p=0.16). Mg disorders, mainly hypomagnesemia, are quite common in clinical practice particularly in older hospitalized patients. Among the other electrolytes’ disturbances, Mg disorders, because of life-threatening significances, may be checked and corrected.
SUN-164 Adrenal Crisis in Early Pregnancy
Authors: Bello Jenny Carolina , Chen Xiaolei , Chen Kenneth K
Published: May 2020

Nausea and vomiting are common symptoms in pregnancy, ranging from occasional nausea to fulminant and intractable vomiting. Many underlying metabolic disorders can mimic this, primary adrenal insufficiency (PAI) being one of them. Here, we present a case of adrenal insufficiency early in pregnancy.

A 28 year old lady G1P0 at 8 weeks of gestations, with a past medical history of Grave’s Disease, presented to our hospital on 3 occasions over one week with severe intractable nausea and vomiting. On prior visits, she had received intravenous fluids and discharged home. Laboratory work-up was ordered on the third visit and she was found to have severe hyponatremia with level of 111mMol/L. TSH and FT4 levels were both within the reference range. AM cortisol level was low at 2.3mcg/dL. ACTH and renin were both significantly elevated confirming diagnosis of PAI. Intravenous hydrocortisone was commenced immediately with rapid resolution of her symptoms and correction of her hyponatremia. She was followed at the endocrinology clinic, with appropriate up-titration of glucocorticoid and mineralocorticoid doses throughout her pregnancy.

Diagnosis of PAI is usually established prior to pregnancy. Presentation during pregnancy is not common, but it should be considered as a differential diagnosis when symptoms are out of proportion to the gestational status. Normal pregnancy is accompanied by progressive increase in circulating CRH and ACTH, increasing the levels of free cortisol as early as 7 weeks of gestation, rising up to 20-fold by the end of pregnancy. These physiologic changes could explain early presentation of adrenal crisis given insufficient glucocorticoid production. A delay in diagnosis and treatment increases the risk of maternal and fetal morbidity and mortality significantly.

Management of PAI during pregnancy can be challenging as there are no established guidelines and they have mainly been based on observational studies (1). The appropriate selection and dose of the glucocorticoid is important for the treatment of PAI to minimize adverse effects on mother and baby (2). At the time of active labor and delivery, stress doses of glucocorticoids need to be administered to prevent adrenal crisis (3).

In conclusion, early diagnosis and appropriate management of PAI during pregnancy is necessary to sustain a healthy pregnancy.

Bibliography

1 Husebye ES, Allolio B, Arlt W, et al. Consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency. J Intern Med 2014; 275: 104– 15.

2 Bandoli G, Palmsten K, Forbess C, et al. A review of systemic corticosteroid use in pregnancy and the risk of select pregnancy and birth outcomes. Rheum Dis Clin North Am. 2017; 43(3): 489–502

3 Chen K, Powrie R. Approach to the use of Glucocorticoids in Pregnancy for Nonobstetric Indications. de Swiet’s Medical Disorders in Obstetric Practice: Fifth Edition. 736-741.
SAT-652 Increased Fibroblast Growth Factor 21 Protein Expression via in Vivo Delivery of a Liver-Specific Expression Plasmid
Authors: Girer Nathaniel , Rontoyanni Victoria , Porter Craig , Elferink Cornelis
Published: May 2020

Fibroblast growth factor 21 (FGF21) is an important liver-secreted hormone that activates thermogenesis in white and brown fat deposits. In various models of obesity, FGF21 administration consistently facilitates weight loss and improved metabolic function. Several FGF21 variants, which have been engineered to improve protein stability and solubility in solutions containing preservatives, are currently in human clinical trials. In addition, in vivo FGF21 gene therapy using viral vector is being explored as an alternative therapeutic approach. In this study, we present a simpler method of in vivo FGF21 gene therapy, in which liver-specific delivery of an unpackaged plasmid construct expressing an HA-tagged FGF21 protein increases de novo hepatic FGF21 production and secretion in mice. Our data show that FGF21 protein expression can be successfully restored into the livers of FGF21 conditional knockout mice for at least two weeks after a single tail vein injection with the expression plasmid, and that the HA-tagged protein is secreted and readily detectable in serum. In wild-type C57BL6/J mice, in vivo plasmid delivery significantly increased hepatic FGF21 protein 2.3-fold after two weeks, and was associated with reduced body mass and a 14% reduction in fasting serum glucose. In addition, elevated hepatic FGF21 levels correlated with a 27% decrease in the ratio of fat to body mass, visibly smaller subcutaneous and visceral white fat adipocytes, and a 3.3-fold increase in uncoupling protein 1-dependent mitochondrial respiration in the white fat. Together, these data suggest that in vivo plasmid delivery may potentially be an effective strategy for promoting hepatic FGF21 expression in models of obesity. We are currently testing this hypothesis with experiments in high-fat diet-challenged mice.
SUN-620 Gender Difference in the Outcome of Patients with Diabetes Admitted for Hyperosmolar Hyperglycemia. from the National Inpatient Sample
Authors: Ahmed Fatima , Abugroun Ashraf , Elhassan Manar , Seyoum Berhane
Published: May 2020

Objective: There is paucity of literature on the impact of gender on outcomes of hyperosmolar hyperglycemic state (HHS) among adult patients with diabetes. The aim of this study was to evaluate the effect of gender on the outcome of these patients. Methodology: The National Inpatient Sample (NIS) was queried for all patients who were admitted with a diagnosis of hyperosmolar hyperglycemic state (HHS) during the years 2005-2014. The primary outcomes of the study were all-cause mortality, acute myocardial infarction (MI), and acute stroke. The secondary outcomes were acute kidney injury (AKI), rhabdomyolysis, acute respiratory failure (ARF), need for mechanical ventilation (MV), length of stay (LOS), and total cost of stay. Results: Overall, 188,725 patients were admitted for HHS. Mean age of males was 53.7, standard error of the mean (SEM: 0.13), and of females was 58.5 (SEM: 0.15), p<0.001. Females were (43.9%), Caucasians were 37.4% while African Americans were 35.2%. Total mortality was 1.1%, MI was 1.3% and stroke was 1.1%. Most common secondary outcome was AKI seen in 31.3% followed by ARF seen in 2.9% of total. The mean cost was 7887 $ (SEM: 84.6) and mean LOS was 4.1 days (SEM: 0.03). Both males and females had equivalent rates of mortality, stroke, ARF and need for mechanical ventilation. Compared to males, females had significantly higher risk for MI 1.6% vs 1.1%, p<0.001, lower risk for AKI 29.3% vs 32.9%, p<0.001, lower risk for rhabdomyolysis 1.1% vs 2%, p<0.001 and higher LOS 4.3 vs 3.9 days, p<0..01 and higher total costs 8165.6 $ vs 7669.3 $, p < 0.001. On multivariable analysis, female gender was independently predictive for higher risk for MI with adjusted odds ratio (aOR) 1.34 [95%CI: 1.08-1.67] p=0.01 and lower risk for rhabdomyolysis with aOR 0.52 [95%CI: 0.42-0.63] p<0.001 and lower risk for AKI with aOR 0.74 [95%CI: 0.7-0.78] p<0.001. In addition, female gender correlated with higher cost and length of stay. Conclusion: Females with hyperosmolar hyperglycemic state are at higher risk for MI and lower risk for AKI and rhabdomyolysis.
SAT-389 Clinical and Biochemical Characterization of Risk Factors for Vertebral Fractures in Patients with Hypoparathyroidism
Authors: Formenti Anna Maria , Filippo Luigi Di , Allora Agnese , Giubbini Raffaele , Giustina Andrea
Published: May 2020

Background: Persistent hypoparathyroidism (PH) is a rare disease due to an impaired secretion of PTH, mostly occurring as a complication of total thyroidectomy. Calcium and calcitriol are currently the most common and inexpensive therapies, although not all the patients easily achieve control of the disease. Recently, our group has reported that BMI at diagnosis can predict calcitriol resistance in PH. Very few studies have been performed with fractures as primary endpoint in hypoparathyroidism, and we still not know if PH could be predisposing to an increased risk of morphometric fractures and possible clinical and biochemical predicting factors. Patients and methods: To that end we retrospectively evaluated the anthropometric, biochemical and fracture characteristics in 71 consecutive patients with PH (F/M= 62/9; median age 58.7 yrs, range: 29-87; 67 with post-surgical PH and 4 with autoimmune PH). All patients were hypoparathyroid from at least one year (median duration of disease: 9 yrs., range: 1-41) and were under standard treatment with calcium and active vitamin D analogs (calcitriol). For each patient anthropometric data (BMI=kg/m2; N= Normal weight patients <25; OO= Obese and overweight patients with BMI > 25) were collected, as well as biochemical parameters, such as calcium (mg/dl) and 25 OH vitamin D (25OHD expressed as ng/ml). We considered well controlled (C) patients with calcium between 8.2 and 9.2 mg/dl and not controlled (NC) under 8.2 or above 9.2 mg/dl. Vertebral fractures (VF) were assessed by a quantitative morphometric approach by using images provided by DXA and classified according to Genant classification. Results: Thirteen out of 71 patients (18%) were fractured. We showed a positive linear correlation in the overall population between BMI and calcitriol intake (p=0.006, CI 95% [1.2-6.9]) while no significant difference in prevalence of VF in OO vs N group (8/40 vs 5/31, p=0.76) was found. However, almost half (6/13, 45%) of patients with VF were OO NC. Moreover, 86% of NC vs only 30% of C fractured patients (6/7 vs 2/6) were OO Discussion: We report a high prevalence of VF in hypoparathyroidism. Moreover, we confirm that increased BMI is associated with higher needs of calcitriol to obtain calcium control. Interestingly, our data suggest for the first time that OO hypoparathyroid patients with NC disease are those at highest risk of fracture. Therefore, in this subset of patients a more intensive and proactive biochemical and bone monitoring should be adviced if these results will be confirmed in larger studies.
OR05-01 Small Heterodimer Partner Modulates Antigen Presenting Myeloid Cells to Impair Regulatory T Cell Expansion, Promoting Anti-Tumor Immunity in Models of Breast Cancer
Authors: Shahoei Sayyed Hamed , Nelson Adam T , Henn Madeline A , Mathews Ashley E , Chen Joy J , Vembar Varsha , Vardanyan Anna , Ma Liqian , Wang Yu , Apetoh Lionel , Nelson Erik Russell
Published: May 2020

Immune checkpoint blockade has had underwhelming responses in breast cancer, in part due to the highly immune suppressive microenvironment. As a result, breast cancer continues to be the second most common cancer-related mortality amongst women, providing strong rationale for the development of new therapeutic approaches. Elevated circulating cholesterol is a poor prognostic, while breast cancer patients taking cholesterol-lowering drugs display increased time to recurrence. We and others have previously demonstrated that cholesterol metabolites mediate these effects by promoting breast cancer growth and metastasis, in part by suppressing the immune system. Therefore, given the demonstrated importance of cholesterol and its metabolites in breast cancer pathophysiology and immunology, we hypothesized that proteins involved in the regulation of cholesterol homeostasis would influence cancer progression. Through informatics analysis of breast tumors, we found that elevated expression of Small Heterodimer Partner (SHP; NR0B2) was a favorable prognostic. Antigen presenting cells such as macrophages and dendritic cells were found to express SHP, and manipulation of SHP altered the expression of genes involved in cross-talk with T cells. Intriguingly, when activated T cells were co-cultured with macrophages overexpressing SHP, there was a decrease in the expansion of regulatory T cells (Tregs) and vice versa in the absence of SHP. Adoptive transfer studies confirmed that loss of SHP resulted in immune suppressive Tregs. We hypothesized that myeloid cell-expressed SHP would promote immune surveillance and tumor clearance. In support of this hypothesis, tumors in the MMTV-PyMT model of mammary cancer grew at an accelerated rate in SHP-knockout mice. Tumors from these mice had significantly more Tregs and fewer effector T cells. Furthermore, orthotopic mammary tumor grafts grew at an increased rate in mice lacking SHP expression in myeloid cells (SHPfl/fl;LysMCre), compared to controls. A small molecule agonist of SHP impaired primary and metastatic tumor growth, and significantly enhanced the efficacy of immune checkpoint blockade in murine models of mammary cancer. Therefore, SHP represents a potential target to decrease suppressive Tregs, thereby allowing for immune-clearance of tumors.
SAT-258 Surprising Transformation of a Microprolactinoma to a Macroprolactinoma
Authors: Athonvarangkul Diana , Hosier Hillary Wyeth , Wojeck Brian , Inzucchi Silvio E
Published: May 2020

Background: Microprolactinomas are typically benign tumors that rarely become macroprolactinomas. We present a rare case of a microprolactinoma that, after discontinuation of dopamine agonist (DA) therapy, transformed into a macroprolactinoma over a period of 6 years.Clinical Case: A 16-year-old woman initially presented for evaluation of galactorrhea without menstrual irregularities and was found to have elevated prolactin (68 ng/ml, normal range: 0-20), and a 4 mm pituitary microadenoma on MRI imaging. The patient was otherwise asymptomatic and other pituitary hormone levels were normal. She was treated with DA therapy (cabergoline 0.50 mg/week) which normalized her PRL level and improved but did not completely resolve the galactorrhea. She was then lost to follow up for 6 years. During that time, she discontinued cabergoline, but was still able to conceive, delivering a healthy baby after 2 years and breastfed briefly. She re-presented to her gynecologist 4 years after delivery for galactorrhea and secondary amenorrhea, both persistent since childbirth. Re-evaluation at that time revealed a much higher PRL level (432 ng/ml) and significant interval growth of the previous microadenoma to a 2.6 cm macroadenoma, now with extension into the left cavernous sinus, suprasellar cistern, with mass effect on the optic chiasm. The patient was retreated with cabergoline up to 3 mg/week, with a near-normal PRL level being achieved at 9 months (28 ng/ml). Repeat MRI revealed modest decrease of the adenoma to 2.4 cm. Galactorrhea resolved with reduction in PRL. However, amenorrhea persisted. Estradiol (30 pg/mL, 19-357 pg/mL) was low normal with normal withdrawal bleeding to medroxyprogesterone (MPA) challenge indicating reasonable estrogenization. She was treated with MPA to achieve regular cyclic bleeding every 3 months. Conclusion: This is an unusual case demonstrating significant growth of a microprolactinoma, which is typically a stable/indolent neoplasm, to a macroprolactinoma with invasive features. Previous studies of untreated microprolactinomas have shown that they undergo only subtle to minimal growth over 3 to 6 years and none transformed to a macroprolactinoma despite significant rises in PRL levels. In this clinical case, given the 6 intervening years that had elapsed in between MRIs, we cannot determine whether this represented moderate, progressive growth during that period after the discontinuation of DA therapy or whether the tumor had grown during pregnancy with its known stimulatory effects from hyperestrogenemia. The patient will require close follow-up to ensure ongoing shrinkage or at least stability of the adenoma and ongoing control of her hyperprolactinemia.References:1. Fertility and sterility39, 753-760 (1983). 2. Dietemann, J.L et al. Neuroradiology25, 133-138 (1983). 3. Garcia, M.M et al. Journal of endocrinological investigation18, 450-455 (1995).
OR33-03 Congenital Leptin Deficiency: Clinical Insights from the First Reported US Cases
Authors: Torchen Laura C , Hakamy Beth , Gordon Leo I , Marsh Erica E , Yaseen Nabeel R , Neff Lisa M
Published: May 2020

Background: Congenital leptin deficiency (CLD) is a rare autosomal recessive form of monogenic obesity caused by loss-of-function mutations in the leptin gene. Targeted therapy is available in the form of recombinant human leptin (metreleptin). Previous case series have reported dramatic weight loss and metabolic improvements with treatment, but metreleptin’s only FDA-approved indication is acquired generalized lipodystrophy (AGL). Metreleptin has a black box warning for risk of T-cell lymphoma, which has been reported in AGL patients, both treated and untreated with metreleptin.

Clinical Case: Two sisters ages 18 yrs (sister A; BMI 45.2 kg/m2) and 20 yrs (sister B; 45.0 kg/m2) were referred for evaluation of obesity. They are of Pakistani origin with a family history of consanguinity. Birth weight was normal, but hyperphagia and excessive weight gain developed by age 3 months. They had been seen by endocrinologists, obesity specialists, and a geneticist during childhood but work-up for monogenic obesity was not pursued. They were treated with combination OCPs in adolescence due to primary amenorrhea and hypogonadotropic hypogonadism. Sister A was diagnosed with type 2 diabetes at age 15 years. Sister B had comorbidities of hydrocephalus s/p VP shunt, developmental delay, hyponatremia, autoimmune thyroid disease, growth hormone deficiency, and prediabetes. At the time of their present evaluation, serum leptin levels were obtained and were undetectable in both sisters. After discontinuing OCPs, testing confirmed hypogonadotropic hypogonadism. Both patients were homozygous for the pathogenic variant c398delG in exon 3 of the leptin gene (LEP), which causes a frameshift/premature stop codon. On MR elastography performed for hepatic steatosis, sister B had an incidental finding of axillary lymphadenopathy. Surgical biopsy and staging work-up confirmed diagnosis of nodular lymphocyte predominant Hodgkin lymphoma (a B cell lymphoma), Stage II disease. She was treated with R-ABVD with adjuvant radiation and achieved clinical remission, prior to treatment with metreleptin. The patients were enrolled in an observational treatment protocol, and responses to metreleptin therapy will be reported in future.

Conclusion: To our knowledge, these are the first cases of CLD diagnosed in the U. S. In previous reports, CLD and other monogenic obesity disorders were prevalent among children with severe obesity in a consanguineous Pakistani population. Leptin deficiency should be considered in all patients with early onset obesity and hypothalamic amenorrhea. Furthermore, to our knowledge, this is the first report of lymphoma in a patient with CLD, occurring prior to any treatment with metreleptin. The risk for lymphoma associated with metreleptin may relate to preexisting autoimmune disease or immunologic abnormalities related to leptin deficiency rather than medication adverse effect.