bluuebunny/crossref_metadata_2025 huggingface dataset:
MON-130 Improving the Accuracy and Reliability of Free Thyroxine (FT4) Measurements Through the CDC Clinical Standardization Programs (CSP)
Authors: Ribera Ashley , Poynter Krista , Sugahara Otoe , Zhang Li , Danilenko Uliana , Vesper Hubert
Published: May 2020

Reliable free thyroxine (FT4) measurements are essential for assessing thyroid function and for correctly diagnosing and treating thyroid disorders. Thyroid hormones play an important role in normal brain development of the fetus, and abnormal FT4 during pregnancy is associated with adverse pregnancy outcomes. Standardization of FT4 measurements, is critical to improving the accuracy and reliability of current methods and thus to improve diagnosis, treatment and prevention of thyroidal illnesses. Currently, there are no serum-based reference materials available for FT4 to assess the accuracy and reliability of FT4 assays. CDC CSP is collaborating with the International Federation of Clinical Chemistry and Laboratory Medicine, and the Partnership for the Accurate Testing for Hormones to address these issues through development of an accurate and sensitive higher-order Reference Measurement Procedure (RMP) for FT4 that will be used to assign target value to serum-based materials. The CDC CSP FT4 reference method is using equilibrium dialysis in combination with liquid chromatography tandem mass spectrometry (LC-MS/MS). FT4 in serum is isolated from the binding proteins in 1 mL equilibrium dialysis cells for 4 hours at 37oC. FT4 is further isolated by extractions prior to LC-MS/MS analysis. To determine the concentration of FT4 in serum, certified primary reference materials are used to prepare calibration materials. Chromatographic separation is achieved using a C18 reverse phase column with a gradient of methanol and water with 0.1% formic acid. Quantification by selective reaction monitoring is performed in the positive mode using electrospray ionization. Two transitions are monitored for each analyte and internal standard, and triplicate injections are used to minimize instrument instability. The within- and between-day imprecision for the CDC RMP are 2.2–3.9% and 1.8–2.6%, respectively. By comparisons with the RMPs at Ghent University in Belgium, Radboud University Medical Center in the Netherlands, and the Reference Material Institute for Clinical Chemistry Standards in Japan, the CDC RMP reported a bias within +2.5% of the mean for all labs. Factors affecting measurement accuracy were investigated, to maximize recovery for optimum performance of the method. FT4 was detectable in all samples, and thus, suitable for analysis of hypo-, eu-, and hyperthyroid patients. A comparison among hypo-, eu-, and hyperthyroid patients of a commercially available immunoassay and the CDC RMP indicated a mean bias of -37.7%. The CDC CSP has also evaluated the RMP for accurate measurement of FT4 in pregnant individuals. This candidate reference method for FT4 in serum demonstrates good accuracy and precision, and can be used as a viable base for accuracy to which routine methods for FT4 can be compared. 1. Van Houcke, S.K., et. al. Clin. Chem. Lab. Med. 2011, 49, 1275–1281.
MON-650 Glucocorticoid- Induced Hyperglycemia, Higher Mortality and Morbidity? a Retrospective Analysis
Authors: Delfs Neele , Struja Tristan , Gafner Sandra , Muri Thaddäus , Bächli Ciril , Mueller Beat , Schuetz Philipp , Blum Claudine
Published: May 2020

Introduction: Glucocorticoid (GC)-induced hyperglycemia is a frequent side effect in hospitalized patients. Guidelines recommend treat-to-target treatment between 6-10 mmol/l with insulin, but patient-specific outcome has not been well-studied.

Methods: In this retrospective data analysis, all patient records of a Medical University Clinic from January 2014 to April 2018 were screened for GC administration. We investigated the incidence of hyperglycemia in hospitalized patients after administration of at least 10 mg prednisolone equivalents daily and a minimal length of stay of 3 days. The primary combined endpoint consisted of mortality, cardiovascular events, and infections until 30 days after admission.

Results: 2424 hospitalized patients received systemic GCs and met the inclusion criteria, of which 511 patients (21%) had an underlying diagnosis of diabetes. The overall incidence for GC-induced hyperglycemia was 33.5% (812 patients) and 3.7% of patients (n=89) had at least one documented hypoglycemia during the hospital stay. Compared to normoglycemic patients, GC-induced hyperglycemia was associated with a 40% increase in the risk for the combined primary endpoint (unadjusted odds ratio 1.39, 95%CI 1.16-1.66). This was also true after adjusting the analysis for age, Charlson comorbidity index and GC dose (adjusted odds ratio 1.68, 95% CI 1.25-2.26). Hypoglycemia was also associated with a doubling in the risk for the combined primary endpoint (odds ratio 1.95, 95% CI 1.2-3.17).

Discussion/Conclusion: Mortality, cardiovascular events and rate of infections were markedly higher in patients with GC-induced hyperglycemia compared to normoglycemic patients. Hypoglycemia was infrequent, but also associated with higher risk for adverse outcome. Future studies should evaluate whether glucose control with novel treatment modalities has a beneficial effect on clinical outcomes in patients with GC-induced hyperglycemia.
MON-190 Telomere Length as a Novel Prognostic Marker of Cushing Complications
Authors: Tatsi Christina , Faucz Fabio Rueda , Flippo Chelsi , Sinaii Ninet , Stratakis Constantine A
Published: May 2020

Telomeres are small sequences at the end of chromosomes, protecting them from abnormal degradation. Certain conditions, like cancer, have been associated with changes in telomere length (TL), which, in turn, may predict outcomes of the disease. Studies on the effect of cortisol on TL have not led to conclusive results or are limited in stress induced hypercortisolemia. Moreover, no study has focused on effects of persistent endogenous hypercortisolemia during childhood, a known important period for telomere modifications.

We hypothesized that TL is affected in pediatric patients with endogenous Cushing syndrome (CS) and it correlates with markers and complications of hypercortisolemia.

We studied 10 pediatric patients (mean age: 13.3 years, 7 females), diagnosed and treated successfully for Cushing disease. TL of total lymphocytes and their subtypes (Naïve T-cells, Memory T-cells, B-cells and NK-cells) were measured before and 1 year after treatment. TL was compared to age-matched control samples (6-8 per age group) and was correlated with clinical and biochemical characteristics. Paired or two-sample parametric or non-parametric statistical tests were performed, as appropriate.

Lymphocyte TL of patients with active CS did not differ from controls (p=.43). B-cell and NK-cell TLs were shorter after cure compared to active CS [mean B-cell TL difference: -1.44 Kb (-15%), p=.001; mean NK-cell difference: -0.51 Kb (-7%), p=.10] and controls [mean B-cell TL difference: -0.98 (-11%), p=.039; mean NK-cell difference: -1.3 Kb (-16%), p=.005]. Lymphocyte TL in active CS and the change of TL before and after cure did not correlate with measured markers of hypercortisolemia (morning and midnight cortisol, urinary free cortisol or ACTH levels). However, there was a strong inverse correlation between the difference of TL in active disease compared to controls and triglyceride level for all lymphocyte subtypes (range r= -0.74 to -0.86, range p= .003 to p=.022), suggesting that the higher the triglyceride levels, the shorter the TL in patients with CS. Additionally, inverse correlation was observed for weight and BMI SDS and B-cell TL, specifically (r= -0.76, p= .019 and r= -0.76, p= .018, respectively). Furthermore, there appeared to be an implication for shorter TL in CS patients with dyslipidemia compared to those without (mean TL difference from controls: -1.1 Kb in patients with dyslipidemia vs 0.53 Kb in those without, p= .067).

We conclude that although TL in active CS does not seem to differ from controls, B-cell and NK-cell TLs are affected after cure, and this may be related to acute changes that occur in the immune system peri- and post-operatively. Interestingly, the level of TL shortening correlates strongly with several complications of CS, including weight, BMI and dyslipidemia. This suggests that TL may be used as a surrogate prognostic marker of hypercortisolemia-related complications.
SUN-593 Variants in Known Monogenic Causal Genes of Hypertriglyceridemia Are Not Major Contributors for Hypertriglyceridemia in Lipodystrophy Due to a LMNA Mutation
Authors: Ueda Masako , McIntyre Adam D , Remaley Alan T , Hegele Robert A , Rader Daniel J
Published: May 2020

Background: Lipodystrophy is a heterogeneous disorder of adiposity, and one common lipid manifestation is hypertriglyceridemia (HTG). The LMNA gene, which encodes for nuclear envelope proteins, is a known causal gene for heritable lipodystrophy. At present, underlying mechanisms for each clinical manifestation of lipodystrophy due to a LMNA mutation are unknown.

Hypothesis: A likely explanation for HTG in lipodystrophy is the paucity of adipose tissue where excess triglycerides (TGs) are normally stored, thus it may not be due to a specific defect in lipoprotein metabolism. Consequently, rare variants in HTG-associated genes would not be expected to be major contributors for HTG in lipodystrophy with LMNA mutations.

Method: A proband and her father with a clinical diagnosis of lipodystrophy were recruited into an IRB-approved study investigating molecular etiologies of dyslipidemia at the University of Pennsylvania. Next-generation sequencing (NGS) with the LipidSeq panel, targeting causal genes for lipodystrophy, and monogenic HTG was performed, and confirmed by Sanger sequencing. Also, unweighted TG-polygenic scores by summing the number of TG-raising alleles from 14 single nucleotide polymorphisms (SNPs) associated with TG levels were assessed.

Results: The proband and her father were diagnosed with lipodystrophy of two different subtypes, generalized in the daughter and partial in the father. The proband reported a gradual loss of subcutaneous fat starting around age 10. A highest reported TG in the proband was19,000 mg/dL with eruptive xanthomas, whereas TG in the father was never >500 mg/dL. Their BMI’s and DEXA body fat% were 12.9 kg/m2 and 7% in the proband, and 25.7 kg/m2 and 25% in the father, corresponding to their fat storage capacities.

The molecular analyses revealed only a lipodystrophy causal mutation in LMNA, c.29C>T, T10I with no other significant findings in18 other lipodystrophy-related genes. No deletion or duplication was identified by a targeted array CGH of LMNA.

As predicted, no rare monogenic variants in HTG-causal genes (LPL, GPIHBP1, APOA5, APOC2, LMF1, GPD1) were identified in either subject. However, TG-polygenic scores were 17/28 (95th %ile) in the proband, and 13/28 (50th %ile) in the father, the same trend as the level of HTG levels seen in them. Apolipoprotein E genotypes were non-contributory, (3/3) in the proband, and (3/4) in the father.

Conclusion:

Our findings support that the pathophysiology of HTG in lipodystrophy is likely to be due to lack of TG-storage space (adipose tissues), and is unlikely due to a defect in lipoprotein metabolism seen in patients with rare monogenic HTG-variants. Although the HTG-polygenic score was higher in the proband, and the accumulative effects of the at-risk alleles may be contributor to the HTG phenotype, it is unlikely to be the leading cause of severe HTG seen in the proband.
SAT-139 STAT5A Regulation by Serine Phosphorylation in Breast Cancer
Authors: Woock Alicia E , Grible Jacqueline M , Zot Patricija , Harrell J Chuck , Michael Idowu , Clevenger Charles V
Published: May 2020

The neuroendocrine hormone prolactin (PRL) and its cognate receptor (PRLr) have been implicated in the pathogenesis of breast cancer. PRL signaling relies on activating kinases such as the tyrosine kinase Jak2 and serine/threonine kinases ERK1/2, Nek3, PI3K, and AKT. In the canonical pathway of PRL signaling, Jak2 phosphorylates the transcription factor Stat5a at tyrosine residue 694 (pY694-Stat5a), preceding Stat5a nuclear translocation and transcriptional activity. However, Stat5a exists with functional duality as a transcription factor, having both pro-differentiative and pro-proliferative target genes. Other Stat family members (Stats 1, 3, and 6) have been shown to have transcriptional activity in the un-phosphorylated (upY) state, distinct from that of pY-Stat activity. This distinction (upY vs. pY) may underlie the duality of Stat5a, coupled with additional regulatory non-canonical post-translational modifications. Within this notion, Stat5a contains two serine residues, S726 and S780, whose phosphorylation are necessary for hematopoietic transformation. However, their functions in PRL-mediated breast cancer pathogenesis have not been examined. We hypothesize that Stat5a serine phosphorylation regulates Stat5a nuclear activity in a non-canonical fashion, contributing to its role in mammary oncogenesis. As shown in a tissue microarray (TMA), human breast cancer tissues express both pS726- and pS780-Stat5a. Nuclear Allred score for pS726-Stat5a increases two-fold with increasing tumor grade, with no difference in staining associated with estrogen or progesterone receptor (ER, PR) status, nor other clinical characteristics. Likewise, patient derived xenograft (PDX) tumors of various molecular subtypes express pS726- and pS780-Stat5a. Phosphorylation of S726-Stat5a is PRL-responsive in vitro. Pharmacologic inhibition of ERK1/2 prevents this phosphorylation, uncovering a novel pathway in which ERK1/2 mediates Stat5a activity in response to PRL in breast cancer. To examine the functional significance of Stat5a serine phosphorylation in vitro, we have performed Stat5a knockdown (KD) in the breast cancer cell line MCF7. Following Stat5a KD, cells were rescued with phospho-site specific Stat5a mutant constructs. Characteristics of breast cancer examined in these mutation-carrying cells, including anchorage-independent growth and proliferation, show distinct phenotypes compared to controls. PRL-induced expression of the CISH gene is significantly decreased up to 65% in the mutation-carrying cells compared to wild type Stat5a. Mechanistic studies will examine the ability of these Stat5a mutants to undergo nuclear translocation and interact with other transcription factors. Collectively, these studies have the potential to provide novel insights into the role of the non-canonical pathway of Stat5a activation in breast cancer pathogenesis.
SAT-740 Plasma Glucocorticoids and Mineralocorticoids Are Associated to Metabolic Syndrome Features in Women
Authors: Ostinelli Giada , Adamski Jerzy , Tchernof André
Published: May 2020

Background: Excess visceral adipose tissue accumulation on anatomical structures such as the greater omentum and mesentery are strong predictors of obesity-associated comorbidities (1). High glucocorticoid levels have been associated with body fat distribution and preferential visceral fat accumulation as well as features of the metabolic syndrome (MetS) (2). These effects are thought to be mediated by the glucocorticoid receptor, a nuclear receptor showing affinity for both glucocorticoids and mineralocorticoids. In this study, we examined plasma concentrations of glucocorticoids and mineralocorticoids in women with or without the MetS. In addition, we assessed the ability of these steroids to predict fat accumulation and features of the MetS.

Methods: In a sample of 49 women (age 47 ± 4.99 years; BMI 26.4 ± 4.70 kg/m2), plasma concentrations of cortisol, 11-deoxycortisol, cortisone, aldosterone, corticosterone and 11-deoxycorticosterone were analyzed by electrospray ionization-liquid chromatography-tandem mass spectroscopy (ESI-LC-MS/MS). Metabolic parameters were assessed to establish the presence of the MetS using NCEP-III criteria. Subcutaneous and visceral adipocyte cell size was measured by histomorphometry.

Results: We found HDL-triglycerides to be positively associated with levels of 11-deoxycorticosterone, 11-deoxycortisol, corticosterone, cortisone and cortisol (p<0.05 for all). 11-deoxycorticosterone concentration was also negatively associated with waist circumference (-0.294, p<0.05), LDL-cholesterol and LDL-triglyceride content (-0.264 and -0.362, p<0.05) whereas cortisone level was positively associated with fasting glucose (0.3, p<0.05). Our model including mineralocorticoids predicted systolic blood pressure (R2=0.303), while the one including glucocorticoids predicted HDL-cholesterol (R2=0.495). In addition, as expected, we found that women with the MetS were characterized by significantly higher percentage body fat and displayed subcutaneous and visceral adipocyte hypertrophy (p<0.05). Interestingly, women with the MetS also showed a trend for lower plasma cortisol concentrations (p=0.07).

Conclusion: Our data suggest that glucocorticoids and mineralocorticoids are associated with individual components of the MetS in women.

(1) Tchernof et al.(2013), Physiol Rev, 93(1);

(2) Constantinopoulos et al., (2015), Eur J Endocrinol, 172(1)
SUN-594 Pubertal Timing and Hormonal Correlates in Male Obesity
Authors: De Schepper Jean , Berlanger Evy , Van Helvoirt Monique , De Guchtenaere Ann , Basslé Eddy , Anckaert Ellen , Vanbesien Jesse , Gies Inge
Published: May 2020

An early, normal or delayed pubertal onset have been described in overweight/ obese males(1). A greater prepubertal adiposity has been associated with a greater risk for delayed puberty in males, but an underlying mechanism was not explored(2). We investigated whether an increased testosterone aromatization or an higher degree of low-grade inflammation might be more prevalent in obese males with a delay in genital development. Pubertal status assessment by Tanner staging and measurement of morning serum testosterone, estradiol, leptin, and hSCRP by standard laboratory methods were performed in 191 male adolescents, aged between 10 and 18.6 yr (median 12.8 yr) with overweight (BMI z-score > 1.3), starting an ambulatory (n = 138) or a residential weight loss program (n = 55). Their median (range) BMI z-score was 2.32 (1.34 – 3.38). Delayed / slow and early / rapid genital development was defined by a Tanner genital stage respectively above the 90th or below 10th percentile age distribution (national Flemish standards of 2004). In 3 males pubertal development was advanced, while in 34 it was delayed. In the remaining 154 adolescents genital stage was normally timed. Males with a delayed timing or progression of genital development were older (median(range) age:14.8 (11.6-18.6) yr vs 12.3 (10-18.6) yr; p< 0.005) and shorter (height sds: -0.55 (-1.90- 1.48) vs 0.49 (-3 – 3.19); p < 0.005), and had a higher birthweight (birthweight z-score: 0.15(-3.51-2.75) vs -0.34(-4.7-3.30); p = 0.058), but a similar BMI and waist z-score in comparison with males with a normally timed puberty. Median serum estradiol, leptin, and hSCRP concentrations did not differ significantly between those with a normal or a delayed pubertal onset or progression. In conclusion, pubertal delay is more frequently observed than early puberty in males referred to obesity clinics. Neither low grade inflammation nor increased estradiol production appear to be associated with a later onset of slower progression of genital development in male obesity. References (1) Li W et al. Int J Environ Res Public Health. 2017 Oct 24;14(10) (2) Lee JM et al. Arch Pediatr Adolesc Med. 2010 Feb;164(2):139-44.
SAT-006 A New Concept for the Endocrinology of Pre-Eclampsia: The Role of Spiral Steroids
Authors: Chasalow Fred I , Bochner Ron
Published: May 2020

Background: In 1987, Graves observed that during the 3rd trimester, some patients with pre-eclampsia had high levels of unknown materials that could be detected with assays for digoxin (DLM). In 2018, we characterized a new candidate for the DLM, Ionotropin. It is a phosphocholine (PC) ester of a novel steroid with 23 carbon atoms. As Ionotropin shares structural features (a) with spironolactone (both have spiral lactones in the E-ring) and (b) with digoxin (E-ring lactone and 3α-5β configuration), we have proposed that Ionotropin may function as a potassium (K+) sparing diuretic. This suggestion is supported by the observations that [1] patients who cannot make Ionotropin (7-dehydrosterol reductase deficiency) are K+ wasting and [2] breast cyst fluids with high K+ levels also have high Ionotropin levels.

Hypothesis: During the 3rd trimester, fetal requirements for K+ reach a maximum, fetal blood pressure increases and aldosterone signaling is blocked. This blockage leads to fetal sodium (Na+) wasting and is essential for formation of amniotic fluid. These events are consistent with a normal role for an unknown endogenous K+ sparing hormone and would be the basis for a modest elevation of maternal DLM during the 3rd trimester. Our hypothesis is that if any of the functions were inadequate, then the fetal-placental unit would synthesize excess PC-spiral steroids; the woman would exhibit symptoms of K+ sparing hormone excess (hypertension and proteinuria) and would be diagnosed with pre-eclampsia.

Experimental Results: We have just reported a pilot study associating elevated PC esters of spiral steroids in women with pre-eclampsia. In brief, 12 of 19 women had elevated levels of at least one of the PC steroids (Z-score > 2) when compared to the levels in 20 pregnant women matched for gestational age and fetal sex. There are two basic mechanisms for this dichotomy: (a) there may be episodic secretion with of a DLM with a short half-life or (b) there may be two different underlying biochemical causes. In prior studies, there has been no indication of episodic secretion of DLM similar to that observed with glucocorticoids, Ionotropin or other PC spiral steroids.

Discussion: There are two basic types of K+ sparing diuretics. Type A: Spironolactone functions by regulating the NaK-ATPase. Type B: Triamterene functions by blocking synthesis of epithelial Na+ channels. Thus, Type A would have high levels of spiral steroids and Type B would have low levels of spiral steroids. Type A patients would be expected to have higher risk of long-term consequences when compared to the Type B patients.

Conclusion: The recognition of the division of pre-eclampsia into two separate diseases might be the key observation for developing Type-specific diagnosis and therapy. For example, a Type A patient might benefit from a low salt diet but that diet would not be expected to benefit a patient with Type B disease.
MON-205 Effectiveness of Pre-Op α-Blockade on Intra-Op Blood Pressure Control in Patients with Pheochromocytoma
Authors: Lake Julia Caroline Wingate , Comi Richard J
Published: May 2020

Pheochromocytoma are rare tumors arising from catecholamine producing chromaffin tissue. Surgical manipulation of pheochromocytoma inevitably leads to supraphysiologic levels of circulating catecholamines. Such manipulation has the potential to lead to an intra-operative hypertensive crisis, cardiac arrhythmia, myocardial infarction, or pulmonary edema. When inadequately primed pre-operatively, a patient exposed to such surges may experience life-threatening consequences.

Phenoxybenzamine is a non-competitive, non-selective α 1 and α 2 receptor antagonist that prevents blood pressure liability during surgical resection of pheochromocytoma. Previous literature has suggested that phenoxybenzamine affords more pronounced peri-operative systolic blood pressure control as compared to selective alpha-blockers. This superior control potentially is at the cost of postoperative hypotension owing to the irreversible nature of phenoxybenzamine.1

Our study compares the effects of pre-operative phenoxybenzamine on perioperative outcomes at a single tertiary medical center from 2004 to 2019. The cumulative pre-operative phenoxybenzamine dose was compared to the maximum intra-operative blood pressure, need for IV blood pressure lowering medications, duration of vasopressor need, volume replacement need, duration of time in the OR, duration of hospital stay, and pre-operative catecholamine levels. We speculate that increased phenoxybenzamine exposure will result in reduced peak intra-operative blood pressure and need for IV blood pressure lowering medications but may increase the need for post-resection intra-operative vasopressors and post-resection volume replacement.

After IRB approval, (ID #00031606), we performed a data warehouse query for the ICD 9 and 10 codes of “pheochromocytoma” and “paraganglioma”. Patients who did not have confirmed pheochromocytoma on pathology were excluded. Data was collected retrospectively on 30 patients who underwent adrenalectomy for pheochromocytoma. 14 charts were excluded due to incomplete intra-operative anesthetic documentation.

Our results suggest that there is no significant correlation between peak intra-operative MAP and cumulative phenoxybenzamine exposure. The cumulative dose of pre-operative phenoxybenzamine did not correlate with the number of anti-hypertensive medications used intra-operatively. An increased cumulative dose of pre-operative phenoxybenzamine was not associated with an increased duration of intra-operative vasopressor medications. Intra-operative volume replacement needs were surprisingly reduced with increased cumulative pre-operative phenoxybenzamine exposure.

1 P.A. van der Zee, A. de Boer. Pheochromocytoma: A review on preoperative treatment with phenoxybenzamine or doxazosin. The Netherlands Journal of Medicine. May 2014; Vol. 72 No 4, 190-201.
SAT-184 Silent Pheochromocytoma Complicated by Adrenal Insufficiency After Unilateral Adrenalectomy
Authors: Aftab Hassaan B , Madhavan Parvathy , Dulipsingh Latha
Published: May 2020

Background: Adrenal insufficiency (AI) following unilateral adrenalectomy for pheochromocytoma (PCC) is an exceedingly rare occurrence described previously in 1 study in only 4 out of 13 patients with unilateral PCC. We discuss an unusual case of a patient with incidentally discovered PCC who underwent unilateral adrenalectomy and subsequently developed AI.

Clinical Case: 61-year-old male in overall good health taking no medications presented with left flank and groin pain after a handlebar injury in a bicycle crash. CT angiogram Abdomen & Pelvis revealed a complex enhancing left adrenal mass with internal necrosis measuring 13 x 12 cm. He denied history of headaches, diaphoresis, chest pain or hypertensive crisis. He did endorse palpitations which had resolved with reduced caffeine intake. Labs showed plasma free metanephrine 3,295 pg/mL (ref range <57) and normetanephrine 68,472 pg/mL (<148), 24hr urine metanephrine 192,677 ug (52-341), 24hr urine normetanephrine 171,880 ug (88-444), 24hr urine vanillylmandelic acid (VMA) 182 mg (1.8-6.7), serum aldosterone 8.1 ng/dL (<39.2), serum free cortisol 0.47 ug/dL (0.07-0.93), 24hr urine cortisol 41.6 ug (<60), DHEA sulfate 37 ug/dL (42-290). He was started on phenoxybenzamine and underwent left adrenalectomy. Of note patient remained only minimally hypertensive with tumor manipulation intraoperatively. Pathology was consistent with PCC with no evidence of regional or distant metastases. Postop-labs showed plasma free metanephrine <25 pg/mL and normetanephrine 122 pg/mL. Calcitonin and parathyroid hormone levels were normal. Patient was evaluated in endocrinology clinic 4 weeks after surgery for complaint of severe fatigue, weight loss, anorexia and myalgias. Adrenocorticotropic hormone (ACTH) level was 31 pg/mL (7.2-63) with AM cortisol of 2.1 ug/dL (5-23) which increased to 7.4 ug/dL 1 hour after Cosyntoprin 250 mcg stimulation. He was started on prednisone 10 mg once daily with significant improvement in his symptoms.

Conclusion: PCCs typically manifest as sustained or paroxysmal hypertension, episodic headaches, palpitations or diaphoresis. Our patient was found to have a PCC with strikingly elevated levels of catecholamines without typical signs and symptoms of PCC. To the best of our knowledge this is the 5th reported case where a patient developed AI after unilateral adrenalectomy for PCC. There are case reports describing PCCs which secrete both catecholamines and ACTH. However, our patient lacked clinical or biochemical evidence of hypercortisolism preoperatively and his tumor cells in path sample stained negative for ACTH. Other possible pathophysiologic mechanisms include ectopic corticotropin releasing factor production leading to subclinical Cushing syndrome (SCS). Clinicians should have a high suspicion for SCS in the setting of PCC to promptly diagnose and treat AI after unilateral adrenalectomy.
SAT-239 Combination of Immune Check Point Inhibitors Causing Hypopituitarism
Authors: Dhillon Puneet , Grover Harshwant , Slusser Jonathan , Gopisetti Neethu , Patel Tirth
Published: May 2020

Introduction: Immune Check Point inhibitors (ICI) have been associated with immune related adverse events including a wide array of Endocrinopathies particularly when a combination of ICIs is used. We present a case of Hypopituitarism secondary to CTLA-4 inhibitor Iplimumab and PD-1 inhibitor Pembrulizumab in a patient with Vulvar Melanoma.

Case Description: 49-year-old female with past medical history of Type 2 Diabetes and Vulvar Melanoma presented with nausea, vomiting and fatigue. The patient had surgical excision of Vulvular Melanoma and had been on chemotherapy with Pembrolizumab and Ipilimumab for 1 month. She was found to be hypotensive in the ER, but blood pressure improved after fluid resuscitation. Her blood sugar levels were 76 MG/DL. She denied using any insulin in the last 24 hours. AM Cortisol was <1 UG/ML. TSH was 0.205 UIU/ML with free T4 at 0.74 NG/DL. FSH was 2.5 MIU/ML. LH was 0.5 MIU/ML. Prolactin was 90.2 NG/ML. ACTH was less than 9 PG/ML. MRI of the brain showed mildly enlarged pituitary gland with suprasellar extension, measuring 10.5 mm in craniocaudal height and normal homogeneous enhancement. A diagnosis of Hypopituitarism secondary Ipilimumab and Pembrolizumab was made. She was started on steroids and thyroid replacement. The patient’s symptoms resolved, and she was discharged home in a stable condition with outpatient Endocrinology follow up.

Discussion: Immune checkpoint inhibitors (ICI) includes PD1(Programmed cell death receptor 1) inhibitors like Pembrolizumab and CTLA-4 (Cytotoxic T Lymphocyte Antigen-4) inhibitors like Ipilimumab. CTLA-4 inhibitors have more frequently been associated with Hypophysitis leading to particularly ACTH and TSH deficiencies and causing secondary adrenal insufficiency and secondary hypothyroidism. Posterior Pituitary involvement is less common. MRI usually shows mild to moderate enlargement of the pituitary gland. ICI therapy usually does not need to be stopped. Patients commonly require long term glucocorticoid and thyroid replacement.
SUN-573 Use of PCSK9 Inhibitors Post-Transplant
Authors: Matthews Juliana , Donald Dustin , Carranza-Leon Barbara Gisella
Published: May 2020

Background:

Dyslipidemia is common in patients after transplant. While statins are the mainstay of therapy, interactions with immunosuppressants such as calcineurin inhibitors (CNIs) can limit dose titration or lead to intolerance of this important drug class. Withdrawal of statin therapy can precipitate hyperlipidemia and potentially accelerate cardiovascular disease in transplant recipients, including coronary allograft vasculopathy (CAV) in heart transplant (HT) patients. Proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9i) may provide a safe, effective option for such patients. PCSK9i profoundly reduce low-density lipoprotein (LDL) and subsequently the risk of cardiovascular events in nontransplant patients. Further, these novel agents have no known interactions with CNIs. There is a paucity of data describing PSCK9i use post-transplant, with only a few small case series reported in HT recipients. Here, we summarize our experience along with available literature on this topic.

Methods:

In this retrospective case series we investigated adult recipients of heart transplant who were treated with PCSK9 inhibitors from July 2015 to 2019 because of statin intolerance or refractory hyperlipidemia. We compared the data of patients at baseline and after various durations of therapy with the PSCK9i evolocumab and alirocumab using the median and interquartile range (IQR). Specifically, we evaluated PCSK9i efficacy, effect on immunosuppressant levels, cardiac function and adverse events.

Results:

Five patients (4 men; median age 54, IQR 52-60) underwent heart transplant an average of 7.4 years ago. Median treatment duration of evolocumab or alirocumab was 12 months (IQR 7-17). This led to a reduction of total cholesterol by 94 mg/dl (p=0.04) (47% decrease) and LDL cholesterol by 83 mg/dl (p=0.04) (69% decrease). No statistically significant difference in HDL cholesterol, triglycerides or liver function tests (LFTs) were observed. There were no episodes of rejection. Immunosuppressant levels remained at goal. One patient noted a few days of fatigue after alirocumab injections but otherwise no side effects were reported.

Conclusion:

The PCSK9 inhibitors evolocumab and alirocumab are promising alternatives to statin therapy in transplant recipients with statin intolerance or refractory hyperlipidemia. Our study showed their potential to significantly reduce LDL cholesterol in heart transplant patients without altering IST levels. No episodes of transplant rejection were noted. Further long-term studies to establish the safety and efficacy of PSCK9 inhibitors post-transplant are needed.
MON-448 Detection of Thyroid Cancer Recurrence in Patients with Positive Thyroglobulin Antibody Receiving Immunoglobulin Therapy
Authors: Taiwo Adeyinka , Dokun Ayotunde
Published: May 2020

Introduction: Differentiated thyroid cancers such as papillary and follicular thyroid cancer make up more than 90% of all thyroid cancers. The presence of thyroglobulin autoantibodies makes interpretation of the thyroglobulin level unreliable, as it could be falsely low or falsely high. Studies have shown that rising thyroglobulin antibody levels, could be used to monitor for disease recurrence in patients with negative thyroglobulin and imaging studies. However, there are challenges in detecting recurrence in patients with normal thyroglobulin level and thyroid imaging studies, who are on lifelong immunoglobulin therapy and who have increasing thyroglobulin antibody levels.

Clinical case: A 63 yr old female was found to have an incidental left thyroid nodule at age 48yrs from a carotid ultrasound. She underwent US guided FNA of the thyroid nodule and was found to have papillary thyroid cancer. She had total thyroidectomy a month later, with removal of a 1.4cm primary, with no evidence of extrathyroidal extension, clear margins and no evidence of lymphovascular invasion – Stage T1bN0M0. There was left level 6 neck dissection with no carcinoma identified in the 2 lymph nodes removed. She received 105.3 mCi radioactive iodine (RAI) and whole body thyroid scan done 7 days later revealed, increased uptake involving the thyroid bed likely residual thyroid tissue. Activity was noted inferolateral to the right thyroid bed which most likely represents a lymph node. There was no evidence of distant metastasis.

She was commenced on levothyroxine post operatively. Her other past medical history is significant for idiopathic urticaria and angioedema, immune deficiency disorder with low IgG and IgM and asthma. She was commenced on monthly IV immunoglobulins 5yrs post RAI therapy, due to recurrent sinusitis, rhinitis and chronic diarrhea. She was later transitioned to weekly SQ immune globulin – Hizentra which she is on till date.

Over the past 15 years, serial neck ultrasounds post radioiodine ablation have been negative for recurrence. Her TSH ranged 14.91 to 0.04 (ref 0.27-4.2 uiu/ml) and thyroglobulin (Tg) titer remains <0.1 (ref <0.1). Her thyroglobulin antibody titers have trended up from <0.2 (ref <2.0) 5yrs post RAI therapy to 49 (ref <4 iu/ml)) on her most recent test this year. She is currently undergoing further work up to rule out recurrence of her cancer. In our review of the literature we found one report that showed use of Liquid Chromatography–Mass Spectrometry (LC-MS) was able to differentiate thyroid cancer recurrence in an individual with positive antithyroglobulin antibody receiving immunoglobulin therapy.

Conclusion: In patients with negative Tg levels, but elevated thyroglobulin antibody while receiving immune globulin therapy, thyroglobulin antibody levels may not be a reliable indicator of thyroid cancer recurrence. Measurement of Tg levels using a LC-MS may provide some clarity.
SAT-491 Transient Thyrotoxicosis with Immune Checkpoint Inhibitors Therapy: The Importance of Endocrine Evaluation
Authors: Martins Diana Cruz , Guelho Daniela , Vicente Nuno , Ventura Mara , Vieira Alexandra
Published: May 2020

Introduction

The immune checkpoint-blocking antibody nivolumab is recognized as having a crucial role in different malignancies by blocking programmed death-1 (PD-1) receptor immune cells. Besides its benefits, nivolumab may cause endocrine immuno-related adverse events (irAEs), including thyroid dysfunction (TD).

Clinical case

A 71-year-old man, with an uneventful past medical history, was diagnosed with stage IIIB (T4N2M0), epithelial-growth-factor-receptor (EGFR) wild type, lung adenocarcinoma.

The patient underwent 4 cycles of first line chemotherapy with cisplatin/vinorelbine and then radiotherapy, obtaining a partial response.

After 4 months, tumor progression was identified, as assessed by whole-body 18-Fluorodeoxyglucose positron emission tomography (FDG-PET) scan, showing pleural and nodal metastasis. Nivolumab, 3 mg/kg every 2 weeks, was started at this point.

While pre-nivolumab thyroid function was normal, 3 months after starting the therapy, a low serum TSH level of 0.04 mUI/mL (0.38-5.33) was found, associated with a normal level of FT4, of 10.8 pmol/L (7.9-14.4). Thyroid antibody (Ab) tests, including TSH-receptor Ab, were negative. At ultrasound examination, thyroid gland parenchyma was normo-echoic, demonstrating an isoechoic thyroid nodule in the right lobe, with regular margins, measuring 14mm diameter. Previous medical history was negative for thyroid disease.

One week after the referred thyroid function tests, nivolumab was discontinued due to progressive disease as assessed by abdominal magnetic resonance, demonstrating right adrenal metastasis and patient started cisplatin/permetrexed chemotherapy. One month after nivolumab suspension, patient had already normalized thyroid tests, with TSH 2.27 mUI/mL and FT4 9.1 pmol/L. More recently (6 months after nivolumab discontinuation), thyroid function tests continued stable, with TSH 1.05 mUI/ml and T4L 9.4 mmol/l. At this point, patient was receiving permetrexed maintenance therapy.

Conclusions

Immune checkpoint molecules as nivolumab, play a crucial role in anti-tumor immunity evasion. Besides its benefits, it may cause irAEs, including TD.

We believe it’s essential to perform thyroid function tests at baseline and before the administration of each nivolumab dose, if possible. Additionally, large prospective studies are required in order to assess, the impact of autoimmunity on the development of TD induced by nivolumab, and its potential effect on overall survival and specific cancer survival data.
MON-005 Inhibition of Glucocorticoid Signaling in SRC-1/-2 Double-Deficient Mice Results in Impaired Lung Maturation and Delayed Parturition
Authors: Mishra Ritu , Chen Jingfei , Gao Lu , Mendelson Carole R
Published: May 2020

The mechanisms that lead to the initiation of parturition are incompletely defined. Parturition timing is mediated by signals from both mother and fetus. Our previous findings using mice that were double-deficient in steroid receptor coactivators (Src)1 and 2 (Src-1/-2d/d) suggest that the fetus signals its mother when it is ready to be born through fetal lung production of surfactant components, surfactant protein A (SP-A) and platelet-activating factor (PAF). Notably, mice that are double knockout for Src-1/-2 die at birth of respiratory distress, due to decreased surfactant lipoprotein production. Intriguingly, we observed that wild-type (WT) mothers carrying Src-1/-2d/d fetuses manifested a ~38 h delay in parturition compared to WT mothers carrying WT fetuses. This was associated with decreased production of SP-A and PAF by the Src-1/-2d/d fetal lungs. Our findings suggested that these effects of Src-1/-2d/d were caused by impaired glucocorticoid receptor (GR) transcriptional activity in fetal lung cells. To identify other genes in fetal lung that were affected by Src-1/-2d/d, we conducted RNA-seq analysis of lungs from 18.5 days post-coitum Src-1/-2d/dvs. WT fetuses. We observed that one of the genes most highly downregulated in Src-1/-2d/d fetal lungs was 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). 11β-HSD1 catalyzes the conversion of inactive cortisone or 11-dehydrocorticosterone into active cortisol or corticosterone, respectively, which are ligands for the glucocorticoid receptor (GR). We validated the RNA-seq results by RT-qPCR and immunoblotting and observed a striking reduction of 11β-HSD1 mRNA and protein in lungs of Src-1/2d/d fetuses, compared to WT. Others observed that glucocorticoids potently increased 11β-HSD1 expression in various cell types via activation of transcription factors C/EBPα and C/EBPβ, providing a potential positive feed-forward loop. Notably, we observed that C/EBPα and C/EBPβ mRNA and protein were markedly reduced in Src-1/-2d/d fetal lungs, compared to WT. Deletion of the Cebpa gene in respiratory epithelium of fetal mice caused respiratory failure at birth due to surfactant lipid and protein deficiency. This was associated with increased expression of TGF-β2, which inhibits fetal lung maturation. Notably, we observed that expression of TGF-β2 and TGF-β3 were increased in Src-1/-2d/d fetal lungs. Thus, impaired lung development, surfactant synthesis and delayed parturition in Src-1/-2d/d fetuses are likely caused by decreased 11β-HSD1 and GR signaling, resulting in decreased C/EBPα/β expression and increased TGF-β signaling.
SAT-598 Shared Signaling Profile Between Human MRAPα-Induced Human MC4R Constitutive Activity and Obesity-Associated Human MC4R Constitutive Activity
Authors: Botha Rikus , Kumar Shree S , Grimsey Natasha , Kay Emma I , Mountjoy Kathleen Grace
Published: May 2020

The human melanocortin 4 receptor (hMC4R) plays a critical role in the regulation of energy balance with more than 150 distinct human obesity-associated mutations. Most exhibit defective MC4R functionality but six have been reported to associate with constitutive activity. This represents a conundrum since a lean phenotype is expected for enhanced MC4R signaling. Human melanocortin 2 receptor accessory protein alpha (hMRAPα) induces hMC4R constitutive activity in transfected HEK293 cells (1,2). We do not know whether the hMRAPα-induced gain-in-function for hMC4R would cause, or prevent, obesity because of this conundrum. Here, we hypothesize that wild-type hMC4R, obesity-associated constitutively active hMC4R and hMRAPα-induced constitutive active hMC4R can exist in distinct conformational states and elicit distinct signaling profiles. To test this, we compared transiently expressed HA-hMC4R in HEK293 cells for basal and agonist activation for adenylyl cyclase, Cre driven β-galactosidase reporter transcription, and receptor protein expression. Six previously reported obesity-associated hMC4R constitutively active variants were compared with two hMC4R constitutively active mutations not associated with obesity, two hMC4R variants associated with protection from development of obesity, five non-constitutively active hMC4R mutations associated with obesity, hMRAPα co-expressed with hMC4R, and wild-type hMC4R. Our data confirm hMC4R constitutive activity coupling to both adenylyl cyclase and Cre β-galactosidase reporter for only two hMC4R variants associated with obesity (H76R & L250Q), one hMC4R mutation (H158R) not associated with obesity, and hMRAPα co-expressed with hMC4R. We show α-MSH stimulated concentration curves for wild-type hMC4R, H76R, L250Q & H158R hMC4R variants and hMRAPα co-expressed with hMC4R coupling to adenylyl cyclase. Surprisingly, out of these, only wild-type hMC4R and H158R hMC4R variant exhibited α-MSH-stimulated Cre β-galactosidase reporter concentration curves. Western blotting and ELISA showed ~70% reduced cell surface and total receptor protein expression for hMC4R co-expressed with hMRAPα and obesity-associated constitutively active hMC4R variants, compared to wild-type hMC4R. To summarize, two constitutively active hMC4R variants (H76R and L250Q) associated with obesity, and hMC4R co-expressed with hMRAPα, share a signaling profile comprising protein expression and α-MSH stimulated functional coupling to adenylyl cyclase and Cre-reporter gene expression. We conclude (1) if hMC4R is co-expressed with hMRAPα in vivo it would likely contribute to human obesity, and (2) obesity-associated constitutively active hMC4R variants exhibit a signaling anomaly that may underpin development of anti-obesity therapeutics.

1. Kay EI, et al. J Mol Endocrinol. 2013;50:203-215.

2. Kay EI, et al. PLoS ONE. 2015;10(10):e0140320.
SAT-558 A Dedicated Endocrine Hypertension Service Increases the Timely Diagnosis of Primary Aldosteronism
Authors: Yang Jun , Lim Yin Y , Libianto Renata , Shen Jimmy , Young Morag Jennifer , Fuller Peter J
Published: May 2020

Background: Primary aldosteronism (PA) accounts for 3.2-12.7% of hypertension in primary care but is often diagnosed late, if at all. A delayed or missed diagnosis leads to poor blood pressure control and greater cardiovascular risk that could be averted with targeted treatment. An Endocrine Hypertension Service (EHS), encompassing an education program, streamlined diagnostic tests and dedicated PA clinic, was developed to address this issue.

Aims: To analyse the impact of Victoria’s first dedicated EHS on the pattern of PA diagnoses.

Methods: Socio-demographic and clinical data from all patients who attended the EHS since July 2016 (N=267) was collected prospectively. Patients were divided into Year 1 (Y1), Year 2 (Y2), and Year 3 (Y3), based on their first visit.

Results: The proportion of referrals from primary care increased (20% in Y1 to 52% in Y3) with more referrals being made for treatment-naive hypertension (3% in Y1 to 19% in Y3). Patients with a hypertension diagnosis of 5 years or less at the time of referral to EHS increased from 34% in Y1 to 45% in Y3 whilst the percentage of patients with a hypertension diagnosis of more than 10 years decreased from 50% in Y1 to 35% in Y3. Consistent with an earlier presentation, the proportion of patients with end-organ damage at the time of referral decreased from 44% in Y1 to 29% in Y3. Almost a third of the PA patients had unilateral disease; all of those who underwent adrenalectomy had biochemical cure. Patients with bilateral PA were treated with spironolactone. Their systolic/diastolic blood pressure decreased by 15/12 mmHg in Y1, 17/13 mmHg in Y2 and 23/11 mmHg in Y3; while the mean number of antihypertensive medications decreased from 2.9 to 1.8 in Y1, 2.7 to 2.0 in Y2 and 2.2 to 1.6 in Y3

Conclusion: The EHS has facilitated an increase in referrals for PA screening from primary care, resulting in the earlier diagnosis of PA, when less complications are present, and optimised patient outcomes. A broader uptake of such a clinical service, integrated with education outreach, will bridge the gap between the reported high prevalence of PA and the actual low diagnostic rates.