bluuebunny/crossref_metadata_2025 huggingface dataset:
MON-189 Evaluation of Adrenal Insufficiency and Recovery in Rheumatology Patients on Long-Term Glucocorticoid Therapy
Authors: Sagar Rebecca , Mackie Sarah , Stewart Paul Michael , Abbas Afroze
Published: May 2020

Background

Long-term glucocorticoid (GC) therapy is commonly used to treat rheumatological conditions. This may result in tertiary adrenal insufficiency, as a result of suppression of the HPA axis, when GC doses are weaned/withdrawn. There is little published data about tertiary adrenal insufficiency in this group. This study aims to further evaluate prevalence, characteristics and recovery of adrenal insufficiency in these patients at a large UK teaching hospital.

Methods

We retrospectively identified patients seen in outpatient clinics between January 2014 and September 2019 who had received tapering doses of long-term GC to treat their underlying condition (largely patients with polymyalgia rheumatica, giant cell arteritis or other vasculitis) and had either had a 9am cortisol or short synacthen test (SST). Data were collected using a standardised proforma.

Results

There was a total of 238 patients, median age of 71 years with a female preponderance (75%). Mean duration of glucocorticoid use was 63.3 months. Mean peak dose of glucocorticoid was 29.2mg.

142 patients had 9am cortisol as the first line test to assess adrenal function. 65% of these were considered sub-optimal based on local protocol (cortisol <350nmol/L). 38% of these patients went on to have SST, of which 56% continued to show evidence of sub-optimal cortisol production. All patients where baseline 9am cortisol was <100nmol/L failed to reach stimulated cortisol of >500nmol/L on SST, whereas 31% failed SST if 9am cortisol was 250-350 nmol/L.

In total 138 SSTs were performed of which 51% (n=70) were abnormal (cortisol <500nmol/L post synacthen). When baseline cortisol was <100nmol/L on SST, all patients had a suboptimal peak response. However, where baseline cortisol on SST was >350 nmol/L only 3% had a sub-optimal peak cortisol.

32 of these patients with an abnormal baseline SST went on to have a repeat SST within 2 years. 50% (n=16) continued to be suboptimal. Of the 32 patients, 38% (n=12) were switched to hydrocortisone with 33% showing complete adrenal recovery, average time to recovery of 25 months. 62% (n=20) patients did not switch, with 60% demonstrating recovery within the same time period (p=0.05). Mean ACTH levels in patients who had sub-optimal SST were 23.1 ng/L (n=19). ACTH levels were not different between those who recovered and those who did not (p=0.23).

Conclusion

Our study suggests that tertiary adrenal insufficiency is highly prevalent in this cohort of patients with rheumatological conditions requiring long-term glucocorticoid therapy. A 9am cortisol threshold of greater than 350nmol/L excludes most patients with adrenal insufficiency. These data also suggest no significant difference in adrenal recovery if switched to hydrocortisone versus continuing on prednisolone. ACTH levels were not fully suppressed in patients with adrenal insufficiency and did not predict recovery.
SAT-650 Novel Insights into the Entero-Insular Axis in Fibrocalcific Pancreatic Diabetes: An Isoglycemic Intravenous Glucose Infusion (IIGI) Study from India
Authors: verma shivendra , Gupta Riddhi Das , Anoop S Shajith , Thomas Nihal
Published: May 2020

In tropical countries including India, one of the common causes for young onset diabetes mellitus (DM) is “Fibro Calcific Pancreatic Diabetes” (FCPD) characterized by progressive pancreatic destruction. Despite this, glucagon has been found to be elevated in FCPD (1,2). The L-Cells in gut produce glucagon like peptide- 1 (GLP-1) and oxyntomodulin which are products of glucagon gene, thus raising probability of extra-pancreatic glucagon in FCPD. To test this hypothesis we performed 75grams oral glucose tolerance test (OGTT) followed by IIGI on separate days on nine FCPD and six healthy subjects. The latter procedure ensured matched glucose levels achieved during OGTT. Glucagon and incretins were measured at nine pre-specified time points. We found an increase in L-Cell products: GLP-1 (44.5±9.2pM vs. 12.4±4.5pM, p=0.02) and Oxyntomodulin (1252±350pg/ml vs. 859.8±165pg/ml, p=0.43) along with significant rise in glucagon during OGTT (98.8±13pg/ml vs. 63.4±7pg/ml, p=0.03) despite flat basal & stimulated C-peptide (0.43±0.14ng/ml and 1.09±0.3ng/ml, respectively) and Pancreatic polypeptide (12.3±0.0pg/ml and 14.7±1.7pg/ml, respectively) levels.

Paradoxically, gastric inhibitory polypeptide (GIP) levels were low in FCPD (106.8±40.3pg/ml vs. 557.8±96.4pg/ml, p=0.003). We speculate that the hyperglucagonemia is extra-pancreatic (L-Cell) in origin and may also contribute to the dichotomous incretin response in FCPD.

References:

1. Yajnik CS, Shelgikar KM, Naik SS, Kanitkar SV, Orskov H, Alberti KG, et al. The ketosis-resistance in fibro-calculous-pancreatic-diabetes. 1. Clinical observations and endocrine-metabolic measurements during oral glucose tolerance test. Diabetes Res Clin Pract. 1992 Feb;15(2):149-56.

2. Dasgupta R, Naik D, Thomas N. Emerging concepts in the pathogenesis of diabetes in fibrocalculous pancreatic diabetes. J Diabetes. 2015 Nov;7(6):754-61.
MON-693 Strongyloides Stercoralis Hyper Infestation Syndrome in Type 2 Diabetes: An ANCA Positive Case Report from India
Authors: Dash Kalpana , Tippisetty Surekha , Kolukula Vamsi Krishna
Published: May 2020

A 53-year old male patient with T2D and hypertension for 13 years, presented to Apollo Sugar Clinic, Raipur with recurrent abdomen pain, but no vomiting, constipation, diarrhea or fever. The patient has a past history of asthmatic bronchitis, recurrent eosinophilia, and one month prior to hospitalization, recovered from erythematous maculopapular serpentine rash measuring 6.0 x 1.5 cm over the abdomen post anti-allergic treatment. The patient was neither suffering from immunosuppressive condition nor was on immunosuppressant therapy, had normal vitals but the laboratory findings revealed high total leukocyte count and raised absolute eosinophil count (52%). The provisional diagnosis was made as hypereosinophilic enteritis in a long-standing T2D and hypertension. Immunological tests antinuclear antibody (ANA) and antineutrophil cytoplasmic antibodies (ANCA) resulted in positive ruling out vasculitis. Stool examination detected rhabditiform larvae of S Stercoralis and diagnosed as Strongyloides hyper infestation syndrome. The patient was managed with IV antibiotics, IV fluids, IV insulin and when abdomen pain reduced started with the oral diet. To remove larvae load, unlike routine treatment, the patient was put on albendazole and ivermectin for three consecutive days. After 15 days follow-up patient was completely asymptomatic; at 6 weeks TLC, stool test, ANCA and ANA titer were negative indicating no parasite load. These antibodies detected could be due to molecular mimicry triggered by parasite antigens which may help in diagnosing and monitoring the disease course. ANA and ANCA positive results have been rarely reported in the past for S stercoralis. This unique case of S stercoralis infestation in T2D may enlighten the health care physicians to investigate for this infestation in immunocompromised T2D patients with pain abdomen. Precise diagnosis with timely management can prevent steroid therapy due to eosinophilic enteritis which can be harmful to the patients.
SAT-486 A Case of Severe Thyroid Ophthalmopathy Requiring Emergency Orbital Decompression and Total Thyroidectomy
Authors: Leonard Talayna , Subramanian Preethi , Mahmood Ruyam , Shahlapour Mahmood , Vazquez Bianca , Horani Mohamad Hosam
Published: May 2020

Introduction: Graves is the most common cause of hyperthyroidism (5). In graves orbitopathy (GO) the activation of T-cells causes fibroblast proliferation and accumulation of hydrophilic glycosaminoglycans, causing osmotic muscle swelling and inflammation resulting in increased orbital pressure (5). Mild GO is managed with selenium, moderate GO with high dose steroids (methylprednisolone) (2). Rituximab is an alternative treatment (4). Severe GO is treated with orbital decompression surgery (2).

Case presentation:A 43-year-old incarcerated male with a history of Graves disease of 4 years,on methimazole, dry eye syndrome, and proptosis, presented to the ED with 5 days of increasing right eye pain, decreased vision and inability to close his right eye. In the ED he had increased intraocular pressure. Glaucoma was considered and the patient was treated with acetazolamide. His ocular pressures improved slightly but vision did not correct. Labs revealed: TSH <.005, FT3 5.48, FT4 1.75, Alkphos 318, TPO Ab 153, TS immunoglobulin >500. Steroids were given but ineffective. Treatment with potassium iodide lowered FT3 to 2.18 and FT4 to 1.27. With continuing eye pain rituximab was started, but was not tolerated. Selenium was not considered due to the severity of GO. The patient was cleared for acute surgical decompression that successfully improved ocular symptoms. The patient’s GO was so severe that a total thyroidectomy was completed for long-term treatment, without complications.

Discussion:In the setting of GO it has been shown that thyroglobulin passes to the orbit where autoantibodies cause inflammation, preventing correction even when hormone levels have been managed (3). Smoking is a known risk factor for GO, cessation is one of the first keys to management (2). A complete thyroidectomy is favored compared to radioiodine (worsens orbitopathy) or antithyroid drug therapy. Surgery has been shown to have a positive impact on the regression of GO Rituximab is a relatively safe and viable treatment that is superior to glucocorticoids or saline for patients with moderate to severe GO.

(1).References:1 Regression of Ophthalmopathic Exophthalmos in Graves’ Disease After Total Thyroidectomy Indian Journal of Surgery. 2017;79(6):521–526

2.The 2016 European Thyroid Association/European Group on Graves’ Orbitopathy Guidelines for the Management of Graves’ Orbitopathy. European Thyroid Journal. 2016 Mar 2; 5(1): 9–26

3.Does autoimmunity against thyroglobulin play a role in the pathogenesis of Graves’ ophthalmopathy: a review. Clinical Ophthalmology (Auckland, NZ). 2015;9:2271–2276.

4. Rituximab in the Treatment of Thyroid Eye Disease: A Review. Neuro-Ophthalmology (Aeolus Press). 2015;39(3):109–115.

5. Thyrotropin receptor autoantibodies are independent risk factors for Graves’ ophthalmopathy J Clin Endocrinol Metab. 2006;91(9):3464.
MON-187 Prevalence and Assessment of Overnight Dexamethasone Suppression Tests for Screening Endogenous Hypercortisolism When Serum Dexamethasone Is Below Threshold
Authors: Farinelli Denise Genaro , Kater Claudio E
Published: May 2020

Background: The 1mg-dexamethasone (DXA) suppression test (DST) is used to verify cortisol (F) autonomy in Cushing’s syndrome (CS) and subclinical hypercortisolism (SCH) of adrenal incidentalomas (AI), based on the ability of DXA to suppress F by inhibiting the HPA axis. A post-DST serum F >1.8 μg/dL usually defines autonomy. Aim: 1) determine the prevalence of invalid tests in a large series of DST used to investigate hypercortisolism during a 12y period in a single institution; 2) assess the percentage of negative tests (normal F suppression) among the subpopulation of invalid DST; 3) examine for interfering substances and clinical conditions that may justify and low DXA levels. Methods: DXA-controlled 1mg-DST was carried out in 162 control subjects (Cont; 107F/55M; 20-75y [median 50y]), to determine a valid threshold for serum DXA, and in 768 patients (80% female; 11-91y [median 53y]), investigated from 2007-19, for F autonomy (a total of 1,300 tests, with 41% repetitions). F and DXA were determined by specific RIA. We search our laboratory data bank for “invalid” DST, tests in which post-DST serum DXA values were below the cutoff established from the control subjects. Results: we set a cutoff for post-DST serum DXA at 140 ng/dL, the lowest value obtained from controls in whom post-DST serum F levels were < 2.5 µg/dL. From the 1,300 DST examined, 146 (11.2%) were considered invalid (DXA <140 ng/dL), and in 36 of them (25%), DXA was undetectable. Also, 35 DST (25%) gave F results below 1.8 µg/dL. Of all 146 invalid DST, 8 (6%) did not take DXA the night before as directed and 14 (10%) admitted being on glucocorticoids (GC), most of them from the undetectable DXA subgroup. Also, 21 patients (14%) were on anticonvulsants, another 21 (14%) were using other moderate or potent CPY3A4 inducers (phenytoin, rifampicin, efavirenz), and 15 (10%) subjects had gastrointestinal abnormalities (colectomy, colostomy, erosive gastritis and disabsorptive syndromes). Conclusions: Test accuracy depends on the serum levels reached by DXA, after adequate ingestion and absorption. Inappropriately low values may result in false-positive test results. One-fourth of “invalid” tests, presented DXA levels below the assay limit of sensitivity, suggesting patient noncompliance. Adherence to verbal and written recommendations and use of medication are essential to interpret the test. Conditions that alter gastric pH, as well as surgical procedures in the GI tract may reduce absorption or accelerate GI transit affecting DXA absorption. DXA metabolism by cytochrome p450 enzymes, mainly CYP3A4, can be enhanced by inducing drugs, making mandatory DXA dosage to validate the test. The wide individual variability in DXA metabolism may be associated not only with environmental and health factors, but also with CYP gene polymorphisms, which can modify drug clearance.
SAT-549 Identification of Somatic Mutations in CLCN2 as a Cause of Aldosterone-Producing Adenomas
Authors: Rege Juilee , Nanba Kazutaka , Blinder Amy R , Else Tobias , Tomlins Scott , Vats Pankaj , Kumar-Sinha Chandan , Giordano Thomas J , Rainey William E
Published: May 2020

Background: Primary aldosteronism (PA) results from both unilateral and bilateral adrenal disease. Unilateral disease is most often caused by aldosterone-producing adenomas (APAs). We recently identified aldosterone-driver somatic mutations in approximately 90% of APAs using an aldosterone synthase (CYP11B2) immunohistochemistry (IHC)-guided DNA sequencing approach. In the present study, we analyzed DNA from APA samples found to be mutation negative. Methods: Formalin-fixed paraffin-embedded tissue samples from PA patients who underwent adrenalectomy were studied. Genomic DNA was isolated from 118 APAs (identified by CYP11B2 IHC). Next generation sequencing (NGS) was performed to identify known aldosterone-driver mutations in KCNJ5, ATP1A1, ATP2B3, and CACNA1D. APA DNA that was mutation negative and the adjacent normal adrenal tissue DNA were subjected to Whole Exome Sequencing (WES). Results: Targeted NGS and WES detected two variants in the voltage-gated chloride channel ClC-2 (encoded by CLCN2), which were confirmed by Sanger sequencing. One of the CLCN2 mutations (p.Gly24Asp) was identical to that previously found to cause germline early-onset PA. The second CLCN2 mutation, which would affect the same region of the protein, was an unreported PA mutation (p.Met22fs). The presence of these variants in two tumors suggests that CLCN2 mutations as a cause of APAs are rare with an approximate prevalence of 1.7% (2/118 APAs). Conclusion: In this study, we identified somatic mutations in CLCN2, in two of 118 APAs. Germline variants in this gene have previously been shown to cause of familial hyperaldosteronism type II and the current findings indicate that similar mutations cause a small proportion of APAs. These findings also indicate that WES of CYP11B2-guided mutation negative APAs can help determine rarer genetic causes of sporadic PA.
OR15-06 Integrative and Analytical Review of the 5 Alpha Reductase Type 2 Deficiency Worldwide
Authors: Batista Rafael Loch , Mendonca Berenice Bilharinho
Published: May 2020

Introduction: The conversion of testosterone into dyhidrotestosterone is catalyzed by the 5 α reductase type 2 enzyme which plays a crucial role in the external genitalia virilization. It is encoded by the SRD5A2 gene. Allelic variants (AV) in this gene cause a 46,XY DSD with no genotype-phenotype relationship. It was firstly reported at early 70’s from isolated clusters. Since then, several cases have been reported. Putting together, it will expand the knowledge about the molecular bases of androgen regulation. Methods: We searched for SRD5A2 AV in the literature (Pubmed, EMBASE, Medline) and websites (ensemble, HGMD, ClinVar). Only cases with AV in both alleles, either in homozygous (HM) or compound heterozygous state (CH) and 5ARD2 phenotype were included. The AV were analyzed according to ethnicity, exon, domain, aminoacid (aa) conservation, age at diagnosis, sex assignment, gender change, external genitalia virilization and functional studies. External genitalia virilization was scored using Sinnecker scale. Conservation analysis was carried out using CONSURF platform. For categorical variables we used X2 test and Cramer’s V. Continuous variables were analyzed by t test or ANOVA. Concordance was estimated by Kappa. Results: We identified 434 cases of 5ARD2 deficiencies from 40 countries. Most came from Turkey (23%), China (17%), Italy (9%), and Brazil (7%). 69% were assigned as female. There were 70% of AV in HM and 30% in CH state. Most were missense variants (76%). However, small indels (11%), splicing (5%) and large deletions (4%) were all reported. They were distributed along all exons with exon 1 (33%) and exon 4 (25%) predominance. AV in the exon 4 (NADPH-binding domain) resulted in lower virilization (F=10.5; p<.0001). The positions 55, 65, 196, 235 and 246 are hotspots making up, 25% of all AV. Most AV (76%) were located at conserved aa. However, AV at non-conserved aa were more frequently indels (28% vs 6%; p<.01). The overall rate of gender change from female to male ranged from 16% to 70%. The lowest rate of gender change occurred in Turkey and the highest in Brazil. Virilization was similar between those who changed and kept their gender. The gender change rate was significantly different across the countries (V=0.44; p<.001) even with similar virilization scores. There was no concordance between genotype and phenotype in all recurrent AV (196, 235 and 246; k 0.6, 0.12 and 0.19). Conclusion: 5ARD2 deficiency has a worldwide distribution. AV at NADPH-ligand region cause lower virilization. Genitalia virilization influenced sex assignment but not gender change which was influenced by cultural aspects across the countries.
SUN-624 Low Risk of Major Adverse Cardiovascular Events After Pancreas Transplantation Alone
Authors: Kaur Ravinder Jeet , Smith Byron H , Rizvi Shafaq R , Batthula Sreedhar , Kukla Aleksandra , Dean Patrick G , Kremers Walter K , Stegall Mark D , Kudva Yogish C
Published: May 2020

INTRODUCTION: Type 1 Diabetes (T1D) patients have an increased risk for major adverse cardiovascular events (MACE). Pancreas Transplantation Alone (PTA) in patients with T1D achieves near normal glucose control for a prolonged period but limited data are available to date regarding MACE during a 10 year follow up period after the procedure.

OBJECTIVE: We studied incidence of MACE after PTA in T1D patients over a 10 year follow-up period.

METHODS: Retrospectively, we studied 113 T1D recipients of PTA at Mayo Clinic, Rochester with the procedure performed between January 1998 and August 2018 and follow up of at least 1 year. Data were collected before transplantation and up to 10 year follow up after the first PTA. MACE data were gathered until primary non function, re-transplantation, or complete loss of c-peptide (<0.01ng/ml). We report vascular risk factors including hypertension, hyperlipidemia, smoking and BMI along with MACE (defined as cardiac events as unstable angina, Myocardial Infarction (MI), need for re-vascularization, cardiac death, cerebral events as Transient ischemic attack (TIA), stroke, need for re-vascularization and peripheral arterial disease as need for re-vascularization, gangrene and amputation).

RESULTS: Eighteen subjects had pre-transplant MACE. A total of 14 subjects had graft failure within 24 to 36 hours due to thrombosis, with 3 in pre-transplant MACE cohort and 11 in no MACE cohort. Thus, we followed 99 subjects for the development of post-transplant MACE for a period of 6.3 ± 3.6 years. T1D subjects with MACE (n=15) had baseline characteristics: Age 48± 7.8 years, gender F/M 9/6,, duration of diabetes 33 ± 12 years, BMI 26± 3.1(Kg/m2), HbA1c 9.3 ± 1.5% and C-peptide 0.09 ng/ml. 84 T1D patients without MACE were age 42 ± 10.6 years, gender F/M 55/29, duration of diabetes 26.5 ± 10.7 years, BMI 26 ± 5.2(Kg/m2), HbA1c 6.7 ± 2.5 and C-peptide 0.09 ng/ml. There are a total of 584 person-years of follow up to first MACE event and 632 person-years of graft failure, death or last follow-up. Nine patients developed 11 MACE events post-PTA. Therefore, the event rate is 1.5 MACE events per 100 person-years for first MACE event and the total event rate is 1.7 MACE events per 100 person-years of follow-up. Age, smoking (yes), gender, duration of diabetes, HTN and Hyperlipidemia presence did not show any significant impact on post-transplant MACE outcome based on univariate Cox regression but the pre-transplant BMI (HR = 1.14; CI = (1.04, 1.26); p = 0.008) and pre-transplant HbA1c (HR = 1.26; CI = (1.06, 1.51); p = 0.01) showed statistically significant impact.

CONCLUSIONS: At our center, MACE is low in PTA recipients. There is no impact of presence of pre-transplant MACE on development of post-transplant MACE but pre-transplant BMI and HbA1c account for risk of MACE.
SAT-672 An Unusual and Enigmatic Etiology for Diabetic Ketoacidosis: Safety Needles
Authors: Modi Ankur , Cryar Keith
Published: May 2020

Diabetic ketoacidosis is associated with a mortality rate of upto 6.1% and accounts for an estimated 115000 hospital discharges per year in the United States. In order to reduce mortality related to DKA, precipitating causes must be identified and addressed. The most common precipitant for DKA is infection with other precipitating factors including acute illness, medications and inadequate insulin therapy (1).

A 76 year-old woman with type 2 diabetes was transferred from her assisted living facility for hyperglycemia. This was her fifth admission in the last month and a half attributed to either hyperglycemia or DKA. Her medications included insulin glargine and insulin aspart. She mentioned compliance with her insulin as well as her diabetic diet. In the ER, her vitals were stable with physical examination showing an obese woman in no acute distress. Her labs showed a blood glucose of 780, an anion gap of 17 and positive serum ketones. Further investigation did not reveal a source of infection or ischemia. The patient was treated in the ICU with intravenous insulin and fluids with resolution of her ketoacidosis. The patient was discharged with a 67% increase in her prandial insulin. On further review, her facility had recently required safety needles to be used for insulin pens. Patient was asked to demonstrate her technique with observation that patient was not pushing down enough to allow for the needle to enter her skin with subsequent trapping of her insulin within the needle. Prior to discharge, she was educated on proper administration of her insulin and since her discharge, she has had no subsequent readmissions for hyperglycemia.

Hospitals and long-term facilities are the primary utilizers of needles with a retractable safety shield. Reduction of accidental puncture, elimination of reuse of needles and helping patients overcome anxiety about needles are some of the key advantages of these needles. Upon application of pressure onto the skin, the automatic shield or plastic cannula retracts and thus hides the needle before, during and after the injection. The major disadvantage is insulin being deployed while the needle is outside the body if incorrectly applied. Therefore, appropriate administration must be taught to the patient, including perpendicular insertion of the needle into the subcutaneous tissue and ensuring a more firm surface by injecting into a lifted skin fold. Legislation in the US has been passed requiring safety-engineered devices when feasible.In situations where the safety-engineered devices can impair effectiveness or cause harm, alternative approaches can be utilized, including insulin syringes or self-administration of insulin along with safe work procedures (1).

1. Yu Catherine H.Y.. “Safety” technology: a hidden cause of diabetic ketoacidosis. Canadian Medical Journal Journal. 2012 Mar 20;184(5):557–558.
SUN-253 PROKR2 Neurons of the Amygdalohippocampal Area in Reproductive Function
Authors: Larios Brenda Cisneros , Elias Carol F
Published: May 2020

Kallmann Syndrome (KS) is characterized by infertility and anosmia due to deficiency in gonadotropin releasing hormone (GnRH) neuronal migration and olfactory bulb dysgenesis. Genetic studies have revealed that KS is caused by loss-of-function mutations in several genes including the prokineticin receptor 2 (PROKR2) gene (Abreu et al., 2008, Hardelin & Dode 2008). Mice with global deletion of Prokr2 replicate the phenotype of KS patients (Ng et al., 2005, Matsumoto et al., 2006). Whereas the role of PROKR2 during development is defined, little is known about PROKR2 neurons in adult reproduction. PROKR2 mRNA are highly expressed in reproductive control sites of the adult mouse brain (Cheng et al., 2006). Previous studies in our lab found PROKR2 mRNA and Prokr2-Cre GFP+ cells highly expressed in the amygdalohippocampal area (AHi, also called posterior nucleus of the amygdala) in a sexually-dimorphic pattern. Male mice have higher PROKR2 expression in the AHi compared to female mice (Mohsen et al., 2017). The amygdala is an important site of socio-sexual inputs and reproductive neuroendocrine responses in rodents and primates, including humans. We hypothesize Prokr2-Cre neurons in the AHi have a role in both male and female reproductive function. Using genetic tracing techniques, we mapped AHi Prokr2-Cre neuronal projections in both male and female mice and found dense innervation to reproductive control sites such as the medial preoptic area and the ventral premammillary nucleus in a sexually dimorphic pattern. A soiled bedding exposure test in sexually experienced male mice showed that an estimated 45% of cFos + cells in the AHi express Prokr2-Cre GFP. Dense sex steroid receptors expression was observed in AHi Prokr2-Cre GFP neurons of both male and female mice. Our preliminary data suggests AHi Prokr2-Cre neurons have a reproductive function in male and potentially also in female mice. Future studies will focus on selective activation and inhibition of these neurons using chemogenetic technology to determine putative inputs to brain sites that control the hypothalamo-pituitary-gonadal axis. We expect our studies will contribute to the understanding of the role of PROKR2 neurons in adult reproduction and reproductive deficits associated with PROKR2 mutations.
SAT-651 Ethnic Differences in the Relationship Between Uric Acid Clearance and Insulin Sensitivity
Authors: Armiyaw Abdul-Latif , Fosam Andin , Sarcone Camila , Aradhya Ahimsa , Walter Mary , Rabel Antoinette , Muniyappa Ranganath
Published: May 2020

Background: Hyperuricemia is associated with gout, type-2 diabetes, hypertriglyceridemia, and other insulin resistant (IR) states. Impaired clearance of uric acid (UA) has been proposed to play a role in hyperuricemia in IR. In a small study, urinary UA clearance was negatively associated with IR. African-Americans (AA) are more insulin resistant than Caucasians (CA). However, plasma UA levels are lower in AA. Ethnic differences underlying the relationship between UA clearance and insulin sensitivity (Si) remain unknown.

Objective: To compare the relationships between UA production, clearance, and Si in AA and CA.

Design: In a cross-sectional study, AA (n = 40; age 43 ± 10 years; BMI 41.3 ± 9.7 kg/m2) and CA (n = 88; age 44 ± 13 years; BMI 32.9 ± 8.2 kg/m2) subjects underwent an intravenous glucose tolerance test (IVGTT) to derive Si using the Minimal Model. Plasma UA and creatinine (Cr), were measured in the NIH Department of Laboratory Medicine. Urinary UA and Cr levels in spot urine samples were measured using a colorimetric assay. Fractional Excretion (FE) of UA and urine urate-to-creatinine ratio (UUCR), a measure of uric acid production, were calculated.

Results: AA had a significantly higher BMI (p < 0.0001), percent body fat (45.8 ± 8.9 vs. 39.7 ± 11.5 %, p = 0.0007), A1C (5.8 ± 0.4 vs. 5.5 ± 0.3 %, p = 0.0006), diastolic BP (74 ± 9 vs. 71 ± 8 mm of Hg, p = 0.02), and lower Si (2.36 ± 2.7 vs. 4.43 ± 3.4 min−1·μU·ml−1, p = 0.0004) compared to CA. Stepwise multiple regression analysis was performed with independent variables A1c, fasting glucose, fasting insulin, triglycerides, and Si. Among these, Si was a significant predictor of FE of UA in CA (r = 0.33, p=0.001), but not AA (r = - 0.02, p=0.92).There was also a negative association between Si and plasma UA in CA (r = 0.48, p < 0.0001), but not in AA (r = 0.06, p = 0.70). There was no association between Si and UA production in both groups (AA: p = 0.33, CA: p = 0.69).

Conclusion: These findings suggest that reduced insulin sensitivity may not play a major role in the pathogenesis of hyperuricemia in AA in insulin-resistant states.
SUN-485 Combined Treatment with Laser Ablation and Tyrosin Kinase Inhibitors. a Novel Multimodality Approach to Locally Advanced Thyroid Cancer?
Authors: Papini Enrico , Monti Salvatore , Coccaro Carmela , Persichetti Agnese , Presciuttini Federica , Deiana Maria Grazia , Bizzarri Giancarlo , Bianchini Antonio , Guglielmi Rinaldo
Published: May 2020

Background. Direct loco-regional treatments are considered for local control of cervical metastasis of thyroid cancer. In our feasibility study, laser ablation was employed for initial debulking of an unresectable radioiodine-refractory thyroid cancer in a combined treatment with tyrosin kinase inhibitors (TKI).

Clinical case. On June 2016, a 69-year-old woman underwent partial resection of a papillary thyroid cancer with extensive tracheal infiltration. On August 2016, whole body scan performed after 131-I treatment (8140 MBq) demonstrated nearly absent thyroid bed uptake. Due to progressive increase of the cervical mass, the patient experienced dysphonia and dysphagia and, after multidisciplinary consultation, was treated with laser ablation (LTA). After local anesthesia, two 300 nm fiberoptics were inserted into the lesion through 21G spinal needles. Two illuminations with 4-watt output power and 3600 Joules energy delivery were peformed with a diode-laser source. LTA resulted in rapid mass volume decrease (28 x12 x16 mm, 2.8 mL, vs 52 x 29 x 29 mm, 22.7 mL) and improvement of pressure symptoms that lasted 6 months. In May 2017, due to initial regrowth of the tumor mass, the patient started therapy with Lenvatinib, at 10-24 mg/day. The cervical tumor burden remained controlled until April 2019, when occurred rapid disease progression and death of the patient.

Discussion. These preliminary results suggest that locally-advanced unresectable and radioiodine-refractory thyroid tumors can be managed with preliminary LTA mass debulking, for rapid control of local disease, followed by long-term TKI treatment.

References. Mauri G et al. Cardiovasc Intervent Radiol. 2016 Jul; 39(7):1023-30; Park KW et al. Ann Surg Oncol 2011; 18:2564-2568. Schlumberger M et al. NEJM 2015 12; 372(7):621-30.
OR24-06 USP8 Genetic Variants May Contribute to the Development of Bilateral Adrenal Hyperplasia and ACTH-Independent Cushing Syndrome
Authors: Settas Nikolaos , Kassi Eva , Angelousi Anna , Faucz Fabio Rueda , Stratakis Constantine A
Published: May 2020

Background: Bilateral adrenocortical hyperplasias (BAHs), including primary pigmented nodular adrenocortical disease (PPNAD), isolated micronodular adrenocortical disease (iMAD) and primary macronodular adrenocortical hyperplasia (PMAH), are rare causes of ACTH-independent Cushing syndrome (CS). PPNAD and iMAD usually present in children or adolescents as multiple small (<1cm), cortisol-producing adrenocortical nodules. On the other hand, PMAH is most frequently identified in older patients with multiple large adrenal nodules. Most patients with PPNAD have PRKAR1A mutations whereas patients with PMAH may harbor variants in other genes (ARMC5, MC2R, GNAS, APC, MEN1). Even though several genes have been associated with ACTH-independent CS, there are still cases that the genetic cause has not been elucidated.

Clinical cases: Herein, we present two unrelated patients with ACTH-independent CS that harbor USP8 gene variants. USP8 is mainly known for being mutated in Cushing disease but as a deubiquitinase it may be involved into the Wnt/β-Catenin signaling pathway.

The first patient was diagnosed with BAH on prenatal ultrasound (26 gestational week) and subsequently required bilateral adrenalectomy for CS as she had virilization, hirsutism, hypertension and cardiac hypertrophy 9 weeks old. Adrenalectomy revealed that she had iMAD. She also presented with hemihypertrophy of the right leg, labia and mild newborn hypoglycemia, however she was negative for Beckwith-Wiedemann mutation. Gene analysis of PRKAR1A did not reveal any mutations. After whole exome sequencing (WES), we found a novel heterozygous USP8 variant (c.1387_1393delinsT, p.Ala463_Ile465delinsPhe) at germline level and loss of heterozygosity (LOH) at tumor level. Immunohistochemistry showed significantly lower expression of USP8 protein in both of her adrenals compared to a control tissue.

The second case is a 59-year old female with osteoporosis who failed to suppress cortisol levels after low dose dexamethasone administration. MRI revealed an adenoma on the right adrenal (2.6cm). She underwent right adrenalectomy and was found to have PMAH. We performed WES in germline level and we detected a novel heterozygous missense USP8 variant (c.287A>G, p.Lys96Arg) that is present also at tumor level. Immunohistochemistry showed significantly lower expression of USP8 protein in her adrenal tumor compared to the control tissue. No LOH was identified.

Conclusion: This is the first report of the association of USP8 in ACTH-independent CS and the preliminary findings support UPS8 involvement in the development of adrenocortical disease. We are currently performing further in vitro studies to evaluate the effect of these two USP8 variants into the canonical Wnt pathway which is commonly involved in adrenocortical disorders.
SUN-562 Long-Term Mental Stress Implications to Cardiovascular Disease in an Aged Mouse Model
Authors: Carroll Natalie Grace , Amatya Shripa , Kamberov Lilly , Gomez-Torres Oscar , Orr A Wayne , Woolard Matthew D , Bailey Steven , Topete Diana Cruz
Published: May 2020

While clinical evidence indicates that exposure to mental stress is a linked to a two-fold increased risk for coronary heart disease, even independently from traditional risk factors, the underlying direct mechanisms between psychological stress and cardiovascular health status has not been determined. A growing aging population of adults 65 and older represents a particular patient population vulnerable to chronic mental stressors due to a decline in normal physiologic functions. The decrease in function of the cardiovascular system that occurs during aging leads to the activation of pathological processes associated with an increased risk for heart disease. Using a mouse model of mental stress induced by restraint, we mimic the biochemical and physiologic changes observed in chronically stressed humans, which is characterized by an increase in circulating glucocorticoids, such as cortisol. Middle-aged mice (6 months old) as well as old-aged mice (18 months old) were used to differentiate the effects of aging on the burden of mental stress associated cardiovascular disease. Genes implicated in cardiomyopathy and CVD were found to be significantly up-regulated, not only immediately after a two-week stress period, but remained significantly up-regulated after the mice were allowed to recover stress-free for 5 weeks. Gene expression of the glucocorticoid receptor was down-regulated following exposure to chronic stress, suggesting an involvement of the hypothalamic-pituitary axis negative feedback loop. Gene expression of markers for hypertrophy (MHY7, ACTA1, NPPB) were upregulated and persisted in upregulation after mice were allowed to recover. Hypertrophy was further indicated by heart weight to tibia length ratios. Significant changes in aortic samples also implicate an involvement of the vasculature. Chronic stress in humans and mice leads to an increase in inflammatory and pro-coagulant markers. In our study, inflammatory markers (LCN, IL-6, IL-17c, PTGS2) were shown to be significantly increased immediately after the period of chronic stress, however the markers return to non-significant levels when mice were allowed a recovery period. Chronic mental stress has a lasting and direct deleterious effect on the cardiovascular system and it is essential to understand these implications in an aging population.
MON-522 In Silico Analysis of Polymorphism rs2228638 in Neuropillin-1 Demonstrated That This Variant May Hinder EBV Entry into Epithelial Cells
Authors: Teixeira Elisangela Souza , Almeida Jacqueline Fatima Martins , Teodoro Larissa , Peres Karina Colombera , Bufalo Natassia Elena , Ward Laura Sterian
Published: May 2020

The Epstein-Barr virus (EBV) is the first herpesvirus identified to be associated with human cancers and our group has demonstrated its association to thyroid cancer. It infects the vast majority of the world population causing latent and persistent infection, interfering in the metabolism of the host cells and triggering tumorigenic processes. Neuropillin-1 (NRP-1) is a type I transmembrane glycoprotein distributed on the cell surface of the virus, and considered vital for tumorigenesis. It has been demonstrated that EBV infection was increased by NRP1 expression. However, a conformational alteration of NRP1 could interfere with virus internalization into epithelial cells. The rs2228638 polymorphism of NRP1 may modify the molecule tridimensional configuration. In order to better understand the role of this polymorphism, based on NCBI dbSNP and UniProt databases, we evaluated the effect of the amino acid change in the protein structure using bioinformatics tools including SIFT, Align GVGD, PolyPhen-2, SNAP, PANTHER, PredictSNP, nsSNPAnalyzer, PROVEAN, SNP&GO, PMut and MuPRO. PANTHER prediction indicated that the polymorphic variant could produce a change in function. MuPRO indicated that the amino acid exchange produced by the polymorphism decreases protein stability. However, none of these tools showed conformational alteration. In conclusion, the presence of the rs2228638 polymorphism of NRP-1 may cause functional but not morphological changes that hinder EBV entry into the epithelial cells.
OR07-01 Identification of the First Case of Acquired Autoimmune Parathyroid Hormone (PTH) Resistance Due to PTH1 Receptor (PTH1R) Autoantibodies
Authors: Mandl Adel , Burbelo Peter D , DiPasquale Giovanni , Welch James , Simonds William F , Collins Michael T , Agarwal Sunita Kishore , Blau Jenny , Weinstein Lee
Published: May 2020

Background: Here we describe a patient who presented with symptomatic hypocalcemia and a biochemical picture suggestive of PTH resistance. PTH resistance is a hallmark of pseudohypoparathyroidism, a heterogeneous group of rare disorders caused by genetic or epigenetic alterations of PTH/PTHrP signaling. However, PTH receptor-related autoimmune etiology has not been identified as the underlying mechanism for PTH resistance. Here we describe the first case of acquired autoimmune PTH resistance that is secondary to PTH1R autoantibodies.

Clinical Case: A 60-year-old African-American woman, who previously had normal calcium homeostasis, presented with acute, symptomatic hypocalcemia, hyperphosphatemia and markedly elevated serum PTH, consistent with parathyroid hormone resistance. She did not have other hormone resistance or a clinical phenotype suggestive of pseudohypoparathyroidism. Whole-exome sequencing and GNAS methylation analysis revealed no genetic or epigenetic defects of the PTH/PTHrP signaling pathway. Treatment with Calcitriol and Calcium supplements was initiated with good clinical response. Within 10 years of follow-up, the patient developed autoimmune hypothyroidism, alopecia and an unusual form of membranous glomerulonephritis, raising the suspicion for an autoimmune etiology for PTH resistance. Luciferase immunoprecipitation system assay identified antibodies against PTH1R with mapping to the N-terminal extracellular ligand-binding domain (amino acids 1- 178). Using an in vitro biological assay in GP-2.3 cells, we found that the antibodies derived from the patient’s serum blocked PTH downstream signaling via Gsalpha/cAMP/protein kinase A pathway in a concentration-dependent manner.

The patient’s autoantibody profile led to the diagnosis of additional autoimmune diseases, including atrophic gastritis and Sjogren syndrome. Lymphocyte immunophenotyping using flow cytometry revealed an overall normal B and T cell profile, but with decreased frequencies and numbers of switched and non-switched memory B cell subsets and an increased frequency and number of the CD8+ naïve cell population. Genes associated with autoimmune inflammatory disorders were sequenced but no pathologic changes were detected.

Conclusions: Identification of the first case of autoimmune PTH resistance secondary to PTH1R autoantibodies extends the etiologic spectrum of hypoparathyroidism and should be considered when a patient presents with findings consistent with pseudohypoparathyroidism, especially in the presence of additional autoimmune diseases.
SAT-065 A Novel De Novo GATA3 Gene Mutation in an Adolescent with HDR Syndrome
Authors: Cruz-Aviles Lisa Michelle , Bale Allen , Carpenter Thomas O
Published: May 2020

Background: GATA3 encodes a transcription factor critical for embryonic development of the parathyroid glands, kidney, inner ear, thymus, and the central nervous system. Heterozygous loss-of-function mutations in GATA3 are associated with hypoparathyroidism, sensorineural deafness and renal disease (HDR syndrome). Clinical Case: A 12 yo male with left hip pain underwent a closed reduction for left slipped capital femoral epiphysis. The pre-op evaluation revealed hypocalcemia (serum Ca 7.7 mg/dL; nl: 8.8-10.2), creatinine 0.46 mg/dL (0.5-1.0), TSH 3.16 uU/mL (0.3-4.2), FT4 1.36 ng/dL (0.8-1.8). Oral calcium and vitamin D supplementation was begun, and 2 wks later, follow-up evaluation revealed serum Ca of 9.4 mg/dL, intact PTH 4.6 pg/mL (10-69), phosphorus 5.9 mg/dL (3.3-5.3), 25-OHD 26 ng/mL (30-100), and a normal chromosomal microarray. Bone density (DXA) Z-scores for hip and spine were -1.7 and 0.8, respectively. At age 13 he underwent bilateral osteotomy due to bilateral hip dysplasia and removal of hardware the next year. At age 15 he underwent left total hip replacement for avascular necrosis. In the post-operative period hypocalcemia recurred (5.9-6.7mg/dL), and he was referred for endocrine evaluation. He was of mixed African American and Puerto-Rican descent. He had difficulties in school and required eyeglasses and hearing aids. Past history included congenital scoliosis (right T11-12 rib fusion, wedged L1 vertebra, and incomplete fusion of posterior elements of L4 and L5), a small right kidney (per ultrasound examination), bilateral orchiopexy for undescended testicles (age 2), diagnoses of ADHD (at age 5); sensorineural hearing loss and psoriasis (age 12), and gastroesophageal reflux (age13). Multiple paternal family members were reported to have abnormal calcium levels and hearing/vision problems, but no known diagnosis. On exam, he had no facial dysmorphism, but left supernumerary nipples, lumbar lordosis and thoracic kyphosis, and clinodactyly. He had achieved Tanner 5 secondary sexual characteristics. There was no Chvostek’s sign. Laboratory investigation revealed Ca 7.9 mg/dL, phosphorus 5.9 mg/dL (3.1-4.7), alkaline phosphatase 123 U/L (50-380), 25-OHD 32 ng/mL, intact PTH 10.2 pg/mL. Treatment with calcium carbonate and calcitriol was begun. Whole exome sequencing identified a heterozygous mutation in GATA3 (c.1061C>T, p.Pro354Leu), predicted to be damaging. This variant has not been reported in literature or public database to our knowledge. Conclusion: This case highlights the importance of genetic testing in the setting of unexplained hypoparathyroidism, and identifies a likely novel mutation in GATA3, providing a basis to counsel the family and encourage medical follow up of suspected family members. References: Barakat, A., et al., Familial nephrosis, nerve deafness, and hypoparathyroidism. J Pediatr 91:61-64, 1977
SAT-215 A Case of Polyglandular Autoimmune Syndrome
Authors: Tariq Sarah
Published: May 2020

Background: Polyglandular autoimmune syndrome is defined by the presence of Addison’s disease, Autoimmune thyroid disease and Type 1 Diabetes Mellitus.

Clinical Case: This is a case presentation of a 56 year old female with a multitude of endocrine disorders, classified as polyglandular autoimmune syndrome, type 2, persistently elevated ACTH levels.

Over the years, the diagnoses of Primary Adrenal Insufficiency, Type 1 Diabetes, and Hypothyroidism, had revealed themselves, in this patient.

Her initial diagnosis upon establishment into our clinic was Addison’s disease and hypothyroidism for which she was getting adequate treatment. Her clinical course had been complicated by multiple admissions for DKA, along with adrenal crises.

Following the adrenal crisis, her ACTH levels had been noted to be persistently elevated, at 3362, despite hydrocortisone replacement at optimal dosing and normal AM cortisol levels. Her hyperpigmentation continued to worsen. A 1mg dexamethasone suppression test failed to lower the ACTH levels.

Concern for a possible ectopic ACTH secretion prompted further investigation with imaging studies such as an abdominal Cat scan which showed no adrenal pathology. Pituitary MRI was ultimately performed which showed no evidence of pituitary lesions.

These were following by an 8mg Dexamethasone suppression test which adequately decreased the ACTH level. However re-check of ACTH levels, after weeks of being on her physiological hydrocortisone dosing, showed that her ACTH levels had started to rise again. Given she had also had multiple admissions for adrenal crises, the concern was raised for possible malabsorption.

Given her risk for auto-antibody development, there was concern for another autoimmune process such as Celiac disease, as a potential cause for malabsorption. Her TTG IgA antibodies were checked, however they were absent.

At this point, the decision was made to use prednisone as a means of suppression of ACTH, and she was given three days of 40mg Prednisone daily, followed by ACTH level testing, which showed a decrease from 2009 to 708. These results prompted us to change her hydrocortisone to prednisone daily dosing instead, and we converted her to a slightly higher dose of Prednisone.

In the setting of underlying DM, this may pose an additional challenge with glycemic control, but we plan for close clinic follow up and repeat ACTH levels a few weeks after she has been on the new prednisone regimen.

Conclusion: This is a rare case of a patient with polyglandular autoimmune syndrome, type 2, with a persistently elevated ACTH level, requiring Prednisone, instead of hydrocortisone for treatment of primary adrenal insufficiency in efforts to reduce ACTH levels.

References: Neufeld M, Maclaren NK, Blizzard RM, Two types of autoimmune Addison’s disease associated with different polyglandular autoimmune (PGA) syndromes. Medicine (Baltimore). 1981;60(5):355.