bluuebunny/crossref_metadata_2025 huggingface dataset:
SAT-LB305 Concurrent Peri-Adrenal Paraganglioma and Renal AngiomyolipomaComplicated by Toxic Multinodular Goiter
Authors: Sathavarodom Nattapol
Published: May 2020

A 40 years old woman presented with headache, palpitation and diaphoresis by the past 3 months, and then developed progressive dyspnea on exertion and chest pain 2 weeks ago. She also lost 5 kg of her body weight during the past 6 months. She ever had multinodular goiter and lobectomy was done 12 years ago, after that she lost to follow up. At meantime, toxic multinodular goiter was suspected and high level of free T4, T3, and suppressed thyrotropin were demonstrated. Furthermore, thyroid scan revealed heterogenous tracer uptake at her thyroid bed. Methimazole was started, however her blood pressure and heart rate were all uncontrolled. Pheochromocytoma was suspected and markedly elevated of both urinary normetanephrine and metanephrine were confirmed. Computed tomogram revealed a huge, right supra-renal mass. In addition, hypodensity mass were found at upper pole of right kidney, and the results of 131I-Metaiodobenzylguanidine scintigraphy showed increased tracer uptake at upper abdomen. Right adrenalectomy and partial nephrectomy were performed. The final pathological diagnosis was sympathetic paraganglioma, and angiomyolipoma which confirmed by immunohistochemical staining. We present here an unusual case of concurrent periadrenal paraganglioma and renal angiomyolipoma which was complicated by autonomous toxic multinodular goiter.
MON-057 MODY Diagnosis: Missed Opportunity to Avert Insulin Therapy. A Case Series
Authors: Paulo Remberto , Kirmani Salman , Matlock Kristal Anne , Bowlby Deborah A , Headley Terry
Published: May 2020

BACKGROUND Prevalence of MODY is 1.2% in pediatric diabetes population. SEARCH study reported most of these patients were misdiagnosed as T1DM or T2DM up to 36% and 51% respectively (1). GCK (MODY 2) and HNF1A/HNF4A (MODY3) are the most common forms of MODY. Despite improvement in testing strategy (panel testing instead of step-wise approach) and cost, MODY testing remains underutilized. These conditions do not require insulin therapy, and MODY 2 patients may even be discharged from clinic after diagnosis. We present 4 cases and valuable lessons learned.

MODY 2 Case 1. 4 yo M referred for hyperglycemia in the 300s during surgery. A1c 6.4%. FBG at home 150s, asymptomatic. MGM and MGM’s siblings have diabetes. Diabetes autoantibodies (DAA) negative. C-peptide 5.4 (NL 0.78 - 5.19 ng/ml). MODY panel (GeneDx) showed heterozygous mutation in GCK gene (c.70 C>T). Patient remains off insulin, family reassured and advised to undergo genetic testing.

MODY 2 Case 2. 8 yo M diagnosed at local ED with “T1DM” after presenting with polyuria, polydipsia, and random BG 237. A1c 6.7%, C-peptide 1.9, started on basal-bolus insulin. MODY panel (sent a year later when patient was found to have low insulin requirement, negative DAA) showed pathogenic variant in GCK gene. Weaned from insulin, A1c unchanged (6.3–7%). Mother found to have same mutation. MODY 3 Case 1. 16 yo F referred by PCP who started her on insulin a year prior after an incidental finding of hyperglycemia. A1c was 7.5% at diagnosis. Mom, MGM have diabetes, unknown type (MGM thin by report). DAA neg, C-Peptide 1.74. MODY Panel showed HNF1A heterozygous gene mutation for RI31Q. She was switched to Glyburide, blood glucose 90s. MODY 3 Case 2. 10 yo M referred from the ED for “T1DM” (weight loss, fatigue, A1c 7.6%) started on basal-bolus insulin, but lost to follow up for a year. Brother has MODY 3. DAA neg, C-Peptide 3.1. Targeted gene sequencing showed HNF1A gene mutation. He was switched to Glyburide, A1c improved to 6.7%. However, patient became noncompliant as teenager, A1c now 9.3%.

CONCLUSION MODY remains underdiagnosed. A high index of suspicion should be maintained in nonobese, DAA-negative patients diagnosed with DM before 25yo. Although DAA and genetic testing can be costly, diagnosis can dramatically alter diabetes management as illustrated in all 4 cases, and overall cost of management may be lower in the end. Patients with MODY 2 do not develop vascular complications associated with diabetes, nor require pharmacotherapy. MODY 3 patients may be safely switched to sulfonylurea monotherapy, though degree of diabetes control depends on compliance with medication. Testing gives relatives previously misdiagnosed the opportunity to improve their own quality of life. More education for health care providers is warranted for prompt diagnosis and appropriate management of this condition.

Reference:1. Pihoker, et al. JCEM 2013; 98:4055–62
SAT-LB107 Insulin Sensing by Astrocytes Is Critical for Normal Thermogenesis and Body Temperature Regulation
Authors: Hill Jennifer Wootton , Manaserh Iyad H
Published: May 2020

The important role of astrocytes in the central control of energy balance and glucose homeostasis has only recently been recognized. Changes in thermoregulation can lead to metabolic dysregulation, but the role of astrocytes in this process is not yet clear. Therefore, we generated mice congenitally lacking insulin receptors (IR) in astrocytes (IRKOGFAP mice) to investigate the involvement of astrocyte insulin signaling. IRKOGFAP mice displayed a significant decrease in energy expenditure and a striking decrease in basal and fasting body temperature. When exposed to cold, however, they were able to mount a thermogenic response. Brown adipose tissue in IRKOGFAP mice exhibited increased adipocyte size, more apoptosis, loss of innervation, and decreased βAR3 expression levels. These findings identify a novel role for astrocyte insulin signaling in the development of normal body temperature control and sympathetic activation of BAT. Targeting insulin signaling in astrocytes has the potential to serve as a novel target for increasing energy expenditure.
SUN-LB111 Comparison of Phenotype and Metabolic Abnormalities Among Familial Partial Lipodystrophy Due to LMNA or PPARG Variants
Authors: Vasandani Chandna , Li Xilong , Sekizkardes Hilal , Brown Rebecca , Garg Abhimanyu
Published: May 2020

Familial partial lipodystrophy (FPLD), a rare autosomal dominant disorder, is characterized by marked loss of subcutaneous (sc) fat from the extremities, and predisposition to insulin resistance, diabetes mellitus, dyslipidemia and hepatic steatosis. FPLD2 and FPLD3 due to causal variants in LMNA and PPARG, respectively, are the two most common subtypes. Due to extremely rare prevalence of FPLD3 and limited reports in the literature, whether there are phenotypic differences between the two subtypes remain unclear. Therefore, we compared the anthropometric measurements and prevalence of metabolic abnormalities among 32 FPLD3 subjects (4 M, 28 F; mean ± SD age, 41 ± 17.2 y; body mass index (BMI), 26 ± 4.0 kg/m2) with 271 FPLD2 subjects (66 M, 205 F; age, 37.4 ± 17.0 y; BMI, 26 ± 5.0 kg/m2) from two referral centers in the United States. As compared to those with FPLD2, FPLD3 subjects had borderline higher prevalence of hypertriglyceridemia (66% vs 84%; P = 0.063), but significantly higher prevalence of diabetes (44% vs 72%; P = 0.004), past history of acute pancreatitis (13% vs 52%; P <0.001), and polycystic ovarian syndrome (26% vs 52%; P = 0.011). As compared to FPLD2, FPLD3 subjects had similar fasting triglyceride levels (median 208 vs 255 mg/dL; P=0.15), but lower high-density lipoprotein cholesterol levels (median 37.5 vs 30 mg/dL; P = 0.001), higher fasting glucose (median 95 vs 115 mg/dL; P = 0.05) and HbA1c (median 5.7 vs 7.0 %; P = 0.005) levels. Regional body fat was measured by dual energy X-ray absorptiometry in 19 FPLD3 and 105 FPLD2 subjects. In comparison to FPLD2, FPLD3 subjects had higher total fat (median 21.6% vs 26.1 %; P = 0.018); upper limb fat (median 20.3% vs 27.3%; P = 0.003) and lower limb fat (median 16.0% vs 20.8%; P = 0.007). Skinfold thickness measurements by calipers also revealed less severe fat loss from both the upper and lower extremities in FPLD3 subjects compared to FPLD2 subjects. As compared to FPLD2, FPLD3 subjects had significantly higher triceps skinfold thickness (median 5.5 mm vs 7.5 mm; P = 0.015); and thigh skinfold thickness (median 5.8 mm vs 11.3 mm; P = 0.001). There were no significant differences in the prevalence of fatty liver, plasma alanine aminotransferase and aspartate aminotransferase levels in the two subtypes. We conclude that compared to FPLD2 subjects, those with FPLD3 have milder lipodystrophy phenotype but paradoxically present with more severe metabolic complications, especially diabetes, dyslipidemia and polycystic ovarian syndrome. It is likely that this discrepancy could be due to early recognition of FPLD2 because of severe fat loss versus initial diagnosis of FPLD3 subjects due to severe metabolic complications leading to discovery of milder fat loss.
SUN-LB63 Optic Disc Edema in Patients With Craniofacial Fibrous Dysplasia / McCune-Albright
Authors: Raborn Layne , Pan Kristen , Fitzgibbon Edmond J , Collins Michael , Boyce Alison
Published: May 2020

Background: Fibrous Dysplasia (FD) is a mosaic disorder that involves fibro-osseous lesions in bone. In the presence of coexisting extra-skeletal features, it is termed McCune-Albright Syndrome (MAS). Optic disc edema (ODE) is a potentially serious finding that may progress to optic disc ischemia and nerve atrophy. We sought to determine the prevalence and identify risk factors for the development of ODE in the NIH FD/MAS cohort. Methods: A retrospective review was conducted and identified 7 patients with craniofacial FD/MAS with a diagnosis of ODE. Controls were patients with a normal eye examination and without potentially confounding ophthalmologic conditions. The cohort consisted of 73 patients with craniofacial FD, 7 (10%) of whom were diagnosed with ODE. Results: Radiographic and statistical analysis identified Chiari I malformation (CM1) and mass lesions, including aneurismal bone cysts (ABCs) and arachnoid cysts, as significant risks for developing ODE (odds ratio [OR] 48.8; 95% confidence interval [CI], 5.3 to 633.1; p < 0.01) and (OR 16.3; 95% CI, 2.8 to 81.9; p <0.01) respectively. There was no significant association of ODE with endocrinopathies, medications, optic canal diameter or intracranial volume.Conclusion: ODE can be found in association with craniofacial FD and may be the initial presenting symptom of intracranial mass lesions or CM1, which has previously been shown to be at an increased prevalence in the FD/MAS cohort. Patient with craniofacial FD/MAS and intracranial mass lesions or CM1 are at an increased risk of developing ODE and require close monitoring.
SUN-162 Isolated Primary Pigmented Micronodular Adrenal Disease. Unilateral or Bilateral Adrenalectomy? Two Cases Report
Authors: Chevais Anastassia , Beltsevich Dmitry , Ladygina Daria
Published: May 2020

Background: Isolated primary pigmented nodular adrenal disease (i-PPNAD) is a particular case of micronodular bilateral hyperplasia (MiBAH) leading to Cushing syndrome (CS). We present two patients with i-PPNAD who undergone unilateral adrenalectomy with different disease outcomes.

Case 1: A 56 yo man presented with typical signs and symptoms of CS, including central weight gain, proximal muscle weakness, hypertension and marked osteoporosis. A biochemical investigation showed an assessment of late-night salivary cortisol - 23 nmol/l (n <9), 24h urinary free cortisol (UFC)- 1206 nmol/24h (n-60–413). The 1 mg DST showed post-DST cortisol 617 nmol/l (n<50). ACTH concentration was suppressed at 1.1 pg/ml (n-7–66). Adrenal CT-scan was normal. PPNAD was assumed and the screening for Carney complex components was negative. After left adrenalectomy, histological examination confirmed the diagnosis of PPNAD. However, biochemical remission wasn’t achieved: postoperative UFC-860 nmol/24h. Thus, the right adrenalectomy was conducted.

Case 2: A 40 yo female presented with long term drug-corrected (beta-blockers, ACE inhibitor) arterial hypertension, menstrual dysfunction and clinical features of CS (central obesity, proximal muscle weakness, hirsutism), without osteoporosis. Baseline hormonal evaluation documented slightly increased level of salivary cortisol- 9,8 nmol/l (n <9), post 1 mg DST cortisol - 470 nmol/l (n<50) and ACTH-concentration below detection <1 pg/ml (n-7–66). However, UFC was normal – 215 nmol/l (n-60–413). Abdominal CT-scan revealed micronodular hyperplasia of the left adrenal and was suggestive of possible right adrenal gland hyperplasia. We performed left adrenalectomy. In the early postoperative period, adrenal insufficiency was diagnosed and thus it required hydrocortisone replacement.

Discussion: We obtained two opposite results: in case 1, an expected remission after unilateral adrenalectomy was not achieved, while patient No.2 developed adrenal insufficiency, which was a more favourable prognostic sign and attested to the successful outcome of surgical treatment. A possible explanation of the ineffectiveness of surgical intervention in patient No.1 was primary more severe hypercortisolism. It is also necessary to take into account that according to the CT data of the patient No.1, both adrenal glands were within normal ranges and did not differ from one another, while in the patient No.2, the lesion was more prominent on the right side.

Conclusion: Diagnostic of i-PPNAD and choice of intervention can be precarious, consequently more studies are needed to define to which patients unilateral adrenalectomy could be an efficient treatment modality. It is possible to perform unilateral adrenalectomy with subsequent assessment of cortisol levels, in case of lack of remission the contralateral adrenalectomy is required.
SAT-570 Should Severe Hypertriglyceridemia Also Be Considered as a Contraindication for Use of Glucagon like Peptide 1 (GLP-1) Agonists?
Authors: Guzman Amelia
Published: May 2020

Background: Reported cases of acute pancreatitis have been associated with the use of GLP-1 agonists for treatment of diabetes mellitus. Hypertriglyceridemia is a well-established but underestimated cause of acute and recurrent pancreatitis. At the present time, there is insufficient data to know if there is a casual relationship. Clinical Case: A 46 y.o. male with past medical history of coronary artery disease, hyperlipidemia, type 2 diabetes mellitus, hypertension, and morbid obesity, was admitted to the hospital with severe abdominal pain radiating to the back associated with non-bilious vomiting, for 1 day. Patient endorsed that 4 years ago he was diagnosed with hypertriglyceridemia. Physical exam findings were notable for a distended abdomen with mild epigastric tenderness, heart rate at 120 bpm, and a body mass index of 37 kg/m2. Active medications include: atorvastatin 40 mg PO daily, fenofibrate 45 mg PO daily, metformin 1,000 mg PO twice a day, glipizide 5 mg PO daily, levemir 60 units SQ twice a day, and most recently he had been started on dulaglutide 0.75 mg SQ weekly. Initial tests were consistent with acute pancreatitis and diabetic ketoacidosis: lipase 944 U/L (n 8.0 - 78 U/L), anion gap 18 mEq/L (n 5 - 13 mEq/L), creatinine 1.6 mg/dL (n 0.72 - 1.25 mg/dL), glucose 479 (n 60–100 mg/dL), β-Hydroxybutyrate 5.3 mmol/L (n <0.3mmol/L), urine glucose >1,000 mg/dL (n Negative mg/dL), urine ketones 20 mg/dL (n Negative), Triglycerides (TG) 5,374 mg/dL (n <150 mg/dL) and Hgb A1C 11.9% (n <5.7%). CT abdomen and pelvis without contrast revealed moderate acute pancreatitis. Patient was admitted to the intensive care unit and was started on intravenous insulin, atorvastatin 80 mg PO daily and fenofibrate 145 mg PO daily. Despite optimization of lipid-lowering agents, TG remained above 2,000 mg/dL. Decision was made to start patient on plasmapheresis until TG was <500 mg/dL. Patient’s TG improved to 370 mg/dL after second treatment. Patient’s dulaglutide was discontinued and patient was advised to avoid GLP-1 agonist use, indefinitely. One-month post discharge patient’s TG level was 370 mg/dL. Conclusion: Pancreatitis should be considered in patients on GLP-1 agonists, that present with persistent severe abdominal pain (with or without nausea), and its use should be discontinued in such patients. Use of GLP-1 agonists should be avoided in subjects with severe hypertriglyceridemia. Further research should be made in order to determine if GLP-1 agonists should be contraindicated in patients with severe hypertriglyceridemia, as both increase risk for pancreatitis.
OR12-07 Full Antagonism of Breast Cancer Cell Proliferation Can Result from Many Ligand-Induced Conformational Distortions of the Estrogen Receptor Ligand Binding Domain
Authors: Nwachukwu Jerome , Min Jian , Srinivasan Sathish K , Rangarajan Erumbi , Guillen Valeria Sanabria , Ziegler Yvonne , Carlson Kathryn , Hou Yingwei , Kim Sung Hoon , Izard Tina , Houtman Rene , Katzenellenbogen Benita S , Nettles Kendall W , Katzenellenbogen John A
Published: May 2020

Although most estrogen receptor alpha (ERα)-positive breast cancers initially respond well to endocrine therapies using aromatase inhibitors (AIs) or antiestrogens, after varying time periods the cancer frequently recurs as metastatic disease. A significant fraction of these recurrences are driven by ERs that have acquired activating mutations in their ligand binding domains (LBDs), giving them constitutive activity and thus resistance to AIs. Because these mutations also reduce the affinity and potency of SERMs and SERDs, expanded efforts have been made to vary the structure of antiestrogens to make them more potent.

Typical antiestrogens are comprised of a core element that binds securely in the ligand binding pocket and from which extends a single ring (ring E) having a side chain that sterically interferes with the position of helix-12 by direct antagonism, reorienting it so that it occludes the activation function 2 (AF2) hydrophobic groove for coactivator binding. Through structural studies, we found that bridged oxabicycloheptene-sulfonamide (OBHS-N) core ligands have two rings (E and F) that can be poised to engage in both “direct antagonism” and “indirect antagonism”, the latter of which disrupts the orientation of helix-12 by impinging on helix-11 and the helix-11–12 loop.

In this study, we have placed typical antiestrogen side chains on either the E or the F ring of OBHS-N core ligands and characterized their activities in ERα-positive breast cancer cells. All compounds have full antiproliferative activity and reverse estrogen-regulated gene expression, with the antiproliferative potency of each type of side chain having a distinct preference for E- vs F-ring attachment. Conformational analysis using a multiplexed coregulator peptide interaction assay shows that compounds with an E-ring substitution have interaction profiles similar to 4-hydroxytamoxifen and fulvestrant, whereas the F-ring substitution gives a very different pattern, suggesting that the antagonist activity of the two classes rely on different sets of coregulator proteins. A large number of high resolution (better than 2 Å) X-ray crystal structures reveal that this set of novel ER antagonists disrupt the conformation of the ER LBD in a variety of ways, several of which are distinct from those seen with previous antiestrogens such as Tamoxifen and Fulvestrant.

Our findings expand design concepts by which ERα ligands can block the activity of this receptor and illustrate how direct and indirect modes of ER antagonism can be combined to facilitate the development of more efficacious antiestrogens for breast cancer treatment and possibly for regulating ER-mediated activities in other estrogen target tissues.
SUN-385 Differential Effects of Abaloparatide and Teriparatide on Hip Cortical Volumetric BMD by DXA-Based 3d Modeling
Authors: Winzenrieth Renaud , Ominsky Michael S , Wang Yamei , Humbert Ludovic , Weiss Richard J
Published: May 2020

The osteoanabolic agent abaloparatide (ABL) has been shown to significantly increase total hip BMD over an 18-month period in postmenopausal women with osteoporosis. However, it remains unknown if these gains predominantly occur in the cortical or trabecular compartments of the proximal femur, and how they may differ from the effects of teriparatide (TPTD). Therefore, a 3D modeling approach was applied to DXA images from patients in the ACTIVE trial to estimate cortical and trabecular changes in the proximal femur over 18 months of treatment with placebo (PBO), ABL, or TPTD. A subset of 750 patients, 250 from each of the treatment groups in ACTIVE (PBO, ABL, TPTD) with non-missing BMD data were randomly selected with data stratified by study site and patient race/ethnicity. Hip DXA scans at baseline and months 6 and 18 were subjected to DXA-based 3D modeling to evaluate volumetric BMD (vBMD) in the cortical and trabecular compartments, as well as cortical thickness and cortical surface BMD (sBMD) (3D-SHAPER v2.10.1, Galgo Medical, Spain). Pairwise group comparisons were made for percentage change from baseline data using P-values derived from contrast tests based on an MMRM model adjusting for BMI, age, value at baseline, and DXA scanner. At 18 months, total hip areal BMD was significantly increased in both the ABL and TPTD groups (P<0.001 vs PBO), with gains from baseline significantly greater with ABL versus TPTD (4.2% vs 3.3%; P<0.05). Similar increases from baseline were observed with ABL and TPTD for both trabecular vBMD (9%) and cortical thickness (1.5%) at month 18 (both P<0.001 vs PBO). In contrast, cortical vBMD was significantly increased from baseline with ABL (1.3%) compared with PBO (-0.2%) and TPTD (0.4%) at month 18 (both P<0.05 vs ABL). Cortical sBMD, the product of cortical thickness and vBMD, was also increased with ABL (+2.8%) versus both PBO (-0.2%) and TPTD (+1.8%) at month 18 (both P<0.05). Although ABL and TPTD increased trabecular vBMD and cortical thickness similarly at the hip by DXA-based 3D modeling after 18 months, ABL significantly increased cortical vBMD and sBMD to a greater extent than TPTD. Additionally, ABL appears to increase cortical density relative to TPTD in clinically important regions of the proximal femur. Further studies may be warranted to investigate these differences and how they may impact hip strength.
SAT-415 Clinical Performance of Thyroid-Stimulating Immunoglobulin for Graves′ Disease Diagnosis
Authors: Marui Suemi , Lenczuk Aline , Rocha Nelisa Helena , Watanabe Tomoco , Brito Luciana Pinto
Published: May 2020

INTRODUCTION The diagnosis of Graves′disease (GD) is likely when patient presents hyperthyroidism, symmetrical goiter and orbitopathy and further evaluation is unnecessary. Nevertheless patient with nodular thyroid or in the absence of clinical orbitopathy, measurement of TSH receptor antibodies (TRAb) is recommended to distinguish GD from toxic multinodular goiter, toxic adenoma and other etiologies. Radioiodine uptake (RAIU) also helps to diagnosis when TRAb is unavailable. Third generation TRAb assays measure all types of TSH receptor antibodies: stimulating, blocking and neutral with an excellent sensitivity and specificity for GD diagnosis. Recently, an automated bioassay for the thyroid stimulating immunoglobulin (TSI) was introduced to improve GD diagnosis. OBJECTIVE To analyze clinical performance of TSI and compare with TRAb assay for GD diagnosis. MATERIAL AND METHODS Serum samples of 117 patients with thyrotoxicosis due to GD, toxic multinodular goiter and toxic adenoma were runned simultaneously in two analytical system commercially available. TRAb was analyzed by Elecsys Anti-TSHR assay (Roche Diagnostics, Germany) in a Cobase411 analyzer (Roche Diagnostics, Germany) and results, according to the manufacturer interval reference, were negative if < 1.75 IU/L (analytical range: 0.3 to 40 IU/L). TSI was measured by Immulite TSI assay (Siemens Healthcare, UK) in Immulite XPi 2000 and results, according to the manufacturer interval reference, were negative if < 0.55 IU/L (analytical range: 0.1 to 40 IU/L). Clinical diagnoses of thyrotoxicosis were determined according to ATA guideline (2016). Statistical analyses were performed using SPSS and MedCalc softwares. Comparison were evaluated by regression equations and were considered significant when p values were < .05. RESULTS From 2017 to 2019 a total of 312 serum samples from 117 patients (96 females) were evaluated with mean age 49.5 ±15.8 years-old (18 to 90 yrs). We excluded 26 results above the analytical measurement range of both assays. A high degree correlation was observed with a slope of 0.647 and an intercept -.094 IU/L. Spearman correlation coefficient was 0.858 (p < 0.0001, 95% CI 0.825 to 0.886). TSI assay had higher sensibility and negative predictive value compared to TRAb (95.6% vs 88.5% and 83.6% vs 54.8%, respectively) but lower specificity and positive predictive value (90.3% vs 100% and 97.5% vs 100%, respectively). The results of TSI assay showed good agreement with those of the TRAb assay (k=0.74). A total of 31 samples were discordant, favoring to TSI assay in all but one case of GD according to clinical diagnosis (TRAb positive and TSI negative). CONCLUSION TSI assay showed an excellent performance for GD diagnosis with a better sensibility than TRAb assay.
SAT-417 Personalized Treatment Planning for Radioiodine Therapy of Graves’ Disease;The Collar Therapy Indicator(CoTI)
Authors: Santhanam Prasanna , Simons Zachary , Ganji Suneeta , Sgouros George , Ladenson Paul W
Published: May 2020

Introduction Since its introduction 80 years ago, the therapeutic I-131 dosage has usually been tailored to individual patient requirements based on the uptake of a tracer radio-iodine(RAI) dose. Estimated exposure has typically been extrapolated from the results of activity measurements at one or two time points, e.g., at 4 and 24 hours. We now know that treatment of hyperthyroid Graves disease with these methods lead to a 13–25% rate of failure to cure hyperthyroidism and a 46–80% rate of long-term hypothyroidism in cured patients. There is a need for a much more personalized approach to RAI dosing based on individual RAI tissue uptake, kinetics. This can be achieved only after including multiple data points during the evaluation of tissue uptake. The Collar Therapy Indicator (CoTI), a device placed in cloth collar around the neck resembling a turtle neck sweater collar with a connecting wire and recording box, has been shown in small feasibility studies to provide data regarding radioiodine exposure that correlates with conventional methods of measuring I-123 and I-131 uptakes after diagnostic dose administration and/or therapy for thyroid disorders Methods; We hypothesized that the device’s continuous measurement capability will permit more accurate estimates of radiation exposure to thyroid tissue than conventionally employed methods assessing fractional uptake at one or a few time points. It may also provide information about the extent of variability in the absorbed radiation dose among patients with hyperthyroidism. We performed a feasibility study in a patient with graves’ disease to see the difference between tradition methods of I-123 uptake and the CoTI; (1) We compared the conventional quantitative uptake-derived thyroid time activity curve (TAC) as well as the Area Under the Curve (AUC)(based on percent uptake at 6 hour and 24 hour time points) to that obtained using the CoTI.(2) We evaluated the uptake and clearance kinetics of diagnostic I-123 administered.(3) We also evaluated patient experience in using the CoTI device with a survey instrument. Results; The CoTI plotted TAC and AUC offered a different approach from the conventional methods of calculation (6 hr and 24 hr % uptake) of I-123 TAC and AUC. The patient reported no difficulty in using the device and the device itself was not inconvenient. Conclusions; The calculation of % uptake as well as rate of uptake within the thyroid by CoTI might help us, in achieving a more personalized approach to I-131 RAI dose calculation for treatment of Graves’ disease. The preliminary research findings that we have generated will help us investigate different aspects of RAI uptake within the thyroid and will hopefully lead to solutions, for some of the common issues and problems arising out of random dosing of RAI.
SAT-343 Diagnosis and Management of Pseudohypoparathyroidism Type 1B
Authors: Tahata Shawn , Kohlenberg Jacob , Clarke Bart Lyman
Published: May 2020

Background: Pseudohypoparathyroidism (PHP) is a heterogeneous group of disorders characterized by end-organ resistance to PTH. Most subtypes are caused by pathogenic variants or epigenetic alterations in GNAS, which encodes the alpha subunit of the G protein regulating end-organ response to PTH. PHP type 1B (PHP1B) is caused by methylation defects in GNAS and presents with isolated renal PTH resistance. Clinical Case: A 29-year-old gentleman presented with intermittent muscle spasms, perioral and digital paresthesias, fatigue, and anxiety. Family history was notable for similar symptoms in his sister and nephew. Physical examination revealed normal stature, non-dysmorphic facies, and no soft tissue ossifications or skeletal anomalies. Chvostek sign was positive. Laboratory studies showed total calcium 6.0 mg/dL (n 8.6–10.0 mg/dL), phosphorus 6.8 mg/dL (n 2.5–3.5 mg/dL), creatinine 0.8 mg/dL (n 0.8–1.3 mg/dL), albumin 5.0 (n 3.5–5.0 mg/dL), PTH 231 pg/mL (n 15–65 pg/mL), total 25-hydroxyvitamin D 19 mg/mL (n 20–50 ng/mL), and 1,25-dihydroxyvitamin D 45 pg/mL (n 18–64 pg/mL). Additional endocrine testing showed TSH 6.4 mIU/L (n 0.3–4.2 mIU/L), free T4 1.1 ng/dL (n 0.9–1.7 ng/dL), and TPO antibody <0.3 IU/mL (n <9.0 IU/mL). Renal ultrasound was normal. CT head showed diffuse intracranial calcifications. He was diagnosed with PHP1B and started on calcitriol, cholecalciferol, and calcium carbonate. He declined genetic testing. Repeat laboratory studies were improved with total calcium 8.5 mg/dL, phosphorus 3.9 mg/dL, total 25-hydroxyvitamin D 49 mg/mL, PTH 124 pg/mL, and 24-hour urinary calcium 269 mg (n <250 mg). Conclusion: International consensus guidelines for the diagnosis and management of PHP and related disorders were recently published by Mantovani et al. in 2018. Proposed clinical and biochemical major criteria include PTH resistance, ectopic ossifications, early-onset obesity, TSH resistance, and Albright hereditary osteodystrophy (AHO; round facies, short stature, brachydactyly, developmental delay). Unlike PHP type 1A, PHP1B often presents later in life and features of AHO are usually absent, so diagnosis requires a high degree of clinical suspicion. It is recommended that patients with suspected PHP have molecular confirmation with sequencing, methylation, and/or copy number variant analysis of GNAS. Routine monitoring of calcium, phosphorus, and PTH levels and treatment with active vitamin D analogues with or without calcium supplements are advised to maintain normal calcium and phosphorus and PTH <2 times the upper limit of normal. Other recommendations include renal imaging for nephrocalcinosis, eye exam for cataracts, CT head imaging (in patients with neurological findings) for calcifications, regular dental care, and management of comorbid endocrinopathies. A multidisciplinary approach is needed in this complex, heterogeneous group of disorders.
SAT-102 Height Improvement with Recombinant Human Growth Hormone Therapy at Terminal Stage of Growth
Authors: Kim Dae Hyun , Choi Ju-hee
Published: May 2020

Recombinant growth hormone therapy (rhGH) is known to improve the final adult height in various conditions. The effectiveness of treatment depends on the status of patients, but it is generally known that the younger age the treatment starts, the better effects obtained. The authors experienced that final adult height was dramatically improved with rhGH at the very end stage of deceleration period of growth, so we would like to share our unusual experience. A boy of 13 years and 11 months visited our clinic with cessation of growth. He was 163cm (54%) tall and 62.6kg (78%), and showed Tanner stage IV-V development. There have been no unusual findings in past history and family history. His Mid Parental Height was calculated as 170.5cm (Father: 172cm, Mother: 156cm). After experiencing an acute growth acceleration around 20cm over the past two years, growth rate was abruptly decreased, with 1cm growth in the last nine months. Bone age was 17 years by TW3 method, and pelvic AP x-ray showed Risser stage 4, which is compatible to 17 years in boy. As a result of the above findings, additional height gain was expected to less than 1-2cm and medical intervention for more height gain was expected to impossible. However, the patient and his parents strongly requested rhGH treatment. So, we decided to try rhGH treatment for only three months and then discuss whether or not to extend the treatment after checking up the result. Follow up was conducted every three months, and the height of the patient continued to grow and the closure of the remaining growth plates was confirmed to be delayed. During the one-and-a-half year treatment, no side effects appeared in patient, reaching 173 centimeters, the equivalent of the Korean male standard height. In this case, we experience that the use of Growth hormone can improve the final adult height significantly, even in the end stage of growth, without any other intervention. So, we may consider attempting limitedly to treat growth hormones for height gain, if caregivers or patient strongly request the medical intervention in end stage of the puberty or growth.
MON-622 Rapid Improvement in Glycated Albumin Before Educational Admission Predicts Fair Glycemic Control One Year After the Discharge of Patients with Type 2 Diabetes Mellitus
Authors: Katsuragawa Sho , Tsurutani Yuya , Takiguchi Tomoko , Saito Jun , Nishikawa Tetsuo
Published: May 2020

Background and Aim: Glycated albumin (GA) reflects a short-term glycemic control (about 2 weeks) in comparison to glycated hemoglobin (HbA1c) which reflects a long-term glycemic control. Thus, if the dietary, exercise, or medication therapy before the educational admission is effective, a rapid improvement in GA can be observed. However, the impact of the improvement in GA on the subsequent glycemic control is not well understood. This retrospective study analyzed the association between the change of GA before educational admission and glycemic control one year after the discharge of patients with type 2 diabetes mellitus (T2DM). Method: We analyzed data from 114 T2DM patients who were admitted to our hospital from 2011 to 2016. The GA data within 30 days before admission and on the day of admission were available for all patients. The change of GA per day (ΔGA/day) was calculated as [(GA on admission) - (GA before admission)/number of days between the two measurements of GA]. Patients with renal dysfunction (eGFR < 30 mL/min/1.73 m2) or insulin deficiency [fasting C-peptide (CPR) < 0.5 ng/mL or two-hour postprandial CPR < 1.0 ng/mL] were excluded. Patients achieving an HbA1c of < 7.0 % at one year after discharge were defined as achievers, and the rest were defined as non-achievers. Multiple baseline factors including the ΔGA/day between the two groups were compared. Results: Of the 114 patients, 68 were achievers and 46 were non-achievers. GA significantly declined during before and just after the admission to hospital (median [interquartile range]: 26.0 [22.2 - 32.7] to 25.0 [21.4 - 29.8] %, p < 0.001). The range of the ΔGA/day was between -1.14 and 0.28, with a median value of -0.08 [-0.26 - 0.002]. The age, body mass index, and HbA1c levels at admission were not significantly different between the two groups. The increase in CPR after the glucagon loading test was higher in the achievers than in the non-achievers (1.85 [1.32 - 2.87] vs 1.21 [0.53 - 1.92] ng/ml, p = 0.004). The ΔGA/day was lower in the achievers than in the non-achievers (-0.14 [-0.39 - -0.006] vs -0.04 [-0.13 - 0.03], p = 0.002). A logistic regression analysis demonstrated that the ΔGA/day was the factor associated with achieving an HbA1c of < 7.0% at one year after discharge (Odds ratio: 0.037, 95 % confidence interval: 0.004 - 0.267, p < 0.001). In the receiver operating characteristic curve analysis, the ΔGA/day had an area under the curve of 0.67 in the achievement group and the cutoff value was set as -0.146 for predicting the achievement, with a sensitivity of 0.50 and a specificity of 0.85.

Conclusion: Our results suggest that the change in GA before the educational admission can predict the glycemic control one year after the discharge of T2DM patients.
SUN-302 Incidence Trends in Lung and Gastroenteropancreatic Neuroendocrine Neoplasms
Authors: Alwan Heba , Rosa Stefano La , Kopp Peter , Germann Simon , Maspoli-Conconi Manuela , Sempoux Christine , Bulliard Jean-Luc
Published: May 2020

Abstract

Introduction

The incidence of neuroendocrine neoplasms (NENs) seems to increase worldwide. However, long-term, population-based data that consider differentiation levels are sparse.

Objective

To evaluate the incidence trend of lung and gastroenteropancreatic (GEP) NENs according to the latest International Agency for Research on Cancer/World Health Organization classification over a 41-year time period in two Swiss regions.

Methods

All cases of lung and GEP NENs recorded in the Vaud and Neuchâtel Cancer Registries from 1976–2016 were included. NENs were stratified into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Changes in annual age-standardized incidence rates were calculated for lung and GEP NETs and NECs by sex.

Results

There were 4141 patients diagnosed with NENs, of which 65% were men. The incidence of lung NETs did not reveal any statistically significant trend in men, but increased in women by 4.9%/year between 1976–2016. The incidence of lung NECs in men decreased significantly by 2.6%/year from 1985–2016 whereas the incidence of lung NECs in women increased significantly between 1976–1998 by 6%/year. For GEP NETs, a steady annual increase in incidence occurred between 1976–2016 with a magnitude of 1.7% in men and 1.3% in women. No trend in incidence of GEP NECs was found for both sexes.

Conclusions

The incidence trends of lung NECs in men and women parallel changes in smoking prevalence in the population whereas causes of the increase in incidence of GEP NETs are not fully understood. Our study supports the importance of evaluating the epidemiology of NENs by their differentiation level.
SUN-065 Bone Health Outcomes in a Large, Diverse Pediatric Cohort Undergoing Hematopoietic Stem Cell Transplant
Authors: Swauger Sarah , Sabulski Anthony , Hornung Lindsey , Myers Kasiani , Wasserman Halley , Howell Jonathan Christian
Published: May 2020

Background:

Impaired bone mineral density (BMD) is a known complication of hematopoietic stem cell transplantation (HSCT) in adults and may lead to increased fracture risk. Little is known in pediatrics about the risks for impaired BMD and fragility (low trauma) fractures after HSCT. Factors that may influence the risk of bone disease include underlying diagnosis, glucocorticoid exposure, and HSCT complications (e.g. graft versus host disease (GVHD)). Our study aims to describe the incidence of fragility fractures in a large diverse pediatric HSCT population and to identify risk factors of both fracture and impaired BMD.

Methods:

We reviewed the records of 237 patients (age ≤ 21 years at time of transplant) who underwent HSCT at our institution between January 2015 and March 2018. The primary endpoint was incidence of fragility fractures and the secondary endpoint was assessment of BMD on dual-energy X-ray absorptiometry (DXA). We analyzed DXA results at one-year post-HSCT in 72 out of 206 patients alive at 1 year.

Results:

There were 25/237 (10.5%) patients with evidence of fragility fracture on x-ray. Of those, 18/25 (72%) were spine fractures. For patients who had fractures, median time to fracture was 5.9 months after BMT. Mortality at one-year was proportionally higher, though not significant (p=0.11) in patients who had at least one fragility fracture (24%; 6/25) compared to patients without fragility fracture (12%; 25/212). Vitamin D status at one-year post transplant was sufficient (>20ng/mL) in 94% (160/171) of patients measured. There was no difference in incidence of fracture between vitamin D sufficient and insufficient patients. The median height-for-age adjusted Z-score (HAZ) for spine BMD at one-year post transplant was 0.13 in all patients. The median HAZ spine BMD Z-score in patients with fragility fracture was -1.64, though data was available for only 5 patients.

Conclusions:

The incidence of fragility fractures, especially vertebral compression fractures, after pediatric HSCT is striking and is higher than in adult populations. Furthermore, there are likely additional asymptomatic patients with occult fractures not detected in out cohort. Additional analysis will assess the associations between underlying medical diagnosis, GVHD, and chronic glucocorticoid exposure on fragility fracture risk. The high incidence of fragility fractures seen in this study advocates for establishing bone health screening protocols with attention toward spinal imaging in pediatric patients undergoing HSCT.
OR34-03 Variable and Pulsatile Circulating Aldosterone Levels in Primary Aldosteronism: Implications for Diagnosis and Sub-Type Differentiation
Authors: Yozamp Nicholas , Sacks Barry , Underhill Jonathan , Fudim Tali , Vaidya Anand
Published: May 2020

Introduction: Considerable intra-individual variability in circulating aldosterone levels has been observed in patients with primary aldosteronism (PA). The magnitude and implications of this phenomenon are not well characterized.

Objective: To evaluate the acute variability in aldosterone in patients with confirmed PA.

Methods: 373 patients with confirmed PA underwent adrenal venous sampling (AVS) after appropriate catheterization of bilateral adrenal veins. Peripheral venous aldosterone levels were measured 2 hours prior to AVS while in supine posture. After anesthesia induction with fentanyl and midazolam, AVS was performed while in the same supine posture, and aldosterone levels were drawn from the inferior vena cava (IVC) and in triplicate from the bilateral adrenal veins over 10 minutes. Differences between the pre-AVS and intra-AVS IVC aldosterone levels were analyzed, and regression models used to identify independent predictors of change. Coefficients of variation (COV) between triplicate aldosterone levels in each adrenal vein were calculated.

Results: 81% of patients demonstrated a decrease in aldosterone concentration from pre-AVS to the intra-AVS IVC measurement. The mean decrease in aldosterone was 10.5 ng/dL (95% CI: 7.6–13.3) and the mean relative decrease in aldosterone was 39% (95% CI: 27–51%, P<0.0001). The absolute decrease in aldosterone was striking, with 48% of patients who had a decrease in aldosterone exhibiting an IVC aldosterone of less than or equal to 5 ng/dL. The absolute decrease in aldosterone was significantly associated with a higher aldosterone level (p<0.001) and lower systolic blood pressure at diagnosis (p=0.02). A wide variation in triplicate aldosterone values was seen in the span of 10-minute sampling, ranging from 1–300%, with COV of 21.0% in the left adrenal vein and 25.0% in the right adrenal vein. If the lowest of three aldosterone-to-cortisol (A/C) ratios on the dominant side and highest of three A/C ratios on the contralateral side were used instead of the average of the three values, the interpretation of the AVS would have changed from unilateral PA to bilateral PA in 15.9% of cases.

Conclusions: These findings underscore the pulsatile and variable nature of circulating aldosterone levels in patients with bona fide PA. Aldosterone levels substantially declined in 81% of patients within a period of 2 hours while maintaining a fixed and supine posture. In half of these patients, aldosterone levels declined to 5 ng/dL or below, a threshold typically considered incompatible with PA. Further, adrenal venous aldosterone levels exhibited large variations on repeated sampling within a 10-minute span that could have influenced the interpretation of sub-type differentiation in nearly 16% of cases. Single circulating aldosterone values lack precision and reproducibility and may result in incorrect diagnosis and sub-type differentiation.
SUN-214 A Novel Glucocorticoid Receptor Antagonist (CORT113176) Reveals Unique Developmental and Tissue-Specific Effects in a Neonatal Rat Model of Human Prematurity
Authors: Welhouse Kyle D , Gehrand Ashley , Phillips Jonathan , Siddiqui Hana , Schulgit Matthew , Raff Hershel
Published: May 2020

Premature birth is a major public health problem worldwide and can lead to transient adrenal insufficiency1,2. The stress of premature birth includes the inability to control blood glucose and maintain normal oxygenation leading to hypoxia3. Corticosteroid administration enhances surfactant production and improves oxygenation in preterm humans. However, corticosteroids can also have negative consequences4,5. We have validated a rat model of separation and hypoxia on post-natal day (PD) 2 that emulates the stress and treatment of hypoxia in the preterm human infant6,7. We hypothesized that the role of endogenous glucocorticoids in our neonatal rat model of preterm birth can be evaluated using the novel selective glucocorticoid receptor (GR) antagonist CORT113176 (Corcept) which is devoid of progesterone receptor effects8. Pups (PD 2, 8, or 15; N=6–8 per treatment/timepoint) were given CORT113176 (60 mg/kg IP) or vehicle, then placed into chambers in room air with mild warming to prevent hypothermia due to maternal separation. 60 min later, one group of pups was euthanized and trunk blood collected (baseline). The remaining pups were exposed to hypoxia (8% O2) or normoxia (time control) for 30 or 60 min at which times trunk blood was collected for the measurement of plasma glucose, insulin, ACTH, and corticosterone. Plasma ACTH, corticosterone, and insulin were measured by immunoassay. Glucose was measured by glucose oxidase method and insulin sensitivity calculated (HOMA-IR). Organs were frozen (brain, pituitary, adrenal glands, kidney, liver, muscle, fat) for future assessment of tissue-specific glucocorticoid-sensitive gene expression. In PD2 rats, basal and hypoxia-stimulated plasma ACTH and corticosterone were lower and basal HOMA-IR greater with CORT113176 pretreatment suggesting (unexpectedly) glucocorticoid agonist activity. In PD8 and PD15 rats, basal and hypoxia-stimulated plasma ACTH and corticosterone were augmented after CORT113176 pretreatment demonstrating classic antagonist activity. However, in PD8 rats, CORT113176 effects were tissue-specific acting as a classic antagonist on the HPA-axis, but as an agonist on whole-body insulin resistance. The differential effects of CORT113176 based on age and target tissue indicate that GR regulation changes in early development in our animal model of human prematurity. These findings may have significant implications in the treatment of hypoxia and transient adrenal insufficiency in the preterm infant1,2 as well as give insight into the nuances of the control of glucocorticoid receptor function.

1Lancet 392:1923–1994, 2018

2Curr Opin Endocrinol Diabetes Obes 17:8–12, 2010

3Compr Ther 13:14–19, 1987

4Int Immunopharmacol 66:242–250, 2019

5J Neuroendocrinol 27:468–480, 2015

6Am J Physiol 300:R708-715, 2011

7Am J Physiol 302:R627-R633, 2012

8Med Chem Lett 25:5720−5725, 2015