bluuebunny/crossref_metadata_2025 huggingface dataset:
SAT-403 Is Most “Primary” Hyperparathyroidism Both Tertiary and Preventable?
Authors: Innerfield Ronald Jay
Published: May 2020

Primary Hyperparathyroidism has reached epidemic proportions since the advent of mass screening for laboratory parameters including calcium. Secondary Hyperparathyroidism has been considered by some individuals as “Normocalcemic Primary Hyperparathyroidism” (4th International Workshop on The Management of Asymptomatic Primary Hyperparathyroidism, Florence, 2013 Bilzekian et al:-”Normocalcemic PHPT is a clinical presentation of PHPT: management approach is recommended.”)We report a single case of severe secondary hyperparathyroidism (with severe osteomalacia due to ileal resection) as well as 56 subsequent secondary hyperpararthyroid cases treated with 1,25dihydroxy-D3 (calcitriol) which were associated with significant reduction of parathormone levels *and continued normalization of calcium levels* [as well as significant improvement in bone density.] We are instituting a long-term, double-blind, placebo controlled clinical trial - with design presented here - to determine whether or not the incidence of hypercalcemic hyperparathyroidism can be significantly reduced or even obliterated by treatment with calcitriol.

Mrs. K.E.

Date Ca++ PTH Calcitriol

---------- - ------ ----- ---------

1997/05/01 8.5 344.0 0.25 i po qd

1997/05/28 8.5 388.0 0.25 i po qd

1997/07/21 9.3 102.0 0.50 ii po tid

1997/08/21 9.3 167.0 0.50 ii po qid

1997/11/14 10.4 11.4 0.50 ii po qid

1998/01/26 11.2 0 (!) 0.50 i po tid

1998/04/28 9.7 8.6 0.50 i po tid

1998/06/26 9.5 11.4 0.50 i po tid

1999/04/28 9.4 15.2 0.50 i po tid

2000/02/04 8.7 16.0 0.50 i po tid

2000/05/01 9.3 15.1 0.50 i po tid

Baseline Values Statistic: Ca++ /PTH, Total: 910.70 /4170.00, Average: 9.49/73.16, Count: 57/57, Maximum: 11.70/211.00, Minimum: 4.90 /12.00, Variance: 1.38 /923.70, SD: 2.47/59.34

Post-Treatment with Calcitriol Statistic: Ca++ PTH, Total: 910.70/4170.00, Average: 9.49/73.16,Count: 57/57, 11.70/211.00, Minimum: 4.90/12.00, Variance: 1.38 /923.70, SD: 1.18/43.86

99% confidence interval around the 49.9 pg/ml difference was (-75.5 to -24.3 pg/ml)

Proposed Clinical Trial:- Calcitriol to Prevent Hyperparathyroidism (CaPH) Trial

Double-blind, randomized, parallel-controlled clinical trial stratified by history of nephrolithiasis with follow-up for 5-year duration

Calcitriol Rx to keep PTH< 70 vs Ergocalcitriol to keep 25-OH D3 >30

N=100 patients/arm

Visits q90 days

Bone densitometry [including lateral spine] qyear

Telopeptides, Crosslinks, Alkaline Phosphatase, UV/Pcalcium/creatinine,Flat Plates

Exclusion: Pcreatinine>2.0,mg/dl, Ca++>10.0 mg/dl,Familial HPTH

Inclusion: PTH >70 pg/ml

Primary Efficacy Variable: Number of documented cases of Hypercalcemic Hyperparathyroidism

Secondary Variables: Mortality, Kidney stones, Bone density, Fractures
SAT-338 An Unusual Case of Brown Tumor in the Left Femur Associated with Secondary Hyperparathyroidism
Authors: Garg Dave , Rhyu Jane , Bhat Shalini
Published: May 2020

Background: Brown tumor of hyperparathyroidism (BTHPT) are non-neoplastic bony lesions that arise from increased osteoclastic activity in the setting of uncontrolled hyperparathyroidism, (HPT). The prevalence is low, with a frequency of 3% in primary HPT and 2% in secondary HPT. It is rare as earlier detection and treatment of HPT prevents the progression and development of BTHPT. BTHPT is more common when HPT is untreated. BTHPT are benign tumors which usually show high 18Fludeoxyglucose-PET/CT (FDG) uptake. The mechanism of elevated FDG uptake has been suggested to be the presence of giant cells, and intracellular glucose metabolism of the macrophages may also play a role. We describe a case of a patient who presents with FDG uptake-negative BTHPT of the left femur.

Clinical Case: 62-year-old male with end-stage renal disease (ESRD) and secondary HPT presented with severe left hip pain for many months. The patient had poor access to health care and had not received routine medical treatments at an outside facility prior to presentation at our facility. Laboratory studies showed PTH 1942 pg/ml (14–72), Calcium 8.7 ng/dl (8.4–10.2), phosphorus 3.6 mg/dl (2.5–4.9), Vitamin D total 19.7 ng/ml (30–140), Vit D 1,25 9 pg/ml (18–72), and creatinine 7.75 mg/dl (.66-1.28), alkaline phosphatase 57 u/L (33–94). FDG scan revealed several lucencies in the left proximal femur, with no uptake. The patient underwent left total hip arthroplasty due to impending pathological fracture. Surgical pathology revealed fragments of fibrous tissue with fibroblasts, hemosiderin and interstitial hemorrhage, consistent with brown tumor.

Conclusion: We describe a unique case of BTHPT of the left femur which was the unrecognized cause of hip pain. BTHPT occurs late in the setting of HPT and is considered as a sign of poorly controlled disease. This is the first case of BTHPT to our knowledge that is not FDG-avid. This is unusual given the vascularity seen in these tumors and highlights that glucose utilization may not necessarily reflect the degree of osteoclastic activity in these tumors. Medical treatment has been shown to be sufficient in helping resolve these lesions, although the process is usually slow. Conversely, in cases of refractory disease, subtotal parathyroidectomy may be required. Our case describes an FDG-negative BTHPT, and highlights that although rare, this should be considered in the management of patients with ESRD, secondary HPT and hip pain. Patients can present with various imaging characteristics. Despite being rare, this case underscores the importance of recognition of BTHPT, so that intervention may be rendered early.
MON-172 Comparison of a Late-night Salivary Cortisol Immunoassay and a Cortisol and Cortisone LCMS Assay in Patients with Cushing’s Disease
Authors: Kannankeril Joshua , Carroll Ty Brian , Findling James W , Javorsky Bradley Richard , Gunsolus Ian , Phillips Jonathan , Raff Hershel
Published: May 2020

Late-night salivary cortisol (LNSC) measured by enzyme immunoassay (EIA) is established as a reliable screening test and recommended as a first-line test for Cushing’s syndrome.1,2 However, liquid chromatography-tandem mass spectrometry (LCMS), validated to measure salivary cortisol (F) and cortisone (E), has been proposed to be superior diagnostically as well as helpful in detecting saliva contaminated with topical hydrocortisone (i.e. cortisol).3,4 We measured EIA-F, LCMS-F, and LCMS-E in 913 consecutive late-night saliva samples from patients suspected of Cushing’s syndrome. For the current report, we focus only on the patients with Cushing’s disease (CD) who had at least one elevated salivary result using cutoffs established previously [EIA-F ≥3.3 nmol/L, LCMS-F ≥2.8 nmol/L, and LCMS-E ≥8.7 nmol/L].5 We identified 27 patients who had newly diagnosed CD (n-CD) or had persistent/recurrent CD after pituitary surgery (r-CD). Data are shown as mean (SD). There were 19F/8M patients aged 50 (17) y; their BMI was 35 (11) kg/m2. 8 patients had n-CD and 19 had r-CD. In all 27 patients, EIA-F was 9.1 (6.0), LCMS-F was 5.1 (4.0), and LCMS-E was 19.6 (12.3) nmol/L. In n-CD, EIA-F was 14.3 (7.7), LCMS-F was 7.7 (4.6), and LCMS-E was 29.4 (12.8) nmol/L. In r-CD, EIA-F was 6.9 (3.6), LCMS-F was 4.0 (3.2), and LCMS-E was 15.5 (10.0) nmol/L. Mean EIA-F was greater than mean LCMS-F in all patients, and mean LNSC in n-CD patients was greater than mean LNSC in r-CD patients. The LCMS-F/E ratio was <0.8 in all subjects indicating that no saliva samples were contaminated with topical hydrocortisone.3 Furthermore, there was no difference in the LCMS-F/E ratio between n-CD [0.3 (0.1)] and r-CD [0.3 (0.2)] patients. Using previously identified cutoffs, 9 of the 27 CD patients had normal LCMS-F whereas only 1 patient had a normal EIA-F (P=0.011). The EIA-F results of patients with normal LCMS-F were significantly lower than patients with increased LCMS-F demonstrating that LCMS-F was more likely to provide false negative results with milder hypercortisolism. Most of these false-negative LCMS-F results occurred in the r-CD patients (8 out of 19) who had milder hypercortisolism compared to the n-CD patients (P=0.006). No differences in diagnostic performance were found between EIA-F and LCMS-E. In summary, EIA-F appears to be superior to LCMS-F in identifying CD patients with milder hypercortisolism using established diagnostic cutoffs.5 Neither LCMS-E nor F/E ratio improved the diagnostic sensitivity in newly diagnosed CD or persistent/recurrent CD after pituitary surgery. We suggest that late-night salivary cortisol measured by EIA provides the best sensitivity for CD diagnosis.

1J Clin Endocrinol Metab 2008;93:1526–1540.

2Clin Chem 2003;49:203–204.

3Clin Chem 2012;58:947–948.

4J Clin Endocrinol Metab 2010;95:4951–4958.

5J Endocr Soc 2019;3:1631–1640.
SUN-410 Reverse T3 in Patients with Hypothyroidism, Helpful or a Waste of Time?
Authors: Friedman Theodore C , Wilson Julian B
Published: May 2020

BACKGROUND: The normal thyroid secretes T4 (an inactive precursor), T3 (the active hormone) and reverse T3, a biologically inactive form of T3 that may block T3 from binding to the thyroid hormone receptor. As about 15% of patients on L-T4 replacement with a normalized TSH report continued fatigue and other hypothyroid symptoms, efforts are needed to understand this phenomenon. Decades ago, endocrinologists realized that in severe illnesses, rT3 is often high and T3 is often low and termed this “sick euthyroid syndrome”. However, more recently, alternative or functional doctors have argued that high rT3 is detrimental and can block T3 from binding to the thyroid hormone receptor. Without peer-reviewed publications, these functional doctors rely heavily on rT3 levels to treat patients that may have no other laboratory findings of hypothyroidism and often prescribe them L-T3-only preparations to try to lower the rT3.

Hypothesis: Patients on L-T4 alone will more likely have an elevated rT3 compared to patients on desiccated thyroid or L-T4/L-T3 therapy.

Methods rT3 was measured in 98 consecutive patients seen in a tertiary Endocrinology clinic with possible or confirmed hypothyroidism (all with severe fatigue) with many of them were already treated with different thyroid preparations.

Results: The figure shows the 25%-75% quartiles, ranges and ratio of rT3 above the normal range/patients in that category. The cutoff of 24 ng/dL (upper limit of normal for rT3 at either Quest or LabCorp) is indicated by the line. Overall, 18 of the 98 patients had a rT3 above the normal range. Patients on L-T4 alone or desiccated thyroid plus L-T4 had the highest levels of rT3 and the highest % above the cut-off. Three of the patients with a high rT3 were not on any thyroid medicine, and in 2 of them, the rT3 normalized when repeated. The 8 patients with a high rT3 on L-T4 was a relatively high percentage (29%).

Conclusion: Measuring rT3 may be helpful in patients who are already on T4-containing thyroid treatments who still have hypothyroid symptoms. Based on this data, measuring rT3 in most patients who are not taking thyroid medicine is not recommended, as only a very small percentage of them had an elevated rT3. Future studies are needed to determine if high rT3 levels correlate with hypothyroid symptoms and if adding L-T3 or desiccated thyroid to hypothyroid patients on L-T4 normalizes rT3 and improves hypothyroid symptoms.
SAT-235 Young Male with Persistent Central Diabetes Insipidus After a Car Accident
Authors: Yesaulava Liudmila , Houston Caroline , Sultana Sanjeda
Published: May 2020

BACKGROUND: Central diabetes insipidus (CDI) occurs in 20% of cases of traumatic brain injury (TBI). Most cases of post-TBI CDI resolve within 2–5 days. Only 6% of long-term survivors of TBI have evidence of persistent CDI.1 We report a patient with persistent CDI after TBI. Clinical Case: A 27 year old male was referred for polyuria. Three months prior he was in a rollover motor vehicle accident. At that time, CT head revealed frontal and occipital contusions with scattered subarachnoid, subdural, and intraventricular blood. There was no evidence of skull fracture, mass-effect, or midline shift. On hospital day 4, his urine output increased to > 3L/day, with serum sodium of 146 mEq/L (n 135–145) and urine specific gravity of 1.015 (n 1.005–1.030). Repeat head CT revealed bilateral subdural hematomas causing mild mass effect. During the rest of his 2-month hospitalization, he continued to have polyuria with specific gravity as low as 1.005, and occasional hypernatremia, with a peak serum sodium of 149 mEq/L. Serum sodium on discharge was 144 mEq/L. On presentation to our clinic, his family and caretakers reported polydipsia, polyuria and nocturia. He had no history of diabetes mellitus or lithium use. On exam he was tachycardic but normotensive with no signs of dehydration. Neurologic exam was normal except for distractibility and impaired long- and short-term memory. After 3 hours of water deprivation, laboratory testing revealed serum sodium 150 mEq/L, serum osmolality 307 mOsmol/kg (n 270–295), urine osmolality 119 mOsmol/kg (n 300–900), and ADH 3 pmol/L (n </= 14); consistent with CDI. Oral desmopressin led to resolution of polydipsia and polyuria. Evaluation of anterior pituitary function was normal. Six months post TBI, CT head revealed increased left frontal subdural hematoma with effacement of the right lateral ventricle and 1cm left-to-right midline shift. A burr hole procedure was performed but CDI persisted. Conclusion: Animal studies have shown that neurohypophyseal apoptosis occurs by inducing intracranial hypertension lasting 12 hours or more.2 Persistent DI may herald rising intracranial pressure (ICP), as reflected by our patient’s case.1 Clinicians should be aware of the reciprocal association between increased ICP and persistent CDI following TBI.

References: (1) Tudor R. M., Thompson C. J. Posterior pituitary dysfunction following traumatic brain injury: review. Pituitary. 2019 Jun; 22(3):296–304. (2) Tan H., et al. Assessment of the role of intracranial hypertension and stress on hippocampal cell apoptosis and hypothalamic-pituitary dysfunction after TBI. Sci Rep. 2017 Jun; 7(1):3805.
SUN-093 Prospective Clinical Assessment Study in Children with Achondroplasia: The PROPEL Trial
Authors: Savarirayan Ravi , Kannu Peter , Dambkowski Carl L , Rogoff Daniela , Irving Melita
Published: May 2020

BACKGROUND: Achondroplasia (ACH) is the most common non-lethal form of skeletal dysplasia, affecting between 1 in 15,000 to 1 in 30,000 live births [Horton et al. 2007; Waller et al. 2008]. Children and adults with ACH have disproportionate short stature, with a final height of approximately 131 cm for males and 124 cm for females. They are prone to significant co-morbidities, including obstructive sleep apnea, chronic otitis media with conductive hearing loss, spinal stenosis and a propensity towards obesity. In some infants, narrowing of the foramen magnum may result in compression of the spinal cord with neurologic sequelae, requiring timely neurosurgical intervention. There are currently no approved therapies for the treatment of ACH in either the United States or the European Union, and management is generally supportive in nature. The PROPEL trial is a prospective, non-interventional study examining baseline growth parameters and health status in children with ACH being assessed for potential enrollment into interventional studies with infigratinib, an oral FGFR1-3 inhibitor in development for achondroplasia. Methods: Children with ACH between the ages of 2.5 and 10 years are eligible for enrollment in this prospective, non-interventional trial to evaluate growth parameters and determine clinical status. Participants will be assessed at baseline, month 3, month 6, and every 6 months thereafter. The primary endpoint is annualized height growth velocity. Secondary endpoints include change from baseline in other growth parameters (including body proportionality); analysis of bone biomarkers (e.g., bone alkaline phosphatase, collagen X fragment); and the occurrence of medical events and surgical procedures. Participants will be enrolled in the study for a minimum of 6 months up to a maximum of 2 years before being considered for enrollment in a QED-sponsored phase 2/3 interventional trial. Current status: The PROPEL study is underway with the first patient enrolled in August 2019. Planned total enrollment is 200 children with ACH.
SAT-075 Pulmonary Hypertension in a Patient with Neonatal Graves Disease
Authors: Wee Erica , Ramachandra Ramya , Paez Ana Maria , Brownlee John , Senguttuvan Rajan
Published: May 2020

INTRODUCTION

Neonatal hyperthyroidism is a transient disorder seen in neonates born to mothers with current or past history of Graves’ disease. We present a rare case of a Neonatal Graves’ disease with pulmonary hypertension (PH) which completely resolved with treatment of hyperthyroidism.

CLINICAL CASE

Baby B was a 3200 g term male born to a 40-year-old hypothyroid mother. He was prenatally diagnosed with Trisomy 21 and coarctation of the aorta (CoA). He developed respiratory distress soon after birth and was admitted to the NICU. His echocardiogram (echo) showed a large patent ductus arteriosus (PDA) and increased tortuosity of juxtaductal aorta with no significant gradient. Near-systemic pulmonary artery pressure was noted in the absence of any evidence of left heart failure. Cardiology determined his CoA to be hemodynamically insignificant and not the cause of his PH. Successive trials of 100% FiO2, Nitric Oxide (NO), and Sildenafil resulted in only minimal improvement of his PH.

Thyroid function tests (TFT) obtained on day of life (DOL) 8 showed serum TSH of 0.01 uIU/ml [0.87 - 6.43] and FT4 of 3.5 ng/dl [0.9 - 1.5]. Further interaction with the mother revealed that she had a history of Graves’ disease treated with radioactive iodine (RAI) and resultant hypothyroidism. Baby B’s TSH receptor antibody (TRAb) and thyroid stimulating immunoglobulin levels were elevated at 7.38 IU/l [0-1.75] and 3.38 IU/l [0-0.55], respectively.

He was thus diagnosed with Neonatal Graves’ disease and was started on Methimazole (MTZ) 1 mg/kg/day on DOL 8. Subsequently, potassium iodide was added. FT4 showed gradual normalization by DOL 15. Beta blockers were not added due to absence of hypertension or significant tachycardia. Serial echo showed improvement of PH, consistent with the decline in FT4 levels. Sildenafil and FiO2 were slowly weaned and discontinued by DOL 30. MTZ was then tapered and discontinued. A final echo showed complete resolution of PH, unobstructed aortic arch and persistent PDA.

DISCUSSION

Neonatal hyperthyroidism occurs due to transplacental transfer of TRAb from mother to fetus, stimulating the fetal thyroid to make excessive thyroid hormones. Risk correlates with TRAb titers in the mother. Our patient had pulmonary hypertension which did not resolve with FiO2, NO and Sildenafil. However, it showed complete resolution with normalization of FT4 levels by antithyroid drugs. Hyperthyroidism commonly presents with systemic HTN, but we found 3 neonatal cases in the literature presenting with PH that resolved with treatment of hyperthyroidism. The mechanism is unclear, but hypotheses include increased clearance of pulmonary vasodilators and decreased clearance of pulmonary vasoconstrictor and decreased surfactant production/function(1).

REFERENCES

1) Oden J, Cheifetz IM. Neonatal thyrotoxicosis and persistent PH necessitating extracorporeal life support. Pediatrics 2005-115: e105-8.
MON-008 Estrogen-Responsive and -Unresponsive Gene Expressions Promoted by Enhancers Specifically Hypomethylated in Endometriotic Cells May Become a Molecular Marker in Endometriosis Lesions
Authors: Izawa Masao , Azuma Yukihiro , Hori Naohiro , Taniguchi Fuminori , Harada Tasuku
Published: May 2020

BACKGROUND: Endometriosis is an estrogen-dependent, inflammatory disease, and the role of estrogen is obvious because the symptoms associated with endometriosis often disappear after menopause, and GnRH agonists or progestin relieve the pelvic lesions and endometriosis-associated pain. However, there are limitations to these treatments that target the estrogen reduction in endometriotic lesions. We sought to define an aberrant gene expression derived from an epigenetic background in endometriosis.Objective: In the hope of overcoming the limitations of endocrine treatments in endometriosis, we examined estrogen receptor (ER)-dependent and -independent gene expressions promoted by active enhancers specifically hypomethylated in endometriotic cells.

Patients: Institutional Review Boards approved this project. We obtained the informed consent from all patients. The chocolate cyst lining in ovaries of patients with endometriosis was the source of endometriotic tissue. As the control, the eutopic endometrial tissues were obtained from uteri of premenopausal women who had uterine leiomyoma.Methods: Stromal cells were prepared from endometriotic and endometrial tissues. Gene expression was examined using RT-PCR. The potential function of hypomethylated gene sequence as an active enhancer was evaluated by ChIP analysis using anti-H3K4me1 and anti-H3K27ac antibodies and eRNA expression analysis. Using ChIP-seq and ChIA-PET analysis in silico, ER-specific loci within gene bodies and the up- and downstream regions were extracted. ER-dependent gene expression was examined using estradiol or SERM.Results: ER expression in endometriotic cells.1) Relative expression of ERα mRNA was estimated to be one tenth of that in endometrial cells. 2) Relative expression of ERβ1 mRNA was 40-fold higher than that in endometrial cells, which is at a comparable level of the ERα. 3) ERβ2 mRNA expression was at a comparable level of the ERβ1. From our DNA methylation and gene expression analysis, 6 genes were selected and classified into 3 categories: estrogen-responsive genes with specific methylation (ESR1 and ESR2) or without any methylation (TGFα and GREB1), and estrogen-unresponsive but upregulated genes depending on specific hypomethylation (GATA6 and CYP19). 4) ChIP-seq and ChIA-PET analysis in silico suggested the presence of ER-specific loci within gene bodies and the up- and downstream in estrogen-responsive genes. 5) ChIP and eRNA expression analysis predicted active enhancer regions both in estrogen-responsive and -unresponsive genes. 6) In response to estrogen, TGFα and GREB1 expressions were upregulated, but ESR1 and ESR2 showed marginal responses.Conclusion: We focused on estrogen-responsive and -unresponsive genes linked to the epigenetic environment of endometriotic lesions, and revealed a facet of gene expression in endometriotic cells.
OR34-01 11C Metomidate PET-CT Identifies More Unilateral Primary Aldosteronism Than Adrenal Vein Sampling
Authors: Puar Troy , Tan Colin , Tong Aaron , Zhang Meifen , Khoo ChinMeng , Tan Wai Kit Alvin , Kek Peng Chin , Loh Lih-Ming , Yee Szemen , Lee Daphne Hui Min , Chuah Matthew , Reilhac Anthonin , Totman John , Robins Edward , Foo Roger
Published: May 2020

Introduction. Adrenal vein sampling (AVS) is the current reference test to identify unilateral, surgically-curable primary aldosteronism (PA). However, AVS is invasive and technically difficult. Even in AVS-proven unilateral PA, up to 6% of patients with fail to have biochemical cure after surgery using the PASO criteria. 11C-Metomidate PET-CT offers a non-invasive alternative. We compared the accuracy of both PET-CT and AVS using post-surgery cure (PASO criteria) as the reference.

Methods. This multi-centre prospective trial recruited 25 patients with confirmed PA, and all underwent CT, AVS, and PET-CT tests. Sequential AVS under ACTH-stimulation was done by an experienced interventionalist, and cortisol gradient of >5 was taken to be successful cannulation. Lateralization ratio >4 was consistent with unilateral PA. All results were reviewed at a multidisciplinary meeting to decide on the diagnosis (unilateral or bilateral PA) and management (secondary outcome). Primary outcome was biochemical cure using PASO criteria at 6 months post-surgery (ClinicalTrials.gov: NCTxxxxxxxx).

Results. Recruitment for the study has been complete with 25 patients, 49.2 ± 9.5 yr, 14 females (56.0%). All 25 patients had successful AVS. 22 of 25 patients (88.0%) had unilateral PA, and 3 patients (12.0%) had bilateral PA. PET-CT identified unilateral PA in 18 of 22 patients (sensitivity 81.8%), while AVS identified unilateral PA in 15 of 22 patients (sensitivity 68.2%). In one patient, repeat AVS done simultaneously without ACTH-stimulation aided to identify unilateral PA, when initial AVS failed to do so. Other cases where AVS failed to identify unilateral PA were due to venous anomalies, and limitation of the lateralization cut-off of 4. 18 of 22 patients have undergone surgery, with 3 patients awaiting surgery, and 1 opting for medical treatment. Post-surgery, all patients had complete normalization of aldosterone-renin ratio, and hypokalemia (if present). 2 patients had bilateral PA on both PET-CT and AVS. 1 patient had discordant AVS and PET-CT results, with AVS lateralizing to right, and PET-CT to left. This patient was classified as bilateral PA and treated medically.

Conclusion. This is the first study to demonstrate that 11C-Metomidate PET-CT may identify cases of unilateral PA not detected with AVS, using the stringent PASO criteria for post-operative biochemical cure.
SUN-480 An Unusual Clear Cell Carcinoma in the Thyroid. Where Is the Primary?
Authors: Lin Kuan-yu , Shih Shyang-Rong , Lee Jih-Hsiang
Published: May 2020

Background: Clear cell carcinoma in the thyroid gland is rare. It is important to distinguish primary thyroid clear cell carcinoma from metastases, since its clinical behaviors and treatment options were different.

Clinical Case: A 47-year-old woman without past medical history presented to our outpatient surgery department with right neck mass for 8 months. Thyroid ultrasonography revealed a 3.9 cm nodule in the right thyroid. Thyroid function test was within the normal range. Fine needle aspiration cytology of the nodule showed suspicious for neoplasm. She underwent radical total thyroidectomy and lymph node dissection. Pathology revealed an unusual carcinoma comprising cuboidal cells with irregular nuclear contours, some eosinophilic or clear cytoplasm, arranged in infiltrating nests or cords with marked stromal hyalinization, highly suggestive of a clear cell carcinoma. Ectopic thymic tissue was present adjacent to the tumor. By immunohistochemical (IHC) staining, tumor cells were p63 (+), TTF-1 (-), thyroglobulin (-), PAX8 (-), synaptophysin (-), CD5 (-), and CD117 (-). Tumor genetic sequencing detected EWSR1-CREM fusion genes. For disease extent evaluation, two out of seven lymph nodes obtained during operation were positive of tumor metastases. Whole body computed tomography (CT) 3 months after operation revealed no residual thyroid tissue, neck lymphadenopathies or intra-abdominal metastases. A pulmonary ground-glass opacities of 7mm in diameter was found, which was stationary at a repeated CT scan 6 months later.

Clinical Lesson: Clear cell carcinoma in the thyroid gland could be primary, arising from clear cell change of follicular or papillary thyroid carcinoma. The negative IHC stain of thyroglobulin, TTF, PAX8, as well as lack of papillary or follicular architecture made primary thyroid clear cell carcinoma unlikely. Most of the metastatic clear cell carcinoma to the thyroid gland arose from renal primary. However, there was no clinical or radiographic evidence of renal tumor in our case. Although ectopic thymic tissue was identified on pathology, negative IHC staining of PAX8, CD5 and CD117 made thymic origin less likely. Positive IHC staining of p63 and a novel EWSR1-CREM fusion gene confirmed the diagnosis of salivary clear cell carcinoma. According to our literature review, there were only 3 cases of clear-cell carcinoma with EWSR1-CREM fusion gene (1), and our case is the first case who presented with clear cell carcinoma in the thyroid. In conclusion, the importance of IHC stain and molecular testing in determining the primary origin of clear cell carcinoma were addressed in our case.

Reference: (1) Chapman E, et al. Am J Surg Pathol. 2018;42(9):1182-1189
MON-185 ACTH-Derived Peptide Antagonists as an Alternative Treatment Strategy for Congenital Adrenal Hyperplasia
Authors: Schubert Tina , Nicke Lennart , Schanze André , Reisch Nicole , Geyer Armin , Koehler Katrin , Huebner Angela
Published: May 2020

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder caused by different enzyme deficiencies in the steroid hormone synthesis leading to a disturbed cortisol biosynthesis. The medical treatment of CAH includes suboptimal ACTH-suppressing high glucocorticoid doses to reduce adrenal hyperplasia and overproduction of androgens. These inappropriate corticoid substitutions are often associated with undesirable side effects such as arterial hypertension, growth failure and obesity. Since the current therapy of patients with CAH is often unsatisfactory, innovative treatment options are required.

The aim of our study was to specifically block the melanocortin 2 receptor (MC2R) signaling pathway as an alternative treatment strategy for CAH. We tested ACTH-derived selective peptides with incorporation of various synthetic non-natural amino acids in the activation motif of ACTH. To study the antagonistic activity of the peptides, cAMP production of MC2R/MRAP stably transfected human embryonic kidney (HEK) 293 cells were measured. All new synthesized peptide antagonists reduced ACTH-stimulated MC2R activity as competitive inhibitors indicated by a reduced in vitro cAMP response. Cells pre-incubated with peptide LNP009 showed the most efficient blockade of the MC2R and the highest shift of EC50 of ACTH (33.8 nM ± 0.08 vs. 7.3 nM ± 0.09). LNP009 was additionally tested for specificity concerning the other known melanocortin receptors and showed no antagonistic effect up to 1 μM on MC3, MC4 or MC5 receptor transiently transfected HEK 293 cells. To further investigate the inhibitory effect of our most potent antagonist peptide LNP009 on the steroid hormone response, we assessed steroidogenic enzyme expression of the human adrenocortical tumor cell line NCI-H295RA and performed mass spectrometry analyzes of steroids in the cell culture supernatant. Pre-incubation with LNP009 reduced the expression of the genes CYP21A2, CYP11B1 and HSD3B2 in NCI-H295RA cells and significantly reduced the synthesis of aldosterone (P=0.046; n=3), cortisol (P=0.020; n=3) and corticosterone (P=0.035; n=3).

With the successful blocking of the ACTH binding and signal transduction by our antagonistic peptides, we anticipate an alternative approach for optimizing the treatment of CAH patients lacking the side effects of the currently used ACTH-suppressing corticoid therapy.
MON-159 High Mortality Rate in Oral Glucocorticoid Users: A Case-Control Study
Authors: Einarsdottir Margret , Ekman Per , Trimpou Penelope , Olsson Daniel S , Johannsson Gudmundur , Ragnarsson Oskar
Published: May 2020

Objective. Long-term oral glucocorticoid (GC) use is associated with increased mortality in patients with rheumatoid arthritis and inflammatory bowel disease. The aim of the study was to investigate whether there is excess mortality among oral GC users, regardless of the underlying disease.

Methods. This was a retrospective case-control study. Information on dispensed prescriptions was obtained from the Swedish Prescribed Drug Register. Patients receiving ≥5 mg prednisolone (or equivalent dose of other GC) daily for ≥21 days between 2007-2014 were included. For each patient, a control person, matched for age and sex, was included. The cause of death was obtained from the Swedish Cause-of-Death Registry. Hazard ratio (HR) for mortality was calculated by using Cox proportional hazard model and by the log-rank test. The GC users were divided into four groups according to the length of GC treatment: 1) single-occasion users 2) occasional users (<300 tablets/year); 3) medium-term users (> 300 tablets/year for ≤ 2 consecutive years); and 4) long-term users (>300 tablets/year for > 2 consecutive years).

Results. Of 1,585,335 inhabitants in Western Sweden, 223,211 GC users (women 55.6%) were identified for the analysis. The mean age was 48 ± 24 years. Median follow-up time was 3.6 years for GC users and 3.9 years for matched controls. The overall HR for death in oral GC users was 2.26 (95% CI 2.21-2.31). After exclusion of patients with malignant neoplasm, the HR for death was 1.41 (95% CI 1.38-1.45); 1.33 (95% CI 1.27-1.38) in single-occasion GC users (n=112,196), 1.36 (95% CI 1.30-1.42) in occasional users (n=63,862), 1.89 (95% CI 1.79-1.99) in medium-term users (n=19,129) and 1.67 (95% CI 1.51-1.84) in long-term users (n=7,191). The highest HRs were observed for deaths from heart failure (HR 1.71, 95% CI 1.63-1.80), sepsis (HR 1.71, 95% CI 1.51-1.94), and pulmonary embolism (HR 1.87, 95% CI 1.58-2.21).

Conclusion. GC users have excess mortality compared to the background population. This illustrates the importance of surveillance for patients on oral GC treatment where adverse effects should be monitored and, when indicated, appropriately treated.
MON-134 Incorporating Transgender Competent Care into the Medical School Curriculum
Authors: Lamos Elizabeth M , Quezada Sandra , Malek Rana
Published: May 2020

BACKGROUND: According to recent estimates, the US transgender population has doubled in the last decade. Incorporating transgender competent care into medical education is a growing need, and a focus of the AAMC. Care of the transgender individual is multifaceted, and medical school curriculae on transgender care are limited and lack standardization. Similarly, strategies for measuring effectiveness and impact of these curriculae remain limited.

Methods: Over 3 years, the use of a transgender clinical correlation in the endocrine section of the second-year medical student pre-clerkship curriculum progressed to the use of a triple modality intervention. This included (1) a self-directed written handout with terminology and the basic tenants of medical transition therapy with an optional podcast, (2) a traditional presentation covering social, ethical and multi-disciplinary transgender care, and (3) an interactive session with a transfemale and transmale patient. An anonymous 8 question pre-and post-intervention survey using an electronic clicker system was performed. Questions included interest level, comfort level with various aspects of transgender-competent care and resource awareness.

Results: Prior to the intervention, 74% of students were interested in learning more about transgender competent care. After the learning intervention, in all questions focusing on knowledge and skills of transgender care, students reported a significant increase in their comfort level (Figure 1, p<0.5, all). This included reporting now higher comfort levels regarding goals of hormone therapy (8 to 63%), use of transgender affirming medications (19 to 44%), barriers to care (30 to 79%), and long term and multi-disciplinary care (8 to 63% and 13 to 71%, pre- and post-intervention respectively). At the end of the intervention, students felt they had more resources to access information about transgender-competent care (pre-23% to post-94% p= <0.05).

Conclusion: Knowledge and skills in the care of transgender individuals is poor in the pre-clerkship medical school years. The interest to learn about transgender care is positive. This multi-modality intervention was successful in increasing medical student comfort and knowledge about comprehensive transgender care, and increased student awareness of available resources. Introduction of transgender care should be implemented early in medical student training.

1. Hembree WC et al. Endocrine Treatment of Gender-Dysphoric/ Gender-Incongruent Persons: An Endocrine Society Clinical Practice Guideline. Endocr Pract. 2017 Dec;23(12):1437.

2. Harris M, Johnson C. Only Human. Trans Kids Update: Dating, PMS, And, Yeah, Bathrooms. NYPR WNYC Studios, 2017.

Figure 1. Change in student comfort across transgender competent care.

* p < 0.05
SUN-559 Involvement of Sarco/Endoplasmic Reticulum Ca- ATPase (SERCA) in Membrane Progesterone Receptor Alpha (PAQR7)-Mediated Progesterone Induction of Vascular Smooth Muscle Relaxation
Authors: Pang Yefei , Thomas Peter
Published: May 2020

Progesterone (P4) exerts multiple beneficial effects on the human cardiovascular system through its actions on vascular endothelial cells and also by acting directly on vascular smooth muscle cells (VSMCs). Membrane progesterone receptor alpha (mPRα) has been shown to mediate the rapid P4-induction of human VSMC relaxation through activation of MAPK, Akt/Pi3k and RhoA/ROCK signaling pathways and the resulting reduction of calcium influx through calcium channels. In this study, we demonstrate that treatment of cultured human VSMCs with P4 for 1-2 hours increases both the mRNA and protein expression of sarco/endoplasmic reticulum Ca- ATPase (SERCA), the major transporter of calcium from the cytosol into the sarcoplasmic reticulum (SR) during muscle relaxation. Knockdown of mPRα with siRNA completely blocked this stimulatory effect of P4 as well as that of OD 02-0, a mPR selective agonist, on SERCA protein expression. In contrast, expression levels of phospholamban (PLB), a SR protein that reversibly inhibits SERCA were downregulated by this P4 treatment, and mRNA expression of a channel that releases calcium from the SR, inositol trisphosphate receptor (IP3R), was unaltered after treatment with P4. Moreover, treatments with P4 and OD 02-0, but not with R5020, a nuclear PR agonist, increased PLB phosphorylation, which would result in disinhibition of SERCA function. P4 and OD 02-0 significantly increased calcium levels in the SR detected with Fluo-5N, a specific SR calcium indicator, and caused VSMC relaxation. These effects were blocked by cyclopiazonic acid (CPA, a SERCA inhibitor), suggesting that SERCA plays a critical role in P4 induction of VSMC relaxation. Similarly, the effects of P4 and OD 02-0 on relaxation of umbilical artery rings measured with a myograph were significantly attenuated by CPA, which confirms the critical role of SERCA in the rapid action of P4 and 02-0 on vascular muscle relaxation. P4 has previously been shown to activate MAPK and Akt signaling pathways to induce VSMC relaxation. The P4- and OD 02-0-induced increases in calcium in the SR were blocked by MAPK and Akt/Pi3k signaling inhibitors, AZD6244 and wortmannin. Taken together, these results suggest that the direct, rapid effects of P4 on relaxation of VSMCs through mPRα involves regulation of the expression and function of the SR proteins SERCA and PLB through MAPK and Akt signaling pathways.
MON-681 Dulaglutide Commonly Known as Trulicity; An Anti-Diabetic Medication Causing Small Bowel Obstruction
Authors: Gandhi Ankita , Khanam Verisha , Peterson Daymon , Patel Fenil , Kulairi Zain
Published: May 2020

Introduction Small bowel obstruction is a common and life threatening surgical emergency. The general causes are intra and extra-intestinal mechanical obstruction, such as from post-operative adhesions, malignancy, hernias, Crohn’s disease, and volvulus. Less frequently neurologic, metabolic, and medications interfere with intestinal motility and lead to obstructive features. Here, we present a rare case of small intestinal obstruction caused by the anti-diabetic glucagon-like peptide 1 (GLP-1) agonist, Dulaglutide (Trulicity). Case A 52-year-old male with Diabetes Mellitus, presented with two weeks of severe nausea and vomiting, accompanied by four days of diffused abdominal pain. CT scan of the abdomen showed multiple mildly distended dilated loops of the proximal jejunum. The results lead to suspect the presence of fecal stasis with an apparent transition zone of a normal caliber bowel. This is strongly indicative of partial or evolving small bowel obstruction. The patient was treated with conservative management of bowel rest and NG tube per the surgery on board. However, patient deteriorated too quickly and the partial bowel obstruction lead to full obstruction and eventually taken for an emergent surgery. With careful investigation to identify underlying causes of small bowel obstruction revealed no mechanical, structural, or metabolic explanation. However, a review of patient’s medication list disclosed a daily consumption of Dulaglutide (Trulicity). The medication was started 3 weeks prior to admission. He started developing partial bowel obstruction symptoms within one week of starting the medications. Unfortunately, surgeon ended up performing a partial resection a small bowel due to severe ischemia. Patient improved clinically in four to five days and was discharged home with an alternative anti-diabatic medications. He follows up with us in the clinic and has no signs of bowel obstructions with the other anti-diabatic medications. Discussion: Dulaglutide (Trulicity) is associated with small bowel obstruction. The side effect is more common in males and in patients who are using the medication for less than one month. A total of 8 cases were reported in 2017 with majority of them requiring surgical intervention for the small bowel obstruction. In our patient, it also required a surgical intervention and was life threatening. Unfortunately, the actual mechanism Trulicity causing the small bowel obstruction is unknown; however the moderate side effect of Trulicity is constipation. In this case, our patient was not constipated. He had normal bowel movements on a regular basis. Also, he never had any history of abdominal surgeries which can cause adhesion and lead to small bowel obstruction. All the other caused of small bowel obstructions had been ruled out and finally concluded Trulicity was the culprit of this unfortunate case.
SAT-392 The Role of β-arrestin2 in Bone Catabolic Response to Hyperparathyroidism In Vivo
Authors: Feng Gilberto Li , Grynpas Marc , Mitchell Jane
Published: May 2020

Primary hyperparathyroidism (PHPT) is an endocrine disorder characterized by elevated parathyroid hormone (PTH) levels and hypercalcemia caused by the overactive parathyroid glands, resulting in negative impacts on the skeleton including bone loss and increased bone fragility1. PTH binds and activates parathyroid hormone type 1 receptor (PTH1R) which primary couples to Gαs, stimulating the downstream effectors that mediate bone remodeling processes2. PTH1R activity is regulated by arrestins, specially β-arrestin2 (β-arr2), through signal termination and receptor internalization2. Previously, we have seen anabolic effects of hyperparathyroidism (cPTH) on trabecular bone in mice overexpressing Gαs3. We hypothesized that increased Gαs protein levels in osteoblasts outcompete β-arr binding to PTH1R, leading to reduced signal termination and increased bone formation. To test this hypothesis, we are testing if the deletion of β-arr2 will also result in an anabolic response to cPTH in this study. The response of β-arr2 knockout (KO) mice to cPTH have yet to be documented. The hypothesis of this study is that β-arr2 KO mice treated with cPTH will exhibit anabolic effects on the trabecular bone. Nine-week-old wild-type (WT) C57BL/6 and β-arr2 KO mice were treated for 14 days with either rPTH1-34 (80ng/g/day) or saline (PBS) using micro-osmotic pumps to simulate hyperparathyroidism. There are 8 groups (n=10 per group) including both sexes, 2 genotypes (WT and KO), and 2 treatment groups (PTH and PBS). Two 30 mg/kg doses of 0.6% calcein green were administered subcutaneously to mice at 7 and 2 days prior to euthanasia to label bones. Decalcified tibiae were embedded in paraffin for histological analysis. Undecalcified tibiae were embedded in plastic for dynamic histomorphometry. Micro-computed tomography (μCT) was used to access bone microarchitecture of femurs and vertebrae followed by biomechanical testing of bone strength. The μCT data of distal femurs show that cPTH treatment increased bone volume in female KO mice (6.864 ± 2.318 vs 4.690 ± 1.555 %; P= 0.0328; n=9 per group) and maintained bone in male KO mice (13.37 ± 2.860 vs 13.38 ± 3.135; P= 0.9968, n= 10) compared to control. Histological analysis show higher osteoclastic activity in both sexes and genotypes when treated with cPTH, suggesting that the anabolic response may be at the level of osteoblasts and osteocytes. These promising results support our hypothesis that arrestin-mediated PTH receptor downregulation plays an importance role in bone weakness associated with hyperparathyroidism. These studies are important for understanding the clinical phenotype of PHPT patients and suggest that inhibition of β-arr2 in PHPT could be a path for drug therapy.

References: (1) Mosekilde L. Clin Endocrinol 2008;69:1-9. (2) Ferrari SL et al., J Biol Chem 1999; 274:29968–29975 (3) Zhang L. PhD thesis University of Toronto, 2018.
SAT-232 Pheochromocytoma Presenting Rare Skin Findings: Livedoid Vasculopathy and Raynaud’s Phenomenon
Authors: Kyo Chika , Usui Takeshi , Yamada Kanako , Torii-Hanakita Mizuki , Kosugi Rieko , Yonemoto Takako , Ogawa Tatuo , Kotani Masato , Tamura Naohisa , Inoue Tatsuhide
Published: May 2020

BACKGROUND: Oversecreted catecholamines from pheochromocytoma (PCC) is responsible for a large variety of clinical signs and symptoms, including skin lesions, due to their effects on hemodynamics and metabolism, as well as the putative effects on the blood coagulation system. Livedo reticularis had been reported as the skin complications of PCC, but there was no pathological evidence. Livedoid vasculopathy, a subtype of livedo reticularis is a noninflammatory thrombotic condition. Here we firstly showed that livedo reticularis accompanying PCC.

Case: A 36-year-old female with hypertension, hyperglycemia, and right adrenal mass had referred to our hospital. She had violaceous reticular lesions on bilateral lower limbs, a three-year history of recurrent ulcers around her right ankle with severe pain. She also had frequent Raynaud’s phenomenon. On admission, the blood examination showed that her hemoglobin concentration was 16.3g/dl and her platelet count was 408,000/ml. Plasma catecholamines and the metabolite levels were elevated. The abdominal CT scan showed the right adrenal mass, approximately 6.5cm in diameter, and MRI showed a heterogeneous mass with high signal intensity on T2-weighted images. MIBG scintigraphy showed uptake in the mass. We diagnosed her as PCC. A skin biopsy revealed occlusions of the lumen of small vessels in the mid dermis without vasculitis. Administration of doxazosin revealed the improvement of the clinical parameters including the pain and the ulcer of the right ankle. The laparoscopic right adrenalectomy was performed. Histopathological study of the adrenal tumor was consistent with PCC. Genetic testing and MLPA analysis for RET, VHL, SDHx, SDH-AF2, MAX, and TMEM127 showed no mutations or copy number alterations. Postoperatively, hypertension and hyperglycemia improved, and Raynaud’s phenomenon and reticular macules disappeared.

Discussion: Among the various clinical signs of PCC, skin disorders are relatively rare. Limited reports showed that the livedo reticularis was a complication of PCC, but its mechanism had not been elucidated. Livedoid vasculopathy is a rare cutaneous disease manifesting as recurrent ulcers on the lower extremities, which is a noninflammatory thrombotic condition associated with hypercoagulation. The catecholamine excess could induce arterial vasospasm in addition to relative hypercoagulation tendency, which could result in livedoid vasculopathy.

Conclusion: The present study showed first pathological evidence of that the livedo reticularis accompanying PCC was livedoid vasculopathy.