bluuebunny/crossref_metadata_2025 huggingface dataset:
SAT-385 A Normal FGF23 Does Not Preclude Tumor Induced Osteomalacia (TIO)
Authors: Nandam Neeharika , Ejaz Sadia , Styner Maya
Published: May 2020

BACKGROUND: The phosphaturic, bone-derived hormone FGF23, mediates bone loss in TIO. Tumor resection typically results in skeletal healing and reversal of biochemical defects.

Case: A 45-year-old Caucasian man with no past medical history presented with non-traumatic fractures of bilateral metatarsals. Over the subsequent 2 years, he sustained fragility stress fractures in bilateral femurs, eventually rendering him non-ambulatory; though he continued to work as a property manager in an office setting. History included 30 pack-years of smoking as well as osteochondrosarcoma in his mother. Labs showed a low phosphorus at 2.1 mg/dL [2.7–4.5], along with calcium 8.8 mg/dL [8.4–10.4], iPTH 48 pg/mL [12–88], and ALP of 155 [IU]/L [34–104]. 25-OH vitamin D and 1,25-(OH)2 vitamin D were 27 ng/mL [30–80] and 12 pg/mL [20–80], respectively. Free testosterone was 4.4 ng/mL [5–21] and LH 2.2 mIU/mL [3.0–10.0]. Other pituitary hormones and brain MRI were unremarkable.

Vitamin D3, calcitriol, phosphate and testosterone were prescribed. Testosterone was discontinued 6 months later, after diagnosis with DVT/PE. Incidental rib fractures on CXR prompted a 3-phase 99Tc-MDP bone scan, revealing multiple sites of uptake: ribs, scapulae, sternum, thoracolumbar spine, sacrum, bilateral ankles and feet. DXA revealed T-scores of -2.8 in the spine and -1.9 in the femoral neck.

Labs pointed to ongoing phosphate wasting, despite compliance with calcitriol 0.25 mcg, cholecalciferol 5000 IU and phosphorus 2250 mg in divided doses. Calculated TRP was 64% [>80%] and TmP/GFR 1.74 mg/dL [2.5–4.5], consistent with low phosphate reabsorption. Urine 24-hour calcium was 244.8 mg. Testing for causal mutations of hypophosphatemic rickets and osteogenesis imperfecta was negative. FGF23 was within the reference range at 138 RU/mL [LabCorp ELISA 44–215], interpreted as inappropriately normal given ongoing phosphate loss. This prompted a search for a suspected TIO locus.

Two years after presentation, 18F-FDG-PET exhibited a hypermetabolic focus at the left suprapatellar recess. Biopsy was consistent with a mesenchymal tumor and chromogenic in situ hybridization (Mayo Clinic) was positive for FGF23 mRNA. After surgical resection of the 1.7 cm tumor, serum FGF23 declined to <50 RU/mL and was 90 RU/mL 3 weeks later [Mayo <180 RU/mL]. Calcitriol and phosphorus supplementation were discontinued. One year post-operatively phosphorus was 3.6 mg/dL [2.5–5.0], with a normal calcium, iPTH and 25-OH vitamin D. Lumbar spine T score improved to -1.0 (+46.43%).

Conclusion: A high clinical index of suspicion is required for TIO in the setting of phosphaturic osteomalacia, particularly with a normal serum FGF23. Recently, similar microRNA profiles were noted in osteosarcomas and TIO1. This, along with our patient’s family history raises the question of a possible predisposition to skeletal neoplasms.

1. Green et al. Bone Reports, 2017.
MON-463 Thyroid Abscess Due to Intravenous Drug Use: A Rare Cause of Thyroid Storm
Authors: Mathai Christine , Coppola Anthony , Vaz Cherie
Published: May 2020

Objective: Our objective is to discuss the clinical presentation, diagnosis and management of thyroid storm due to thyroid abscess.

Methods: We report a case of thyroid abscess due to intravenous drug use (IVDU) resulting in thyroid storm.

Results: A 28 year old female with history of IVDU and no known thyroid disease presented with neck pain and fever after injecting heroin into her neck 10 days prior. CT Neck showed an early bilateral thyroid abscess 3.0 cm on the left and 2.0 cm on the right, with heterogeneous enhancement in the rest of the thyroid concerning for thyroiditis. TSH 0.4 m[iU]/L (0.34–5.60 m[iU]/L). She was started on antibiotics but left AMA. She returned 9 days later with worsening neck swelling and pain. CT neck showed a multiloculated, bilateral thyroid abscess 8.6 cm on the left and 5.3 cm on the right. She suffered a cardiac arrest, was intubated, and resuscitated with defibrillation and epinephrine. WBC 25.9 K/mm3, ANC 9.8 K/mm3, TSH <0.01 m[iU]/L (0.34–5.60 m[iU]/L), fT4 4.25 ng/dL (0.89–1.76 ng/dL), T3 96.0 ng/dL (70–204 ng/dL), TSI <89 (<140%). Burch-Wartofsky score was 60. She was treated with propylthiouracil (PTU) and hydrocortisone. She developed transaminitis post-arrest due to shock liver, AST 2881 U/L (15–37 U/L), ALT 981 U/L (16–61 U/L) and PTU was discontinued. Two days later TSH <0.005 m[iU]/L (0.4–4.5 m[iU]/L), fT4 3.06 ng/dL (0.89–1.76 ng/dL), T3 62.0 ng/dL(60.0–181.0 ng/dL). Neck ultrasound showed enlarged, heterogeneous thyroid with numerous loculated fluid collections. Incision and drainage (I&D) drained 100 cc of pus and drains were left in situ. Cultures grew MRSA. Patient was treated with vancomycin, clindamycin, and metronidazole. Following I&D, thyroid function improved to normal and eventual hypothyroidism by postoperative day 8, fT4 0.59 ng/dL, T3 32.1 ng/dL, TSH 1.2 m[iU]/L. She was initiated on levothyroxine 50 mcg daily with follow up testing for possible resolution of thyroiditis-induced hypothyroidism.

Discussion: Thyroid abscess causing acute suppurative thyroiditis presenting as thyroid storm is rarely seen1. There are no reported cases of thyroid storm occurring as a complication of IVDU. Acute suppurative thyroiditis has been reported following MSSA bacteremia from a forearm abscess due to IVDU, TSH 0.02U/mL, fT4 3.89ng/dL, fT3 of 5.1pg/mL2. Presentation was consistent with thyrotoxicosis but not thyroid storm2. It is important to consider thyroid abscess as a rare cause of thyroid storm, in patients with risk factors such as IVDU. Management with antithyroid drugs (ATD), steroids, antibiotics, and I&D produced successful outcomes in this patient after cardiac arrest.

Conclusion: Thyroid abscess resulting in thyroiditis can be a rare cause of thyroid storm that resolves following I&D. Successful management includes use of antibiotics, steroids, and ATD for thyroid infection, thyroid inflammation and thyroid hormone levels.
SAT-408 Bioactivity of Long Acting PTH Fusion Molecules Tested in a Novel Non-Surgical Animal Model of Hypoparathyroidism
Authors: Wilkinson Ian R , Ramezani-Pour Narjes , Esfahani Sayyed Hamid Zarkesh , Eastell Richard , Ross Richard John M
Published: May 2020

Introduction: There is an unmet need for the development of long-acting PTH molecules to treat patients with hypoparathyroidism. We have established a novel non-surgical rodent model of hypoparathyroidism using oral Cinacalcet-HCl to test long acting analogues of PTH. Here we have tested the pharmacodynamics properties of two long acting PTH fusion molecules.

Methods: PTH fusion molecules tested: Fusion-1 is PTH (1–34) linked to GHBP (residues 1–238), and Fusion-2 is a Hybrid PTH-PTHrP (1) linked to GHBP (residues 1–238). For in vivo studies, normal male wistar rats were gavaged with 30 mg/kg Cinacalcet-HCl, immediately followed by a subcutaneous dose of PTH Fusion at 20 nmol/kg. Control animals received PTH (1–34) and vehicle only. Serum samples were taken and analysed for ionised calcium (iCa).

Results: Oral administration of Cinacalcet-HCl caused a reduction in iCa that was significantly different from vehicle controls at 2 to 24hrs post dose (ANOVA P < 0.0001). PTH 1–34 maintained iCa levels for 2 hours after administration above that of Cinacalcet-HCl (AUC±SD (mmol/L).hr from baseline, 0.076 ±0.047 and 0.168±0.0874, t-test P=0.0289) but then levels fell and recovered as for Cinacalcet-HCl alone. Subcutaneous doses of both fusions were able to abrogate the effects of Cinacalcet-HCl from 4hrs post dose onwards giving a prolonged response, with iCa levels quicker to return to baseline levels at 48hrs compared to Cinacalcet-HCl. The AUC±SD (mmol/L).hr from baseline for iCa over 72 hours was 3.93±1.4 for Fusion-1, 5.0±2.7 for Fusion-2 & 10±2.8 for Cinacaclet-HCl and were significantly reduced for both fusions compared to Cinacalcet-HCl alone (t-test P = 0.0028 & P = 0.019, respectively) and not significantly different from vehicle only.

Conclusions: Cinacalcet-HCl behaved as expected in terms of iCa lowering (2). PTH maintained iCa but only for 2 hours. Both PTH fusion molecules showed a delayed and prolonged response and reduced the impact of Cinacalcet-HCl induced low iCa levels from 4hrs to 24hrs. These data provide proof of concept for long acting biological activity of these novel PTH fusion proteins.

References:

1. Shimizu M, Joyashiki E, Noda H, Watanabe T, Okazaki M, Nagayasu M, et al. Pharmacodynamic Actions of a Long-Acting PTH Analog (LA-PTH) in Thyroparathyroidectomized (TPTX) Rats and Normal Monkeys. J Bone Miner Res. 2016;31(7):1405–12.

2. Nemeth EF, Heaton WH, Miller M, Fox J, Balandrin MF, Van Wagenen BC, et al. Pharmacodynamics of the type II calcimimetic compound cinacalcet HCl. The Journal of pharmacology and experimental therapeutics. 2004;308(2):627–35.
SAT-312 Beta-Arrestin 2 Is Required for Dopamine Receptor Type 2 Inhibitory Effects on Akt Phosphorylation and Cell Proliferation in Pituitary Tumors
Authors: Mangili Federica , Giardino Elena , Treppiedi Donatella , Barbieri Anna Maria , Catalano Rosa , Locatelli Marco , Lania Andrea G , Spada Anna , Arosio Maura , Mantovani Giovanna , Peverelli Erika
Published: May 2020

Dopamine receptor type 2 (DRD2) agonists are the first-choice treatment for PRL-secreting pituitary tumors but are poorly effective in non-functioning pituitary neuroendocrine tumors (NF-PitNETs). DRD2 reduces AKT phosphorylation in lactotrophs, but no data are available in NF-PitNETs. DRD2 effects on AKT are mediated by a β-arrestin 2-dependent mechanism in mouse striatum.

The aim of this study was to investigate DRD2 effects on AKT phosphorylation and cell proliferation in human primary cultured NF-PitNET cells and in rat tumoral lactotroph cells MMQ, and to test β-arrestin 2 involvement.

We found that DRD2 agonist BIM53097 induced a reduction of p- AKT /total-AKT ratio in MMQ (-32.8±17.6%, p<0.001 vs basal) and in a subset (n=15/41,36.6%) of NF-PitNETs (subgroup 1). In the remaining NF-PitNETs (subgroup 2), BIM53097 induced an increase of p- AKT. The ability of BIM53097 to reduce p-AKT correlated to its antimitotic effect, since the majority of subgroup 1 NF-PitNETs was responsive to BIM53097 and nearly all subgroup 2 NF-PitNETs were resistant. β-arrestin2 was expressed in MMQ and in 80% of subgroup 1 NF-PitNETs, whereas it was undetectable in 77% of subgroup 2 NF-PitNETs.

In MMQ, β-arrestin 2 silencing prevented DRD2 inhibitory effects on p-AKT and cell proliferation. Accordingly, β-arrestin 2 transfection in subgroup 2 NF-PitNETs conferred to BIM53097 the ability to inhibit both p-AKT and cell growth.

In conclusion, we demonstrated that β-arrestin 2 is required for DRD2 inhibitory effects on AKT phosphorylation and cell proliferation in MMQ and NF-PitNETs, paving the way for a potential role of β-arrestin 2 as a biomarker predicting NF-PitNETs responsiveness to treatment with dopamine agonists.
SUN-075 A Guide to Professional Development: Funding Your Research Through NICHD
Authors: Eisenberg Esther , Halvorson Lisa , Ravindranath Ravi , Winer Karen
Published: May 2020

The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) leads research and training efforts to understand human development, improve reproductive health, enhance the lives of children and adolescents, and optimize abilities for all. Under the “New Strategic Plan 2020”, NICHD will focus on priorities to: 1. Understand the Molecular, Cellular, and Structural Basis of Development; 2. Promote Gynecologic, Andrologic, and Reproductive Health; 3. Set the Foundation for Healthy Pregnancies and Lifelong Wellness; 4. Improve Child and Adolescent Health and the Transition to Adulthood; and 5. Advance Safe and Effective Therapeutics and Devices for Pregnant and Lactating Women, Children, and People with Disabilities. Cross-cutting topics include health disparities, prevention, infectious disease, nutrition and global health. NICHD is committed to funding the largest number of meritorious projects, while allowing flexibility to support high program priorities and respond to emerging scientific opportunities. Mechanisms to support individual research and training include research project grants (RPGs), training and career development awards (K awards) and fellowships (Pre and Postdoctoral). There are specific eligibility requirements for each of these mechanisms. Applicants are advised to contact a program officer (PO) and discuss the idea, its relevance to program priorities of NICHD, and potential funding opportunities available. While preparing your application, receive guidance on the grantsmanship from the PO, in addition to peers working at your institution. The PO can help you to understand the peer review process at NIH and suggest study sections with a good fit to review your application. The peer review process is independent of the program administration at NIH. Applicants can avoid some common errors in writing applications by reviewing the NIH website and understanding the NIH grants process. The NIH has recently revised its approach to the review and monitoring of vertebrate animal and human subject research. Applicants may receive guidance both at their institution (from which the application is submitted) and NIH. NICHD has developed new guidelines and processes to enhance and improve clinical trials. Currently, applications may be submitted to separate funding opportunity announcements for “clinical trials required” and “clinical trials optional”. The goal is to ensure adequate clinical trial-specific information in the grant applications for thorough review. Additional new review criteria consider training in good clinical practice and expanded registration and results reporting in ClinicalTrials.gov.
MON-673 Use of Metabolic Syndrome Severity to Assess Treatment with Vitamin-E and Pioglitazone for Non-Alcoholic Steatohepatitis
Authors: DeBoer Mark Daniel , Mack Jasmine A , Gurka Matthew J
Published: May 2020

BACKGROUND: Non-alcoholic steatohepatitis (NASH) represents inflammatory and fibrotic changes in the setting of non-alcoholic fatty liver disease (NAFLD) and can progress to cirrhosis. While clinical management of NASH has proven difficult, the Pioglitazone, Vitamin E or Placebo NASH study (PIVENS) demonstrated that treatment with either pioglitazone or vitamin-E increased odds of NASH-resolution. NASH is strongly associated with insulin resistance and the metabolic syndrome (MetS) as both a predictor and an outcome, though this has only been studied using dichotomous MetS criteria (e.g. ATP-III). We previously formulated a sex- and race/ethnicity-specific MetS severity Z-score (MetS-Z) that serves as a continuous measure of metabolic dysregulation. We hypothesized: 1) there would be a decrease in severity of MetS over the course of intervention in PIVENS and 2) the degree of decrease in MetS-Z early in the course of treatment would be a predictor of future NASH resolution. METHODS: Participants in PIVENS (n=201) had biopsy-confirmed NASH at baseline and were randomized to receive pioglitazone, vitamin E or placebo for 96 weeks, when they received repeat biopsy to assess for NASH resolution. We compared levels of MetS-Z and its standardized effect size (the absolute observed difference in MetS-Z for an individual divided by the overall baseline standard deviation of MetS-Z) at baseline, 48 weeks and 96 weeks and used logistic regression to determine associations between baseline MetS and the change in MetS from 0–48 weeks on ultimate NASH resolution—both overall and by intervention group. RESULTS: During the 96 weeks of intervention, 73 participants (363%) exhibited NASH resolution. Baseline MetS-Z was inversely associated with odds of NASH resolution, such that those with higher MetS severity at baseline were less likely to experience NASH resolution (odds ratio [OR] per 1-SD of MetS-Z-score: 0.54, 95% confidence interval [CI] 0.33,0.88). Of the three intervention groups, the decrease in MetS-Z during initial 48 weeks of intervention was greatest for pioglitazone treatment (effect-size: -0.31, CI -0.15,-0.48). During treatment with vitamin E, those with significant 48-week changes in MetS-Z tended to be those with vs. without ultimate NASH resolution (-0.18 vs. -0.05). In the group overall, 48-week change in MetS-Z was inversely associated with NASH resolution (OR of per 1-SD change: 0.56, CI 0.35,0.88). CONCLUSION: Individuals with more severe metabolic derangement at baseline were less likely to exhibit NASH resolution, suggesting that individuals may have a threshold of MetS-severity beyond which successful treatment is unlikely. As hypothesized, a decrease in MetS-Z over time was associated with improved odds of NASH resolution. As an integrated marker of metabolic abnormalities, MetS-Z may be a new way non-invasively follow for successful treatment of NASH.
SAT-120 Humoral Hypercalcemia of Malignancy Caused by Squamous Cell Carcinoma of the Penis
Authors: Kanta Romana , Ansari Mohammad Jamal Uddin , Ali Mariam , Rehman Anis , Jabri Hadoun , Parveen Sanober , Jakoby Michael G
Published: May 2020

Background. Humoral hypercalcemia of malignancy (HHM) accounts for approximately 80% of hypercalcemia associated with cancer. We present an unusual case of HHM caused by recurrent squamous cell carcinoma of the penis. Case. A 45 year old male was brought to the emergency department (ED) due to worsening confusion over 48 hours. History was notable for squamous cell carcinoma of the penis initially diagnosed 12 years ago and managed by partial penectomy and ilioinguinal lymphadenectomy. Recurrence had been diagnosed approximately 30 days before presentation to the ED. The patient was somnolent, disoriented, and unable to follow commands. Admission laboratories were remarkable for new occurrence of hypercalcemia (serum calcium corrected for low albumin 17.0 mg/dL, 8.6–10.3) and acute renal failure (Cr 1.7 mg/dL, 0.6–1.3; BUN 44 mg/dL, 7–25). No masses or hemorrhages were observed on head imaging, though computed tomography of the chest, abdomen, and pelvis revealed multiple lung and liver masses and lytic bone lesions. Biopsy of a rib mass confirmed metastatic squamous cell carcinoma. Intact PTH level was suppressed at 1 pg/mL (12–88), but parathyroid hormone related protein (PTHrP) was significantly elevated at 120 pM (0.0–2.3). HHM due to PTHrP was diagnosed. Corrected calcium level reached a nadir of 9.5 mg/dL on hospital day seven after saline hydration, calcitonin, and zoledronic acid, but high dose denosumab (120 mg weekly) was started hospital day 10 after corrected calcium level increased to 11.7 mg/dL. Despite corrected calcium levels consistently in the range of 10.5–11.5 mg/dL for the remainder of hospitalization, the patient’s mental status failed to improve. He expired on hospital day 24. Conclusions. Squamous cell carcinoma of the penis is rare in the United States, with only about 2,000 cases diagnosed annually. Though squamous cell carcinomas are collectively the most common cause of PTHrP-related hypercalcemia, there are only a few cases of PTHrP-related hypercalcemia due to squamous cell carcinoma of the penis documented in the peer reviewed literature. As in our patient’s case, other penile carcinoma patients with PTHrP-related hypercalcemia have had regionally advanced or metastatic disease and limited therapeutic response to bisphosphonates. Our patient’s survival after occurrence of hypercalcemia was also similar to other published cases of penile carcinoma complicated by PTHrP-related hypercalcemia. This case confirms the potential for penile carcinoma to cause HHM through hypersecretion of PTHrP like squamous cell carcinomas of the lung, head, and neck. Denosumab may be a more effective treatment option than a bisphosphonate based on the therapeutic experience in this case and others. PTHrP-related hypercalcemia appears to be a strong indicator of limited life expectancy for penile carcinoma as for other malignancies.
MON-920 Pediatric Parathyroid Carcinoma Presenting With Acute Progressive Genu Valgum
Authors: Hu Tina Y , Berman Loren , Parkes William J , Franzone Jeanne M , Mody Tejal , Conard Katrina , Gannon Anthony W
Published: May 2020

BACKGROUND: Parathyroid carcinoma (PC) is exceptionally rare in children and its clinical features are poorly understood. Available reports have identified that very high serum calcium and parathyroid hormone levels would be expected in this disease. Definitive therapy for PC requires en bloc resection of the parathyroid tumor to reduce the risk of disease recurrence. Unfortunately, there are very few treatment options for metastatic PC and patients with recurrent PC have a high risk of mortality related to their disease. Because of the rarity of the condition, there are very limited data including pediatric patients.

Case: A previously healthy 13-year-old girl initially presented to primary care with bilateral foot and ankle pain in the context of acute and progressive genu valgum, referred to the orthopedic clinic. Lab evaluation prompted by imaging demonstrated severe hypercalcemia (15.6 mg/dL) and hyperphosphatasia (Alkaline phosphatase 2056 units/L). She was urgently referred to our clinic where we found her to have a firm right sided neck mass within the thyroid. Lab testing at that time confirmed profound hyperparathyroidism (PTH 2970 pg/mL). Neck ultrasound confirmed the presence of a 5.8 cm hypoechoic lesion adjacent to the right lower lobe of the thyroid. The patient received IV fluid resuscitation before undergoing urgent parathyroid surgery. The parathyroid lesion was grossly adherent to the thyroid gland and she received en bloc resection of the tumor and right lobe of the thyroid. Post-operatively, PTH rapidly declined to <3.4 and she developed a prolonged hypocalcemic phase. PTH function improved, but she continued to require high doses of calcium carbonate to address hungry bone syndrome over subsequent weeks. Comprehensive evaluation included testing for genetic mutations, deletions, and duplications in CASR, CDC73, CDKN1B, MEN1 and RET, all of which were negative. Extensive genetic testing of the parathyroid tumor did not identify any specific mutations which have been previously associated with PC. Six months post-operatively, her labs have vastly improved, although she has clinical evidence of PTH resistance and her alkaline phosphatase has not yet normalized. Neck ultrasound, F-18 FDG PET/MRI imaging and Sestamibi scans show no evidence of persistent disease.

Conclusions: While parathyroid carcinoma is extremely rare in pediatric patients, the diagnosis must be considered in cases of hypercalcemia with marked elevations in PTH and palpable neck mass. Although rarely described, bone changes related to PC may be dramatic and may result in lasting morbidity - including genu valgum requiring surgical intervention as well as prolonged hungry bone syndrome and metabolic bone disease. Genu valgum is a unique pediatric feature of this disease because this may only evolve in individuals whose physes are open.
SAT-688 Rare Case of 48 XXYY Syndrome with Suspected Type 1 Diabetes Mellitus
Authors: Aftab Hassaan B , Mirza Faryal Sardar
Published: May 2020

BACKGROUND: 48 XXYY syndrome is a rare aneuploidy characterized by the presence of an extra X and Y chromosome in males. Patients share features of Klinefelter syndrome such as tall stature, hypogonadism, congenital malformations and neurocognitive issues. Hypogonadism may cause abdominal adiposity hence increasing risk of insulin resistance and type 2 diabetes mellitus (DM). Klinefelter syndrome has been associated with certain autoimmune diseases however there is no autoimmune disease link described with XXYY syndrome. We present a patient with XXYY polysomy with insulin requiring DM.Clinical Case: A 26-year-old intellectually disabled male with history of XXYY polysomy presented with seizures and was evaluated for DM management. At age 18, he was noted to have hyperglycemia while undergoing dental extractions for brittle enamel leading to the diagnosis of DM. He was initiated on oral medications for a short period of time and transitioned to insulin due to significant hyperglycemia. Endocrine evaluation at the time also revealed hypergonadotropic hypogonadism and evaluation for Klinefelter syndrome revealed 48 XXYY aneuploidy.Patient’s history was significant for poorly controlled hyperglycemia with HbA1C ranging in 12–14% range in the last few years. History was negative for diabetic ketoacidosis (DKA) as per his primary endocrinologist, despite being noncompliant with his insulin therapy. History was negative for retinopathy, nephropathy or macrovascular complications, although he did have distal extremity paresthesia. On exam, he was noted to be edentulous with tall stature, BMI 21.7, facial dysmorphism, pes planus and 5th-digit clinodactyly bilaterally. Family history was positive for type 2 DM in father and prediabetes in mother.He presented with seizures and was diagnosed with brain abscess. Hyperglycemia was initially managed with IV insulin, followed by basal/bolus therapy. Fasting labs 20 hours after receiving insulin glargine showed glucose of 284 mg/dL, C-peptide 0.6 ng/mL (ref range: 0.8–3.5), proinsulin less than 1.6 pmol/L (less than 8.0), insulin 4 uIU/mL (3–19) suggestive of type 1 DM. Anti-GAD65 and anti-ICA antibody levels were negative. Additional antibody evaluation for type 1 DM (islet antigen 2, insulin autoantibody, micro-insulin and zinc transporter 8) is currently pending at the time of writing.Conclusion: Prevalence of XXYY syndrome is 1:18 000–1:40 000 in males. There are few case reports describing the association of type 2 DM with this syndrome. Our patient’s low BMI, low insulin and C-peptide with hyperglycemia indicate type 1 DM, although the absence of DKA in the setting of noncompliance suggests residual beta cell function or maturity onset diabetes of the young (MODY). Neither T1DM nor MODY has been reported with 48XXYY previously. Clinicians should be aware of this association as it has implications in terms of management of DM.
SUN-720 LC-MS/MS Measurements of Parathyroid Hormone-Related Protein (PTHrP): Association Between Ca, PTH and PTHrP in Clinical Samples
Authors: Kushnir Mark M , Straseski Joely A
Published: May 2020

Parathyroid hormone related protein (PTHrP) is involved in intracellular calcium (Ca) regulation and homeostasis. The main clinical utility of PTHrP as a biomarker is to assist with determining the cause of unexplained hypercalcemia (UH). Considering that PTHrP, along with parathyroid hormone (PTH), is involved in Ca homeostasis, we evaluated associations between concentrations of Ca, PTH, PTHrP and age, and the between-sex differences in clinical patient samples. We reviewed historic data on Ca, PTH and PTHrP concentrations measured in routine patient samples (n=2,701) submitted for testing to a large clinical diagnostic laboratory. Among the analysed samples 31.1% were from adults (18-59y), 52.9% from older adults (60-79y) and 16.9% from elderly (>79y). Out of the samples, 60.5% were from women (W) and 39.5% from men (M). PTHrP was measured using a validated LC-MS/MS method; Ca and parathyroid hormone (PTH) were measured using the Cobas 8000 (Roche). The imprecision of all assays was <10%. Reference intervals (RI) for PTHrP were <3.3 pmol/L and <2.2 pmol/L in W and M, respectively; RI for calcium was 8.4–10.2 mg/dL, and for PTH was 15–65 pg/mL. Median (mean) PTHrP concentrations in samples from adults, older adults and elderly were 1.5 (7.9), 2.5 (8.7) and 3.2 (5.3) pmol/L, respectively. Median (mean) concentrations in samples from W and M were 2.4 (6.3) and 2.5 (10.4) pmol/L, respectively. Statistically significant difference in PTHrP concentrations was observed between W and M from adult (p=0.0005) and older adult (p=0.0038) groups; between W from adult and elderly groups (p=0.0113); and between M from older adult and elderly groups (p=0.028). No significant difference among the age groups was observed in concentrations of Ca and PTH. As expected, direct relationship was observed between concentrations of Ca and PTHrP (ρ=0.189, p<0.0001), while inverse relationships were observed between concentrations of Ca and PTH (ρ=-0.393, p<0.0001), and PTH and PTHrP (ρ=-0.226, p<0.0001). Assessment of the distribution of PTHrP concentrations in samples from W (n=472) and M (n=446) with UH (Ca >10.2 mg/dL and PTH< 15 pg/mL), revealed elevated PTHrP concentrations in 35.0% of W and 59.4% of M; with odds ratio for PTHrP as cause of UH of 0.7 and 2.2, in W and M, respectively. Among the study samples, PTHrP concentrations in 29.3% of samples from W and 54.2% of samples form M were above the sex specific RI. The PTHrP positivity rates in adult, older adult and elderly W (M) were 22.1%, 28.2% and 44.2% (41.2%, 58.5% and 70.5%), respectively. We observed higher prevalence of elevated PTHrP concentrations in M than in W, and in older individuals. PTHrP concentrations above the RI were observed in 39.1% of the analyzed samples. Our data suggest that hypercalcemia caused by elevated PTHrP concentrations is more common for pathologic conditions, which have higher prevalence or specific of M.
SAT-512 Thyrotoxicosis Followed by Hypothyroidism Post Total Laryngectomy and Hemithyroidectomy
Authors: Aljehani Faisal , Funke Katalina , Fernandes Jyotika Kanwar
Published: May 2020

BACKGROUND:

Thyrotoxicosis has been described in few case reports after non thyroid neck surgeries but only in one case report after total laryngectomy and hemithyroidectomy. Subacute lymphocytic thyroiditis has been reported in one case post thyroid lobectomy in a patient with thyroid cancer. Total thyroidectomy or lobectomy are common practice as a part of laryngeal cancer treatment.

Clinical Case:

57- year old male with history of laryngeal cancer was admitted for total laryngectomy, bilateral neck dissection, left hemithyroidectomy. Post-operative Day 3 patient reported feeling anxious and palpitations. On exam he had tachycardia up to a heartrate of 150s/min. His baseline TSH, FT4 and Ft3 were all normal one week before the surgery. On the 5th day after the surgery, TSH was undetectable, FT4 was 3.3(range 0.71 - 1.48), while FT3 was normal 2.66 (range 1.71 - 3.7). Thyroglobulin were high (range 2.8 - 40.9) while Thyroglobulin antibodies, anti TPO and TRAB were all normal. Thyroid US was not done because of technical difficulties given the patient neck surgery. The patient had Burch-Wartofsky Point Scale of 35 at that time. He was started on a beta-blocker and heart rate improved to 110-120. Over the next 5 days his FT4 Improved and was normal by day 10 after the surgery. His TSH and Ft4 showed hypothyroidism 6 weeks after the surgery and levothyroxine was started. He was seen 4 months after the surgery with high TSH concerning for medication noncompliance.

Conclusion:

On our review of literature this would be the second case report of a thyrotoxicosis after total laryngectomy and hemithyroidectomy. Unique to our case is the devolvement of hypothyroidism after the initial phase of thyrotoxicosis resolved while in the other case reported in literature the patient did not develop hypothyroidism. Subsequent hypothyroidism in our case could be from underlying subacute lymphocytic thyroiditis or secondary to hemithyroidectomy.

Reference:

1.

Blenke EJ, Vernham GA, Ellis G. Surgery-induced thyroiditis following laryngectomy. The Journal of laryngology and otology. 2004;118(4):313-4.

2.

Choi YS, Han YJ, Yeo GE, Kwon SK, Kim BK, Park YH, et al. Subacute lymphocytic thyroiditis after lobectomy in a patient with papillary thyroid carcinoma: a case report. Journal of medical case reports. 2013;7:3.
SUN-413 Thyroid Stimulating Hormone Levels Amongst Reproductive Age Latinas: Findings from the ELLAS Study
Authors: Ulrich Nicole D , Waldo Anne , Batchelor Jourdin , Valbuena Felix , Bryce Richard , Neff Lisa , Marsh Erica Elizabeth
Published: May 2020

BACKGROUND: National population data on thyroid disease in women comes largely from NHANES. Prior research utilizing data from NHANES 1999-2002 indicated a 3.1% prevalence of hypothyroidism and 0.6% prevalence of hyperthyroidism among reproductive aged women. In this dataset, Mexican Americans had a similar risk of hypothyroidism but a slightly higher rate of hyperthyroidism when compared to non-Hispanic whites. We present data from a prospective cohort study of reproductive aged Hispanic women residing in the United States (US) in order to examine thyroid disease prevalence in this population.

Methods: The Environment, Leiomyomas, Latinas and Adiposity Study (ELLAS) is a prospective NIMHD funded longitudinal cohort study of reproductive age Latinas/Latinx females in Southeast Michigan. Demographic and health data were collected via bilingual interviewers. Height, weight, and body composition were measured by trained staff using a Tanita MC780U scale. Fasting morning venipuncture was performed and samples were collected in a serum separating tube and sent to a commercial lab (Labcorp – Burlington, NC) for TSH electrochemiluminescence immunoassay [normal reference range 0.45-4.5 mIU/L]. The data were analyzed using SAS version 9.4 (Cary, NC).

Results: 516 patients have enrolled in ELLAS and 450 of these have completed the first study visit. Mean age, BMI, and body fat % were 37.7 ± 7.0 years, 29.9 ± 6.8 kg/m2, 36.3% ± 6.6% (mean ± SD) respectively. Reported countries of birth were Mexico (76.2%), US (9.8%), Central America (6.7%), South America (5.6%), and the Caribbean Islands (0.7%). 34 (7.6%) participants reported a pre-existing thyroid condition. Of those, 28 reported they had been treated for a thyroid condition in the past, and 14 were currently taking prescription medication for thyroid disease. TSH levels were available on 418 women. Of those with a known thyroid condition, 6.5% had TSH values < 0.45 and 16.1% had elevated TSH values (> 4.5) at the time of their study visit, compared to 1.7% and 7.4% overall. 0.2% had TSH > 10. Among those without a known history of thyroid disease, 1.3% had TSH < 0.45 and 6.7% had TSH > 4.5 at their visit. BMI, body fat %, and country of birth were not associated with TSH levels, but there was a small yet significant effect of age on TSH (p=0.009).

Conclusion: In this US cohort of Hispanic women of reproductive age, we observed a high prevalence of thyroid dysfunction in those without pre-existing disease. In women with a known thyroid condition, the prevalence of abnormal TSH values was also high, representing both under- and over-treatment with thyroid hormone. Screening for thyroid disease in this population is important and presents a potential opportunity for intervention in an often underserved population.
SAT-653 Exploring the Role of Brown Adipokines on Hepatic Insulin Resistance Using a Microfluidic Organ-On-Chip
Authors: Tanataweethum Nida , Lee Chaeeun , Trang Allyson , Zhong Franklin , Kim Kihwan , Mehta Jhalak , Cohen Ronald Nelson , Bhushan Abhinav
Published: May 2020

The development of insulin resistance (IR) in liver is a key of pathophysiologic response in type 2 diabetes. Although insulin resistance impairs its ability to suppress hepatic glucose production, insulin regulation of lipogenesis is maintained (1). Currently available insulin sensitizers are effective at lowering glucose levels, but have significant adverse effect on weight gain due to triglyceride accumulation, which highlights a need to develop new therapeutic treatment options for type 2 diabetes. Brown adipose tissue (BAT) has been studied as a new target for anti-obesity and type 2 diabetes as BAT stimulation increases energy expenditure, reduces adiposity, and improves insulin sensitivity (2). However, the underlying mechanisms are not completely understood. To identify the role of BAT adipokines on hepatic insulin resistance, we developed an insulin resistant liver organ-on-chip model and then perfused primary mouse brown adipocyte conditioned media through the hepatocytes. Our results demonstrate that IR hepatocytes treated with brown adipocyte - conditioned media restores insulin sensitivity and improves glucose metabolism. This was verified by significantly increased expression of Phospho-Akt (Ser473) and glucose production gene markers (G6pc and PEPCK), lowered glucose production, increased glucose uptake, and increased glycogen synthesis in treated hepatocytes over IR group (p < 0.05). Our results also indicate that brown adipocyte - conditioned media treatment has the potential to suppress lipogenesis in hepatic insulin resistance. This was confirmed by significantly reduced expression of a lipogenesis gene marker (SREPB1) and fatty acid uptake in treated hepatocytes over IR group (p < 0.05). Current efforts are focused towards identifying the BAT adipokine via mass spectrometry. We conclude that BAT-derived endocrine factors could be a potential target for new drug discovery for obesity and type 2 diabetes treatment.

Reference: (1) Langlet et al. Cell. 2017 Nov;171(4):824-835. (2) Subhadraw et al. Am J Physiol Endocrinol Metlab. 2015 Jun;308(12):E1043-E1055.

Nothing to Disclose: NT, CL, AT, FZ, KK, JM, RC, AB
SUN-219 Electron Transport Chain Complex 2 in Mitochondrial Pregnenolone Synthesis
Authors: Bose Himangshu S , Marshall Brendan , Debnath Dilip , Perry Elizabeth W , Whittal Randy M
Published: May 2020

The mitochondrial P450 family of enzymes (SCC), which require the electron transport chain (ETC) complexes III, IV and V, initiate steroidogenesis by cleaving the sidechain of cholesterol to synthesize steroid hormones, an essential component for mammalian survival. SCC is required for full-term gestation, and aberrant expression may cause pseudohermaphroditism, breast cancer or polycystic ovary syndrome. Complex II or succinate dehydrogenase (quinone) is shared with the TCA cycle and has no proton pumping capacity and no known role in steroid synthesis. We now show that succinate is an intermediate metabolite in the TCA cycle and plays a central role physiologically. Specifically, complex II is required for SCC activation, where the proton pump facilitates an active intermediate state conformation at the matrix, so that in the presence of succinate, ATP can add phosphate. A longer intermediate equilibrium state generates a transient stabilization to enhance the binding of phosphate anions in the presence of succinate anions, resulting in higher enthalpy and activity. An inhibition of the processing at the intermediate state stops phosphate addition and activity. We further describe that phosphate circulation brings the molten globule, an intermediate, to an active folded state. This is the first report showing that an intermediate state activated by succinate facilitates ETC complex II interaction with complexes III and IV for metabolism.
SAT-365 Severe, Symptomatic Hypocalcemia Due to Denosumab and Vitamin D Deficiency in an Osteopenic Post-Menopausal Female
Authors: Berquist John , Kaplan Jason , Zazaian Andrew
Published: May 2020

BACKGROUND: Denosumab is a monoclonal antibody used in the treatment of osteoporosis to prevent bony injuries by increasing bone density. It has a very rare side effect of severe hypocalcemia (1) and a patient should take supplemental Vitamin D and calcium for prevention. There is debate among experts on when denosumab should be discontinued and if so, whether an alternative therapy should be started (2).

Case Report: A female in her 8th decade of life presented to the ED with a complaint of intermittent and diffuse numbness and confusion. She had a history of MGUS and osteoporosis; however, her most recent SPEP did not detect MGUS and her most recent bone scan showed a T score indicating osteopenia. She had been receiving denosumab for the past four years with her last injection three weeks prior. Physical exam revealed 5/5 strength and intact sensation in all four extremities. Her serum calcium level on presentation was 4.3 mg/dL (8.5-10.1), ionized calcium was 3.9 mg/dL (4.6-5.4), 25 Hydroxy Vitamin D 8.8 ng/ML (30-100), and intact PTH was appropriately elevated at 702.7 pg/mL (14.0-72.0). Her phosphorus level was also appropriately low at 2.1mg/dL (2.5/4.9). She had a serum creatinine level of 0.9 mg/dL (0.6-1.0) and an eGFR 63 mL/min. ECG showed normal sinus rhythm without any QT changes. She received 4 grams of calcium gluconate intravenously over the next 24 hours without improvement in her calcium, as trending chemistries continually showed a calcium level less than 5.0. She was started on a calcium gluconate continuous infusion along with calcitriol, Vitamin D3 5,000 IU per day, and oral calcium 500 mg with Vitamin D 600 IU three times daily. Her calcium levels improved, albeit still low, to 6.5 mg/dL and the calcium continuous infusion was stopped. A 1, 25-Dihydroxy Vitamin D level showed improvement as well resulting at 82 pg/mL (20-79). Her numbness and confusion symptoms resolved, and she was discharged on the aforementioned oral calcium and vitamin D regimen with instructions to follow up and discontinue use of denosumab.

Conclusion: There are two primary takeaways from this clinical case. The first is to ensure a patient receiving denosumab is also taking supplemental Vitamin D and calcium to prevent hypocalcemia and to periodically measure serum levels to rule out deficiency. The second is the emphasis on having a provider-patient discussion on alternative therapies when the patient may no longer be a candidate for denosumab while considering the patient’s risk for fracture.

References:

Bone, Henry G. et al. 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trail and open-label extension. Lancet Diabetes Endocrinology. 2017. 5: 513-23

Tsourdi, E. et al. Discontinuation of Denosumab therapy for osteoporosis: A systematic review and position statement by ECTS. Bone 2017. 105: 1-17.
SUN-424 Treatment of Antithyroid Drug-Induced Agranulocytosis with Granulocyte Colony-Stimulating Factor: A Meta-Analysis
Authors: Santos Maria Regina C , Lim Christian Emmanuel T , Javier Ramon Jason M , Calavera Alma R
Published: May 2020

BACKGROUND: Hyperthyroidism, a common condition seen by physicians, is predominantly treated with antithyroid drugs. Agranulocytosis, a potentially fatal complication, is their most serious side effect. Conflicting studies are present between the risks and benefits of the use of exogenous granulocyte colony-stimulating factor (G-CSF) in its treatment, since its pathogenesis has not been established. The objective of this study is to determine the benefit of G-CSF in antithyroid drug-induced (ATD) agranulocytosis, through a meta-analysis.

Methods: Studies were included after extensive literature search in five electronic databases; all met the inclusion and exclusion criteria, and were critically appraised. The primary outcome was days to hematologic recovery, defined as neutrophilic rise to >0.5 x 109/L. Data were treated as continuous data, obtaining the standard mean difference through a Forrest Plot using the Review Manager 5.3 application.

Results: Five of the studies were non-concurrent cohort, while one was a randomized clinical trial. The duration of the studies was from 1970s to 2014. Age range of the population was from 8 to 87 years old, with more females. G-CSF dose ranged from 75 to 300ug/day, injected subcutaneously or intramuscularly. Primary outcome measured common to all the studies included hematologic recovery. Five of the six studies showed shorter number of days to hematologic recovery for the treatment group compared to the control group (with a standardized mean difference of 1 day, confidence interval (CI) of 0.45 to 1.54).

Conclusion: Exogenous G-CSF administration in ATD agranulocytosis contributed to faster hematologic recovery in terms of days, shortening recovery by a mean of 1 day.

References:

1. Tamai, H., et al. Treatment of methimazole-induced agranulocytosis using recombinant human granulocyte colony-stimulating factor (rhG-CSF). J Clin Endocrinol Metab.

1993;77(5):1356-1360.

2. Andres, E., et al. Haematopoietic growth factor in antithyroid-drug-induced agranulocytosis. Q J Med. 2001;94:423-428.

3. Fukata, S., Kuma, K., Sugawara, M. Granulocyte colony-stimulating factor (G-CSF) does not improve recovery from antithyroid drug-induced agranulocytosis: a prospective study. Thyroid. 1999;9(1):29-31.

4. Tajiri, J., Noguchi, S. Antithyroid drug-induced agranulocytosis: how has granulocyte colony-stimulating factor changed therapy? Thyroid. 2005;15(3):292-297.

5. Watanabe, N., et al. Antithyroid drug-induced hematopoietic damage: a retrospective cohort study of agranulocytosis and pancytopenia involving 50,385 patients with Graves’ disease. J Clin Endocrinol Metab. 2012;97(1):E49-E53.

6. Clauna-Lumanta, M.M., Yao, C., Bolinao, J.F. The effects of GCSF on the recovery time and duration of hospitalization in patients with anti-thyroid drug-induced agranulocytosis in a tertiary hospital. JAFES. 2016;31(2):131-136.
SUN-091 Change in Sex of Rearing in Individuals with Disorders of Sex Development
Authors: Knoll Michele , Egan Anna , Strickland Julie , Gatti John , Koenig Joel , Jacobson Jill Diane
Published: May 2020

Introduction: Differences of Sex Development (DSDs) encompass variations in formation of internal or external sex characteristics. Historically, sex assignment in children with DSDs depended on phenotype, and gender was thought to be malleable. Attention in DSD has recently shifted toward reducing gender dysphoria and preserving fertility potential. Our multidisciplinary DSD clinic was formed in 2008 with these goals and includes specialists from Endocrinology, Gynecology, Urology, Psychology, Social Work, Genetics, and Chaplaincy.

Subjects: A chart review was done on all patients seen in our DSD clinic between April 2008 and June 2019 to determine rates of sex reassignment and gender dysphoria. Two hundred patients were seen: 23 were found to not have DSDs; 61 were 46,XX; 66 were 46,XY; 31 had a sex chromosome DSD; 5 had gonadal dysgenesis without known chromosome mosaicism; and 14 had syndromic genital atypia. Mean age of follow-up is 8.77 years.

Results: Only 2 patients underwent sex reassignment at our institution. One was assigned male at birth, but was found to be 46,XX with 21-hydroxylase deficiency and was reassigned female at 1 month of age. The second was assigned male at birth and was found to be 46,XY with an NR5A1 variant. Sex was reassigned female at two months of age. Two additional patients had a sex reassignment outside our institution. One was born abroad and assigned male at birth. The patient was found to be 46,XY with an NR5A1 variant, and was reassigned female. The second patient was assigned male at birth, but was found to be 46,XX with P450 oxidoreductase deficiency. The parents changed the sex of rearing to female at 19 months of age. To date, none has signs of gender dysphoria.

A total of three patients experienced gender dysphoria and underwent transition. The first had genital ambiguity with sex chromosome mosaicism in the gonads and was assigned female at birth. We held care conferences with the family and discussed the possibility of gender dysphoria. At age 3, the patient declared that he was male, and parents socially transitioned him at that time. Two were assigned female after receiving the diagnosis of 46,XX 21-hydroxylase deficiency. Both declared male gender identity later, one at 12.5 years of age, and one at 20.5 years of age.

Conclusion: Whereas our patient population is still relatively young, it is reassuring that the overall rate of gender dysphoria is low. The rate in patients with CAH is similar to previous reports in the literature. Careful attention to sex assignment in early childhood may reduce the rates of gender dysphoria in children with DSDs.