bluuebunny/crossref_metadata_2025 huggingface dataset:
MON-LB63 Hypocalcemia-A Clue to Digeorge Syndrome; A Very Rare Case Diagnosed in a 41 Year Male
Authors: Tharu Biswaraj , Bishal Khanal , Basnet Sijan , Adhikari Nawaraj , Tharu Sunraj
Published: May 2020

41-year-old male with history of anxiety, bipolar disorder, depression, cognitive developmental delay, Idiopathic Thrombocytopenic Purpura (ITP), Vit D deficiency, tinnitus, suicidal attempt, auditory hallucination, borderline intellectual functioning comes to the PCP’s office for regular follow-up. The PCP has noted that the patient was hypocalcemic on multiple visits. On exam, vitals were in normal range, height 5 feet 2 inches, BMI 31 kg/m2.Despite the patient being on calcium and Vit D2 pills for a couple of months, his Calcium level were low ranging from 5.8–7.8mg/dl (normal 8.5-10.1) with normal albumin; ionized calcium was low 0.9-0.97mmol/l (normal 1.12-1.23); Magnesium was normal 2mEq/L (normal 1.5-2.5), phosphorus slightly high 5 mg/dL (normal 2.5-4.9), PTH (ParaThyroid Hormone level) was low-normal 18.8pg/ml (normal 11.1-79.5), vitamin D 25 OH low 16ng/ml (normal 30-100); 1,25 di OH vitamin D low 8ng/ml (normal25-40).Thyroid ultrasound showed 2 benign nodules, no further work-up done. TSH and free T4 were normal. FISH (Fluorescence In Situ Hybridization) came positive for DiGeorge syndrome (deletion at 22q11.2). He was treated with calcium 600 mg 4 pills daily, calcitriol 0.25 mcg two pills daily, Vit D2 50000 IU weekly and thiazide diuretic. His labs improved.

DISCUSSIONHypocalcemia can be due to low magnesium level, drugs or associated with high or low PTH. The patient had normal magnesium and he was not on any medication that causes hypocalcemia. This rules out first two casues. Hypocalcemia with high PTH (pseudohypoparathyroidism or low vit D levels) doesn’t fall in our differential because our patient had low PTH. For hypocalcemia with low PTH, differentials include post-surgical condition (no surgical history), autoimmune (history and labs not suggestive of), infiltrative diseases (eg hemochromatosis- he had normal iron study, Wilson disease- normal copper level, granulomas- contrary he had low 1,25 Di OH vit D). Hypocalcemia secondary to genetic parthyroid gland anomaly was thought to be most likely in our patient. So FISH was pursued.

Conclusion: For patients with cognitive issues, persistence of chronic hypocalcemia (with low PTH) despite treatment should prompt for genetic disorders like DiGeorge. DiGeorge is usually the diagnosis of children. Perhaps this is the first case of DiGeorge diagnosed so late at age of 41.
MON-LB66 Altered Mental Status and Hypercalcemia: A Rare Presentation of Pure Osteolytic Metastatic Prostate Cancer
Authors: Kulkarni Ajinkya , Kulkarni Mrunal , Ellangovan Rithikaa , Thirumaran Rajesh
Published: May 2020

Background: We present a rare case of hypercalcemia with the concomitant presence of parathyroid adenoma, secondary hyperparathyroidism due to kidney disease and hypercalcemia of malignancy. Mild hypercalcemia due to primary hyperparathyroidism often precedes the acute, more severe hypercalcemia of malignancy. Prostate cancers are usually known to cause osteoblastic lesions. We present a rare case of prostate cancer with pure osteolytic metastasis.

Case: 73 year old male with past history of ESRD on hemodialysis was brought to the ER with change in mental status. Labs showed elevated serum calcium 13.3 mg/dl (8.6-10.2 mg/dl) and creatinine 7.0 mg/dl (0.60-1.30mg/dl). Patient underwent emergent hemodialysis. Additional lab work revealed, elevated phosphorus level of 5.8mg/dl (2.5-5 mg/dl), low vitamin D 25-hydroxy of 22 ng/ml (30-100 ng/ml) and vitamin 1-25 dihydroxy level of 7 ng/ml (20-79 ng/ml). Both PTH 172.6 pg/ml (12-88 pg/ml) and PTHrP 64 pg/ml (14-27 pg/dl) levels were elevated. Parathyroid scan showed increased uptake in left inferior parathyroid gland indicating the presence of a parathyroid adenoma. Serum calcium levels remained persistently elevated despite being continued on dialysis with a low calcium bath and receiving calcium lowering therapy with calcium binding agent- cinacalcet, calcitonin, bisphosphonate. Further work up for refractory hypercalcemia revealed an elevated prostate-specific antigen (PSA) level of 1420 ng/ml (0-3.999 ng/ml). Bone scan showed no evidence of osseous metastasis. CT abdomen & pelvis showed extensive lytic bony metastases, with metastasis to lung and lymph nodes in mesenteric root and in the pelvis. Prostate gland showed asymmetric contour along the left posterolateral zone suspicious for malignancy with extracapsular spread.Biopsy from the left iliac lytic bone lesion was done that showed poorly differentiated metastatic adenocarcinoma, consistent with a prostatic primary. The patient was started on treatment with anti-androgen medication- Bicalutamide and prednisone and was planned to be started on Leuprolide as outpatient.

Discussion: Hypercalcemia is uncommon in advanced prostate cancer compared to other malignancies where osteolytic metastasis is more common than osteoblastic metastasis. Incidence of malignancy in patients with primary hyperparathyroidism and vice-versa is high, hence serum PTH and PTHrP should be measured in hypercalcemic patients with malignancy. If PTHrP and PTH are both elevated, it indicates co-existent primary hyperparathyroidism. Prostate cancers are usually known to cause osteoblastic lesions and pure osteolytic metastasis from prostate carcinoma is extremely rare. Radio-nucleotide bone scan preferentially detects osteoblastic metastasis. CT or MRI is indicated to look for osteolytic lesions if suspicion for bone metastasis is high.
SAT-LB81 Carbohydrate Crash: A Rare Case of Thyrotoxic Periodic Paralysis
Authors: Sittol Rani , Allen Juliann , Lofters Jason , Ran-Castillo Dan , Williams Karlene
Published: May 2020

IntroductionThyrotoxic Hypokalemic Periodic Paralysis (TPP) is an uncommon diagnosis in the western world and may be the initial presentation of hyperthyroidism. CaseA healthy 37 year old Asian male was visiting the US when he had sudden onset lower limb weakness after carbohydrate rich meal on Saturday night. He reported hand tremors for 1 month and a 10kg weight loss. On examination he was anxious with a fine hand tremor, BP 158/80mmHg, and HR 106bpm. He had grade 2/5 power to lower limb proximal muscles and brisk reflexes. Thyroid and eyes were normal. Laboratory results significant for potassium (K) 3.2mmol/l, TSH 0.005 (0.270-4.4uiu/ml), FT4 2.6 (0.8-2.2ng/dl), FT3 12.4 (2.77-5.27 pg/ml) and TSH Receptor antibody was 23.9% (<16%). Thoracolumbar MRI was normal. Repletion of K resulted in total resolution of paresis. He was given propranolol and methimazole and chose to complete workup in China.Clinical LessonTPP results in paralysis due to hypokalemia and hyperthyroidism and can be the initial presentation of hyperthyroidism. It is most common in Asian males 20-40 years with incidence 1.9%, but only 0.2% in the west. Proximal muscles are affected more. Attacks may be precipitated by carbohydrate load, rest after exercise, or stress. Patients tend to present on weekends between 2100-0900hrs. It is hypothesized that K metabolism is diurnal, with influx to muscle at night or at rest. Once euthyroid, TPP will not recur unlike familial hypokalemic periodic paralysis which is recurrent and of earlier onset. The underlying reason remains unclear. It may be related to the action of thyroxine on Na/K-ATPase pump. TPP is usually associated with Graves’ disease, but other causes of hyperthyroidism have been reported. TPP is a treatable rare illness in Asians, and very uncommon in the West. Physicians must be aware of its subtleties, as it may be confused with other more common conditions.ReferencesChang-Hsun Hsieh, Shi-Wen Kuo, Dee Pei, Yi-Jen Hung, Sandra Chyi-Fan, Ling-I Wu, Chih-Tsueng He, Tsao-Chin Yang, Wei-Cheng Lian, and Chien-Hsing Lee, Thyrotoxic periodic paralysis: an overview, Ann Saudi Med. 2004 Nov-Dec; 24(6): 418-422. doi:10.5144/0256-4947.2004.418Annie W. C. Kung, CLINICAL REVIEW: Thyrotoxic Periodic Paralysis: A Diagnostic Challenge, The Journal of Clinical Endocrinology and Metabolism 91(7):2490-2495, Copyright © 2006 by The Endocrine Society doi: 10.1210/jc.2006-0356
SUN-LB70 Bone Mineral Density, Vitamin D Status and Bone Turnover Markers in Thai Youth With Graves’ Disease: A Pilot Study
Authors: Wiromrat Pattara , Panamonta Ouyporn
Published: May 2020

Background: Several studies in adults and limited studies in youth have demonstrated decreased bone mineral density (BMD) and increased bone turnover in people with Graves’ disease (GD) with hyperthyroidism state. These negative impacts on bone loss can be reversed, in some extent, after normalizing of thyroid hormone. Low 25(OH)D was also prevalent in adults with GD that may worsen bone health. However, there has been no study evaluating 25(OH)D and its associations with BMD and markers of bone turnover in youth with GD. Objective: To evaluate BMD, bone turnover markers and 25(OH)D concentrations and the associations among these measures in youth with GD with varying thyroid status. Methods: Thirty participants with GD [age range 8-20 years; female 75%; mean BMI %tile 61±29 kg/m2, median Tanner stage 4 (3, 5)] were included in the study. Seventeen (57%) participants underwent radioactive iodine ablation. Twelve, seven and three participants had hyperthyroidism, euthyroidism/subclinical hypothyroidism and overt hypothyroidism, respectively. Participants were grouped according to free triiodothyronine [FT3] tertiles [low 2.3±0.8; medium 3.5±0.4; high 10.9±0.9 pg/ml]. Lumbar [L-BMD] and total body headless BMD [TBHL-BMD] were measured with Hologic Discovery A densitometry and compared with reference value (BMD z-score, BMDz). Morning serum concentrations of osteocalcin [OC], procollagen type 1 N-terminal propeptide [PINP], β-crosslaps [β-CTX] and 25(OH)D were also analyzed. Results: Mean L-BMDz and TBHL-BMDz in youth with GD were 0.256±1.064 and 0.011±0.898, respectively. Osteopenia was found in only one participant [L-BMDz -1.6 and TBLH-BMDz -1.2] who had thyrotoxicosis. L-BMDz (p=0.713) and TBLH-BMDz (p=0.91) were not significantly different between FT3 tertiles. There were no significant differences in OC [p=0.481], PINP [p=0.37], β-CTX [p=0.71] and 25(OH)D [p=0.91], adjusting for age, sex and BMI %tile, between FT3 tertiles. There were no significant associations among FT3, OC, PINP, β-CTX and BMDz. However, FT3 was negatively correlated with 25(OH)D [r=-0.574, p=0.032]. Participants with GD had mean 25(OH)D of 21.5±5.1 ng/ml. Twenty-nine out of 30 participants (97%) had 25(OH)D concentrations < 30 ng/ml. Of these, 11 participants (38%) had 25(OH)D < 20 ng/ml. Further, 25(OH)D was associated with L-BMDz [β (95%CI): 0.284 (0.091-0.477), p=0.013] and β-CTX [β (95%CI): 0.078 (0.020-0.136), p=0.011], independent of age, sex and BMI%tile. Conclusions: Vitamin D insufficiency/deficiency is prevalent in Thai youth with GD. Moreover, 25(OH)D concentrations, but not thyroid hormone, is independently associated with spine BMD and bone turnover. Therefore, evaluation and prompt treatment of vitamin D insufficiency/deficiency in pediatric GD are needed to prevent negative skeletal consequences.
SUN-197 Giant Adrenal Myelolipoma Associated with Prolonged ACTH Elevation in a Patient with Congenital Adrenal Hyperplasia (CAH)
Authors: Kaluarachchi Vidumini , Arshad Muhammad Fahad , Balasubramanian Sabapathy , Lim Chern Beverly Brenda , Bull Matthew , Ross Richard John M
Published: May 2020

Background: Myelolipomas are rare benign tumours which consist of adipose tissue and mature hematopoietic tissue. The incidence ranges from 0.08 to 0.4% and they constitute 15% of adrenal incidentalomas. We report the case of a massive adrenal myelolipoma in a patient with CAH. Clinical Case: A 51year old man with salt losing CAH due to 21 hydroxylase deficiency presented to the emergency department with abdominal pain. CT scan of the abdomen revealed a 15 x 16 x 19cm mass in the left adrenal gland. There were concerns about malignancy, however expert radiology review diagnosed a massive adrenal myelolipoma. The patient was diagnosed to have salt losing CAH during infancy and managed with cortisone acetate and fludrocortisone during childhood, then dexamethasone 0.5mg nocte, 0,25mg mane as an adult. At 27 years he was reviewed and found to be Cushingoid with abdominal striae, obesity and hypertension. A CT scan of the abdomen done at that time showed a normal left adrenal gland with nodular right adrenal gland. While he was on dexamethasone, his 17-OHP was 14 nmol/l (NR: 0–6.0 nmol/l). His dexamethasone was reduced, then he was transferred on to prednisolone and then to hydrocortisone. 17-OHP level and ACTH levels have risen with each change in medication. At the time of referral with abdominal pain, he was on hydrocortisone 10 mg mane, 10 mg midday and 5mg at 1700h and his biochemistry showed: ACTH 486ng/l (NR 7.2–63.3), 17-OHP 101.1nmol/l (0–6.0nmol/l), renin 5.5 nmol/l/hr (NR 0.2–3.3) and androstenedione 26.6 nmol/l (NR 0–7.8). He underwent laparoscopic hand-assisted left adrenalectomy with the removal of a 2030 gram adrenal myelolipoma. He made an uneventful recovery with remarkable clinical improvement in general wellbeing. Histology confirmed adrenal myelolipoma. Conclusion: Chronic exposure to high ACTH levels causes metaplasia of adrenocortical cells, but a direct causal relationship for myelolipomas is not established. The role of ACTH in development of myelolipomas is supported by the increased incidence in patients with Addison’s disease, Nelson’s syndrome and ACTH dependent Cushing Disease. Our case supports the role of ACTH as the myelipoma developed after the reduction of patient’s glucocorticoid treatment and ACTH levels were high for years. Myelolipomas are usually asymptomatic but can present with abdominal pain, spontaneous rupture, and spontaneous retroperitoneal haemorrhage. There are no set guidelines but for large and rapidly growing tumours, surgery may be considered..
SAT-LB17 Triplication of SHOX Downstream Region in Mild Short Stature
Authors: Bunyan David J , Gevers Evelien F
Published: May 2020

Deletions of the downstream flanking regions of the SHOX gene that contain conserved non-coding cis-regulatory DNA elements are a known cause of Leri-Weill dyschondrosteosis or idiopathic short stature (ISS). Functional and comparative genomic studies have demonstrated the existence of four CNE enhancers downstream of SHOX which have transcriptional activity, and a fifth has recently been suggested at approximately X:970,000. Duplications of these downstream regions have also been described in patients with ISS, although with a variable phenotype. We present a family with ISS and the first ever reported SHOX downstream triplication. The index case was a 12-year-old Caucasian female of unrelated parents, born with normal weight and length, and normal hearing/vision and development. At the age of 12, her height was -1.87 SD (-1.35 SD adjusted for parental height). Her growth chart showed a height on the 90th centile at birth, slowly crossing centiles for the first 5 years to the 2nd centile, which she then followed. She had normal proportions and head circumference, and no dysmorphic features apart from inverted nipples. Baseline investigations for short stature were normal, including IGF1, karyotype and celiac screen. Bone age was 1.5 year delayed. Family history: arthritis in the father, early menopause in the mother. Analysis of SHOX and its flanking regions was carried out using Multiplex Ligation-dependent Probe Amplification (MLPA) and direct sequencing of all coding exons. MLPA analysis showed a SHOX downstream triplication with a minimum size of 66kb (X:963670-1029779) and a maximum size of 428kb (X:899389-1327688). The size of the duplication was further defined using array comparative genome hybridization (ACGH) analysis which showed the minimum size to be ~325kb (X:907457-1232802). This triplication includes the proposed regulatory element at ~ X:970,000. The triplication was subsequently shown to be present in the proband’s mother and brother who also have mild ISS. Further analysis of these and other family members is ongoing. The triplication is of a single-sized fragment, and the fragment size is identical to one that has been seen in duplicated form in several other patients, increasing the likelihood that the triplicated fragments are in tandem. The precise mechanism of the pathogenic effect of the triplication is unknown, but it likely exerts a negative effect on SHOXtranscription, reducing its expression and ultimately resulting in SHOX haploinsufficiency. In conclusion, we describe a family with mild ISS and a downstream triplication of the proposed X:970,000 SHOX downstream regulatory element. This provides further evidence for this previously proposed regulatory element downstream of SHOX and adds additional proof that increased dosage of this regulatory element region is a cause of short stature.
SUN-LB74 Radiofrequency Echographic Multi-Spectrometry (REMS) for the Assessment of Bone Strength and Fracture Risk Prediction
Authors: Ciardo Delia , Conversano Francesco , Pisani Paola , Casciaro Sergio
Published: May 2020

Introduction Fragility bone fractures impact patient’s quality of life and worldwide healthcare systems: accurate technologies and device are required in order to early diagnose and monitor the effect of osteoporosis on a mass-population basis. Several studied have analysed the pros and cons of the numerous technologies available nowadays for the diagnosis and monitoring of bone health, highlighting the need of further tools able to better define and estimate bone strength and to predict the risk of fracture [1].

Objectives The aim is to assess the state of the art about Radiofrequency Echographic Multi-Spectrometry (REMS).

Methods A review of the available literature was performed, considering full papers, reviews and abstracts on REMS published before January 31th 2020.

Results REMS has been recently presented by an ESCEO consensus paper as a valuable technology for osteoporosis diagnosis and fracture risk estimation [1]. It is based on the automatic processing of the raw unfiltered signals obtained with an ultrasound scan, thus overcoming the main drawback of dual-energy X-ray absorptiometry (DXA) and computed tomography (CT)-based technologies [2]. Moreover, REMS scans are performed at axial skeleton reference sites, i.e. lumbar spine [3] and femoral neck [4], differently from quantitative ultrasound (QUS) technology, which is usually applied to peripheral sites [3]. Clinical performance has been confirmed by a multicentre clinical trial enrolling over 1900 Caucasian women, demonstrating a high correlation between bone mineral density (BMD) estimated by REMS and DXA. In addition, high performance in terms of precision and intra- and inter-operator repeatability of REMS have been assessed [6]. Prospective studies have demonstrated the predictive ability of incident fragility fractures [7] and the high concordance with DXA in terms of measured BMD in patients with rheumatoid arthritis and pre/post-menopause [8, 9].

Conclusions REMS is an innovative approach for the early diagnosis, short-term monitoring of osteoporosis and risk fracture prediction. The available data envisaged for further applications in paediatric patients, pregnant women and patients at risk of secondary osteoporosis (e.g., diabetic, nephropathic, oncological patients). The EchoS system, a device implementing the REMS technology, has recently received the approval from the U.S. Food and Drug Administration (FDA).

References 1. Diez-Perez et al. Aging Clin Exp Res 2019;31(10):1375–89 2. Iwaszkiewicz & Leszczyński. Forum Reumatol 2019;5(2):81–8 3. Hans & Baim. J Clin Densitom 2017;20(3):322-3 4. Conversano et al. Ultrasound Med Biol 2015;41:281–300 5. Casciaro et al. Ultrasound Med Biol 2016;42:1337–56 6. Di Paola et al. Osteoporos Int 2018;30:391–402 7. Adami et al. Ann Rheum Dis, vol.78, supp.2, 2019, p.A928 8. Bojincă et al. Exp Ther Med 2019;18(3):1661-68 9. Kirilova et al. Clin Cases Miner Bone Metab 2019; 16(1):14-17
MON-LB124 Euglycemic Diabetic Ketoacidosis on Initiation of Ertugliflozin in a Patient With Type 2 Diabetes Mellitus Precipitated by a Ketogenic Diet
Authors: Richstein Ryan , Palmeiro Christopher
Published: May 2020

Background: Diabetic ketoacidosis (DKA) is defined by metabolic acidosis, ketosis and hyperglycemia. It is considered to be a consequence of significant insulin deficiency and/or insulin resistance and is usually precipitated by the presence of hyperglucagonemia or other counterregulatory hormones. In patients on oral sodium-glucose cotransporter 2 (SGLT2) inhibitors, decreased carbohydrate availability through renal glucose excretion can cause serum glucose levels to be lower than what is normally seen (< 200 mg/dL) in DKA cases, masking the diagnosis. This phenomenon is termed euglycemic DKA (EuDKA). Existing evidence suggests that EuDKA in the setting of SGLT2 inhibitor use is rare and occurs mostly in patients with type I diabetes mellitus (T1D) and seldom in type 2 diabetes mellitus (T2D). Most published reports of EuDKA in patients with T2D describe patients on SGLT2 inhibitors with clear inciting events such as decreased insulin doses, surgery, or severe acute illness. To our knowledge, none have reported EuDKA precipitated by ertugliflozin. This is also the first report of EuDKA of a patient in the United States with T2D initiating SGLT-2 inhibitor use while on a low carbohydrate diet. Clinical Case: A 53-year-old female with a history of poorly controlled T2D was admitted to the hospital with EuDKA within seven days of starting ertugliflozin and alogliptin. Patient admitted to strict adherence to a low-carbohydrate diet for one week prior to admission. On admission, the patient was afebrile. Initial labs showed blood glucose 104 mg/dL, serum bicarbonate 8 mmol/L, anion gap 22, pH 7.100, beta-hydroxybutyrate 66.94 ng/mL (0.20-2.81), and a hemoglobin A1c of 11.2%. Urinalysis revealed glucosuria ≥500 mg/dL, ketonuria 80 mg/dL, hyaline cast 20/lpf, no nitrites or leukocyte esterase, WBC 1/hpf. Flu PCR negative. WBC count was 17.4 x10e3/uL initially, though all CBC cell lines decreased with fluid administration. CXR was negative for acute pulmonary disease. All oral T2D agents were held and our patient was initiated on a DKA protocol based on ADA guidelines. Her EuDKA subsequently resolved with successful transition to a weight-based basal-bolus insulin regimen. Conclusions: There are no published case reports identifying patients with T2D developing euglycemic DKA precipitated only by a low carbohydrate diet and ertugliflozin initiation. We hypothesize that our patient’s ketogenic diet lowered the threshold for a euglycemic ketoacid crisis resulting directly from the new addition of the SGLT2 inhibitor in the setting of pre-existing glucose toxicity. In patients considering, starting and being maintained on ertugliflozin or other SGLT2 inhibitors, the importance of effective, early and frequent dietary counseling with close follow-up cannot be overstated. Further, this report of EuDKA in a patient starting ertugliflozin supports that EuDKA is an SGLT2 inhibitor class risk.
SUN-LB4 Androgenic Profiles of Patients With Severe Insulin Resistance
Authors: Jha Smita , Turcu Adina , Brookner Brittany , Abel Brent Samuel , Startzell Megan , Auchus Richard Joseph , Brown Rebecca J , Merke Deborah P
Published: May 2020

Background Patients with severe insulin resistance have ovarian hyperthecosis, high testosterone (T) and minimal adipose tissue. Recent studies have found elevated levels of 11-oxygenated (11-oxy) androgens in women with polycystic ovary syndrome (PCOS) compared to age and sex-matched controls. 11-oxy-androgens are produced by CYP11B1, an enzyme expressed predominantly in the adrenal, with minor ovarian expression. We analyzed 11-oxy-androgens in women with severe insulin resistance. Methods We performed retrospective analysis of women with severe insulin resistance (lipodystrophy or insulin receptor defects) seen at the NIH and identified 19 patients with testosterone ≥ 80 ng/dl (immunoassay) and available serum samples. Quantitation of androgens was performed by LC-MS/ MS and compared to age, sex and BMI-matched controls. Data between groups was compared using non-parametric Mann-Whitney U test. Correlation analyses utilized the Pearson and Spearman’s rho. Results Median patient age was 18yrs (IQR 17-26) with median fasting insulin of 63mcU/ mL (IQR 40-184). Serum insulin correlated strongly with fold elevation of T in patients relative to controls (r= 0.47, P=0.04). Median levels of all androgens except 11-hydroxytestosterone (11OHT) were significantly higher in patients than controls, including 11-ketotestosterone (11KT), a clinically relevant androgen in both congenital adrenal hyperplasia and PCOS [69 ng/dl (IQR 27-82) vs 24 ng/dl (IQR 16-40), P < 0.001]. 11KT/ T was lower in patients (0.30, IQR 0.12-1.15) compared to controls (1.1, IQR 0.41-1.5, P = 0.04). All 11-oxy-androgens correlated with each other (rs range: 0.6-0.8, P < .05) in both groups. There was no difference in the proportionate contribution of 11-oxy-androgens to the total circulating androgenic pool in patients vs. controls. Conclusion: Elevated 11-oxy-androgens in patients with severe insulin resistance suggests that both adrenal and ovarian androgens are upregulated by hyperinsulinemia. Lower 11KT/T in patients compared to controls despite higher 11-oxy-androgens than in controls is consistent with predominant ovarian T excess in patients with severe IR. Correlation between insulin and fold elevation of T relative to controls supports hyperinsulinemia as the cause of high T in states of hyperinsulinism. Acknowledgement: This research was supported by the Intramural Program of NIH Clinical Center and NIDDK.
SUN-LB113 A Continuous Remote Care Intervention Utilizing Carbohydrate Restriction Including Nutritional Ketosis Improves Markers of Metabolic Risk and Reduces Diabetes Medication Use in Patients With Type 2 Diabetes Over 3.5 Years
Authors: McKenzie Amy , Athinarayanan Shaminie , Adams Rebecca , Volek Jeff , Phinney Stephen , Hallberg Sarah
Published: May 2020

Novel lifestyle, pharmaceutical, and/or surgical therapies for type 2 diabetes (T2D) are under study to assess lasting impact on metabolic risk. Among them, carbohydrate restriction including nutritional ketosis (CR) has emerged as a safe and effective nutrition therapy for reducing hyperglycemia in patients with T2D1, yet longer term effects are unknown. At the conclusion of a 2-year study assessing a continuous remote care intervention utilizing CR (CCI) among patients who selected this therapy, intervention participants were offered the opportunity to consent to participate in a 3-year extension assessing outcomes at 3.5- and 5-y following initial enrollment. 143 of 169 extension-consented participants provided data at 3.5-y follow up. Among 3.5-y completers, linear mixed effects models were used to assess change over time in diabetes-related outcomes and McNemar’s tests were used to assess for a difference in the proportion of participants meeting certain criteria at baseline compared to follow-up. At enrollment, 3.5-y completers were (mean±SE) 55±1 y of age, 40.8±0.7 kg/m2, and 8±1 y since diagnosis. Following treatment with the CCI for 3.5 y, significant improvements compared to baseline were observed in HbA1c (-0.6±0.1 from 7.4±0.1%; P = 1.9x10-5), weight (-10.9±1.1 from 117.4 kg; P = 6.9x10-17), nonHDL-C (-10±4 from 139±3 mg/dL; P = 0.005), triglycerides (-41±11 from 189±10 mg/dl; P = 2.1x10-4), and HDL-C (+9±1 from 43±1 mg/dl; P = 3.0x10-11); total cholesterol and LDL-C were statistically unchanged. The percentage of participants prescribed diabetes medication decreased from 84.6 to 67.1% (P = 5.0x10-6), while 50.2% of diabetes medications and 71.4% of diabetes medications other than metformin were discontinued. The percentage of participants treated with no pharmaceuticals or monotherapy increased from 52.5 to 81.9% (P = 1.3x10-8). 45.5% (65/143) of participants achieved HbA1c <6.5% with either no medication (34/65, 52%) or only metformin (31/65, 48%) at 3.5 y; 37.8% of participants maintained this status from 1 through 3.5 y of treatment. 22% of participants achieved diabetes remission at 3.5 y, and 17.5% of participants maintained remission status from 2 through 3.5 y of treatment. This demonstrates that clinically meaningful improvements across multiple markers of metabolic risk can be sustained in patients with T2D who selected treatment with this CCI for 3.5 y. Improvements in metabolic risk markers reduced the need for diabetes medication, allowing some patients to achieve and sustain diabetes remission. This ongoing trial will assess 5-y effects.

1. American Diabetes Association. Standards of Medical Care in Diabetes. Diabetes Care. 2020; 43(Supplement 1): S48-S65. 2. Athinarayanan SJ, et al. Front Endocrinol. 2019; 10:348.
SUN-LB42 The Sexually Dimorphic Response of the Mouse Adrenal Inner Cortex to Thyroid Hormone Treatment
Authors: Zheng Huifei Sophia , Lyu Qiongxia , Huang Chen-Che Jeff
Published: May 2020

The gender bias in adrenal diseases has been noticed for a long time. Mouse studies have shown that the adrenal gland is sexually dimorphic at different levels, such as transcriptome, histology, and cell renewal. However, the mechanism behind this sexual dimorphism is not fully understood. Here, we used RNA-seq to demonstrate how male and female adrenals respond differently to the same external cue, the thyroid hormone (T3) treatment, which directly elicits its function on the adrenal inner cortex by changing the cell fate of this population. Through the comparison of the adrenal gland transcriptomes from males and females with T3 or saline treatment, we found that more genes in female adrenals were responsive to the T3 treatment, whereas the fold change of the gene expressions was greater in male adrenals. Statistical analysis identified 104 sexually dimorphic T3-responsive genes. Immunostaining results showed that many of these genes were expressed in the adrenal gland inner cortex, which contains a unique cell population called X-zone (20-alpha-HSD positive). Previous studies showed that T3 treatment leads to the expansion of the 20αHSD-positive zone both in males and in females. Here we found that the top sexually dimorphic T3-responsive gene was expressed in the adrenal inner cortex partially colocalized with X-zone. Under T3 treatment, this unique cell population that surrounds the 20-alpha-HSD positive X-zone became obvious only in females but not in males. Our findings not only identified several novel marker genes for the adrenal inner cortex but also highlighted the sex-specific response of thyroid hormone action in the mouse adrenal gland.
MON-LB103 Hyperactivation of Reward and Cognitive Control Brain Regions in Response to Food Images in Women Compared to Men With Obesity
Authors: Getachew Ethiopia D , Plessow Franziska , Van De Water Avery , Pulumo Reitumetse L , Hauser Kristine , Asanza Elisa , Kerem Liya , Harshman Stephanie G , Holsen Laura , Lawson Elizabeth A
Published: May 2020

Background: Obesity is a major public health concern with an estimated two thirds of the population being overweight or obese. Women have a higher rate of obesity than men (40% vs. 35%), twice the rate of class 3 obesity (10% vs. 5% with BMI>40), and greater increases in obesity prevalence from 2005-2014. While emerging evidence highlights the role of food motivation circuitry in eating behavior and obesity risk, sex-specific neurobiological mechanisms have not been well defined in this population but are important to guide individual treatment strategies. Using a well-established food motivation functional magnetic resonance (fMRI) paradigm, we ran a preliminary set of analyses to investigate whether sex modulates the brain response to visual presentations of food items. We hypothesized that in a fasted state, women would demonstrate greater blood-oxygen-level-dependent (BOLD) activation in response to food images in reward-related brain regions compared to men.

Methods: Twenty-nine adults with obesity (16 female, age (mean±SD): 31.2±4.9 years, and BMI=36.5±4.1 kg/m2) completed fMRI imaging in a 3T scanner while viewing images of food (high-calorie vs. low-calorie), non-food items, and fixation stimuli following a 10-hour overnight fast. Functional MRI data were analyzed using SPM12. Regions of interest included the nucleus accumbens (NAcc), amygdala, caudate, anterior insula (aINS), hypothalamus, putamen, orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DLPFC), dorsal anterior cingulate cortex (dACC), and supplementary motor area (SMA). Statistical significance of p<0.05 is reported at the whole brain level given the small sample size.

Results: Women with obesity exhibited greater activation than men in response to food (vs. non-food) stimuli in NAcc (t=2.44, p[uncorrected]=0.011), caudate (t=2.9, p[uncorrected]=0.004), DLPFC (t=3.32, p[uncorrected]=0.001), and dACC (t=3.17, p[uncorrected]=0.002) in a fasted state. There were no regions in which men exhibited greater activation than women.

Conclusion: Our preliminary results show that during a fasting state, women with obesity (vs. men) show greater activation in brain regions processing reward (NAcc) and control over behavior (DLPFC, dACC) in response to food (vs. non-food) stimuli. Future studies with larger sample sizes are needed to investigate the link between the highlighted sex differences in neural responses to food in the context of obesity and eating behavior and weight to further inform whether men and women would benefit from different approaches in the treatment of obesity.
SAT-LB12 Once-Weekly Somapacitan vs Daily Growth Hormone in Growth Hormone Deficiency: 2-Year Safety Results From Real 3, a Randomized Phase 2 Trial
Authors: Savendahl Lars S , Rasmussen Michael Højby
Published: May 2020

Growth hormone (GH) replacement therapy currently requires daily injections. Somapacitan is a long-acting GH-derivative being developed for once-weekly (OW) use in children and adults with GH deficiency (GHD). A phase 2, multinational, randomized, open-label, controlled trial (ClinicalTrials.gov: NCT02616562) investigated the efficacy and safety of OW somapacitan compared with daily GH (Norditropin® FlexPro®). GH-treatment-naïve prepubertal children with GH deficiency received 0.04 (n=16), 0.08 (n=15) or 0.16 mg/kg/wk (n=14) subcutaneous (sc) OW somapacitan, or sc GH 0.034 mg/kg/day (0.24 mg/kg/wk; n=14) for 52 wks, followed by a 104-wk safety extension with all patients on somapacitan receiving 0.16 mg/kg/wk while GH dose was unaltered. Safety endpoints included frequency of adverse events (AEs), including injection-site reactions, and occurrence of anti-somapacitan/anti-human growth hormone (hGH) antibodies. The 52-wk efficacy and safety results have been reported. We report here safety results at 104 wks’ total treatment. Number of AEs (% of patients) was as follows: OW somapacitan 0.04/0.16 mg/kg/wk, 51 (75%); 0.08/0.16 mg/kg/wk, 89 (80%); 0.16/0.16 mg/kg/wk, 89 (100%); and for daily GH, 82 (100%). Nasopharyngitis, influenza, allergic rhinitis and gastroenteritis were the most common AEs across all treatment groups. Pyrexia was more common in the OW somapacitan 0.04/0.16 mg/kg/wk (43.8%) and 0.08/0.16 mg/kg/wk (26.7%) groups vs the higher-dose OW somapacitan and daily GH groups (7.1% each). Most AEs were mild to moderate and unlikely related to treatment. Ten serious AEs were reported in five (8.5%) children and unlikely related to treatment, except two AEs of moderate severity during the first 26 wks: generalized edema and vomiting in one child on 0.16 mg/kg/wk OW somapacitan, rated as probably related to treatment although she was also given intravenous antibiotics for suspected infection. Injection-site reactions were reported in the 0.04/0.16 mg/kg/wk (n=2) and 0.16/0.16 mg/kg/wk (n=1) OW somapacitan groups and in the daily GH group (n=1). Four children (0.04/0.16 mg/kg/wk) and one child (0.16/0.16 mg/kg/wk) had transient anti-somapacitan antibodies; one child (0.16/0.16 mg/kg/wk) had low-titer anti-somapacitan antibodies at two consecutive visits; in one child (daily GH group) with persistent low-titer anti-hGH antibodies, treatment was discontinued at wk 52. All antibodies were non-neutralizing. In conclusion, OW somapacitan was well tolerated at all doses, with no new safety or tolerability issues identified after up to 104 wks of treatment. The frequency, severity and type of AEs were similar in the OW somapacitan and daily GH treatment groups except for pyrexia, which was unlikely related to treatment and more frequently reported in the lowest dose somapacitan group.
SAT-LB87 Golimumab Induced Thyroiditis
Authors: Mai Mo M , Karam Jocelyne G , Lynn Nyein , Singh Gurbaj , Singer Elizabeth Sedlis
Published: May 2020

Background:

Subacute thyroiditis is caused by an inflammation and a destruction of the thyroid cells, leading to hyperthyroidism due to leakage of thyroid hormones, followed by possible hypothyroidism and/or full recovery of thyroid function. This is a case report describing a rare occurrence of drug-induced thyroiditis secondary to golimumab.

Clinical Case:

A 79-year-old female with HTN, hyperlipidemia, dementia and rheumatoid arthritis was brought to the ER for abnormal behavior including visual hallucinating and insomnia.Initial ER evaluation showed UTI for which antibiotic therapy was initiated. Dementia workup was performed including a negative head CT, nonreactive RPR, and borderline low vitamin B12 level. TFT obtained showed low TSH of 0.2mlU/L, elevated serum FT4 of 1.72ng/ml (n=0.58-1.64ng/ml) and elevated serum FT3 4.38pg/ml (n=2.5-3.9pg/ml), suggestive of hyperthyroidism. The patient reported no heat intolerance, hyperdefecation, or weight changes, but had intermittent palpitations. She denied any history of thyroid problem and did not take thyroid medication, amiodarone, biotin, or any new drug. She reported no fever or URI symptoms within the few weeks prior to admission. In addition to prednisone and methotrexate, she was taking golimumab 50mg every 30 days for the last 22 months for RA. The patient had a family history of hypothyroidism of two daughters and sister. She denied smoking, alcohol, or any other recreational drug use. Her home medications included prednisone 5mg daily, methotrexate, folic acid, lisinopril, simvastatin, and golimumab. On physical examination, she did not appear thyrotoxic and had no exophthalmos, thyroid tenderness, thyroid enlargement or thyroid nodules. Her HR range was 80bpm.Further analysis revealed normal TSI, TPO, and TgAb levels. The thyroglobulin level was very high at 2505ng/ml (n=1.6-59.9ng/ml). Her thyroid sonogram revealed bilateral thyroid nodules, largest at 1.9cm in the right mid pole. A 24-hr RAIU scan showed very low uptake (1.8%) consistent with thyroiditis (hyperthyroid phase).Endocrinology team did not recommend any antithyroid medications. In addition, she did not warrant NSAIDs or beta blockers as she was not symptomatic or tachycardic. In the absence of an autoimmune or an obvious viral process, her subacute thyroiditis was thought to be induced by golimumab.

Conclusion:

TNFɑ inhibitors used to treat chronic inflammatory diseases, have been rarely associated with subacute thyroiditis as described in case reports with adalimumab and etanercept use. We report the first subacute thyroiditis associated with golimumab use. We suggest that drug-induced subacute thyroiditis should be one of the differential diagnoses of thyroid dysfunction in patients treated with golimumab.
MON-LB001 Ovulation Induction Results in Altered Growth and Metabolic Dysfunction in Mice Offspring
Authors: Harner Royce , Albarran Saul Lira , Chalas Celine , Donjacour Annemarie , Liu Xiaowei , Rinaudo Paolo
Published: May 2020

Nearly 15% of couples are affected by infertility and a large proportion of individuals will need to use ovulation induction (OI) or assisted reproductive technologies (ARTs) to conceive. Previous studies have shown that offspring conceived by ARTs are predisposed towards increased insulin resistance and glucose intolerance. However, the long-term effects of OI alone on offspring health have not been studied. This rodent study was designed to elucidate the effects of maternal superovulation on offspring growth and development.

C57Bl/6 females were either naturally mated (control= C) or super-ovulated (5 IU PMSG; 5IU hCG, OI group) and mated to C57Bl/6 males with one Agouti viable yellow (Avy) allelic mutation. The Avy allele contains an intracisternal A particle whose methylation levels determine expression of the agouti protein which alters coat color and can be used as a phenotypic readout for global methylation. Offspring (n= 108 control and n = 69 OI) were followed through 13 weeks of age to measure birth parameters, growth rate, fasting glucose, GTT, and body composition (EchoMRI). Parametric and non-parametric tests were used as indicated. Only results with p<0.05 are reported.

Results: Surprisingly, while litter size was not different (C = 7, OI = 6), superovulated mothers had fewer surviving pups (C=6.5 pups, OI=5 pups). No major differences in coat color frequencies were observed between the two groups, suggesting no changes in DNA methylation. All OI pups had decreased anogenital distance (males C = 2.1mm, OI = 1.7mm; females C = 1.74mm, OI = 1.48mm), while OI female had lower birthweights (C = 1.38g and OI = 1.23g). Starting at four weeks of age, OI male had lower weight compared to control males. As early as 3 weeks, significant differences in fasting glucose levels were noted (C = 162 mg/dL, OI = 149.5mg/dL). Additionally, superovulated males had lower lean mass at 8 weeks of age (tested by EchoMRI: C = 23.6g, OI = 19.3g) and higher insulin levels at 13 weeks (120 min post injection, C = 339 mg/dL, OI = 213 mg/dL).In summary, we found that the process of OI alone has profound effects on offspring development in a sexual dimorphic fashion. Additional studies will be performed up to 30 weeks of age. Funding: R01 HD092267-01to P
SAT-LB131 Examination of Hepatic Gene Expression Following Developmental Exposure to Dieldrin in Trachemys Scripta and Discovery of a Novel Hepacivirus
Authors: O’Brien Mara H , Callard Ian P
Published: May 2020

The Massachusetts Military Reservation (MMR) is a Superfund site where ground water has been contaminated by a mixture of pollutants. Exposure to these chemicals is a public health concern and reproductive impairments have been observed in a population of turtles (Chrysemys picta) endemic to this site. We hypothesize that developmental exposure to endocrine disrupting compounds originating from the MMR might lead to abnormalities seen in adult animals. Upon examination of egg yolk from turtles at the impacted site, we found the presence of dieldrin and p,p’-DDE. Turtles from a reference site were also found to have p,p’-DDE present in the yolk. In order to investigate these chemicals in the laboratory we used a closely related turtle (Trachemys scripta) and applied vehicle, dieldrin, or p,p’-DDE to the eggshells. Absorption of p,p’-DDE through the eggshell was limited. Although there were variations in absorbance, we were able to achieve levels of dieldrin in the yolk similar to what was seen in animals from the impacted site. Following in ovo exposure to dieldrin, we used RNAseq to examine hepatic gene expression in neonates and found that several transcripts were repressed at least 1.5-fold in the dieldrin-treated animals. QPCR was carried out to confirm differences in gene expression. We found that hepatic gene expression (fold ± SEM) of Gamma-Butyrobetaine Hydroxylase 1 (Bbox1) was higher in vehicle-treated animals (1 ± 0.60) compared to dieldrin-treated animals (0.29 ± 0.12). Bbox1 catalyzes the last step in the L-carnitine biosynthetic pathway, which is necessary for mitochondrial beta-oxidation. Dieldrin-induced reduction in L-carnitine production may be a critical factor in adult reproductive function. Further, Protein-L-Isoaspartate (D-Aspartate) O-Methyltransferase Domain Containing Protein 1 (Pcmtd1) was higher (1± 0.76) in vehicle-treated animals compared to dieldrin-treated animals (0.13 ± 0.044), and DENN Domain Containing 5B (Dennd5b) was also found to be higher in vehicle-treated (1 ± 0.39) compared to dieldrin-treated (0.28 ± 0.10) turtles. We found that dieldrin exposure did not alter gene expression of Cytochrome p450 1a (Cyp1a) a marker of aryl hydrocarbon receptor signaling, or Vitellogenin 2 (Vtg2) a marker of estrogen signaling. In our RNAseq analysis we unexpectedly discovered a hepacivirus infecting T. scripta. In the dieldrin-treated group, we used QPCR to examine gene expression of potential markers of hepacivirus infection. Neither Interleukin 1 Beta (Il-1β), SMAD Family Member 6 (Smad6), C-C Motif Chemokine Ligand 5 (Ccl5), or TNF Receptor Superfamily Member 9 (Tnfrsf9) was found to differ in turtles carrying the virus, compared to non-infected animals. In conclusion, we found that developmental dieldrin exposure of T. scripta slightly reduces neonatal expression of several gene transcripts which may be correlated to adult reproductive fitness.
SAT-LB26 A Dual Role for IGF-1R in Mammary Tumorigenesis
Authors: Obr Alison , Maingrette Krystopher , Chang Yun-juan , Bulatowicz Joseph , Wood Terri L
Published: May 2020

The insulin-like growth factor type 1 receptor (IGF-1R) is now thought to have a dual function in breast cancer. Several studies have shown overexpression of the IGF-1R pathway results in increased tumor cell proliferation and survival. Recent loss-of-function models have shown decreased mammary tumorigenesis latency and increased metastasis. These recent studies correlate with analyses of human patient datasets identifying worse overall survival with low IGF-1R expression. Similarly, inhibition of IGF-1R in the clinic has had no affect or has led to worse outcomes supporting the hypothesis that the IGF-1R may have tumor suppressive properties. Our prior published studies revealed loss of IGF-1R function results in heightened tumor epithelial stress, which alters the tumor microenvironment to be permissive for metastasis. Therefore, we asked does the loss of IGF-1R inherently change the tumor epithelium or is it simply the alterations of the microenvironment that lead to a metastatic primary tumor? We first analyzed cell invasion of primary tumor epithelial cells from a mouse tumor model driven by the Wnt1 oncogene (MMTV-Wnt1) and with reduced IGF-1R signaling by expression of a dominant-negative transgene (MMTV-dnIGF-1R). Epithelial cells from the MMTV-Wnt1/dnIGF-1R (bigenic) tumors invaded at the same rate as MMTV-Wnt1 tumor epithelial cells by tail vein injection suggesting invasive capacity is unchanged with reduced IGF-1R signaling. Interestingly, size of lung micrometastases from tail vein injected bigenic tumor epithelial cells was significantly reduced and the number also decreased over time in part due to a proliferative defect determined by immunostaining for pH3. Similarly, bigenic primary tumor epithelial cells injected into the mammary gland fat pad failed to form tumors suggesting alterations in cell adhesion. Consistent with this observation, E-cadherin gene and protein expression were decreased in the bigenic tumor epithelium compared to MMTV-Wnt1 tumors. In vitro analysis of cell adhesion in MMTV-Wnt1 primary epithelial cells resulted in both K8+ (luminal) and K14+ (basal) tumor epithelial cells adherence, while only K14+ cells from bigenic tumors adhered to collagen. Similarly, the lung micrometastases from tail vein injections exhibited predominantly K14+ cells. Analysis of MMTV-Wnt1 and bigenic primary tumors using single cell RNAseq revealed alterations in both stromal and epithelial populations that may contribute to bigenic primary tumor growth and metastasis. These data support the conclusion that inhibiting IGF-1R signaling results in both alterations to the tumor epithelium (partial EMT) and microenvironment that result in metastasis, but also, that the IGF-1R deficient metastatic cells need a niche or paracine signaling to proliferate.