bluuebunny/crossref_metadata_2025 huggingface dataset:
MON-282 Treatment of Hyperprolactinemia with Ropinirole: An Open-Label Dose Escalation Study
Authors: Tsang Amanda , Dimino Cara , Khandji Alexander G , Panigrahi Sunil Kumar , Page-Wilson Gabrielle
Published: May 2020

Purpose

Treatment of hyperprolactinemia and prolactinomas with ergoline dopamine agonists (DAs) can be complicated by intolerance and resistance. Ropinirole (ROP) is a low cost selective D2/D3 receptor non-ergot DA, approved for treatment of Parkinson’s disease and Restless Leg Syndrome, that has been shown to acutely lower prolactin levels (PRL). This study investigated the efficacy and tolerability of long-term ROP therapy in patients with hyperprolactinemia.

Methods & Results

Ten healthy women (21-45 yrs) with hyperprolactinemia were treated with ROP (0.25-6.0mg/d) for 6 months in an open-label dose escalation study. Clinical and biochemical status was assessed monthly and ROP doses were up-titrated to achieve normal PRL levels, restore menses, and eliminate galactorrhea. Two subjects had macroprolactinomas, 7 had microprolactinomas, and 1 had idiopathic hyperprolactinemia. 8/10 had previously been treated with cabergoline and/or bromocriptine. 5/10 were intolerant and 1/10 was resistant to ergot DAs. Pituitary MRIs were performed at baseline and 6 months.ROP was initiated at 0.25mg QHS in 9/10 subjects. One subject with severe DA intolerance was initiated on 0.125mg QHS. Subjects reaching a total daily dose (TDD) > 2.0mg/d were transitioned to ROP extended release. At study completion, TDDs ranged from 1-6mg/d, with a median TDD of 2mg/d. Baseline PRL levels were 136 ± 49ng/ml (1.9-25ng/ml). Stable PRL normalization was achieved in 50% of subjects. Of the subjects achieving normal PRL, 4 had microadenomas and 1 had idiopathic hyperprolactinemia, and the median effective TDD was 1mg/d (1-4mg/d, range). Among those not achieving PRL normalization, PRL decreased 46 ± 5.4% (Mean ± SEM) from baseline, at a median TDD of 4.0mg/d (2-6mg/d, range). In the subject with documented resistance to ergot DAs, PRL decreased from 529 to 320ng/ml, after 3 months of ROP on the maximum dose studied (6mg/d), but rose to 690ng/ml at 6 months. During ROP treatment, menses normalized in 57%, and galactorrhea resolved in 67% of affected subjects. At study completion, tumor size was unchanged in 7/8 prolactinomas. A 20% decrease in tumor size was observed in one macroadenoma, accompanied by a 30% reduction in PRL levels. There were no changes in BP, HR, weight, renal or kidney function. Mild adverse effects (AEs) were recorded in 80% of subjects. Fatigue (60%), nausea (40%), and headache (20%) were most common. Reported AEs declined after month 1 and ROP was not discontinued due to intolerance.

Conclusion

These data provide support for the efficacy of ROP in the treatment of hyperprolactinemia in patients with microprolactinomas and idiopathic hyperprolactinemia. While further study is needed, ROP treatment for hyperprolactinemia could be considered in patients with ergot DA intolerance or significant cardiac valve disease.
SUN-143 Prostatic Acid Phosphatase Is Not Regulated by Androgens During Prostate Development and Tumorigenesis
Authors: Izadmehr Sudeh , Yao Shen , Kirschenbaum Alexander , Levine Alice C
Published: May 2020

INTRODUCTION: Prostatic acid phosphatase (PAP) is a soluble factor secreted by prostate luminal epithelial cells. PAP expression correlates with prostate cancer (PCa) bone metastases and poor survival. The androgenic regulation of PAP in prostate development and tumorigenesis is not fully understood. We investigated the relationship between PAP and androgens in human prostate specimens and in vivo. HYPOTHESIS AND OBJECTIVES: We hypothesized that PAP expression was independent of androgens. Our objectives were to determine the immunohistochemical expression of PAP in human fetal prostate tissue, human PCa bone metastases, and xenograft and surgical castration mouse models. METHODS: Immunohistochemical staining for PAP and three androgen-regulated proteins, the Androgen Receptor (AR), Prostate-Specific Antigen (PSA), and ETS-related gene (ERG) protein, was carried out on human fetal prostate (9.5, 11.5, 13, 16.5, 18 and 20 weeks of gestational age), archival human PCa bone metastases, and PCa mouse models. For xenograft studies, PAP-expressing PCa cell lines, LNCaP, C42B, and VCaP cells, were inoculated subcutaneously into SCID mice. A castration study with surgical or sham castration was performed after VCaP tumors were palpable. Mouse tumor growth and weight were measured biweekly, and tumor tissue isolated after mouse sacrifice. RESULTS: PAP expression was observed in the fetal prostate as early as 11.5 weeks of gestational age. Strong PAP expression was noted in all human PCa bone metastases examined, both treatment-naive and castrate-resistant (n=10). However, AR and ERG expression was absent in two of four castrate-resistant specimens. PSA was weakly expressed in human castration-resistant bone metastatic prostate specimens. In vivo, PAP expression was observed in all tumor models; however, the expression of PAP differed among androgen-sensitive models; LNCaP (low PAP), C42B (moderate PAP) and VCaP (high PAP). Castrated VCaP tumors underwent tumor stasis and were significantly smaller compared to intact mice. Strong expression of PAP was observed after castration. In contrast, AR, PSA, and ERG expression were reduced in castrated VCaP tumors compared to tumors from intact mice. Double staining of tumors for PAP and AR demonstrated a population of cells that were positive for PAP but negative for AR expression located in hypoxic areas near necrosis. CONCLUSIONS: Our findings demonstrated that PAP is expressed early in normal human fetal prostate development prior to the secretion of significant androgens or expression of AR. In mouse xenografts and human PCa bone metastases, androgens did not significantly regulate PAP expression. These data demonstrate that PAP is a marker of early progenitor cells in the normal prostate and is persistently expressed after castration. PAP may be a suitable target for the treatment of castration-resistant metastatic disease.
MON-361 Late Diagnosis in Adult Form of Hypophosphatasia
Authors: da Silva Marina Sousa , Borges Joao Lindolfo
Published: May 2020

INTRODUCTION/BACKGROUND:

Hypophosphatasia is a rare inborn error of metabolism that presents with important foot and thigh pain due to stress fractures. The diagnose of the adult form is routinely neglected, even though it presents symptomatic and with persistent low serum alkaline phosphatase (ALP).

CLINICAL CASE (DIAGNOSTIC EVALUATION, TRATMANET AND FUP):

A 43-year-old amateur athlete woman presented with pain in the right femur without any local trauma. Physical examination evidenced prolonged right tight pain and no other findings. Bone mineral density evaluated by dual-energy x-ray absorptiometry was unremarkable. Biochemical investigations showed normal inorganic phosphate, calcium, zinc, and magnesium, but low ALP. The patient had six previous ALP measurements and all of them were below the lower limit of normality (46 a 116 U/L). These measurements were done in regular ob-gyn checkups with no further investigation or follow-up. In light of the hypophosphatasemia and pathologic fracture, the serum pyridoxal 5’-phosphate concentration was measured and found to be elevated 35,8 mcg/L (normal 5,0 a 30,0 mcg/L).

CLINICAL LESSONS/CONCLUSION:

Hypophosphatasia occurs due to a deactivating mutation (or mutations) of the gene encoding Tissue-Nonspecific Alkaline Phosphatase (TNSALP), leading to a global deficiency of TNSALP activity and inadequate skeletal mineralization and fractures. The adult form presents during middle age with stress fractures. The first complaints maybe foot pain, which is due to stress fractures of the metatarsals, and thigh pain, due to pseudo fractures of the femur. Our patient illustrates the importance of low serum ALP activity in the assessment of these patients. The correct diagnosis should help to avoid the use of traditional therapies for osteoporosis or osteomalacia, which would be ineffective or potentially harmful.
SAT-437 Influence of Smoking on Thyroid Function in Japanese Subjects: Longitudinal Study for One Year of On-Off Smoking
Authors: Nakajima Yasuyo , Yamada Sayaka , Nishikido Ayaka , Yoshioka Masayuki , Katano-Toki Akiko , Ishida Emi , Yamada Eijiro , Horiguchi Kazuhiko , Yoshino Satoshi , Matsumoto Shunichi , Yamada Masanobu
Published: May 2020

Recent studies showed that various factors, including age, gender, race, iodine intake, obesity, the thyroid peroxidase antibody (TPO-Ab), and/or smoking, influence the thyroid status. In the present study, we analyzed and investigated the effects of these factors, particularly smoking and the thyroid peroxidase antibody (TPO-Ab) in Japanese euthyroxinemia individuals with serum free T4 level within normal range. A total of 12,289 subjects who underwent health check-ups were analyzed in a cross-sectional and longitudinal study. The mean age of subjects was 50 ± 10 years (age range: 21–88 years). Serum TSH levels and the prevalence of positivity for TPO-Ab increased with age in Japanese euthyroxinemia subjects. Mean and median serum TSH levels increased with age in smokers and non-smokers, but were significantly lower in smokers than in non-smokers among men and women in most age groups; the median 97.5th percentiles of TSH levels were 1.2 mU/liter and 2.9 mU/liter in smokers, and 1.4 mU/liter and 3.9 mU/liter in non-smokers in 31- to 40-year-old men, p<0.01, and 1.4mU/liter and 4.3 mU/liter, and 1.8mU/liter and 6.2 mU/liter in 61- to 70-year-old men, p<0.01. However, smoking had a negligible effect on serum TSH levels in women older than 50 years; 1.3 mU/liter in smokers and 1.6 mU/liter in non-smokers in 31- to 40-year-old women, p<0.01, and 1.5 mU/liter and 1.8 mU/liter in 51- to 60-year-old women, p=0.3. Furthermore, the present study confirmed that serum free T4 levels in men progressively decreased with age, whereas no significant change was observed in women. Smoking did not affect the relationship between age and serum free T4 levels in men or women, except for men in their 20s. Serum TSH levels were significantly higher in subjects with positivity for TPO-Ab than in those with negativity at all ages and in both genders; however, smoking did not affect free T4 levels or the positivity for TPO-Ab. The rate of smokers in men was significantly higher in patients with subclinical hyperthyroidism (25%) than in those with subclinical hypothyroidism (10%, p<0.05). Furthermore, the results of the longitudinal study revealed a significant decrease in serum TSH levels one year after the start of smoking in men (p<0.05). Since smoking appears to lower serum TSH levels in Japanese euthyroxinemia subjects careful consideration of the smoking status is needed when evaluating subclinical thyroid function.
MON-461 A Rare Case of Thyroglobulin Deficiency with Ectopic Thyroid Tissue
Authors: Venkataraman Sandhya , Koshy Sharmila
Published: May 2020

Background: The production of thyroglobulin (TG) is initiated by TSH binding to the TSH receptor leading to the transcription and production of TG protein. TG protein then gets transported to the lumen of the follicular cell where its tyrosine amino acids get iodinated and coupled to form T3 and T4. TG deficiency is a rare autosomal recessive genetic condition characterized by congenital thyroid goiter, increased thyroid uptake and primary hypothyroidism.

Clinical Case: A 21 year old South Asian female with a history of TG deficiency, hypothyroidism, and thyroid goiter status post thyroidectomy presented with a right sided neck mass. She was diagnosed hypothyroidism with a goiter at the age of five. Levothyroxine replacement was initiated and she had normal growth and development. At the age of ten upon transferring care to our health network, there was concern for enlargement of the goiter. Labs showed TSH of 2.85 uIU/mL (normal: 0.36-3.74 ulU/mL), thyroid binding globulin of 18.2 ug/mL (normal: 13-30 ug/mL), TG antibody less than 20 IU/mL (normal: less than 40 lU/mL) and TG level less than 0.2 ng/mL (normal: less than 55 ng/mL). Thyroid uptake and scan showed overall increased uptake. Genetic studies revealed homozygous mutation of thyroglobulin deficiency. Further history obtained confirmed patient’s parents were first cousins with heterozygous thyroglobulin mutations. Due to enlarging multinodular goiter with thyroid gland measuring 6.2 cm x 4 cm on the right and 6.2 x 3.6 cm on the left, total thyroidectomy was completed in 2012. Pathology showed benign thyroid tissue. In May 2019 the patient skipped levothyroxine replacement due to lapse in prescription refill and TSH increased to 28 ulU/mL. Around that time, she noticed an enlarging right sided neck mass. MRI of the neck showed an enhancing mass posterior to the submandibular gland measuring 1.6 x 1.4 cm. Fine needle aspiration in August 2019, showed a mixed population of lymphocytes and few benign appearing glandular cells. Pathology obtained after resection of the right neck mass in September 2019 revealed benign thyroid tissue with no lymphoid tissue, staining positive for TTF-1 and PAX-8.

Conclusion: TG deficiency has an incidence of 1:100,000 live births and is more common in cases of genetic consanguinity. There have been over fifty mutations of varying penetrance identified leading to differing consequences in TG production and processing. These mutations can cause structural changes in the TG protein, decreased tyrosine residue on TG leading to poor iodination and ineffective TG transport within the follicular cell. We propose that the right sided neck mass was regrowth of residual thyroid tissue due to the stimulatory effect of TSH after missed doses of levothyroxine caused TSH elevation. Our case is the first of TG deficiency wherein the patient developed ectopic thyroid tissue proliferation after a period of thyroid hormone deficiency.
MON-209 Identification of a New Heterozygous Germline ARMC5 Deletion in a Familial Case of Primary Bilateral Macronodular Adrenal Hyperplasia Co-Secreting Cortisol and Aldosterone
Authors: Salle Stefanie Parisien-La , Dumas Nadine , Lacroix André , Bourdeau Isabelle
Published: May 2020

Context. Approximately 50% of familial cases of primary bilateral macronodular adrenal hyperplasia (PBMAH) are caused by mutations in the ARMC5 gene.

Case report. We report the case of a 37 year-old patient of Haitian origin, who presented with resistant hypertension. His workup showed high aldosterone (410 pmol/L) with suppressed renin levels (0.2 ng/mL/h) with an aldosterone to renin ratio (ARR) of 2050. Patient also had suppressed ACTH levels (<0.5 pmol/L (N: 2-12)) and high UFC (1103 nmol/d (N: <330)). He had an aberrant cortisol and aldosterone response to catecholamines and vasopressin (V1R). An abdominal CT scan showed bilateral enlargement of adrenal glands and a 3.3cm dominant nodule on the right gland. Moreover, a 2.8cm mass on the pancreatic tail was present. Patient underwent left laparoscopic adrenalectomy and distal pancreatectomy; the pathology confirmed PBMAH and a pancreatic neuroendocrine tumor (NET). Following surgery, ARR and UFC remained high and patient was treated successfully with B-blockers and MR antagonists. A head MRI showed no sign of intracranial meningiomas.

Genetic analyses. Following genetic counselling, MEN1 gene analysis was performed using sequencing/MLPA techniques but did not reveal a mutation. Initial genetic testing included ARMC5 gene analysis using direct Sanger sequencing which was negative. However, using Next-Generation Sequencing (NGS) and MLPA analysis, a heterozygous germline ARMC5 deletion of exons 5-8 was identified. The deletion is predicted to prematurely truncate the protein product and cause loss of function. The ARMC5 deletion segregated with the disease in his 24 yo son who had bilateral adrenal adenomas that appeared to be non-functional. The patient’s father was also known for having bilateral adrenal masses and hypertension.

To our knowledge we report the second case of ARMC5 deletion in familial PBMAH. Suzuki et al. reported two patients, a mother and her son, carrying ARMC5 deletion of exons1-5 and interestingly they were also affected by PBMAH co-secreting cortisol and aldosterone (1). As in this case report, the ARMC5 deletion was missed using Sanger sequencing initially.

Conclusion. These cases demonstrate that large deletions may be missed by Sanger sequencing and that the real prevalence of ARMC5 mutations may have been underestimated. The link between deletion of ARMC5 and correlation with PBMAH co-secreting aldosterone and cortisol remains to be determined but may be a step forward for genotype-phenotype correlation.

1.Suzuki S, et al. Endocrine practice: official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2015;21 (10):1152-60.
MON-679 What’s in a Bottle? the Importance of Careful Medication Review to Prevent Life Threatening Hypoglycemia
Authors: Banerjee Ela , Doshi Sejal B , Lebastchi Jasmin , Fernandes Amanda
Published: May 2020

Background: Over 1 in 9 emergency department (ED) visits are due to drug-related adverse events (1) and careful medication review is essential for patient safety.

Clinical Case: A 73-year-old male presented to the ED after his family found him to be tremulous with a blood glucometer reading of 30 mg/dL. He was given glucagon and oral glucose however this did not help his blood glucose and he was brought in for further evaluation. He had a history of chronic kidney disease, hepatocellular carcinoma (HCC) and diabetes mellitus type 2 for which he was on no medication at the time of presentation. He reported being on Glipizide nine months ago. In the ED, he had a temperature of 98.3°F; pulse of 76 beats/min; respiratory rate of 18 breaths/min and blood pressure of 166/71. On physical examination, he was in no acute distress with normal neurologic, cardiac and respiratory exam. Laboratory workup was notable for glucose 40 mg/dL, HbA1c 5.0%, Cr 2.55 mg/dL, eGFR 24, ALT 7 IU/L and AST 23 U/L. CT abdomen and pelvis was consistent with known diagnosis of HCC. The patient was given 4 boluses of D50W and started on a continuous dextrose infusion along with octreotide infusion due to persistent hypoglycemia. Patient’s blood glucose improved one day later and he remained stable off the dextrose and octreotide infusions. Further laboratory evaluation revealed ACTH 9 pg/mL (ref 6-50), Random Cortisol 16.1 at 1:36pm, TSH 1.40uIU/ml, Free T4 1.09 ng/dL, Cosyntropin stimulation test at baseline 15.4 ug/dL; at 30 min 22 ug/dL; at 60 min 28.3 ug/dL and Beta-Hydroxybutyrate 0.11 mmol/L. With a blood sugar level of 32 mg/dL, he was found to have Insulin level 35.9 (ref 3.0-25.0mU/L), Pro-insulin 55.6 (ref < 18.8pmol/L) and C-peptide 9.21 (ref 0.8-3.85ng/mL). The patient’s family brought his medications for review with no clear discrepancies noted. Closer inspection of the tablets inside each pill bottle revealed that the pills inside the Docusate-Senna container did not match the description for the same but instead matched the description for Glipizide. The patient disclosed that he had emptied the Glipizide tablets into the bowel regimen container for “safe keeping” when it was discontinued. He was inadvertently taking two Glipizide tablets twice a day as the VNA had mistakenly used these pills to fill his pill box. This serious error in confirming the patient’s medications resulted in his severe hypoglycemia. His Sulfonylurea screen returned positive for Glipizide.

Conclusion: Sulfonylureas, an essential component of diabetes management, have a dangerous side effect of hypoglycemia and errors in its administration can be fatal. Therefore, thorough medication reconciliation and review of the actual pills is essential to prevent such errors.

Reference: Zed PJ, et al. Incidence, severity and preventability of medication-related visits to the emergency department: a prospective study. Can Med Assoc J. 2008;178(12):1563-1569.
MON-635 FDXR Regulates Iron Metabolism and Glucose Metabolism in Liver
Authors: Sakuma Ikki , Yokoyama Masataka , Yamagata Kazuyuki , Hashimoto Naoko , Nakayama Akitoshi , Shulman Gerald I , Tanaka Tomoaki
Published: May 2020

Iron is an essential cofactor for many proteins that function in electron transport or oxygen transport as heme or iron-sulfur cluster. On the contrary, iron also has the potential to cause oxidative damage if not carefully regulated and when in labial iron excess. Clinical studies show that elevated serum ferritin levels are observed in most patients with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). In this context, p53 is shown to induces some mitochondrial iron regulatory genes. The role of crosstalk between p53 and iron metabolism has not been sufficiently examined in the pathogenesis of diabetes and NAFLD.

Here, we examined the role of ferredoxin reductase (FDXR), a key mitochondrial regulator for iron metabolism, as p53-inducible gene with focusing on the hepatocyte and liver. We confirmed that p53 induced FDXR expression in HepG2 cells and SKEHP1 cells. Biochemical analysis demonstrated that FDXR regulated ROS levels via iron metabolism. In vivo analysis, high-fat diet activated the p53-FDXR pathway in mice liver. We generated transgene expression in mice liver using adenovirus infection carrying shRNA or CRISPR Cas9 system. Treatment with the FDXR knockdown increased hepatic iron content and aggravated glucose intolerance. Besides, forkhead box protein O1 (FOXO1), a key transcriptional factor that induces phosphoenolpyruvate carboxylase and glucose-6-phosphatase increased ratio of nuclear localization, indicating hepatic gluconeogenesis activation. Consistently, biochemical analysis in HepG2 cells demonstrated that FDXR regulated insulin-dependent FOXO1 nuclear exclusion through oxidative stress.

In conclusion, p53-inducible FDXR regulates iron metabolism and oxidative stress. FDXR inhibits iron accumulation and oxidative stress in liver and links to suppression of hepatic gluconeogenesis via insulin-dependent FOXO1 nuclear exclusion. The results of this study provide important new insights into relationship between iron metabolism and glucose metabolism as well as potentially identify novel therapeutic targets for the treatment of diabetes and NAFLD.
SAT-481 Pembrolizumab-Induced Thyroiditis with Negative Thyroid Peroxidase Antibody
Authors: Ragunanthan Branavan , Zmeili Omar Suheil
Published: May 2020

Introduction: Immune checkpoint inhibitors (ICI) have reformed oncology treatment through its immunomodulatory effect on T-lymphocytes to target metastatic and locally advanced cancers but have been known to produce immune-related adverse events (irAEs). Thyroiditis is a well-documented endocrinopathy occurring in patients receiving ICI; however, a Thyroid Peroxidase Antibody (TPO Ab) negative case of ICI induced thyroiditis suggests that its pathogenesis is independent of antibody mediated thyroid destruction and more associated with an alternative immunoregulatory mechanism. Case Description: A 60-year-old Caucasian, male with a 37-year smoking history and lung adenocarcinoma with metastasis to the brain was referred to Endocrinology clinic for evaluation of suppressed thyroid stimulating hormone (TSH) level. Patient was treated with a four-month course of IV Pembrolizumab every three weeks. TSH was <0.015 (NL 0.465-4.680 IU/mL) four weeks before being seen at the office. TSH level was normal 2.359 before starting immunotherapy. Patient reported occasional anxiety and heat intolerance, but did not experience other hyperthyroid symptoms. Physical examination in office demonstrated no significant thyromegaly, nodules, or tenderness. Vital signs were normal. Thyroid function tests obtained during the office visit were consistent with subclinical hypothyroidism. TSH was mildly elevated 7.545 with normal Free T4 of 0.94 (NL 0.78 - 2.19 ng/dL) and normal Free T3 level of 3.61 (NL 2.77 - 5.27 pg/mL). TPO antibodies were negative. Four weeks later, patient developed overt hypothyroidism; TSH level was higher 12.437 with low Free T4 of 0.71. Patient was then complaining of fatigue and cold intolerance. A diagnosis of drug-induced thyroiditis from Pembrolizumab was made. The patient was prescribed levothyroxine 75 mcg daily and followed closely. Discussion: While literature exists documenting the rare side effect profile of ICI endocrinopathies, few studies illustrate the implications and correlations of TPO Ab negative findings in ICI induced thyroiditis. The role of thyroid autoantibodies in the presumed antibody mediated pathogenesis of thyroid abnormalities is unclear and warrants further longitudinal studies to determine its function in these patients. This case report hopes to both identify the deficit of pathophysiological knowledge contextualizing irAEs while encouraging current healthcare practitioners to continue close monitoring of patients receiving ICI.
MON-088 Impact of Vertebral Fracture on Auxological Profile and Insulin-Like Growth Factors of Children After Acute Lymphoblastic Leukemia Treatment
Authors: Ahn Moon Bae , Lee Yoon Ji , Lee Nayeong , Kim Seul Ki , Kim Shin Hee , Cho Won Kyoung , Cho Kyoung Soon , Jung Min Ho , Suh Byung Kyu
Published: May 2020

Purpose: To investigate the overall prevalence of vertebral fractures (VF) following childhood acute lymphoblastic leukemia (ALL) treatment and examine the association of VF with growth trajectory and insulin-like growth factors. Methods: Children (n=172; 59.3 % male) diagnosed with ALL at age between 2 and 18 years were assessed for VF by screening the lateral thoracolumbar spine radiographs (Genant’s semi-quantitative method) when treatment was completed (baseline). Anthropometric measurements between pre- to post-treatment period were obtained and the association of VF with insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) were examined. Results: Thirty-five children (20.3 %) had vertebral fractures at baseline. Among children with vertebral fractures, 97.1 % had either mild or moderate deformity, and the 5th lumbar vertebrae was the most frequently injured site (20.0 %). Median lumbar spine bone mineral density Z-score was -1.0 (IQR of -1.6 and -0.8) in children with VF. Baseline Z-scores for height and weight were lower in children with VF than without VF (-0.5±1.3 and 0.0±0.9, P=0.01; -0.2±1.6 and 0.3±1.1, P=0.04, respectively). Height Z-score in children with VF had greater height decline than without VF (0.5±0.6 and 0.2±0.8; P=0.02). Children with VF had lower IGF-1 and IGFBP-3 Z-score than without VF at baseline (-1.2±1.0 and 0.0±0.8, P<0.01; -2.3±1.1 and -1.3±1.0, P<0.01). Decrease in IGF-1 level was associated with the presence of VF (OR=0.3(95 % CI of 0.2-0.5), P<0.01). Conclusion: Substantial number of children encounter VF after ALL treatment is completed and the presence of VF might be associated with compromised auxological state, prominent height decline and IGF-1 deficiency.
MON-451 An Unusual Case of Follicular Thyroid Cancer with Pulmonary Metastasis and Concurrent Hyperthyroidism
Authors: Monsour Elio , Zuazaga Dewid Zayas , Chacko Jay , Abdelmasih Randa , Ramharrack Frank
Published: May 2020

Introduction: Follicular Thyroid Cancer (FTC) accounts for approximately 12 % of all thyroid cancers and is the second most common cause of differentiated thyroid cancer. However, coexisting hyperthyroidism and thyroid malignancy is considered a rare event and is thought to have a prevalence of 0.21–9.0 %. We describe a compelling case of metastatic FTC initially presenting with subclinical hyperthyroidism progressing to overt hyperthyroidism.

Clinical Case: An 88-year-old man with a history of prostate cancer, previous tobacco dependence, and hypertension initially presented with complaints of a chronic non-productive cough associated with unintentional weight loss and fatigue. Initial imaging included a chest CT that showed several bilateral pulmonary nodules suspicious for metastatic disease, as well as an enlarged left-sided thyroid mass, which extended from the inferior pole into the mediastinum. FDG PET/CT showed avid disease identified in the lung. CT-guided lung biopsy was performed, and histopathology revealed FTC. Thyroid function tests (TFTs) revealed a Tg level of 1427 (0.00–33.70), TgAb <1.0 (< 13.6), TSH 0.05 (0.40–4.50), FT4 1.1 (0.8–1.8) and FT3 3.4 (2.3–4.2). Biochemical testing was consistent with subclinical hyperthyroidism. Neck ultrasound showed bilateral thyroid nodules, the largest located on the left mid-pole measuring 3.4 x 3.2 x 3.7 cm. He underwent a whole-body I-131 diagnostic scan, which showed intense uptake of the radionuclide within the thyroid gland, more evident on the left, but additional metastatic lesions elsewhere in the visualized body were not possible. TFTs were repeated, which showed a TSH of 0.01, FT4 of 2.0, and FT3 of 6.4. He was subsequently started on methimazole daily and eventually became euthyroid. Due to advanced age, significant mediastinal extension, and lung metastasis, the patient was not a candidate for surgical resection and treatment with a targeted tyrosine kinase inhibitor. He ultimately opted for an observational approach.

Conclusion: Although metastatic FTC carries a poor prognosis, concurrent hyperthyroidism is thought to be associated with a more aggressive disease course and higher mortality compared to differentiated thyroid cancers in euthyroid patients.

Sources: 1. Pazaitou-Panayiotou, K., Perros, P., Boudina, M., Siardos, G., Drimonitis, A., Patakiouta, F., & Vainas, I. (2008). Mortality from thyroid cancer in patients with hyperthyroidism: the Theagenion Cancer Hospital experience, European Journal of Endocrinology, 159(6), 799–803.

2. Benjamin Momo Kadia, Christian Akem Dimala, Ndemazie Nkafu Bechem, Desmond Aroke. BMC Res Notes. 2016; 9: 369.

3. Parameswaran R, Shulin Hu J, Min En N, Tan WB, Yuan NK. Patterns of metastasis in follicular thyroid carcinoma and the difference between early and delayed presentation. Ann R Coll Surg Engl. 2017;99(2):151–154.
MON-499 Nivolumab-Induced Hypothyroidism Is Irreversible in Most Patients
Authors: Yoon Jee Hee , Park Ji Yong , Hong A Ram , Kim Hee Kyung , Kang Ho-Cheol
Published: May 2020

Background Thyroid dysfunction caused by the immune checkpoint inhibitor (ICPI) is common, however mild dysthyroidism could occur easily in cancer patients due to other causes. The aim of this study was to investigate the incidence and clinical course of ICPI-induced hypothyroidism requiring thyroid hormone replacement. Patients and methods We analyzed baseline and follow up thyroid function tests of cancer patients treated with nivolumab between March 2016 and March 2019 at Chonnam University Hwasun Hospital retrospectively. Results Among 265 cancer patients treated with nivolumab therapy, six patients were excluded from the study because they were on thyroid hormone replacement therapy before starting nivolumab therapy. Twenty-one patients (8.1%) newly developed thyroid dysfunction during nivolumab therapy and sixteen patients (6.2%) required thyroid hormone replacement therapy due to drug-induced hypothyroidism. Cancer diagnoses included lung cancer (n=7), renal cell carcinoma (n=4), malignant melanoma (n=2), hepatocellular carcinoma (n=2), and esophageal cancer (n=1). Six patients (37.5%) showed thyrotoxic phase prior to overt hypothyroidism and the others (n=10, 62.5%) revealed hypothyroidism without thyrotoxic phase. Most ICPI-induced hypothyroidism was irreversible, only one patient was able to discontinue thyroid hormone replacement after quitting nivolumab therapy. Conclusion A significant number of patients treated with nivolumab developed ICPI-induced hypothyroidism requiring thyroid hormone replacement and its clinical course was irreversible in most patients.
OR26-07 Mild Physiologic Hyperglycemia Does Not Affect Glucose Mediated but Impairs Insulin-Mediated Suppression of Plasma Glucagon in Healthy Normal Glucose Tolerant Subjects
Authors: Tripathy Devjit , chen Xi , merovci aurora , Trejo Jonathan , DeFronzo Ralph
Published: May 2020

Plasma glucagon levels are regulated by plasma glucose concentrations as well as intra-islet and circulating insulin concentrations. Hyperglycemia adversely affects skeletal muscle and hepatic insulin sensitivity (glucotoxicity). However, the effect of physiologic hyperglycemia on glucose-mediated and insulin-mediated suppression of glucagon is not known. The aim of the present study was to evaluate effect of chronic (48 or 72 hours) physiologic increase (+45 mg/dl) in plasma glucose concentration on the suppression of plasma glucagon concentration in healthy NGT individuals: 12 without family history of T2DM (FH-) (9M/3F, age = 50± 4 yrs, BMI = 27 ± 1 kg/m2) and 8 with FH of T2DM (FH+) (4M/4F, age = 48±2, BMI = 26±1 kg/m2). Subjects received an OGTT and 2-step hyperglycemic (+125 and +300 mg/dl) clamp (duration of each step = 80 minutes) before and after 72 hour glucose infusion. On another occasion subjects participated in a 3-step hyperinsulinemic (10, 20, 40 mU/m2·min) euglycemic clamp before and after a 48 hour glucose infusion. Plasma insulin and C-peptide concentrations were obtained every 2-5 minutes during each hyperglycemic clamp step and plasma glucagon concentrations were measured every 10 minutes. The ratio of insulin/glucagon was measured and used as an index of insulin-medicated suppression of plasma glucagon. FPG concentration increased from 97±4 to 140±4 mg/dl during the 72 hour glucose infusion. Following chronic glucose infusion, plasma insulin levels were significantly higher during the basal state and during each hyperglycemic clamp step (by 59% and 78%). There was no difference in plasma glucagon levels following chronic glucose infusion and the degree of suppression of glucagon during 2-step hyperglycemic (+125 and +300 mg/dl) were similar. However, the plasma insulin/glucagon ratio was significantly higher during the fasting state (by 76%) and during the first (by 128%) and second (by 178%) hyperglycemic clamp steps. Similarly during the three step euglycemic clamp (10, 20, 40 mU/m2·min) studies following 48 hr glucose infusion, despite similar plasma glucose concentrations during each clamp step, plasma insulin and glucagon concentrations were higher following chronic glucose infusion. These results demonstrate that sustained physiologic hyperglycemia for 48 hrs or 72 hours (i.e. glucotoxicity) does not affect the glucose mediated suppression of glucagon, but impairs insulin-mediated suppression of glucagon, and could contribute to fasting and post-prandial hyperglycemia in T2DM patients.
SUN-298 Spectrum of Imaging in Immune Checkpoint Inhibitor Induced Hypophysitis
Authors: Quandt Zoe , Kim Stephanie , Villanueva-Meyer Javier , Coupe Catherine , Tyrrell J Blake , Bluestone Jeffery A , Anderson Mark Stuart , Masharani Umesh
Published: May 2020

Background: Hypophysitis (HP) is a known immune related adverse event of immune checkpoint inhibitors (CPIs), commonly associated with CTLA-4 inhibitors and rarely with PD-1/PD-L1 inhibitors. Prior studies of MRIs at HP diagnosis noted pituitary enlargement with resolution within a few weeks. In this study, we examine MRI changes in patients with CPI-induced HP.

Methods: Subjects with biochemical evidence of central hypothyroidism or central adrenal insufficiency and MRIs were reviewed by endocrinology and neuroradiology. MRIs were classified relative to HP diagnosis: baseline (at least 21 days prior), diagnosis (within 21 days), and follow up (over 21 days). Patient characteristics included age at CPI initiation, sex, race/ethnicity, personal and family history of autoimmunity, type of cancer and CPI.

Results: Twenty-six subjects met the inclusion criteria. The mean age was 59 years; 62% were male and 86% were non-Hispanic white. Nineteen percent had a personal history and 31% a family history of autoimmunity. Fifty percent had melanoma. At HP diagnosis, 46% were on PD-1/PD-L1 inhibitors, 42% were on combination PD-1/CTLA-4 inhibitors and 12% were on CTLA-4 inhibitors.

Median time from CPI initiation to HP diagnosis was 95 days. Time to HP was shorter on a CTLA-4 inhibitor combination or monotherapy (median 82 days) compared to a PD-1/PD-L1 inhibitor monotherapy (median 220 days; Wilcoxon rank sum, p <0.01). Central adrenal insufficiency was present in all patients not yet on steroids. Central hypothyroidism was common (10/19) in those without primary thyroid disease and was not associated with type of CPI (Fisher’s exact, p=0.18).

Thirteen subjects had baseline MRIs, 18 had MRIs at HP diagnosis and 13 had MRIs in the follow up period. Baseline MRIs were normal in 12/13; one subject had an enlarged pituitary. At diagnosis, 10 had an enlarged pituitary, 7 a normal pituitary and 1 a partially empty sella. CTLA-4 inhibitor exposure was associated with pituitary enlargement at diagnosis: 9/11 compared to 1/7 on PD-1/PD-L1 inhibitor (Fisher’s exact, p <0.04). Of the subjects who had follow-up MRIs, 3 had an enlarged pituitary, 7 a normal pituitary and 3 a partially empty sella. Follow up imaging did not differ between treatment types (Fisher’s exact, p >0.05). Timing of MRI was significantly associated with pituitary appearance (Fisher’s exact, p <0.01).

Conclusion: The MRI appearance of HP presents as a spectrum, from a partially empty sella, normal pituitary to an enlarged pituitary. HP diagnosed in the setting of CTLA-4 inhibitor treatment occurs earlier and is more likely to induce an enlarged pituitary gland compared to PD-1/PD-L1 monotherapy, which occurs later and is associated with a normal appearing MRI at diagnosis. This suggests that the pathogenesis of HP following CPI exposure may vary depending on the type of CPI.
SAT-039 The Short-Term Effect of Multiple Kinase Inhibitor (Lenvatinib) on Spermatogenesis in Mice
Authors: Lue Yanhe , Gianoukakis Andrew G , Fueger Patrick T , Teramoto Darren , Irimia-Domingues Jose , Bloom-Saldana Elizabeth , Wang Christina C L , Swerdloff Ronald S
Published: May 2020

Lenvatinib, a multi-kinase inhibitor, is used in the treatment of solid malignancies. Lenvatinib belongs to a family of tyrosine kinase inhibitors and targets VEGF receptors 1-3, FGF receptors 1-4, PDGF receptor alpha, RET and KIT. However, it is not known whether Lenvatinib like other chemotherapeutic drugs affects spermatogenesis. The objective of this study was to examine whether Lenvatinib induces damage to spermatogenesis in mice. Twenty adult mice (C57BL/6) were randomly divided into 2 groups to receive daily gavage of either water (as control) or Lenvatinib (10 mg/kg) for 6 weeks. All mice were euthanized at the end of the study. We identified that Lenvatinib significantly (p<0.05) decreased testis weight (TW: 91.75±1.49mg) compared to control mice (TW: 111.9±3.07mg). This difference in testis weight however, became non-significant after correcting for body weight. The cauda epididymal sperm count was significantly (p<0.01) decreased in the Lenvatinib treated (0.82±0.04 million/mg cauda) as compared to control (1.26±0.07 million/mg cauda) mice. There were no differences in plasma testosterone concentrations between Lenvatinib treated (29.76±7.67ng/dl) and control (31.72±6.89ng/dl) mice. Lenvatinib did not induce notable morphological changes in testicular histology. We conclude that 6 weeks of Lenvatinib treatment had minimal effect if any on mouse spermatogenesis. The long-term treatment effect of Lenvatinib on spermatogenesis remains to be determined.
SAT-514 Nivolumab Related Primary Hypothyroidism: 3 Years of Follow-Up
Authors: Baby Ann Pia , Goldberg Michael
Published: May 2020

BACKGROUND: Primary hypothyroidism is one of the most common endocrinopathies related to the use of nivolumab, a monoclonal antibody against the immune checkpoint molecule programmed death-1 (PD-1). The long-term course of this condition, especially after the completion of nivolumab treatment, has not been widely reported.

CLINICAL CASE: A 70-year-old man presented with weight gain despite poor appetite, cold intolerance, and constipation. He noticed these symptoms after receiving the first three months of treatment with nivolumab for renal cell carcinoma. His heart rate was 66, blood pressure was 130/79 mm Hg, and body mass index was 28.3. The thyroid gland was normal-sized without palpable nodules, deep tendon reflexes were normal, and cardiac and pulmonary exams were unremarkable. Laboratory test results were consistent with primary hypothyroidism: thyroid-stimulating hormone (TSH) was elevated at 97.11 mIU/L (normal, 0.35-4.70 mIU/L), and total thyroxine was less than 1 mcg/dL (normal, 4.5-12.0 mcg/dL). Both anti-TPO antibody (222.6 IU/ml, normal<5.6 IU/ml) and anti-thyroglobulin antibody (10.6 IU/ml, normal <4.1 IU/ml) levels were elevated. There was no prior history of thyroid disease; two of the patient’s sisters had chronic hypothyroidism. Treatment with levothyroxine resulted in rapid resolution of symptoms. With dose titration of levothyroxine over the course of a few months, the patient achieved biochemical euthyroidism. Nivolumab therapy was continued for more than two years, during which a stable levothyroxine dose was maintained, and the patient remained clinically and biochemically euthyroid. Ultimately the renal cell carcinoma was determined to be in remission, and nivolumab therapy was stopped. Subsequently, the anti-TPO antibody titer was observed to have returned to the normal range (2.3 IU/ml). However, as of five months following discontinuation of nivolumab, and 32 months since the onset of thyroid dysfunction, the patient’s hypothyroidism persists as reflected by non-suppressed TSH values on levothyroxine treatment.

CONCLUSION: We have observed the course of nivolumab-induced primary hypothyroidism over almost three years in an individual patient. The hypothyroidism has persisted, requiring ongoing levothyroxine replacement at a dose of approximately 1.4 mcg/kg daily. An interesting feature of this case is the disappearance of anti-TPO antibody positivity after discontinuation of nivolumab. We speculate that the ongoing hypothyroidism despite the absence of detectable autoantibodies may be related to progressive thyroid cell apoptosis. Further long-term observations will determine whether permanence of nivolumab-induced hypothyroidism is the rule.
MON-913 Testosterone Secreting Ovarian Tumor: A Rare Cause of Erythrocytosis and Pulmonary Embolus
Authors: Friedman Naomi , Friedman Seth Gerald , Klein Victor , Sternchos Jason A
Published: May 2020

Background: Ovarian testosterone producing tumors are an uncommon cause of hirsutism, pulmonary embolus and polycythemia.

Clinical Case: A 67-year-old Caucasian postmenopausal woman was referred for Endocrine evaluation of a one-year history of hirsutism, weight gain and elevated total testosterone level of 672 ng/dL (n <75 ng/dL). She reported increased hair growth on her chin for the past year. She denied any male pattern hair loss or any increased hair growth on her legs or chest. She also reported unintentional weight gain of thirteen pounds and low energy levels. Past medical history is remarkable for gastroesophageal reflux disease. Her last menstrual period was at age forty and periods occurred at regular intervals without heavy bleeding. She never became pregnant by choice. At this time physical exam was notable for shaved terminal hair on her chin, vellus hair on abdomen, there was no hirsutism or voice change noted. There were no abdominal striae, moon facies, buffalo hump.

Labs from the initial visit included a total testosterone of 672 ng/dL (n<75 ng/dL), 2pm cortisol 5.6 ug/dL (2.7-10.5 ug/dL in PM), TSH 2.28 uiU/mL (0.27 – 4.20), Androstenedione 133 ng/dL (n<10-93 ng/dL), 11 deoxycortisol 29.3ng/dL (n <32), ACTH 12 pg/mL (n<46), DHEAS 87 ug/dL (13-130 ug/dL) free testosterone index 24.2 (n<2.1), 17-hydroxyprogesterone 207ng/dL (n<272), FSH 26.1 miU/mL (25.8-134.8), LH 17.9 IU/L (7.7-58.5), Hemoglobin 18. g/dL (11.7-15g/dL), hematocrit 50.4% (35-45%), HbA1c 5.4%.

Four months after this initial presentation, the patient developed acute onset of chest pain and shortness of breath and was diagnosed with a right pulmonary embolus on CT Chest Angiogram. Evaluation with imaging for an ovarian mass revealed a negative workup. CT Abdomen Pelvis did not reveal any adrenal masses. Transvaginal Ultrasound did not demonstrate any ovarian masses. MRI of pelvis did not show any adnexal masses.

Despite the negative imaging, because of the markedly elevated testosterone levels, this presentation was thought to correspond to a testosterone secreting ovarian tumor. Furthermore, the normal adrenal hormone levels and significantly elevated testosterone level is consistent with neoplasm range. High levels of testosterone are known to cause a hypercoagulable state leading to a PE. Furthermore, testosterone causes an increase in RBC mass leading to marked elevations in hemoglobin. The patient was referred for bilateral oophorectomy. Pathology of the right ovary revealed a 2 cm steroid cell tumor, not otherwise specified.

Conclusion: This is the first known case of a steroid cell ovarian tumor, not otherwise specified, that secretes testosterone leading to pulmonary embolism and erythrocytosis. Furthermore, testosterone secreting tumors should be considered in the diagnosis of PE as a rare cause of hypercoagulable state.
SUN-606 Identification of NASH Using Data from NHANES III
Authors: Friedman Theodore C , Shaheen Magda , Kermah Dulcie , Pan Deyu , Schrode Katrina , Najjar Sonia Michael
Published: May 2020

Nonalcoholic steatohepatitis (NASH) is a serious liver condition marked by hepatic steatosis (HS), cell damage and inflammation. Patients with NASH are at risk for developing cirrhosis and hepatic cancer. Currently, the definitive method of diagnosing NASH is by liver biopsy. To avoid the costs and risks associated with biopsy procedures, there has been considerable effort to develop a non-invasive method of identifying patients with NASH. However, none of these methods has become accepted as a “gold standard.” Our objective was to compare three non-invasive methods of identifying NASH by using data from NHANES III (1988-1994) to determine variables associated with published formulas to identify NASH. We used ultrasound data to identify subjects with moderate - severe HS. Among those with HS, we identified the NASH population using either the HAIR score, the NASH liver fat score, or the Gholam score. The HAIR score was developed in a sample of obese patients, is based on hypertension, insulin resistance and alanine transaminase (ALT) levels, and had an AUROC of 0.9, a sensitivity of 0.8, and a specificity of 0.89. The NASH liver fat score was developed in a Finnish population undergoing gastric bypass, and validated in an Italian population of liver biopsy patients. This score incorporates metabolic syndrome, type 2 diabetes, serum insulin, AST, and ALT. In the Finnish and Italian populations, respectively, it had AUROCs of 0.73 and 0.74, sensitivities of 59.5 and 92.9, and specificities of 79.7 and 32.7. The Gholam score was developed in a sample of obese patients and uses aspartate aminotransferase (AST) and type 2 diabetes diagnosis. It had an AUROC of 0.82, a sensitivity of 0.76, and a specificity of 0.66. We performed multinomial logistic regression to compare each NASH population to the normal population (those with no or only mild HS). We identified 1236 subjects as having NASH by at least one method. 18% of these were identified by all 3 methods, while 20% were identified by 2 methods. All three methods identified significant risk factors for NASH (p<0.05) as being overweight or obese, having elevated AST or ALT levels, and having elevated C-peptide, serum glucose, or serum triglyceride levels. However, the HAIR and Gholam methods also identified being Mexican-American as a significant risk factor, with the NASH liver fat score did not. Being a former alcohol drinker and not meeting guidelines for physical activity were significant risk factors when using the NASH liver fat score. Further refinement of a noninvasive method for identifying NASH is required. Considerable care must be taken in interpreting risk factors, because the results differ depending which method is used. This could have implications in clinical practice as well, where patients and their risk factors may be mis-identified if formulas are used and not liver biopsy.