bluuebunny/crossref_metadata_2025 huggingface dataset:
SUN-275 A Rare Mutation in the TBX19 Gene Leading to Isolated ACTH Deficiency in Two Siblings
Authors: Albers Norbert , Bartels Amelie , Peters Renate , Banzer Jens
Published: May 2020

Hypoglycemia and hyperammonemia (>500µg/dl) in a newborn led to the suspicion of THAN (transient hyperammonemia of the newborn). Subsequently, hypoglycemic and salt losing episodes with low cortisol (<0,1 ug/dl) and ACTH (<0,16 pg/ml) levels pointed to ACTH deficiency. Genetic analysis showed a homozygous mutation c.302G>A for p.(Trp101*) in the TBX19 gene (a positive regulator of the transcription of POMC and the terminal differentiation of the corticotrophs), generating a premature stop codon. This mutation has been described only once and very recently by Abali et al (Hormones 18:229; 2019) in a 4 year old girl, but unlike our patients, this girl was obviously unaffected during her neonatal period. All other pituitary axes in our patient were normal, thus congenital isolated ACTH deficiency was the final diagnosis. Hyperammonemia resolved spontaneously and the suspected diagnosis of THAN could be dismissed. Hyperammonemia had probably been due to metabolic stress.After 16 months, a younger brother was born and showed hypoglycemia, hypotension and respiratory infection during his neonatal period. Cortisol and ACTH levels were also very low, thereafter, the same TBX19 mutation was detected.Both brothers were successfully treated with oral hydrocortisone substitution (6–10 mg/sqm/day q8 with increases during stress) and thrive well, except for several infections of the upper respiratory tract in the younger brother. In summary, we report the very rare condition of familial isolated congenital ACTH deficiency with a mutation of TBX19 that has never been described in newborns. Initial presentation may be accompanied by confounding pathological lab findings, while genetic analysis together with extremely low ACTH and cortisol levels confirm the correct diagnosis.
SUN-481 A Coexisting Primary Papillary Thyroid Carcinoma in a Case of Malignant Struma Ovarii with Follicular Thyroid Carcinoma: 2 Types of Thyroid Cancer in the Same Patient
Authors: Elshimy Ghada , Bhattarai Richa , Tran Kelvin , Correa Ricardo Rafael
Published: May 2020

Introduction: Struma ovarii is a rare monodermal variant of ovarian teratoma diagnosed when thyroid tissue is more than 50% of the overall tissue. It represents only 1% of all ovarian tumors. The vast majority of struma ovarii are benign (95%); however, malignant tumors have been reported in a small percentage of cases. The most common type is papillary carcinoma(PTC), followed by typical follicular carcinoma found in the pathology after surgical oophorectomy. We report a case of malignant struma ovarii with follicular carcinoma in the setting of additional micro PTC found after total thyroidectomy. Case report: A 48-year-old female presented with right-sided pelvic pain and a mobile pelvic mass. Pelvic MRI showed noted a large complex solid mass with cystic components in the right adnexa. It measured 7.7 x 8.4 x 6.7 cm. Subsequently, the patient underwent a robotic hysterectomy, bilateral salpingo-oophorectomy (TAHBSO), bilateral pelvic and para-aortic lymph node sampling, omentectomy and resection of nodules. Final pathology noted an ovary with struma ovarii with well-differentiated follicular carcinoma, peritoneal nodules containing thyroid tissue and benign lymph nodes. Subsequently, iodine 123 SPECT CT showed physiologic uptake in the thyroid with increased uptake in the pelvis, right perirectal region indicating residual thyroid tissue. The patient underwent total thyroidectomy with radioactive ablation with I131 (154.7 mCi). Pathology detected incidental 0.5mm micro PTC and it was classified as staged pT1aN. 6 months postoperatively, thyroglobulin (Tg) and Tg antibodies were undetectable with no abnormalities found on repeat whole-body scans. The patient has been following up with no new issues for the past 5 years indicating a good prognosis with low risk of recurrence. Discussion and Conclusion: In the literature, Struma ovarii containing thyroid-type carcinoma and papillary or follicular thyroid carcinoma metastasizing to the ovary has been documented. The standard treatment of a patient with malignant struma ovarii is TAHBSO and complete surgical staging, including peritoneal washings for cytology, pelvic and para-aortic lymph node sampling, and omentectomy. In cases with the residual malignant disease after surgery, total thyroidectomy and radioactive ablation are recommended. Our case is a unique case given the presence of 2 different thyroid carcinoma in the same patient. In addition, our patient had multiple risk factors for recurrence including large lesions>4 cm, extra ovarian extension, and the coexisting synchronous primary thyroid cancer, however, she had a good prognosis with no recurrence during the 5 years follow up period.
MON-298 IGF-1 in the Early Post-operative Assessment of Acromegaly
Authors: Donegan Diane , Algeciras-Schimnich Alicia , Erickson Dana Z
Published: May 2020

Introduction: Transsphenoidal surgery is recommended as first line therapy in the vast majority of patients with acromegaly. Successful surgical intervention is determined by normalization of insulin like-growth factor (IGF) - 1 and adequate suppression of growth hormone (GH) during glucose GH suppression test or random GH levels <1.0 ng/mL. Given the long half-life of IGF-1, evolution of IGF-1 and GH assays and limitations of GH suppression test, clinicians remain reliant on IGF-1 results 3–6 months following surgery to assess disease remission following surgical intervention. This can lead to delayed treatment of patients with persistent disease and significantly increase patient anxiety.

Aim: To determine if IGF-1 levels at 6 weeks were equally predictive of surgical outcomes when compared to IGF-1 levels at 3–6 months postoperative.

Methods: Retrospective review of patients with newly diagnosed acromegaly who had surgery between 2010–2019 and had post-operative IGF-1 level measured at 6 weeks and 3–6 months. IGF-1 was measured using the Siemens Immulite assay until 2016 when it was replaced by a LC-MS/MS assay. IGF-1 measurements at 6 weeks are obtained based on clinician discretion.

Results: 69 patients (mean age 49 ± 14.8, female 31/69, 44.9%) with acromegaly had surgery and IGF-1 follow-up measurements at 6 weeks and 3–6 months. Persistent acromegaly was noted in 45/69 at 3–6 months. The median IGF-1 pre-operative was 701 ng/ mL (289–1600), 6 weeks postoperative was 286 ng/ mL (109–1038) and at 3–6 months was 267 ng/ mL (77–996). The median pre-operative IGF-1 was significantly higher than the median IGF-1 level at 6 weeks and 3–6 months (P=<0.001). Although a statistically significant difference was seen between IGF-1 levels at 6 weeks and 3–6 months, the mean difference between these time points was small (20 ng/mL, P=<0.001). There was a greater percent reduction in IGF-1 at 6 weeks following surgery in those who had a normal IGF-1 at 3–6 months compared to those who did not (63% vs 35%, P=<0.01). Among patients who were deemed in remission at 3–6 months (24/69, 35%), 3/24 patients (all male with macroadenoma and no cavernous sinus invasion) had mildly elevated IGF-1 levels at 6 weeks (≤1.12 upper limit of normal) which subsequently normalized. In all of these patients, GH was <1 ng/mL post-op. In 1 male (macroadenoma and cavernous sinus invasion), IGF-1 levels increased from normal at 6 weeks to abnormal when measured at 3–6 months.

Conclusion: In the vast majority of patients, 6 weeks post-operative IGF-1 can be used to assess response to surgery avoiding a delay in treatment. However, we would recommend repeating IGF-1 levels at 3–6 months in those who have marginally elevated IGF-1 above normal (≤ 1.12), without cavernous sinus invasion and a post-operative GH of <1 ng/mL prior to intervening if the IGF-1 is elevated 6 weeks as the IGF-1 may normalize.
SUN-158 Testosterone and Cortisol Secreting Large Adreno- Cortical Adenoma
Authors: Madhavan Parvathy , Sukumaran Neenu , Luthra Pooja
Published: May 2020

Background: Functional adrenal adenomas most commonly secrete cortisol or aldosterone. Secretion of multiple hormones is commonly seen in adrenocortical carcinomas and is rare in benign adrenal adenomas. We present a case of a patient with a 6 cm benign adrenal adenoma that was secreting both cortisol and testosterone.

Clinical case: A 44-year-old Caucasian female with past medical history of Grave’s disease, hypertension, prediabetes and hyperlipidemia presented with hirsutism and weight gain. Physical exam was suggestive of cushing’s disease with elevated blood pressure, hirsutism, supraclavicular fullness, moon facies, facial plethora, dorsocervical fat pad and abdominal striae. Further workup revealed elevated testosterone level of 152ng/dL (9-55ng/dl) and elevated androstenedione level of 2.520ng/ml (0.130–0.820 ng/ml). DHEA 0.741 ng/ml (0.630–4.7ng/ml) and DHEAS 65ug/dl (32-240ug/dl) were both within reference range. The 24-hour urine free cortisol was also elevated at 107.1ug/gram of creatinine (< 24 ug/gram of creatinine) with an undetectable ACTH level of < 5 pg/ml indicating adrenal source of Cushing’s syndrome. CT abdomen and pelvis with and without contrast revealed a 6.3 x 5.2 x 5.6 cm left adrenal mass which measured 22 Hounsfield units (HU) on non-contrast imaging, 85 HU on 70 second imaging and 48 HU on 15 min delayed phase. Calculated percent relative washout was 43.5 % and absolute washout was 59.4 %. There was another 1.1 cm low density nodule on left adrenal genu. The right adrenal gland also had a 1.2 cm low density nodule with 0 HU on all phases compatible with a lipid rich adenoma. Patient then underwent left open adrenalectomy. Pathology revealed a 6 cm adrenocortical adenoma. There was no tumor invasion into adjacent sites, no vascular invasion or tumor necrosis noted. MIB1 index was <1 %. Patient had resolution of hypertension and prediabetes after the surgery. Her cortisol and androgen levels also normalized. Biochemical follow up 6 months post-surgery has not demonstrated any increase in cortisol or androgen levels.

Conclusion: Both androgen and cortisol hypersecretion can cause severe hyperandrogenism and virilization but these hormones are commonly secreted in isolation in functional adrenal adenomas. Adrenal masses co-secreting androgen and cortisol are usually indicative of adrenocortical cancer. In this rare case report, both of these hormones were secreted by a unilateral adrenal adenoma, with resolution of symptoms and normalizing of androgen and cortisol levels post left adrenalectomy.
MON-441 Primary Thyroid Maltoma: A Rare Non-hodgkin Malignancy
Authors: Abuaisha Munder , Gibbs Otto , Saand Mariam , Bier Rachel
Published: May 2020

Introduction: Thyroid lymphoma is a rare malignancy; only 2% of extranodal lymphomas arise within the thyroid gland. Furthermore, lymphomas represent no more than 2% of all malignant thyroid tumors and almost always non-Hodgkin type. Case: A 58-year-old female with a medical history of rheumatoid arthritis treated with Golimumab for years. Exam revealed a right thyroid lobe enlargement with bilateral palpable nodules. Labs include TSH of 1.4 mU/L, Free T4 of 1.76 ng/dL, normal anti-thyroid peroxidase antibodies, but elevated anti-thyroglobulin. US of the thyroid showed right-sided, hyperechoic nodule measuring 1.3cm, and left-sided solid hypoechoic nodule measuring 2.2cm. US-guided FNA of the right nodule yielded atypical cells of undetermined significance (2017 Bethesda category III). FNA of the left nodule showed severe, chronic thyroiditis, with small clonal population of cells and suspicion for lymphoma. She underwent total thyroidectomy with left central lymph node dissection. Microscopic evaluation showed a predominant lymphocytic population with plasmacytoid/plasma cells. The histological finding was consistent with extranodal marginal zone lymphoma (EMZL) of mucosa-associated lymphoid tissue (MALT lymphoma or MALToma). However, thyroid tissues were negative for clonal immunoglobulin gene rearrangements (both immunoglobulin heavy and light chains). Immunohistochemistry demonstrated that the tumor cells were CD19, CD 20, CD 22, PAX5, CD78A positive, highlighting predominantly small to medium-sized B- cell lymphocytes, along with plasmacytoid/plasma cells (MUM1 and CD 75A positive). Furthermore, occasional reactive germinal centers (CD10, BCL6 positive, BCL2 negative) were noted. In conclusion, these features were consistent with a low grade, non-Hodgkin’s lymphoma of MALT type. Discussion: EMZL is a clinically indolent non-Hodgkin lymphoma, and growing evidence suggests that numerous cases originate in the background of chronic immune stimulation. MALToma is associated with Hashimoto’s thyroiditis or other immune diseases. Whereas half of EMZL can still arise without a Hashimoto thyroiditis background. Characteristics of the MALToma include reactive follicles, with the neoplastic cells invading the marginal zone (small lymphocytes, marginal zone B-cells, and plasma cells). The key findings are the presence of clonality (light chain restriction), and confirmation of B-cell origin (presence of B-cell markers). The immunophenotype is confirmed by immunohistochemistry and flow cytometry. Localized EMZL of the thyroid can be effectively treated with radiation alone. Surgery is usually used for diagnostic biopsy only. Chemotherapy is usually reserved for those with advanced stages
MON-082 The Neonatal Screen That Cried Wolff
Authors: D’Ambrosio Fabiola , Nur Laika M , Mantis Stelios , Minutti Carla Z
Published: May 2020

Introduction:

Hypothyroidism is one of the major causes of preventable mental retardation. Neonatal screening aids in the prompt diagnosis of newborns with congenital hypothyroidism. There are other clinical conditions that can alter thyroid function during the newborn period, including exposure of high iodine concentrations.

Case Presentation:

One day old female born at 37 3/7 weeks of gestational age by C-section with imperforated anus and congenital heart disease was transferred to our children’s hospital within the first day of life for a hybrid cardiac procedure of bilateral pulmonary artery banding and PDA stenting. She had an Illinois Neonatal screen done at 36 hours of life that was normal. Her cardiac surgery was performed at 10 days of life, where she was exposed to iodine products transdermally. At 14 days of age, she had a repeat Illinois Neonatal screen that was positive for congenital hypothyroidism with a TSH of 78 mIu/mL (normal < 20 mIu/mL) and reflex total T4 of 5.4ug/dL (normal is > 8ug/dL). No family history of thyroid disease; mother was healthy during pregnancy and was not on medications that could affect baby’s thyroid function. Subsequent serum laboratory testing confirmed a TSH of 74.3mIu/mL and Free T4 of 0.6ng/dL. Patient was diagnosed with Wolff-Chaikoff effect, which is the phenomenon of transient hypothyroidism caused by exposure to high doses of iodine (iodine containing contrast agents or topical antiseptics). Pediatric Endocrinology was consulted at 2 weeks of life and she was started on 25mcg of levothyroxine PO daily. Levothyroxine dose decreased at 16 month of age to 12.5mcg due to stable thyroid function tests. The patient was last seen at 30 months of age by Pediatric Endocrinology. She is still on the low dose of levothyroxine and her thyroid labs have been within normal limits for an infant. She will likely not require lifelong thyroid supplementation.

Conclusion: Risk of hypothyroidism among neonates must be considered seriously after large iodine exposure and monitoring for transient hypothyroidism should be performed. It is thus recommended that attempts should be made to reduce the amount of iodine used during procedures and to carefully monitor thyroid function in all neonates exposed to an excess of iodine.

Reference:

Markou, K., et al. “Iodine-Induced Hypothyroidism.” Thyroid, vol. 11, no. 5, 2001, pp. 501–510., doi:10.1089/105072501300176462.

Linder N, Sela B, German B, et al. Iodine and hypothyroidism in neonates with congenital heart disease. Archives of Disease in Childhood - Fetal and Neonatal Edition 1997;77:F239-F240.

Kovacikova, Lubica, et al. “Thyroid Function and Ioduria in Infants after Cardiac Surgery: Comparison of Patients with Primary and Delayed Sternal Closure.” Pediatric Critical Care Medicine, vol. 6, no. 2, 1 Mar. 2005, pp. 154–159., doi:10.1097/01.pcc.0000154960.59452.06.
SUN-026 Unusual Presentation of Aromatase Excess Syndrome
Authors: Al Sabie Farah Laith , Ghareebian Hagop , Mariash Cary N
Published: May 2020

Introduction: Aromatase excess syndrome is a rare disorder with gynecomastia being the main symptoms. Its prevalence is unknown with approximately twenty cases reported. We describe an unusual case of Aromatase excess syndrome. It was diagnosed incidentally at a much older age than expected while evaluating for hypersomnia. Case presentation: A 28 year old male with no significant past medical history, presented with complaint of hypersomnolence, developed during puberty. He had multiple evaluations with no apparent etiology; sleep study and all his other laboratory tests were normal including testosterone levels, normal IGF-1 and cortisol. When patient was evaluated in the Endocrine clinic, he was found to have bilateral gynecomastia, which he had for many years. His estradiol was 150 pg/ml (Normal <50 pg/ml). Repeat was 137 pg/ml with normal DHEA-S Subsequent concomitant estradiol of 204 pg/ml with an estrone of 35.7 pg/ml (9–36). Total testosterone was normal at 588 ng/dl. Evaluation for a tumor with abdominal CT, testicular ultrasound, and HCG was negative. As his symptoms of fatigue and hypersomnolence were not improving and his estradiol to testosterone ratio was >10, he was started on an aromatase inhibitor and his ratio dropped from 1:40 to 1:24, as his estradiol went down to 75 pg/ml. Discussion: Gynecomastia is the benign proliferation of breast tissue due to imbalance between estrogen and testosterone. It could be caused by medications or medical illnesses. Occasionally its presence can harbor a serious endocrine issue especially if presenting in the prepubertal period. Thus, evaluation is often necessary. Among the pathological causes is the Aromatase excess syndrome. In this syndrome there are three types of cryptogenic genomic rearrangements identified. Those rearrangement affect the aromatase gene CYP19 and results in gain of function of the aromatase enzyme. Patients will have high estradiol and estrone level, lower FSH and LH levels that will normalize after treatment with aromatase inhibitor. Their testosterone levels could be low or normal. For the clinical diagnosis, there are four criteria; bilateralgynecomastia, pre or peripubertal onset, exclusion of other causes of gynecomastia and having a genetic trait. The first three criteria are indispensable for diagnosis while fourth one is not obligatory, but rather pathognomonic. An elevated estradiol to testosterone ratio above 1:10 is a supportive finding, as well as having a low FSH with low to normal LH. Genetic identification of the CYP19 A1 mutation remains the definitive method of diagnosis. Our patient met the first three criteria and also had estradiol to testosterone ratio is > 1:10. Genetic confirmation is challenging. Consequently, whole genome sequencing may be required. Though unusual, this case highlights the importance of looking deep in the differential when evaluating gynecomastia.
SAT-333 Autoimmune Polyglandular Syndrome Type 1 in a Patient with Bipolar Disorder
Authors: Rajwani Aakash , Eckman Ari
Published: May 2020

Autoimmune Polyglandular Syndrome Type 1 (APS-1) is clinically defined as the presence of at least two components of the classic triad of hypoparathyroidism, adrenal insufficiency and mucocutaneous candidiasis. It is commonly seen amongst Finns, Sardinians and Iranian Jews and is a very rare condition, with a challenging set of management.

50-year old female with a known past medical history of Bipolar disorder, Primary Adrenal Insufficiency, Hypothyroidism, Alopecia was transferred from an acute psychiatric facility for medical clearance. Patient was noted to have findings initially suggestive of Subarachnoid Hemorrhage on a CT scan of the Head which was later deemed to be likely dystrophic calcification. During her stay on the medical floors, patient was found to be unresponsive and hypotensive, after a bout of agitation. She had to be urgently intubated and started on stress doses of steroids (Hydrocortisone 100 mg every 8 hours) and was upgraded to the Intensive Care Unit (ICU). Patient was eventually successfully weaned off the ventilator and steroid doses were slowly tapered. During her hospital course she was noted to have gradually decreasing Calcium levels, down to a corrected Calcium level of 7.6. Further workup for the hypocalcemia revealed a Vitamin D Level of 12, and Parathyroid Hormone (PTH) level of 0. Patient was subsequently started on adequate Calcium and Vitamin D supplementation for the same. After a few days when the family was located and contacted through social work support, and a more thorough history was obtained, it was found that one out of the patient’s three sisters had a similar constellation of deficiencies. Patient had previously been diagnosed with a polyendocrine syndrome, however she was irregular with her medication compliance and follow-up outpatient with her endocrinologist due to her persistent psychiatric issues and poor social support.

APS-1 is an autosomal recessive disorder caused by mutation in AIRE, the autoimmune regulator gene which is hypothesized to be playing an important role in the generation of regulatory T cells. Although the complete pathogenesis is unclear, mutation in generation of these regulatory cells leads to autoantibody formation. Hypoparathyroidism or Chronic persistent Mucocutaneous Candidiasis is usually the first manifestation seen during adolescence and adrenal insufficiency usually manifests later. A variation of other autoimmune syndromes can be observed, with Hypothyroidism, Type-1 Diabetes Mellitus and Primary Hypogonadism being a few of them. Treatment primarily involves replenishment of the hormones of the underperforming gland. Management of a complex syndrome like APS-1 in a patient with psychiatric disabilities can be challenging and needs a multi-disciplinary approach involving the endocrinologist, the primary care physician and the psychiatrist.
SUN-417 Long Working Hours Are Associated with Hypothyroidism: A Cross-Sectional Study with Population-Representative Data
Authors: Lee Young Ki , Lee Dong-eun , Hwangbo Yul , Lee You Jin , Lee Eun Kyung
Published: May 2020

Background: Studies have highlighted the adverse effects of long working hours on workers’ health; however, the association of long working hours with thyroid function has not been studied. This study aimed to assess long working hours as a risk factor for thyroid dysfunction.

Methods: This cross-sectional study was based on data obtained from the Korea National Health and Nutrition Examination Survey conducted from 2013 to 2015. A total of 2,160 adults who worked 36–83 hours per week were included. Thyroid function was defined based on the population thyroid-stimulating hormone reference ranges, after excluding individuals with positive results for thyroid peroxidase antibody. The association between working hours and thyroid function was confirmed via multinomial logistic regression.

Results: Hypothyroidism was more prevalent among those with longer working hours (3·5% vs. 1·4% for 53–83 and 36–42 working hours per week, respectively). Individuals who worked longer hours had an increased odds for hypothyroidism (odds ratio 1·46, 95% confidence interval 1·12−1·90, per 10 hour increase in working hours per week), after adjustment for age, sex, body mass index, urine iodine concentration, smoking status, shift work, and socioeconomic characteristics such as occupation, income level, and educational attainment. The association between working hours and hypothyroidism was consistent in various subgroups stratified by sex or socioeconomic characteristics.

Conclusions: To our knowledge, this study is the first to show that long working hours are associated with hypothyroidism. Our findings suggest that appropriate monitoring and treatment of hypothyroidism are necessary among individuals who work long hours.
SAT-499 Myxedema Coma Presenting as Large Pericardial Effusion with Cardiac Tamponade
Authors: Ramos Freyja Diana A , Cheng Matilde Melanie N , Tugna Sheryl N
Published: May 2020

Background

Myxedema coma is a life-threatening decompensated form of hypothyroidism. Current treatment recommendation is intravenous levothyroxine. However, in areas where parenteral form of levothyroxine is unavailable, levothyroxine tablet is the only option.

Clinical Case

A 48-year old male known to have chronic glomerulonephritis and hypertension, came in due to lacerated scalp wound sustained after falling asleep. Pertinent laboratory exams showed mild anemia, hemoglobin 10.6 g/dL (reference range 13–17) and hyponatremia 128mmol/L (reference range 136–145). His estimated creatinine clearance was 60mL/min. Cranial CT scan showed no signs of acute hemorrhage or fracture. There was scalp swelling and laceration with subgaleal hematoma over the frontal region. Electrocardiogram showed low voltage complexes. Chest radiograph showed an enlarged cardiac silhouette suggesting pericardial effusion. Transthoracic echocardiography was requested revealing a massive pericardial effusion with tamponade physiology. Patient underwent emergency pericardial window with pericardiostomy tube placement, debridement and suturing of scalp laceration under general anesthesia. He was able to tolerate the procedure well but noted to have decreased sensorium post-operatively. ABG revealed respiratory acidosis with pH 6.9 and incalculable pCO2. He was subsequently intubated. Further laboratory investigations showed undetected FT4 0.0ng/dL (reference range 0.58–1.64) and elevated TSH 23.87µIU/mL (reference range 0.38–5.33). Anti-TPO was elevated 333 µIU/ml (reference range 0–35). He was started on hydrocortisone followed by levothyroxine 200 µg tablet through NGT daily. His condition improved after few days and was weaned off from mechanical ventilator. Repeat echocardiogram showed resolution of previously noted massive pericardial effusion with preserved systolic and diastolic functions. He was eventually discharged after a month on levothyroxine. Follow-up after 1 month, patient was clinically stable with normal thyrotropin level at 0.67µIU/mL.

Conclusion

Myxedema coma is a life threatening form of hypothyroidism and may be difficult to recognize initially especially in patients with pre-existing kidney disease due to overlap in clinical findings. Treatment with levothyroxine administered enterally is possible especially if the intravenous form is unavailable.
OR14-05 Hepatocyte Peroxisome Proliferator-Activated Receptor Gamma (PPARG) Offsets the Anti-Steatogenic Effects of Thiazolidinediones in Obese Male Mice
Authors: Muratalla Jose T , Lee Samuel M , Remon-Ruiz Pablo , Norris Gregory H , Cordoba-Chacon Jose
Published: May 2020

Pparg is a nuclear receptor that regulates glucose and lipid metabolism. Thiazolidinediones (TZD) are PPARG agonists that may reduce hepatic steatosis through their effects in adipose tissue. However, some studies suggest that expression and activation of hepatocyte Pparg promotes steatosis. In this study, we have assessed the relevance of hepatocyte Pparg, and its TZD-mediated activation in the development and/or reduction of steatosis, with adult-onset hepatocyte-specific Pparg knockout (PpargΔHep) mice. We reported that a single iv injection of AAV8-TBG-Cre in Pparg-floxed mice, knocked out hepatocyte Pparg expression (PpargΔHep mice), and that prevented diet-induced steatosis. In this study, a group of 5 wk-old Pparg-floxed mice were fed a low fat (LF) or a high fat (HF) diet for 7 weeks before generating control and PpargΔHep mice. Then, half of the HF-fed mice in each group were switched to a HF diet supplemented with the TZD Rosiglitazone maleate, for 5 weeks. HF diet induced mild obesity (36.8 +/- 1.4 g of body weight [BW]), while TZD slightly increased BW (41.3 +/- 1.3 g) and insulin sensitivity. Liver weight was not altered in HF-fed mice with or without TZD, and we did not observe any effect induced by PpargΔHep. Due to the mild phenotype observed in this cohort, we generated a 2nd cohort adjusting for age and length of diet. Briefly, 10 wk-old Pparg-floxed mice were fed a LF or HF diet for 16 weeks before generating control and PpargΔHep mice. Then, half of the HF-fed mice in each group were switched to a HF diet supplemented with Rosiglitazone maleate for 7 weeks. In this group of mice, HF diet induced obesity (50.1 +/- 1.05 g BW), and increased liver weight independent of hepatic Pparg expression. TZD treatment exacerbated obesity (62.4 +/- 1.2g BW) and adiposity, but increased insulin sensitivity as compared to mice fed a HF diet without TZD. Interestingly, PpargΔHep mice fed a HF diet with TZD showed enlarged subcutaneous white and brown adipose tissue weight, and a dramatic reduction in liver weight and steatosis as compared to obese control mice treated with TZD. The expression of hepatic Cd36, Cidea, Cidec, and Fabp4 was increased by TZD in a Pparg-dependent manner in HF-fed mice. Altogether, this data suggest that hepatocyte Pparg expression may offset the antisteatogenic actions of TZD in mice with severe obesity. In obese and insulin resistant individuals, TZD-mediated activation of hepatocyte Pparg may exacerbate steatosis.
OR09-04 Common Genetic Variants Associated with SERPINA6 Expression in Liver Influence Cortisol-Responsive Transcriptional Networks in Human Adipose Tissue
Authors: Bankier Sean A , Crawford Andrew A , Wang Lingfei , Sukhavasi Katyayani , Ermel Raili , Andrew Ruth , Ruusalepp Arno , Timpson Nicolas J , Smith George Davey , Bjorkegren Johan L M , Walker Brian R , Michoel Tom
Published: May 2020

A genome wide meta-analysis by the CORtisol NETwork (CORNET) consortium(1) has identified genetic variants spanning the SERPINA6/SERPINA1 locus on chromosome 14, associated with morning plasma cortisol and predictive of cardiovascular disease (Crawford et al, Unpublished). SERPINA6 encodes Corticosteroid Binding Globulin (CBG), responsible for binding most cortisol in blood and putatively mediating delivery of cortisol to target tissues. We hypothesised that genetic variants in SERPINA6 influence CBG expression in liver and cortisol delivery to extra-hepatic tissues, influencing cortisol-regulated gene expression.

The Stockholm Tartu Atherosclerosis Reverse Networks Engineering Task study (STARNET)(2) provides RNA sequencing data in 9 vascular and metabolic tissues from 600 genotyped individuals (mean age 65.8, 70.3% male) undergoing coronary artery bypass grafting. We used STARNET to identify SNPs associated with plasma cortisol at genome wide significance in CORNET as cis-eQTLs for SERPINA6 in liver and as trans-eQTLs for the expression of genes across STARNET tissues. Causal inference methodologies(3) were then employed for the network reconstruction of these trans-genes and their downstream targets.

We identified 21 SNPs that both were associated with cortisol at genome wide significance in CORNET (p ≤ 5x10-8) and were cis-eQTLs for SERPINA6 expression in liver (q ≤ 0.05). Moreover, these SNPs were trans-eQTLs for sets of genes in liver, subcutaneous and visceral abdominal adipose tissue, with over-representation of known glucocorticoid-regulated genes in adipose. The highest confidence gene network identified was specific to subcutaneous adipose, with the interferon regulatory trans-gene, IRF2, controlling a putative glucocorticoid-regulated network. Targets in this network include LDB2 and LIPA, both associated with coronary artery disease.

We conclude that variants in the SERPINA6/SERPINA1 locus mediate their effect on plasma cortisol through variation in SERPINA6 expression in liver, and in turn affect gene expression in extra-hepatic tissues through modulating cortisol delivery. This supports a dynamic role for CBG in modulating cortisol delivery to tissues. The cortisol-responsive gene networks identified here represent candidate pathways to mediate cardiovascular risk attributable to elevated cortisol.

(1) Bolton, et al. (2014) PLOS Genet. 10:e1004474., (2) Franzén et al. (2016). Science 353:827., (3) Wang and Michoel. (2017). PLOS Comput. Biol. 13:e1005703.
MON-029 Polycystic Ovary Syndrome (PCOS) in Adolescent Girls:Toward a Simple On-Treatment Predictor of Post-Treatment Ovulation Rate
Authors: Ibanez Lourdes , Díaz Marta , Cereijo Ruben , Bassols Judit , Lopez-Bermejo Abel , Villarroya Francesc , de Zegher Francis
Published: May 2020

There is no approved treatment for adolescent girls with PCOS. The vast majority of these patients are guided into a trajectory that starts with oral contraceptive (OC) treatment, leads into oligo-anovulatory subfertility, then into the use of assisted reproductive techniques, and ultimately into pregnancies with a double-to-triple risk for complications (such as gestational diabetes, preeclampsia and preterm birth) potentially with lifelong sequelae in the offspring.

Evidence is converging into the insight that adolescent PCOS is frequently driven by hepato-visceral fat excess (“central obesity”) ensuing from a mismatch between (rather restrictive) prenatal and (rather abundant) postnatal nutrition, on a background of genetic susceptibility (Trends Endocrinol Metab 2018;29:815). This insight has prompted the exploration of an alternative PCOS treatment that aims at reducing the central-fat excess (without causing weight loss in non-obese girls) in order to normalize the entire phenotype, including ovulation rate.

So far, this alternative approach has been tested in two randomized controlled pilot studies that were performed in non-obese girls with PCOS and with no need for contraception (total N=62; age 16 yr; BMI 24 Kg/m2; treatment for 1 year; ovulation assessment during the post-treatment year). In these studies, the effects of an OC were compared to those of SPIOMET, which is a low-dose combination of spironolactone (= a mixed anti-androgen and -mineralocorticoid, also activating brown adipose tissue; Diab Ob Metab 2019;21:509), pioglitazone and metformin (= two insulin sensitizers acting through different mechanisms).

Pooled results of the pilot studies confirm the first report (J Adolesc Health 2017;61:446) that SPIOMET has more normalizing effects than OC; there were approximately 3-fold more ovulations post-SPIOMET than post-OC; normovulation occurred only post-SPIOMET; anovulation was >10-fold more frequent post-OC.

Pooled results also disclosed two new features of adolescent PCOS: low concentrations of circulating CXCL14 (= a brown adipokine, signaling activity in brown adipose tissue; Cell Metab 2018;28:750) and miR-451a (= an inhibitor of THRSP-mediated hepatic lipogenesis; Mol Cell Endocrinol 2018;474:260), both of which remain abnormally low on OC, but normalize on SPIOMET treatment. The on-treatment Z-scores of fasting insulin and miR-451a explained together approximately 50% of the variation in post-treatment ovulation rates. This simple duo, if validated in larger and more diverse PCOS populations, may become a first on-treatment predictor of post-treatment ovulation rate.
MON-042 The Effect of Exercise Training on Reproductive and Cardiometabolic Outcomes in Women with Polycystic Ovary Syndrome: A Pilot Randomized Controlled Trial
Authors: Benham Jamie L , Booth Jane E , Doucette Steve , Friedenreich Christine M , Rabi Doreen M , Sigal Ronald J
Published: May 2020

Exercise may improve cardiometabolic, reproductive and psychological outcomes in women with Polycystic Ovary Syndrome (PCOS). Clinical Practice Guidelines recommend exercise to treat PCOS, but the most effective exercise prescription is unclear. The aim of this randomized controlled trial was to evaluate the effects of six months of thrice weekly high-intensity interval training (HIIT) and continuous aerobic exercise training (CAET) programs compared with no exercise in previously-inactive women aged 18–40 years with PCOS. The primary outcome was change in ovulation rate. Ovulation was assessed with daily at home ovulation prediction kits, and confirmed with serum progesterone levels. Fisher’s exact test was used to compare groups. Secondary outcomes included change in BMI, waist circumference, blood pressure, A1C, fasting glucose, fasting insulin, and lipids and were analyzed using repeated measures mixed models. 47 women were randomly assigned to no exercise control (n=17), HIIT (n=16), or CAET (n=14). 22/33 (66.7%) women ovulated during the intervention period: no exercise: 8/12 (66.7%), HIIT: 8/11 (72.7%), and CAET: 6/10 (60%); NS between groups. BMI decreased significantly in the CAET group compared with control (-1 kg/m2, p=0.01) and compared with HIIT (-0.9 kg/m2, p=0.04). Mean waist circumference decreased significantly in all groups with no significant difference between groups. There were no significant within- or between- group changes for body weight. No within- or between group differences were identified for mean blood pressure, A1C, fasting glucose, fasting insulin, or triglycerides. Mean LDL-C was significantly different between the HIIT and CAET groups (-0.33 mmol/L, p=0.03), as LDL-C decreased in the HIIT group but not in the CAET group. HDL-C increased in the HIIT group compared with the no exercise group (0.18 mmol/L, p=0.04), with no significant difference between the CAET and no exercise groups (p=0.47). In conclusion, CAET and HIIT interventions in women with PCOS did not affect ovulation rates. CAET and HIIT both were effective at improving anthropometrics and some cardiometabolic health markers in women with PCOS. Further studies are needed to determine optimal exercise prescriptions for reproductive, anthropometric and cardiometabolic outcomes in women with PCOS.
SAT-299 Chronic Treatment Of Juvenile Hypothalamic Pomc-deficient Mice With RM-493 Prevents The Development Of Obesity
Authors: Thompson Zoe , Shah Bhavik P , Low Malcolm J
Published: May 2020

Arc-Pomc knockout mice have a disruption of the two neural enhancers for the Pomc (proopiomelanocortin) gene, resulting in selective loss of Pomc gene expression in the arcuate nucleus of the hypothalamus. This gene targeting strategy leaves pituitary Pomc expression unaffected. These mice are hyperphagic starting at weaning, and develop progressive obesity, infertility and insulin resistance over their lifetime. RM-493 (setmelanotide) is a melanocortin-4 receptor agonist that has shown promise in treating humans with Pomc null mutations. In this preclinical study, we investigated the effects of chronic RM-493 treatment using subcutaneously implanted osmotic minipumps in two groups of male mice: Arc-Pomc knockout mice, fed regular chow throughout the study period, and their wildtype counterparts, fed a 45% high-fat diet. Each of these groups of mice was randomized into three treatment cohorts at weaning: one that was given RM-493 throughout the entire study period (4–24 weeks of age, “RM-493” group), one that was given RM-493 only for the first 4 weeks of the study (4–8 weeks of age, “switch” group) and then switched to vehicle, and one cohort that received vehicle for the entire study (“vehicle” group). We serially measured body weight, food intake, body composition, glucose tolerance, insulin tolerance, and several measures of metabolism using the Comprehensive Lab Animal Monitoring System, including oxygen consumption, energy expenditure, ambulatory activity and lipid and glucose oxidation.

Among other results, at the end of the study (24 weeks of age), Arc-Pomc knockout mice in the RM-493 group weighed significantly less than either the switch or vehicle groups (p<0.05). Arc-Pomc knockout mice on RM-493 also had higher energy expenditure when compared to the switch and vehicle groups (p<0.05). In addition, RM-493 improved the glucose-insulin index for Arc-Pomc knockout mice (p<0.05). According to our preliminary results, wildtype mice on high-fat diet, treated chronically with RM-493, did not differ in any of these measurements from their switch and vehicle groups.

We conclude that the obesity syndrome caused by a loss of hypothalamic Pomc expression was completely blocked by RM-493 treatment started before the onset of obesity, with no apparent desensitization to the drug’s action over 20 weeks. However, the beneficial effects of a single month’s treatment were steadily reversed within one month after switching to vehicle treatment. In contrast to the dramatic effects of RM-493 in the genetic obesity syndrome, at this time, there does not appear to be any phenotypic changes in wild-type mice with RM-493 administration on the development of obesity or secondary metabolic disruptions in response to high-fat diet consumption.
SUN-286 Lymphocytic Hypophysitis Mimicking Tolosa Hunt Syndrome
Authors: Del Castillo Ma Dolores , Arkun Knarik , Safain Mina , Lechan Ronald M
Published: May 2020

Introduction:

Lymphocytic hypophysitis often presents with headache, hypopituitarism and visual disturbance, the latter from optic nerve compression. Rarely, it can present with diplopia from cranial nerves III, IV and VI (3.7%) and cavernous sinus involvement (1).

Clinical Case:

A 40 year old woman presented with left eye pain, blurry vision, ptosis and diplopia for 2 days, preceded by headache for 2 weeks. Exam was remarkable for left eye ptosis, mild proptosis, downward and outward gaze and inability to adduct her left eye. Endocrinological exam revealed free T4 0.67 ng/dL (Nl 0.70 - 1.48), TSH 0.67 ng/dL (Nl 0.70–1.48), estradiol <10 pg/mL, LH 1.0 mIU/mL, FSH 6.9 mIU/mL, prolactin 23.3 ng/ml (Nl 5.2–26.5) and IGF-1 95 ng/mL (Nl 52–328). Cortisol was not assessed as patient was already on steroids. Work-up revealed atypical ANCA (1:320) but normal C-ANA (<1:20), P-ANCA (<1:20), and the rest of immune work-up was negative including ACE, ESR, CRP, ANA, serine protease and myeloperoxidase. No systemic manifestations were present concerning for systemic autoimmune disease. CSF exam was unrevealing including a normal ACE level. MRI revealed an enlarged pituitary gland with suprasellar extension containing a focal area of T2 hyperintensity and slight T2 hypointensity at the posterior aspect of the gland. There was a midline, thickened infundibulum, enhancement of both cavernous sinuses and narrowing of right internal carotid artery without occlusion. Endoscopic endonasal transsphenoidal biopsy of pituitary lesion confirmed diagnosis of lymphocytic hypophysitis and did not meet criteria for IgG4 hypophysitis. After 4 weeks of prednisone, she had significant symptomatic improvement and repeat MRI showed decreased pituitary size but persistent abnormal enhancement of the pituitary gland and cavernous sinuses.

Conclusion:

The atypical and variable clinical and radiological findings of lymphocytic hypophysitis can mimic other inflammatory, infiltrative lesions, pituitary tumor with apoplexy and Tolosa Hunt Syndrome. Tolosa Hunt syndrome is an idiopathic granulomatous inflammation of the cavernous sinus involving cranial nerves II to VI and often presenting with painful ophthalmoplegia. Pituitary involvement and carotid artery narrowing have been observed (2). Our case highlights a patient with cranial nerve III palsy and significant cavernous sinus involvement, clinically concerning for Tolosa Hunt syndrome, but confirmed by biopsy to be lymphocytic hypophysitis. There are no specific serum markers to distinguish lymphocytic hypophysitis from other entities and when uncertain, diagnosis is best established by biopsy.

References:

1 Caturegli P, et al. Autoimmune hypophysitis. Endocr Rev 2005, 26: 599–614.

2 A. Kambe et al. A case of Tolosa-Hunt syndrome affecting both cavernous sinuses and hypophysis and associated C3 and C4 aneurysms. Surgical Neurology 65 (2006) 304–307.
SAT-361 Familial Hypocalciuric Hypercalcemia Type 3: AP2S1 Mutation
Authors: Kerut Sarah Elizabeth , Cardozo Licy L Yanes
Published: May 2020

Background: Familial hypocalciuric hypercalcemia (FHH) type 3 can appear similar to primary hyperparathyroidism and make the diagnosis of etiology of hypercalcemia challenging.

Clinical Case: A 45-year-old man with hypertension and glaucoma was evaluated in clinic for hypercalcemia. His calcium was 12.3 mg/dL (8.4–10.2), PTH 41.9 pg/mL (15–65), Vitamin D 14.8 ng/mL (6.6–49) and phosphorus 1.7 mg/dL (2.7–4.5). He denied history of thiazide diuretic use, fragility fracture, nephrolithiasis and family history of calcium disorders. Further workup revealed normal kidney function, undetectable PTH related peptide and dual-energy x-ray absorptiometry (DEXA) scan with a T-score of -3.3 at spine L1-L4, -2.7 at femoral neck and -2.1 at distal one-third forearm. A 24-hour urine collection revealed a urinary calcium of 42.4 mg/24-hour (100–300) and calcium: creatinine clearance ratio of 0.003. Diagnosis of primary hyperparathyroidism was made despite low urinary calcium as this was thought to be due to vitamin D deficiency. Sestamibi scintigraphy and four-dimensional computed tomography did not localize a parathyroid adenoma, however, the patient was sent to surgery for four gland parathyroid exploration for primary hyperparathyroidism in setting of high calcium and young age with evidence of end-organ failure of osteoporosis. During surgery, three large abnormal parathyroid glands were identified and one normal parathyroid gland. Patient had a three-gland parathyroidectomy with intraoperative drop in PTH by 26.5%. Pathology returned as benign parathyroid tissues. After surgery, patient had persistently elevated calcium level of 12.6 mg/dL and an inappropriately non-suppressed PTH. He was then started on bisphosphonate and cinacalcet for osteoporosis and hypercalcemia, respectively and sent for genetic testing of FHH. His CASR gene was negative but his AP2S1 gene was positive which confirmed the diagnosis of FHH type 3. His calcium responded well to cinacalcet and repeat DEXA scan showed stability of bone mineral density in spine and hip after two years of treatment with bisphosphonate therapy.

Conclusion: Familial hypocalciuric hypercalcemia type 3 is caused by an inactivating mutation in the AP2S1 gene. This gene encodes the adaptor-related protein complex 2, sigma 1 subunit which is located downstream from calcium-sensing receptor. This genetic mutation can appear similar to primary hyperparathyroidism in that it produces high levels of calcium and PTH and low phosphorus. Hypercalcemia, however, persists despite removal of parathyroid gland. This genetic mutation can be treated with cinacalcet in patients with high levels of calcium (>1 upper limit of normal) or symptoms of hypercalcemia.