bluuebunny/crossref_metadata_2025 huggingface dataset:
OR01-04 Kruppel-Like Factors 9 and 13 Cooperate to Maintain Mammalian Neuronal Differentiation
Authors: Avila-Mendoza Jose , Subramani Arasakumar , Denver Robert J
Published: May 2020

During development of the central nervous system, neural cells respond to several external cues that influence cell proliferation, differentiation, axonal growth and synaptogenesis. Thyroid hormone plays a critical role in each of these processes. Previously, we showed that Krüppel-like factor 9 (KLF9), a zinc finger transcription factor, is strongly and directly induced by liganded thyroid hormone receptors, and it mediates the actions of thyroid hormone on neuronal differentiation during late fetal development. Here we analyzed the molecular mechanisms by which KLF9 maintains neuronal structure, and inhibits regeneration in juvenile and adult neuronal cells. We also investigated the actions of the closely related transcription factor KLF13, which is paralogous to KLF9. We engineered the adult mouse hippocampus-derived cell line HT22 to control Klf9 or Klf13 expression by addition of doxycycline. We also used CRISPR/Cas9 genome editing to generate Klf9 or Klf13 knock out (KO), and Klf9+Klf13 double KO HT22 cell lines. To induce neurite outgrowth, we treated cells with forskolin (FK)+IBMX, which increases intracellular cAMP; elevated cAMP is a hallmark of regenerative responses of neurons to injury. Our results show that FK+IBMX increased neurite length in the parent HT22 cell line, and this action was enhanced in Klf9 and Klf13 single KO cells, and was even greater in double KO cells. By contrast, the stimulatory effect of FK+IBMX on neurite outgrowth was blocked by simultaneous forced expression of Klf9 or Klf13 in parent HT22 cells. This effect on neurite outgrowth was confirmed in primary mouse hippocampal neurons, where electroporation of expression plasmids for Klf9 or Klf13 suppressed FK+IBMX-induced neurite extension compared with empty vector-transfected cells. Analysis of RNA-seq data obtained from HT22 cells following 8 hr of induced Klf9 or Klf13 expression showed that both proteins impact the cAMP signaling pathway. Using transfection-reporter assays and chromatin immunoprecipitation, we confirmed that several genes in this pathway are direct targets of both KLFs. Our findings suggest that KLF9 and KLF13 may cooperate to maintain the differentiated state of mammalian neurons and thereby block regeneration, in part, by repressing the cAMP signaling pathway.
SUN-386 Treatment Outcomes of Intravenous Zoledronic Acid vs Oral Alendronate in Postmenopausal Women with Osteoporosis
Authors: Pyone Zar Chi , Aung Moe Wint , Myint Thein , Khin Than Saw , Hlaing Thinn Thinn
Published: May 2020

In real practice, many patients with osteoporosis are poorly compliant with oral bisphosphonate, partly due to gastrointestinal side effects and partly due to medication procedure leading to premature termination of treatment. Once yearly intravenous zoledronic acid is well tolerated; little or no gastrointestinal effects and effective drug in treatment of postmenopausal osteoporosis with favourable dosing regimen to improve compliance of patients. So this study aims to study treatment outcomes of intravenous zoledronic acid vs oral alendronate in postmenopausal women with osteoporosis. This study was a randomized open label comparative study and included 94 postmenopausal women with osteoporosis. In this study, once yearly zoledronic acid (ZOL) infusion provided a greater reduction of serum procollagen type 1 N propeptide (P1NP) at 3 months than once weekly oral alendronate (ALN). Percentages of P1NP change in ZOL group was -70.25±17.51% and ALN group was -60.61±18.87% (P= 0.012). A decrease of P1NP ≥40% was observed in the majority of patients in both groups (89.4% in ZOL group and 85.1% in ALN group) (P= 0.536). ZOL was non-inferior to ALN in terms of BMD change at lumbar spine (4.8±5.5% in ZOL versus 4.9±4.5% in ALN treated patients) with P value of 0.922 and also at total hip (3.8±8.0% in ZOL versus 3.8±7.5% in ALN group) (P= 0.970). Two cases (4.3%) of new fractures was observed in ZOL group whereas 4 cases (8.5%) of new fractures occurred in ALN group over one year of study. The overall frequencies of treatment related adverse effects were similar between ZOL group (57.4%) and ALN group (42.6%) (P= 0.149). ZOL group showed significantly increased frequencies of musculoskeletal pain (57.4%) and acute phase reaction (12.8%) and 12.8% of participants in ALN group complained of heartburn. The overall preference to continue current medication was higher in ZOL group than ALN group (P= 0.002). The participants treated with ZOL were tend to have more satisfaction (P= 0.026) and willing to receive it longer period (P< 0.001).Compared to weekly oral alendronate therapy in treatment of postmenopausal osteoporosis, yearly infusion of 5 mg zoledronic acid infusion produced a significant greater response in serum P1NP at 3 months and similar change in BMD at one year of treatment and overall frequencies of adverse effects were similar between two treatment groups with excellent patient preference and satisfaction after zoledronate treatment. Reference: (1) Al-Bogami et al (2015) Favorable therapeutic response of osteoporotic patients to treatment with intravenous zoledronate compared with oral alendronate. Saudi Med J. 36(11):1305-1311. (2) Saag et al (2007) A single zoledronic acid infusion reduces bone resorption markers more rapidly than weekly oral alendronate in postmenopausal women with low bone mineral density. Bone. 40:1238-1243.
OR22-04 Relationship of TSH Levels with the Components of Metabolic Syndrome in a Nationally Representative Population of Youth in the United States
Authors: Chen Xinlei , Deng Shuliang , Thaker Vidhu V
Published: May 2020

Introduction: Subclinical hypothyroidism (SH) is defined as elevated TSH with normal thyroid levels, and is often associated with obesity. SH has been linked to cardiometabolic risk factors such as abnormal lipids, elevated blood pressure, atherosclerosis and fatty liver. This study sought to elucidate the association of TSH level with the components of metabolic syndrome independent of BMI in children from the National Health and Nutrition Examination Survey (NHANES).

Methods: NHANES surveys 1999-01 and 2007-12 that measured thyroid function tests were included in the study. Youth aged 2-18 years with TSH levels < 10 uU/mL and normal Total T4 (TT4) levels were included in the analysis. The components of metabolic syndrome were defined as abdominal obesity (waist circumference > 95th %tile), hypertriglyceridemia (TG >=100 for 0-9 years and >=130 mg/dL for > 10 years), low HDL cholesterol < 40 mg/dL), elevated blood pressure (> 95th %tile for age/sex/height) and hyperglycemia (FBG > 100 mg/dL, or diagnosis of diabetes). The association of these components with quartiles of TSH were examined by logistic and linear regression controlling for age, sex, race/ethnicity and BMI. All analyses were performed in R v3.5.1.

Results: After excluding youth with TSH >10 uU/mL and TT4 levels < 12.4 mcg/dL, 2377 subjects (50% female) were included in the study. The mean age of the cohort was 15 ± 1.7 years; 28.2 % were non-hispanic whites and 38.5 % hispanic/latino. Obesity (BMI >95 %tile) was seen in 21.7% individuals. There were 44 subjects with TSH levels >4.5 uU/mL that was not different by BMI (2.5% in BMI >95%tile and 1.7% BMI < 95%tile, p = 0.29). Based on the distribution in the population, TSH levels were divided into 4 quartiles: Q1= 0.01-0.97, Q2= 0.98-1.42, Q3=1.43-2.0, Q4 = > 2.01 uU/mL. A statistically significant association of the Q4 TSH was seen with abdominal obesity, OR 2.44 (1.38-4.39), p=0.002 and elevated BP, OR 1.6 (1.06-2.44), p = 0.02 but not with high TG, OR 1.58 (0.93-2.75), p=0.09, low HDL, OR 0.84 (0.6-1.17), p = 0.31 or those with hyperglycemia and/or diabetes, OR = 1.25 (0.78-2.05), p = 0.36. Linear regression models showed statistically significant association of abdominal obesity, hypertriglyceridemia, elevated BP and hyperglycemia (and/or diabetes) with increase in TSH level.

Conclusions: In children from a representative US population, the prevalence of SH defined as TSH level >4.5 uU/mL is low, even with BMI >95th %tile. The association of measures of metabolic syndrome with linear increase in TSH suggests that the current reference range may require modification.
MON-684 Neuroglycopenia: Avoiding Bias in Patients with Acute Psychosis
Authors: Otuonye Gene Chibuchim , Gibbs Otto , Sittol Rani Delraj , Tavares Matthew V , Abuaisha Munder , Kim Christian
Published: May 2020

Introduction

The neurogenic response to hypoglycemia (HG) is well established. In contrast, neuroglycopenic (NG) manifestations are widely variable and have been erroneously attributed to other diagnoses. Compounding diagnostic uncertainty is the incidence of these symptoms in a patient with a psychiatric illness.

Clinical Case

A 51 year old male with hypertension and schizophrenia maintained on amlodipine, risperidone and benztropine was transported to the ER psychiatric unit by law enforcement. He was detained after he was found wandering the streets demonstrating increased verbal and physical aggressiveness. He was known to the unit, with previous admissions for psychosis secondary to schizophrenia. On presentation vitals were solely significant for tachycardia. Physical and mental status examination revealed a disheveled, agitated and combative male who was disoriented to time, person and location. He was actively experiencing visual and auditory hallucinations with psychomotor agitation, intermittent loosening of association, circumstantial speech and persecutory delusions. Initially given one dose of i.m. haloperidol and benztropine, his psychosis persisted. Biochemical investigations were significant for a glucose of 37 mg/dL; All others including alcohol level, toxicology and TSH were normal. Head CT was unremarkable. His HG was treated with i.v. dextrose with complete resolution of psychotic symptoms within one hour of normoglycemia. He needed no further antipsychotic doses save his maintenance risperidone. Further historical enquiry revealed a recent diagnosis of type 2 DM managed on metformin and glimepiride with poor oral intake. He was discharged on metformin and sitagliptin post extensive DM self-management education, h; glimepiride was discontinued.

Discussion

NG manifestations of hypoglycemia are the direct result of central nervous system glucose deprivation. Uncommonly, they can be the sole presenting complaint in the HG patient. In one study, 27% of patients with insulinomas had only NG symptoms [1]. Interestingly, some case reports suggest acute psychosis may be an important NG feature [2]. Psychiatric patients, particularly those with primary psychotic disorders often face a labyrinthine process when seeking emergent medical care including but not limited to anchoring and ascertainment physician bias. If unrecognized, HG can lead to neuronal death. Clinicians must maintain a high index of suspicion of HG in patients presenting with acute psychosis even in the presence of functional illness so as to reduce morbidity, mortality and medicolegal risk.

References

Dizon AM., Kowalyk S., Hoogwerf BJ. Neuroglycopenic and other symptoms in patients with insulinomas, Am J Med. 1999 Mar; 106(3):307-10.

Klemen P., Grmec S., Cander, D. Hypoglycemia masquerading as acute psychosis in young age. Crit Care. 2000; 4(Suppl 1): P172. doi: 10.1186/cc892.
MON-450 Prophylactic Thyroidectomy in a Patient with Codon 891 Mutation of the RET Proto-Oncogene
Authors: Swami Janya , Howell Nicole R
Published: May 2020

Background: Medullary thyroid cancer (MTC) is a neuroendocrine tumor of the parafollicular or C cells of the thyroid gland, accounting for 1-2% of thyroid cancers in the United States. About 25% MTCs are familial as a part of the MEN2 syndrome or familial MTC (FMTC). Germline mutations in codon 891 are predominantly associated with FMTC. Case: 65-year-old Caucasian male was referred to the Endocrinology clinic after bilateral thyroid nodules were found on thyroid US. The patient had requested an ultrasound of his thyroid after his brother was diagnosed with MTC following fine-needle aspiration for an incidental thyroid nodule prompting total thyroidectomy and genetic testing. The patient’s brother was found to be heterozygous for RET mutation (c.2617T>G;pSer891Ala). This resulted in screening of the other siblings including this patient, also found to be heterozygous for this mutation. Both parents were deceased, and their clinical history is not known. Only one of the remaining two siblings had genetic testing; one brother refused testing for the mutation and one sister was positive for the mutation but had no thyroid nodules on ultrasound. She underwent prophylactic thyroidectomy. Neither the patient, nor his siblings, have any progeny. The patient screened negative for primary hyperparathyroidism and pheochromocytoma. Calcitonin (739, normal </=14.3 pg/mL)and CEA levels (31.7, 0-3.0 ng/mL) were elevated. Thyroid ultrasound (US) showed two solid hypoechoic nodules with lobulated margins and internal coarse calcifications in the right and two in the left thyroid lobe; 1.5 cm and 1.2 cm in maximum diameter, and 1.2 cm and 3 mm in maximum diameter, respectively. Based on elevated calcitonin and CEA levels, known RET mutation and evidence for thyroid nodules, we recommended a total thyroidectomy and central neck dissection. Pathology revealed multifocal, bilateral medullary carcinoma (largest focus of 1.5 cm), with 4/4 lymph nodes positive for metastasis. This was classified as mpT1bN1aM0 (Stage III). Patient was started on levothyroxine with plans to repeat calcitonin and CEA levels and neck ultrasound, 3 months following surgery. CT chest, abdomen and pelvis did not reveal any distant metastasis. Conclusion: Inherited MTCs are rare. Early diagnoses by screening of at-risk family members in MEN2 kindreds is important because MTC can be life-threatening and can be cured and prevented by early thyroidectomy. While our suspicion for FMTC in this patient and his siblings is high, FMTC is now considered a variant of MEN2A and ongoing screening for pheochromocytoma and primary hyperparathyroidism is recommended.
SAT-459 A Grave Complication: Pulmonary Arterial Hypertension
Authors: Butt Wajeeha Saeed , Srinivasan Vijay
Published: May 2020

There is currently emerging evidence that thyroid disease can have an impact on pulmonary pathologies but a direct causation, as opposed to correlation, is yet to be established. We present a unique case of newly diagnosed Graves’ disease with pulmonary sequalae.

69 year old non-smoking female with no known medical history presented to the hospital with acute onset of chest tightness, shortness of breath and palpitations. She had been experiencing night sweats and 10 lbs weight loss in the 3 weeks preceding hospitalization. She did not endorse any pertinent family history. On exam, she presented with tachycardia. The rest of the physical exam remained unchanged. Complete blood count and comprehensive metabolic panel did not reveal any abnormalities. Her TSH was suppressed below lab capability of measurement (<0.015). Free T4 was 5.97 ng/dL, and total T3 was 492 ng/dL. Subsequently obtained TPO antibody level was > 1000 IU/ml and TSI was 29.3 IU/L. EKG showed atrial fibrillation with RVR. Thyroid U/S showed that the thyroid gland was diffusely enlarged to the upper limit of normal but no nodules. CT chest showed diffuse ground glass opacities.

She was treated with propranolol, and methimazole after resolution of acute symptoms. She was placed on diuretics to treat symptoms of pulmonary edema secondary to uncontrolled atrial fibrillation and high output heart failure. On outpatient follow up she continued to have mild shortness of breath on exertion. She had normal systolic and diastolic function of heart but an elevated PAP of 38mm Hg on a transthoracic echocardiogram, and her pulmonary function tests were within normal limits for her age. A follow up CT chest, 6 weeks after discharge, showed no resolution of ground glass opacities.

Current literature shows that there might be pulmonary effects of hyper-thyroidal diseases; such as ventilation disorders, OSA, CSA, and pleural effusions. A 2002 study revealed a strong association of hyperthyroidism with pulmonary hypertension. A 2016 literature review established that there is specifically an association of Graves’ disease with pulmonary arterial hypertension. Both of these studies have had a small patient group. Our case perhaps adds credence to the fairly less known affiliation of hyperthyroidism with pulmonary disease. A unique finding in our patient - unresolving ground glass opacities, suggests a possible thyroid related interstitial lung disease. As with our case, there needs to be an increased awareness in the among clinicians to further work up both thyroid related pulmonary hypertension and interstitial lung disease possibly related to uncontrolled thyroid pathology. Increased vigilance to include hyperthyroidism as a differential for pulmonary hypertension can lead to better clinical outcomes for patients, with less possible invasive and expensive testing of other causes of pulmonary hypertension.
MON-467 A Case of Inoperable Substernal Goiter
Authors: Papaioannou Garyfallia , Sifontes Erick Perez , Manivel Gnanambal , Eswaran Manivel Kumaran
Published: May 2020

Introduction: Goiter is abnormal growth of the thyroid gland. When goiter extends into the mediastinum it is called retrosternal or substernal. Substernal goiter can cause compression of the great vessels, trachea, and esophagus. When it compresses trachea it can result in airway obstruction. In that case treatment of choice is thyroidectomy and Radio Iodine Ablation (RIA). But some patients are considered to be high risk for operation due to multiple comorbidities. We are presenting this case where we tried experimental therapy with airway stent and external beam radiation. Case: An 81 year old female presented to the hospital complaining of chest pain. She also reported dysphagia to solids and liquids and weight loss during one month. Past medical history included congestive heart failure, atrial fibrillation, chronic obstructive pulmonary disease with home oxygen support. On physical exam thyroid was palpable to the level of sternal notch. Arterial blood gases showed hypoxemia (PO2 63), thyroid function tests showed an abnormally suppressed TSH (<0.005 IU/ml), elevated free T4 (2.48 ng/dl) and normal T3. Thyroid stimulating immunoglobulin, IgG, IgM and IgA levels were normal. Thyroglobulin and thyroid peroxidase antibodies were negative. Chest X-ray revealed an upper mediastinal mass. Chest CTA showed a very large substernal goiter with left thyroid lobe of 7.4 x 3.4 x 7.8 cm that extended to the level of the carina causing compression of the upper to mid trachea and of the upper esophagus. The smallest diameter of the trachea was 6 millimeters. Ultrasound revealed an enlarged heterogeneous thyroid with a solid lesion in the left side inferiorly. Due to administration of IV contrast for the CTA, iodine uptake scan was not performed. Patient was determined to be of high surgical risk due to her comorbidities and she did not consent for thyroidectomy. She was treated with methimazole 20mg daily and IV hydrocortisone 50mg TID. Due to the administration of IV contrast she was not candidate for RIA either. Short term beam radiation was started. For the acute relief of respiratory distress the lesion was transversed through flexible bronchoscopy and a 16 mm by 80 mm covered ultraflex tracheobronchial stent was placed in the trachea. The post-stent lumen size was 80% of normal. Patient’s respiratory status improved and the treatments with external beam radiation were continued. Conclusion: The treatment of choice for substernal goiter that causes airway obstruction is surgery. RIA can be an alternative when surgery is contraindicated. Since surgery as well as RIA was not an option for this patient we attempted external beam radiation to reduce the size of goiter. Because this treatment takes several weeks to be effective, temporary airway opening via an airway stent is the option for acute relief of symptoms.
MON-698 Association of Sleep Quality and Painless Diabetic Peripheral Neuropathy in Type 2 Diabetes
Authors: Choi Dughyun , Kim Bo Yeon , Jung Chan-Hee , Kim Chul-Hee , Mok Jioh
Published: May 2020

Aims

Diabetic peripheral neuropathy (DPN) is one of the most common and early manifested complication in T2D. Previous reports have shown that painful sensation of diabetic peripheral neuropathy (DPN) results in sleep problems in type 2 diabetes (T2D)1, 2. However, it is not known that subtype of DPN, the painless DPN also is associated with poor sleep quality in T2D. The purpose of the current study was to investigate the association between painless DPN and poor sleep quality in T2D.

Methods

A total of 146 patients of T2D who did not previously diagnose with symptomatic DPN were recruited into the study. Among the patients, painless DPN was diagnosed by using the current perception threshold (CPT) test. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) questionnaire.

Results

The percentage of painless DPN was significantly higher in the poor sleep quality group than the good sleep quality group (70.0% vs. 35.5%, P<0.001). In the subscale results, stimulus values in 2000 Hz, hypoesthesia and hyperesthesia were significantly higher in the poor sleep quality group, than in the good sleep quality group (45.7% vs. 25.0%, P=0.009; 34.3% vs. 18.4%, P=0.029; 40.0% vs. 19.7%, P=0.007, respectively). The association of painless DPN and poor sleep quality remained significant after adjustment for significant variants (odds ratio, 3.825; 95% confidence interval, 1.674-8.742; P<0.001).

Conclusions

The current study showed that painless DPN was associated with poor sleep quality. Future studies are required to clarify the pathophysiologic causal relationship between painless DPN and sleep quality.

References

1. Gore M, Brandenburg NA, Dukes E, Hoffman DL, Tai K-S, Stacey B. Pain severity in diabetic peripheral neuropathy is associated with patient functioning, symptom levels of anxiety and depression, and sleep. Journal of pain and symptom management. 2005;30(4): 374-385.

2. Zelman DC, Brandenburg NA, Gore M. Sleep impairment in patients with painful diabetic peripheral neuropathy. Clin J Pain. 2006;22(8): 681-685.
SAT-129 Interactions Between Macrophages and Cancer Stem-Like Cells Promote Mammary Tumor Angiogenesis Under Obesity
Authors: Hillers-Ziemer Lauren , McMahon Rachel , Hieptas Margaret , Paderta Gretchen , McCready Jessica , LeBeau Jennelle , Arendt Lisa
Published: May 2020

Obesity is a growing health concern worldwide and increases the incidence of multiple types of cancer, including breast cancer. Obese breast cancer patients often develop more aggressive tumors than lean patients and have increased risk for metastasis, tumor recurrence and mortality. Here, we sought to address how obesity alters the biology of breast cancer to promote aggressive tumors. To induce obesity, we fed mice either a control diet (CD) or high fat diet (HFD) for 16 weeks, then transplanted Met-1 tumor cells into mammary fat pads and monitored tumor growth. At end stage, tumors from HFD-fed mice were significantly larger than tumors from CD-fed mice, suggesting obesity promotes tumor growth. To investigate how obesity promotes tumor aggression, we dissociated the tumors from CD- and HFD-fed mice and plated isolated tumor cells in tumorsphere and invasion assays to test for cells with cancer stem-like cell (CSC) properties. Tumor cells from HFD-fed mice demonstrated increased tumorsphere formation and increased capacity for invasion compared to tumor cells from CD-fed mice, suggesting that obesity selects for tumor cells with CSC properties. Next, to address how obesity impacts the tumor microenvironment, we evaluated tumor necrosis and blood vessel formation through CD31 staining. Tumors from HFD-fed mice had significantly less necrosis and greater CD31 staining than those from CD-fed mice, suggesting that obesity promotes tumor angiogenesis. Since obesity promotes chronic, macrophage-driven inflammation within adipose tissue of the mammary gland, we stained tumors for the macrophage marker, F4/80. As with obese mammary glands, tumors from HFD-fed mice had significantly greater macrophage recruitment than tumors from CD-fed mice, together suggesting that obesity alters the tumor microenvironment. To determine how obesity stimulates tumor angiogenesis, we performed an in vitro assay by culturing dissociated tumor cells from HFD or CD-fed mice alone or with macrophages. Conditioned media (CM) isolated from tumor cells from HFD-fed mice cultured with macrophages enhanced the ability of endothelial cells to form networks in vitro. In contrast, CM from HFD tumor cells alone, macrophages alone, or those from CD-fed mice did not promote network formation. Together, these results suggest that cooperation between macrophages and tumor cells from HFD-fed mice promotes angiogenesis. Next, to investigate how macrophages and tumor cells interacting in obesity, we depleted macrophages using anti-F4/80 antibodies in CD-fed and HFD-fed tumor-bearing mice. In HFD-fed mice, macrophage depletion significantly reduced tumor volume and CD31 staining while increasing tumor necrosis compared to controls. Obesity promotes interactions between tumor cells and macrophages to enhance tumor angiogenesis and progression.
MON-343 The Mystery of Recurrent PTH-Independent Hypercalcemia with Severe Hypophosphatemia
Authors: Shaikh Bilal , Pulipati Vishnu Priya , Meier Garnet
Published: May 2020

Background

The differential diagnoses for PTH independent hypercalcemia with hypophosphatemia are broad. Careful history with systematic evaluation for possible etiologies is necessary for accurate diagnosis and timely therapeutic intervention.

Clinical Case

A 72-year old female was referred to our clinic for evaluation of hypercalcemia with low iPTH level. Review of lab workup over the past two years showed frequent occurrences of mild hypercalcemia, low iPTH and moderate to severe hypophosphatemia. She denied use of calcium, vitamin D, Vitamin A or herbal supplements and over the counter (OTC) medications. Age-appropriate cancer screening was up to date. She had no clinical evidence of granulomatous diseases or malabsorption syndrome. Labs revealed corrected calcium (cCa) 9.9 (8.5-10.5 mg/dL), iPTH 6.36 (12-88 pg/mL), phosphate 1.5 (2.5-4.5 mg/dl), magnesium 1.6 (1.8-2.7 mg/dl), 25-OH Vit D 30 (30-100 ng/mL), PTHrP 12 (14-27 pg/mL), 1,25 OH Vit D 32 (18-72 pg/ml), TSH 1.8 (03-5.6 uIU/mL), GFR 49 (>90 mL/min/1.73 m2) and bicarbonate 30 (23-31 mEq/L). FGF23, 1-mg ODST and SPEP were normal. 24-hour urine phosphate was 3 mg/24h, ruling out renal phosphate wasting.

Two months later, she developed myalgia and generalized weakness. Labs showed cCa 11.3mg/dl, iPTH 3.79 pg/ml, phosphate <1 mg/dl, magnesium 1.2 mg/dl, bicarbonate 33 mEq/L. She was hospitalized for severe hypophosphatemia. Here, she revealed she was intermittently taking a “milky” antacid obtained from Mexico, for her GERD. She required IV phosphate and magnesium replacement and her mineral abnormalities normalized within 24 hours. She was advised to stop use of OTC antacids and provided daily phosphate and magnesium supplementation. 4 weeks later, she developed recurrent hypercalcemia 10.4 mg/dl, hypophosphatemia 1.1 mg/dl and alkalosis with bicarbonate 35 mEq/L, which corrected with supervised phosphate and magnesium supplementation and restricted access to home OTC medications.

Discussion

Milk-alkali syndrome, characterized by the triad of hypercalcemia, metabolic alkalosis and renal failure, has been classically associated with ingestion of large amounts of milk and absorbable alkali. Once a common cause of hypercalcemia, its incidence declined rapidly with advent of new therapies for PUD. Recently, this syndrome, now described as calcium-alkali syndrome (CAS) has re-emerged due to use of high dose calcium carbonate supplements and OTC antacids, with a prevalence of 9-12% among hospitalized patients with hypercalcemia.

We hypothesize our patient’s mineral abnormalities are explained by CAS. High doses of calcium from antacids can bind phosphate in the gut, leading to poor phosphate absorption and hypophosphatemia.

Conclusion

CAS is emerging as a frequent cause of hospital admissions for hypercalcemia. Severe hypophosphatemia can be a rare manifestation. Primary therapy is withdrawal of offending agent.
MON-357 Craniofacial Deformities with Hypercalcemia: A Rare Case of Co-Existing Primary Hyperparathyroidism and Paget’s Disease of the Bone Since Young Adulthood
Authors: Nagaratnam Shamharini , Mustafa Norlaila , Karupiah Malathi
Published: May 2020

Background:

Primary Hyperparathyroidism (PHPT) and Paget’s Disease of the Bone (PDB) are two distinct bone mineral disorders which rarely co-exist. It has been very scarcely reported in the elderly but almost unheard of in young adults.

Clinical case

A middle-aged Indian lady presents with multiple and recurrent facial and jaw bony swellings, since the age of 12. She had normal developmental as a child, without visual, auditory deficits or limb deformities. No family history of hypercalcemia or endocrine disorders was elicited. At initial diagnosis, biochemical parameters were consistent with PHPT, with mild to moderate hypercalcemia (2.6-3.0 mmol) and concomitant hypophosphatemia (0.6-0.8 mmol/L), elevated intact PTH 10.6pmol/L and ALP persistently more than 350 U/L. She had undergone multiple surgeries to remove the bony swellings, presumed to be brown tumours. She developed medullary nephrocalcinosis approximately 30 years after onset of illness. Over a span of three decades, numerous modalities were employed in attempt to localise the parathyroid lesion, including imaging (ultrasonography, sestamibi with SPECT CT, FDG PET),angiography, venous sampling and exploratory neck surgeries which were unsuccessful. Due to failure in localising the offending parathyroid lesion, it was conceded to maintain her on medical therapy.She was initially started on oral phosphate therapy, intranasal calcitonin and subsequently calcimimetics. Aside from rising ALP levels, her other biochemical parameters remained static. Her diagnosis was re-evaluated when she presented with osteomyelitis of the right mandible requiring surgery. Pre -operative CT imaging showed mixed lytic and sclerotic lesions at the mandible, maxilla, facial bones and skull. It also revealed diffuse thickening of the calvarium with narrowing of the posterior fossa resulting in hydrocephalus, requiring a ventriculoperitoneal shunt insertion. Histopathological examination of the mandible showed a background of osteosclerosis. These findings were inconsistent with PHPT and was most often described in PDB. On the other hand, a repeated skeletal survey showed generalised osteopenia in the small bones of the hand with subperiosteal and terminal phalanges reabsorption which was in keeping with PHPT. Her pelvis, spine and long bones remained normal and bone densitometry was preserved. It was concluded that this patient was suffering from dual pathology, PHPT and PDB and was commenced on bisphosphonates.

Conclusion:

This lady presented with two diseases which simulate each other despite not being etiologically linked. The aberrancy in the age of onset and the overlapping clinical features of the dual pathology imposed a significant challenge in making the correct diagnosis. Retrospectively, histopathological examination of the bone at an earlier stage of disease may have been the key to solving this perplexing case.
SUN-662 Praliciguat, a Clinical-Stage Soluble Guanylate Cyclase Stimulator, Improves Lipid Handling and Insulin Sensitivity in Diet-Induced Obese Mice
Authors: Schwartzkopf Chad D , Liu Guang , Hadcock John R , Currie Mark G , Masferrer Jamie L , Jones Juli E
Published: May 2020

Praliciguat (PRL) is a soluble guanylate cyclase (sGC) stimulator which in animal models distributes broadly to tissues and elicits hemodynamic, anti-inflammatory, anti-fibrotic, and metabolic effects. Here, we assessed metabolic effects of PRL in a mouse diet-induced obesity model.

Six-week-old male C57BL/6N mice were maintained on a low-fat diet (LFD, lean mice) or placed on a 60% high-fat diet (HFD, obese mice). At age 14 weeks, one group of obese mice was maintained on HFD (obese controls) and one group of obese mice was switched to HFD formulated with PRL to achieve a Cmax similar to a 6-mg/kg oral dose (PRL-treated mice). After 38 days of treatment, an oral lipid tolerance test (LTT) was conducted. In a 2nd study under the same dosing paradigm, overnight fasted blood and organs were collected on day 28.

As reported previously (1), compared to obese controls, PRL-treated mice had lower fasting insulin (-28%), HOMA-IR (-26%) and triglycerides (-16%) as well as lower plasma triglycerides AUC after LTT (-34%). Gene expression and phosphorylated proteins associated with insulin pathways were measured in liver, skeletal muscle and white adipose tissue. PRL treatment normalized expression of genes involved in lipid handling (liver Pnpla3, Slc27a1, Lpl; muscle Lipe; white adipose tissue Fdft1, Ppara). Expression of proinflammatory genes (liver Tnf; muscle Ccl2; white adipose tissue Akt1, Icam1) was lower in PRL-treated mice than in obese controls. Liver insulin signaling was assessed by determining pAKT (T308) and pAKT (S473), markers of PI3K pathway activity and pERK, a marker of MAPK pathway activity. Compared to lean mice, pAKT (T308) and pERK were lower in obese controls, whereas pAKT (S473) was similar; PRL-treated mice had higher pAKT (T308) and pAKT (S473) compared to obese controls while pERK was unchanged. In skeletal muscle and white adipose tissue, levels of pVASP, a key mediator of the sGC pathway, were higher in PRL-treated mice than in obese controls.

In summary, PRL improved insulin sensitivity and lipids in diet-induced obese mice by affecting mechanisms of lipid handling, inflammation, and insulin signaling in key tissues associated with metabolism.

1. Author information excluded, 1924-P: Praliciguat, a Clinical-Stage sGC Stimulator, Improves Insulin Sensitivity, Lipid Tolerance, and Energy Utilization in a Mouse Diet-Induced Obesity Model Housed at Thermoneutrality. Diabetes, 2019. 68(Supplement 1): p. 1924-P.
MON-184 Disrupted ACTH-Cortisol Temporal Coupling in Healthy Men After an Overnight Fast, and the Modulatory Role of Orally Ingested Macronutrients
Authors: Iranmanesh Ali , Veldhuis Johannes D
Published: May 2020

While long term fasting is reported to augment the corticotropic function, effect of short term (overnight) fasting on ACTH-cortisol coordinated release pattern and potential effect(s) of nutrient intake is not fully defined. Eleven healthy men (age: 33-70 yrs, BMI 20.4-31.5 kg-m2) were studied after overnight fast on 4 separate days, involving oral ingestion of 300 ml of either water, dextrose, protein, or lipid solutions. Test meals were isocaloric (400 kcal). Sessions were 6.5 h long, starting at 0800-0900 hrs. Blood was collected at 10-min intervals for ACTH (pg per mL), and cortisol (µg per dL) measurements. Linear regression, cross-correlation, deconvolution, and ApEn were used for data analyses. ACTH and cortisol concentration time series during short-term fast (water day) were found not to be chronologically coupled per linear regression (r2= 0.0014, P=0.82), and cross-correlation (r= - 0.156, lag=150 min) statistics. Oral intake of the 3 macronutrients improved the temporal relationship between ACTH and cortisol concentrations, verified by linear regression (r2:P- dextrose 0.54:0.0001, protein 0.65: 0.0001, lipid 0.42:0.0001), and cross-correlation (r:lag in min- dextrose 0.8:10, protein 0.77:10, lipid 0.78:20). Oral ingestion of either macronutrient did not significantly alter mean ACTH and cortisol concentrations and their respective secretion pattern (total, pulsatile, basal) over the period of 6.5 hr. However compared to the control (water) session, dextrose ingestion evoked less frequent and larger ACTH secretory bursts, and more regular ACTH and cortisol secretory patterns. In this study, we have observed lack of concordance between ACTH and cortisol after overnight fasting, which is restored with oral intake of macronutrients. This effect appears to be uniform among the 3 macronutrients, except for less frequent and lager ACTH bursts and more regular ACTH and cortisol release events after dextrose intake. These findings and the specific role of nutrients being direct or via physiologic nutrient-induced hormonal adaptation warrants future investigation.
MON-462 Rebel Nodule or Reluctant Gland? the Challenge Presented by Heterophile Antibodies
Authors: Sharma Pranjali , Ding Linda , McGarvey Megan Elizabeth
Published: May 2020

Introduction:

Interpretation of thyroid function tests (TFTs) in background of non-specific symptoms concerning for hypothyroidism, has become challenging with assay interference. Heterophile antibody interferences are both test and laboratory platform dependent. We present a case of a toxic nodule erroneously diagnosed as isolated central hypothyroidism due to heterophile antibody interference.

Case:

A 38 year old lady was referred to Endocrinology for possible central hypothyroidism with symptoms of progressive fatigue, 40lb unintentional weight loss, poor appetite, nausea, intermittent diarrhea/constipation, occasional cold intolerance and intermittent lightheadedness. TFTs suggested low TSH 0.175 mcIU/ml (N 0.35-3.8 mcIU/ml) and low FT4 0.74 ng/dl (N 0.8-1.8 ng/dl). Pituitary hormone evaluation revealed normal ACTH, AM cortisol, IGF-1, prolactin and FSH. A pituitary MRI was normal.

Two months later, she had worsening fatigue, anxiety with palpitations and tremors, and 14lb weight gain. TFTs again confirmed low TSH (0.575 mcIU/ml) and lower FT4 (0.70 ng/dl). Empirical weight-based levothyroxine (LT4) supplementation was initiated for central hypothyroidism. Six weeks later, TFTs showed hyperthyroidism (TSH <0.005 mcIU/ml, FT4 1.57 ng/dl). The patient endorsed worsening lightheadedness and palpitations on LT4, which resolved on LT4 discontinuation. One month later, TFTs were abnormal again (TSH 0.047 mcIU/ml, FT4 0.74 ng/dl).

Due to persistent discordance in symptoms and biochemical tests, TFTs were evaluated for heterophile antibody interference. While HAMA-treated TSH remained low (0.04 mIU/l), FT4 by equilibrium dialysis (FT4 ED) was normal (1.1 ng/dl, regular assay 0.74 ng/dl), suggesting subclinical hyperthyroidism. A thyroid uptake scan confirmed an autonomous toxic right thyroid nodule with suppressed remaining gland. Patient ultimately underwent 15 mCi RAI ablation of the nodule. TFTs done 1 month post-RAI suggested normal TSH (1.2 mcIU/ml) and normal FT4 ED (1 ng/dl). Previous symptoms have since resolved.

Conclusion:

Current methods of TFTs are generally reliable in diagnosing and monitoring thyroid disease. Rarely, medications, supplements, and endogenous antibodies can bind to TSH, T4 or lab reagent, resulting in inaccurate values. This has become increasingly common with use of high dose biotin. TSH with HAMA/heterophile antibodies and FT4 ED are more accurate forms of diagnostic testing.

When approaching patients with symptoms not consistent with typical hypo- or hyperthyroidism and are not responding as expected to therapy, it is important to consider more accurate testing to rule out assay errors.

References:

1. Soh SB, Aw TC. Laboratory Testing in Thyroid Conditions - Pitfalls and Clinical Utility. Ann Lab Med. 2019;39(1):3-14. doi:10.3343/alm.2019.39.1.3

2. Spencer C., PhD. Assay of Thyroid Hormones and Related Substances
SUN-086 Pilot Study Using Aromatase Inhibitor in Puberty of Boys With Partial Androgen Insensitivity: Report of Three Cases
Authors: Maciel-Guerra Andrea Trevas , de Andrade Juliana Gabriel Ribeiro , de Souza Arina Tavares , Campos Mariana Baldini , Marques-Junior Hercules Oliveira , Guaragna Mara Sanches , Fabbri-Scallet Helena , de Mello Maricilda Palandi , Guerra-Junior Gil
Published: May 2020

Background: Partial Androgen Insensitivity Syndrome (PAIS) (OMIM # 312300) is one of the causes of Disorders/Differences of Sex Development with 46,XY karyotype and normal or increased testosterone secretion that results in atypical genitalia. In general, it is caused by inactivating mutations on AR gene (Xq12 - OMIM * 313700), therefore it presents an X-linked recessive inheritance. Individuals raised as males have incomplete puberty with micropenis, sparse hairs, gynecomastia and increased LH, testosterone and estradiol serum levels. Therefore, the use of aromatase inhibitor in these cases becomes a logical indication aiming to increase testosterone levels in the tentative of supplanting its peripheral resistance and decreasing estrogen levels. Objective: To present clinical and laboratory data during the first year of use of aromatase inhibitor in puberty of three boys with confirmed molecular diagnosis of PAIS. Results: All subjects used letrozole (2.5 mg daily during 12 months). None reported significant side effects. Cases 1 and 2 are brothers (p.Ala596Tre). Case 1: Onset of treatment at age 12; height changed from 158 cm (z = +1.15) to 166 cm (z = +1.21), Tanner from G2P2T2 to G3P3T1, penis from 4.0 to 6.5 cm, LH from 7.5 to 18.3 IU/L (NR: 1.5 to 9.3 IU/L), testosterone from 361 to 1,347 ng/dL (NR: 165 to 763 ng/dL), estradiol from 35 to <5.0 pg/mL (NR: < 40 pg/mL) and bone age remained at 13 years. Case 2: Onset of treatment at age 11; height changed from 156 cm (z = +1.71) to 163 cm (z = +1.80), Tanner from G2P2T2 to G3P3T1, penis from 3.5 to 5.5 cm, LH from 4.8 to 12.4 IU/L (NR: 1.5 to 9.3 IU/L), testosterone from 259 to 1,069 ng/dL (NR: 165 to 763 ng/dL), estradiol from 28 to <5.0 pg/mL (NR: < 40 pg/mL) and bone age remained at 12.5 years. Case 3 (p.Ser597Arg): Onset of treatment at age 12; height changed from 153 cm (z = +0.49) to 161 cm (z = +0.55), Tanner from G2P2T1 to G3P3T1, penis from 4.0 to 7.0 cm, LH from 8.5 to 17.2 IU/L (NR: 1.5 to 9.3 IU/L), testosterone from 280 to 889 ng/dL (NR: 165 to 763 ng/dL), estradiol from 32 to <5.0 pg/mL (NR: < 40 pg/mL) and bone age remained at 13.5 years. Discussion: There are no reports in the literature of the use of aromatase inhibitor in PAIS. The results of this pilot study (gynecomastia regression, significant testosterone level increases with decrease in estradiol levels, increment in height without bone age advancing, progression of puberty and penile growth) are sustaining for the indication of this treatment in boys with PAIS during puberty.
SAT-220 A Misdiagnosis Causing a Feared Complication
Authors: Mroueh Gabriela , Burks James K
Published: May 2020

Adrenal incidentalomas are being increasingly found with the widespread use of thoracic and abdominal imaging. Clinicians must determine the nature of the mass to decide what treatment, if any, is needed. All patients should undergo biochemical testing to rule out hypercortisolism, pheochromocytoma and if hypertension is present, primary hyperaldosteronism. These patients should ideally be evaluated by endocrinologists as misdiagnosis can lead to complications.

A 60-year-old African American female with a history of hypertension and type 2 diabetes, was admitted to the internal medicine ward with intractable vomiting, abdominal pain and hypotension. Two weeks prior to admission, she had undergone a left sided adrenalectomy for a diagnosis of primary hyperaldosteronism. An adrenal adenoma was incidentally found 1 year before surgery during abdominal imaging done for diverticulitis. She was immediately referred to a surgeon for further work up and evaluation. The work up done for the adrenal incidentaloma included renin, aldosterone and plasma fractionated metanephrines. Plasma renin was low (0.2 ng/mL/hr, n: 0.5-4.0 ng/mL/hr), and Aldosterone was normal (8.1 ng/dL, n<16 ng/dL) and the Aldosterone/ Renin ratio was elevated. No confirmatory test was done and no evaluation for hypercortisolism was done either. Plasma fractionated metanephrines were normal.

During current hospitalization, an AM cortisol was 1.5 mcg/dL (n: 6-28 mcg/dL). An ACTH stimulation test was done which showed an inadequate response. She was subsequently started on stress dose steroids with rapid improvement in her symptoms. She was discharged with hydrocortisone and has been followed in our endocrinology clinic. She has yet to fully recover HPA axis but is currently on low dose Hydrocortisone and doing well.

This patient was misdiagnosed with primary hyperaldosterenism when she most likely had subclinical hypercortisolism. Patients with primary hyperaldosteronism typically have plasma aldosterone > 15 ng/dL and low levels of plasma renin, with a ratio of plasma aldosterone to plasma renin activity > 20. Low levels of both plasma renin activity and aldosterone suggest nonaldosterone mineralocorticoid excess. Cushing syndrome can cause similar findings. Confirmatory tests should be done, and most patients require bilateral catheterization of the adrenal veins to measure cortisol and aldosterone levels to confirm whether the aldosterone excess is unilateral or bilateral. A 1 mg overnight dexamethasone suppression test is recommended for all adrenal incidentaloma patients to exclude asymptomatic hypercortisolism.
OR19-01 IHC-Guided Capture of Adrenocortical Zones from Archival Formalin-Fixed, Paraffin-Embedded Adrenal Tissue Allows the Study Of RNA Expression Profiles
Authors: Plaska Samuel , Baker Jessica , Blinder Amy , Lim Jung Soo , Rainey William E
Published: May 2020

Introduction: Characterization of human adrenal RNA has relied on fresh tissue, or laser capture from OCT-embedded frozen tissue. These approaches have allowed identification of differences between zones of the adrenal cortex, but the need for fresh or frozen material has limited access for most researchers and has limited the number of samples that can be studied. In order to expand tissue availability and researcher access, we examined the use of archival formalin-fixed, paraffin-embedded (FFPE) adrenals for the capture and analysis of RNA from each adrenal zone.

Methods: 13 normal adrenals were obtained from deceased renal donors. Following FFPE, tissue serial sections were examined for zonal histology. Immunohistochemistry (IHC) was used to guide the capture of specific adrenal zones from FFPE tissue. CYP11B2, CYP17A1, and CYB5A IHC was used to visualize the zona glomerulosa (ZG), zona fasciculata (ZF), and zona reticularis (ZR) respectively. Serial unstained sections were then dissected under a dissection microscope based on IHC-guided visualization of the ZG, ZF, and ZR. Following capture of zones and isolation of RNA, quantitative PCR (qPCR) was used to examine zonal expression of transcripts for the IHC markers. Using housekeeping genes for normalization, specific zonal markers identified successfully isolated zones.

Results: Adrenals with clear zonal expression of CYP11B2 (ZG), HSD3B2 (ZG/ZF), and CYB5A (ZR) were included for study. Based on marker inclusion criteria, 3 ZG, 3 ZF, 3 ZR, and 3 medulla samples were studied. Using these samples, confirmatory markers of ZG (VSNL1), ZF (CYP17A1), ZR (SLC27A2), and medulla (TH) were analyzed by qPCR. Levels of these transcripts segregated as expected in the adrenal zones.

Discussion: The use of archival normal and pathologic adrenal tissue for RNA analysis would increase the number of samples available to many research groups. Our data demonstrates the ability to capture and use FFPE tissue for the capture and analysis of RNA. Future comparison of normal adrenal zones to adrenal tumor phenotypes will improve our understanding of tumor biology and provide potential genetic markers for targeted therapeutics.