bluuebunny/crossref_metadata_2025 huggingface dataset:
MON-118 Reducing Unnecessary Repeat HbA1c Testing in a Tertiary Academic Hospital
Authors: Rajeswaran Vamana , Alexander Lisa , Alwithenani Raad , Jaskolka Diana , Usmani Shirine , Tran Susan , Khan Sarah , Yip Paul , Mukerji Geetha
Published: May 2020

Background

Glycated hemoglobin (HbA1c) is a surrogate marker of glycemia over the preceding three months, where the last 30 days contributes to 50% of the value (1). Therefore guidelines often recommend repeating HbA1c only after 3 months in most situations (2), but repeat testing of HbA1c is often conducted earlier when not warranted (3). We aimed to conduct a Quality Improvement (QI) initiative to reduce unnecessary repeat testing of HbA1c at a large tertiary care academic hospital in Toronto, Ontario by 50% by May 2020.

Methods:

The Model for Improvement Quality Improvement (QI) framework was used in the design of the QI project to reduce repeat HbA1c. Problem characterization was conducted to understand root causes and iterative Plan-Do-Study-Act cycles were used to develop a change intervention. Unnecessary HbA1c tests were the primary outcome and defined as repeat HbA1c testing within 60 days; the top three specialities that ordered unnecessary HbA1c tests were targeted for education prior to implementation of the change intervention.

Results:

Baseline data on all HbA1c tests in 2018 revealed repeat testing in approximately 10% of 15,290 HbA1c tests, with estimated potential savings of more than $11,000 based on the provincial reimbursement rate. The top 3 ordering specialities targeted for education included Nephrology (n=410 repeat HbA1c tests), Cardiology (n=246 repeat HbA1c tests), and Endocrinology (n=136 repeat HbA1C tests). Root cause analysis revealed that providers often ordered repeat HbA1c tests due to being unaware of prior results and a knowledge gap of testing recommendations. A laboratory forced function will be implemented on December 1, 2019 to cancel any repeat HbA1c tests within 60 days and calls to the lab to add HbA1c testing will be tracked.

Conclusions:

Repeat HbA1c testing is frequent in hospital settings and can be an important target for QI efforts. A forced function to cancel processing of repeat HbA1c may be an appropriate QI intervention to reduce repeat testing to promote high-value care. Ongoing data analysis will be conducted to assess the impact of this intervention.

References

(1)

Goldstein DE, Little RR, Lorenz RA, Malone JI, Nathan D, Peterson CM, Sacks DB. Tests of Glycemia in Diabetes. Diabetes Care 2004;27(7): 1761-1773.

(2)

Berard LD, Siemens R, Woo V. Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada: Monitoring Glycemic Control. Can J Diabetes 2018;42(Suppl 1):S47-S53.

(3)

Chami N, Simons JE, Sweetman A, Don-Wauchope AC. Rates of inappropriate laboratory test utilization in Ontario. Clinical Biochemistry 2017;50: 822-827.
SUN-915 Diffuse Large B Cell Lymphoma Presents with Femur Fracture and Involvement of Thyroid Gland
Authors: McNierney Dakota A , Vazquez Bianca , Shahlapour Mahmood , Rahman Samina , Horani Mohamad Hosam
Published: May 2020

Diffuse Large B-Cell Lymphoma (DLBCL) is the most common type of Non-Hodgkin Lymphoma worldwide. It is an aggressive lymphoma that arises from germinal center or post-germinal center B cells. Patients typically present with a rapidly enlarging symptomatic mass, most usually nodal enlargement in the neck or abdomen, but may present with a mass lesion anywhere in the body. However, multiple sites of involvement occur less frequently. We report a case of a 74- year-old woman who initially presented to the hospital for evaluation of a right distal femoral fracture which resulted from a fall at home. Lytic lesions were found in the distal femur and proximal fibula. She was also found to have hypercalcemia with a calcium level of 12.2. A CT- guided biopsy confirmed the diagnosis of Diffuse Large B-Cell Lymphoma with non-germinal center phenotype. A radical resection of the right femur was performed, and a distal femoral replacement hinged knee arthroplasty was done successfully. A venous port was also placed for chemotherapy administration. The patient was admitted to inpatient rehab with plans to initiate chemotherapy. 6 weeks later, the patient presented to the emergency department (ED) with a chief complaint of difficulty hearing, ear discomfort, dysphagia, and dyspnea for 3 weeks. These symptoms prompted her medical oncologist to send her to the ED and postpone chemotherapy that was to begin on that day. Physical examination found the patient to have neck fullness, large palpable lymph nodes, and stridor. Upon evaluation she was also found to have impaired renal function (Blood urea nitrogen 41, Cr 3.10), severe hypercalcemia (Corrected calcium 16.2), and hypokalemia (Potassium 2.8). An EKG demonstrated sinus rhythm and non-specific t-wave abnormality. A chest radiograph showed an enlarged thyroid extending into the superior mediastinum. There was also tracheal narrowing, and tracheal deviation to the left. She was admitted to the Intensive Care Unit (ICU) for treatment of hypercalcemia and stridor. The patient was aggressively treated with fluid management. She also received loop diuretics, steroids, and calcitonin. Once stabilized, a fine needle aspiration of the thyroid gland identified further involvement by diffuse B-Cell Lymphoma. The medical oncologist then initiated R-CHOP chemotherapy. The stridor resolved and the patient’s symptoms significantly improved. After two weeks in the ICU she was discharged to a rehab facility where chemotherapy was continued. This is a rare case of rapidly growing non-germinal center DLBCL that presented with involvement of both the bone and thyroid gland causing life-threatening symptoms. Upon reviewing the literature, there has been no documented cases of DLBCL simultaneously involving the bone and thyroid gland. The patient responded well to R- CHOP chemotherapy and continues to receive treatment in an outpatient facility.
SUN-043 Galactorrhea and Hyperprolactinemia in a Transgender Female
Authors: Unnithan Rachna , Elson Diane Frances , Shenker Yoram
Published: May 2020

Background: Galactorrhea is a rare manifestation of hyper-prolactinemia in males and post-menopausal females, however the hormonal milieu of the transgender female may increase its incidence

Clinical Case: A 43 year old transgender female presented with three years of bilateral breast discharge. She had chronic, stable headaches and fatigue, but no vision changes or other symptoms. Notably, she had breast augmentation surgery with saline breast implants placed shortly before the galactorrhea commenced. She was on a stable dose of estradiol tablets 1 mg twice daily for six years. On physical exam she had pronounced bilateral breast discharge of a milky quality with nipple compression. Prolactin levels were checked several times and were 40-50 ng/mL, TSH was 2.36 uIU/mL. An MRI showed a left inferior pituitary lesion measuring 6 mm x 3 mm x 5 mm with no mass effect on adjacent structures. Her breast discharge was not bothersome to her, and her pituitary lesion was small. It was unclear whether there was a relationship between her prolactin levels and the lesion seen on MRI, as we expected more pronounced prolactin elevation with a prolactinoma. Instead, given the timing of her symptoms in relation to her breast augmentation surgery, her galactorrhea and hyper-prolactinemia were thought to be the result of nipple irritation related to her breast implants combined with a hyper-estrogenemic state.

Clinical Lessons: In the setting of a prolactin secreting micro-adenoma, galactorrhea in a male is highly unusual. This case highlights the importance of recognizing that the unique medical and surgical characteristics of male to female transgender patients can lead to hyper-prolactinemia and galactorrhea.

Reference: Reisman T, Goldstein Z. Case report: induced lactation in a transgender woman. Transgender Health. 2018;3(1):24-26.
SAT-420 Interaction Between Gene Polymorphisms and Urine Iodine Levels on Susceptibility to TPOAb Positivity in the Chinese Population
Authors: Han Bing
Published: May 2020

Objective: Hashimoto thyroiditis, characterized by positive thyroid peroxidase antibodies (TPOAbs), is caused by the interaction of genetic and environment factors. The aim of this study was to clarify the interaction of gene polymorphisms and iodine intake in the incidence of TPOAb positivity. Methods: 1733 subjects were included in this study. Genomic DNA was extracted from peripheral blood white cells. Seven SNPs (rs10944479, rs11675434, rs1230666, rs3094228, rs653178, rs9277555 and rs301799) were selected for genotyping. Thyroid hormones and autoimmune antibodies (TPOAb and TGAb) were determined using the electrochemiluminescence immunoassay method. Results: The mean TSH level in TPOAb-positive subjects was higher than in TPOAb-negative subjects (P<0.001). There were no significant differences in urine iodine and blood iodine between these two groups. Genotype GG of rs9277555 and genotype TT of rs11675434 were associated with an increased risk of TPOAb positivity. Logistic regression analysis showed rs9277555 was associated with TPOAb positivity in all models. Furthermore, rs9277555 was also associated with TPOAb levels in linear regression analysis. The cross-validation consistency and the testing accuracy indicated that there were no significant differences between SNPs and urine iodine interaction. Conclusion: rs9277555 was associated with an increased risk of TPOAb positivity in a Chinese Han population. Furthermore, there was no gene polymorphisms-iodine intake interactions in our cohort.
OR06-06 Pituitary Tumors and Immortalized Cell Lines Generated by Cre-Inducible Expression of SV40 T-Antigen
Authors: Mortensen Amanda Helen , Daly Alexandre , Dudley Lindsey Anne , Camper Sally Ann
Published: May 2020

Pituitary and hypothalamic cell lines have been developed by targeted oncogenesis. This involved using cell-specific transcriptional regulatory sequences to drive expression of large and small SV40 T-antigens in transgenic mice. Invariably, tumors develop in some of the mice, and the cells in these tumors can sometimes be adapted to grow in culture into stable, immortalized cell lines that maintain some of the features of differentiated cells. Cell lines that represent pre-gonadotropes (αT3-1), gonadotropes (LβT2), precursors to the POU1F1 lineage (GHFT1, Pit1-zero), differentiated cells of the POU1F1 lineage (Pit1-triple, TaT1, and Pit1-PRL), and GnRH neurons (GT1-1) have been made by this approach. Tumors often develop early and cause infertility or death. To increase the opportunity for generating cell lines and to make it feasible to follow the process of tumorigenesis, we developed a mouse strain that expresses SV40 T-antigens in response to cre-recombinase. Using CRISPR/Cas9 we inserted an 8 kb cassette with coding sequences for SV40 T-antigens and IRES-GFP into the Rosa26 locus, downstream from a stop sequence flanked by loxP sites: Rosa26LSL-SV40-GFP. 30% of the progeny born from hybrid zygotes injected with template DNA, CRISPR/Cas9, and sgRNA had correctly targeted the Rosa26 locus. These mice were mated with previously established Prop1-cre and Tshb-cre transgenic lines. The majority of Rosa26LSL-SV40-GFP/+; Prop1-cre and Rosa26LSL-SV40-GFP/+; Tshb-cre mice developed dwarfism and large tumors by 4 wks. The pituitaries of Rosa26LSL-SV40-GFP/+; Tshb-cre mice appear grossly normal at birth, but they are enlarged and showing evidence of increased vascularization by 2 wks. Flow-sorted GFP-positive cells from Rosa26LSL-SV40-GFP/+; Prop1-cre and Rosa26LSL-SV40-GFP/+; Tshb-cre mice express Prop1 and TSH, respectively. Tumors from Rosa26LSL-SV40-GFP/+; Tshb-cre mice were adapted to growth in cell culture. We have established a thyrotrope-like cell line that expresses Cga and Pou1f1. These studies demonstrate the utility of the novel, Rosa26LSL-SV40-GFP mouse line for reliable targeted oncogenesis and development of unique cell lines.

The authors have nothing to disclose.
SAT-741 Salivary Cortisol and Cortisone Measurement Provide a Novel and Non-Invasive Method of Monitoring Medical Therapy in Cushing’s Syndrome
Authors: Manson Megan Elizabeth , Adam Safwaan , Steimer Anna-Elisabeth Minder , Abdullah Noor Rafhati Adyani , Higham Claire Emily , Meredith Suzanne , White Anne , Cottrell Elizabeth Claire , Monaghan Phillip , Keevil Brian George , Trainer Peter James
Published: May 2020

Introduction:

Salivary glucocorticoids (cortisol [SalF], cortisone [SalE]) are collected non-invasively, unaffected by variation in cortisol binding globulin (CBG) and an established tool in the investigation of Cushing’s syndrome (CS). We have previously shown a strong correlation between salivary glucocorticoids and circulating free serum cortisol, better than that with total serum cortisol. Measurement by liquid chromatography with tandem mass spectrometry (LC-MS/MS) permits lower limits of quantification, eliminates cross-reactivity both between cortisol and cortisone, and by metyrapone-induced elevations in 11-deoxycortisol.

Previous studies in CS have demonstrated that a mean (based on 5 samples during a single day) serum cortisol (serumF) of 150-300 nmol/l equates to a normal isotopically calculated cortisol production rate. We report the use of salivary glucocorticoid measurement in metyrapone-treated CS patients undergoing dose titration to achieve a mean serumF of 150-300 nmol/L.

Methods:

Seventeen (11 females; age-range 24-74 years) patients with CS undergoing dose titration with metyrapone were studied on 44 occasions: 15 ACTH-dependent (5 ectopic) and 2 adrenal.

24 healthy male volunteers (HV) were also studied.

Both cohorts had paired serumF and SalE and SalF samples collected at 5 time-points (10:00; 11:30; 13:00; 14:30; 16:00).

Serum and salivary glucocorticoids were measured using LC-MS/MS.

The TR for salivary glucocorticoids was determined from the mean SalE and SalF in HV whose mean serumF (n=20) was in the desired range (150-300 nmol/L). In CS patients the metyrapone dose had been titrated to achieve a mean serumF of 150-300 nmol/L on 14 (out of 44) occasions.

Results:

Mean SalE (r=0.70; p<0.001) and mean SalF (r=0.51; p<0.001) showed a significant correlation with serumF. The TR from HV for mean SalE and mean SalF were 5.8–24.7 nmol/L and 0.6-5.4 nmol/L respectively.

In CS patients, SalE had greater sensitivity (79% vs. 75%) and specificity (80% vs. 57%) in predicting a mean serumF in the TR than SalF.

Conclusion:

We have demonstrated a close correlation between mean SalE and mean serumF in metyrapone treated CS patients. Salivary glucocorticoids within the derived TR were highly predictive for a target serumF. It is unsurprising, due to the effect of CBG on serumF measurements, that the sensitivity and specificity of SalE and SalF are not greater than reported. Consequently, SalE and SalF, as surrogates for free serum F, have the potential to be superior than serumF when assessing adequacy of medical therapy in CS and may permit out-of-hospital monitoring. Further work is required to validate these findings.
SAT-093 Two Cases of Autosomal Dominant Familial Central Diabetes Insipidus: A Novel Variant in Neurophysin II Region of AVP Gene
Authors: Ramirez, Biochemist Pablo , Vaiani Elisa , Marino, Biochemist Roxana Marcela , Perez-Garrido, Biochemist Natalia Isabel , Morales Cintia , Rubio Betty , Rivarola Marco A , Belgorosky Alicia
Published: May 2020

Central diabetes insipidus (CDI) is a disorder of water balance characterized by polyuria and polydipsia owing to partial or complete deficiency of the antidiuretic hormone, arginine vasopressin (AVP). Although non-hereditary causes are the most frequent, Familial CDI forms, due to heterozygous mutations in the AVP gene, have also long been recognized. Inheritance occurs mostly in an autosomal dominant manner with almost complete penetrance. The AVP gene encodes for a 164 aminoacids preprotein: the AVP preprohormone which consists of a signal peptide, AVP hormone (9 amino acidpeptide), Neurophysin II (AVP carrier), and a glycoprotein, Copeptin. The AVP preprohormone, is produced in the hypothalamus sand is targeted to the endoplasmic reticulum (ER) by the signal peptide. After cleavage and processing, the AVP hormone is packaged within protein carrier NPII and are transported by axonal trafficking to the neurohypophysis where they can be stored and secreted.

Structural changes in NPII have been associated with intracellular accumulation of mutant AVP precursors that have been postulated to be cytotoxic and decreased cell viability of vasopressin-producing neuronsin the neurohypophysis.

In this study we describe two index cases from two families of four-generation kindred suspected to have Familial neurohypophyseal diabetes insipidus (FNDI), with absent or barely visibleposterior pituitary by MRI. A water deprivation test was performed in both cases, resulting confirmatory for DI in case 1 while it was inconclusive in case 2.

In both cases, molecular studies revealed a pathogenic variant in heterozygous state in the NPII region of the AVP gene, in case 1 we found a previously reported and well characterized variant p.Cys116Gly, cysteine at codon 116 is involved in disulfide bridge important for the secondary structure of NPII. While in case 2 we found a novel variant, p.Gly45Val, in which all in silico tools predict deletereous, whereas there are a previously reported patogenic variant at the same amino acid residueand in 3D modeling it can be observed that structural and conformational changes occur in binding bridge of NPII.

We are reporting two novel non related familial CDI cases, even though lack of functional studies, the clinical phenotype in each pedigree suggest this diagnosis, and support the genetic counseling.
SUN-207 Modelling Long Term Glucocorticoid-Induced HPA Axis Suppression in Mice
Authors: Romano Nicola , Duncan Peter James , Nolan Oscar , Tissier Paul Roussel Le , Shipston Mike , Chambers Thomas
Published: May 2020

Glucocorticoids are prescribed for >3 months to 1% of the UK population. 10-50% of these long-term glucocorticoid treated patients develop persistent HPA axis suppression associated with mortality and morbidity. We have developed a mouse model of glucocorticoid-induced HPA axis dysfunction to determine the mechanisms resulting in persistent HPA axis suppression.

Experiment 1: 36 C57BL/6 adult male mice received Dexamethasone (DEX,~10µg/day) or vehicle (CTL) via drinking water for 28 days, following which treatment was stopped and tissues were harvested at 0, 7 and 28 days. DEX suppressed waking serum corticosterone at days 0 and 7, recovering by day 28. Adrenal size remained lower 28 days following DEX withdrawal. DEX had no effect on whole pituitary pomc, nr3c1 or crhr1 expression, although avpr1b was increased at day 0. In the adrenal, hsd3b2 and cyp11a1 expression were reduced at time 0; normalising by 28 days.

Experiment 2: 24 POMC-GFP male mice were treated as above. Tissues were collected at day 0 (n=6), 7 (n=3) and 10 (n=3) following withdrawal. Pooled corticotrophs (groups of 3) were isolated by FACS and RNA extracted for qPCR. DEX reduced corticotroph pomc expression at time 0 (x20 fold reduction), with x5 fold suppression at day 7, which recovered with evidence of compensation by day 10. DEX increased expression of avpr1b but not crhr1.

CONCLUSION: 28 days dexamethasone treatment in mice suppresses the HPA axis. HPA suppression is evident 7 days following withdrawal of dexamethasone in the adrenal, corticotroph population and corticosterone production. Further analysis will determine mechanisms for delays in HPA axis recovery.
SAT-041 Testosterone Reduces Atherosclerosis and Plaque Specific Inflammatory Markers in the ApoE-/- Mouse Model
Authors: Bateman Lauren , Dalton Caroline , Maitre Christine Le , Jones Thomas Hugh , Kelly Daniel Marcus
Published: May 2020

Low serum testosterone in men is an established cardiovascular risk factor and epidemiological evidence demonstrates an association between low testosterone and with coronary events. Clinical evidence suggests that testosterone therapy (Tth) can improve key cardiovascular risk factors in men and surrogate measures of atherosclerosis, the chronic inflammatory process underlying cardiovascular disease. Atherosclerotic plaque-specific testosterone actions are not fully understood. The present study investigates the influence of testosterone on mediators of vascular inflammation and plaque burden in an in vivo model of atherosclerosis. ApoE-/- mice were either sham operated, castrated or castrated and received fortnightly intramuscular injections of physiological doses of testosterone (mixed testosterone esters, Sustanon 100) to create 3 experimental groups; normal testosterone, testosterone deficient and testosterone replaced respectively. All groups were fed a high-fat ‘Western’ diet for 16 weeks. Lipid deposition in the aortic root was assessed by Oil Red O as an indication of atherosclerotic burden. Plaque composition was assessed immunohistochemically for indicators of stability including collagen content via Masson’s trichrome, and α-smooth muscle actin (αSMA) as well as markers of inflammation including vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), endothelial-leukocyte adhesion molecule 1 (E-Selectin), and a pan monocyte/macrophage marker (MOMA2). Testosterone deficient castrated mice had significantly increased lipid accumulation in the aortic root compared to testosterone replete sham-operated littermates (48% intima-media area vs 40%, p<0.05). Tth in castrated mice reversed this effect (39%, p<0.05). Plaque stability was not altered between groups. MOMA2 staining indicated increased infiltration and localisation of monocytes/macrophages in the plaques of castrated mice compared to sham-operated (positive staining (% of plaque) 77% vs 59%, P=0.062) and Tth treatment reduced this (77% vs 63%, P=0.1). Vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1) expression were reduced in castrated mice receiving Tth compared to castrated mice receiving saline (33% vs 46%, p<0.05; and 39% vs 58%, P=0.084 respectively). No significant difference in expression of E-Selectin and αSMA were observed between groups. These findings demonstrate that low testosterone increases aortic root lipid deposition and inflammatory composition in a mouse model of atherosclerosis. Increasing testosterone levels through Tth reduces plaque specific inflammatory markers and atherosclerotic burden. This indicates an anti-inflammatory mechanism by which testosterone can protect against the development and progression of atherosclerosis to reduce cardiovascular risk in men.
SAT-683 A Case of Autoimmune Polyglandular Syndrome Type 2 and Guillain-Barré Syndrome
Authors: Cutler Jason , Brutsaert Erika
Published: May 2020

Background: Autoimmune polyglandular syndrome type 2 (APS2) is defined by the occurrence of two or more autoimmune diseases, with Addison’s disease being most prevalent, and autoimmune thyroid disease and type 1 diabetes mellitus also being common. Guillain-Barré syndrome (GBS) is an acute inflammatory demyelinating polyradiculopathy that is also autoimmune in nature, resulting in ascending muscle weakness or paralysis.

Clinical Case: A 49 year old female with past medical history of vitiligo, subclinical hyperthyroidism, and Guillain-Barré syndrome (GBS) presented to our institution with fatigue, nausea, vomiting, polyuria, and polydipsia. She had no history of diabetes. Her history was also significant for GBS, diagnosed 5 months prior to her current admission. She was treated with intravenous immunoglobulin (IVIG) and had partial improvement of motor impairment. On exam, she was noted to have dry mucous membranes, epigastric tenderness, and patches of hyopigmented skin. Laboratory studies were consistent with diabetic ketoacidosis, and she was admitted to the ICU for management.

Labs from 5 months prior were significant for a HbA1c of 6.4% (4.0-5.6%), TSH <0.002 mIU/L (0.350-4.7 mIU/L), total T3 154.9 ng/dL (79-149 ng/dL), and free T4 1.7 ng/dL (0.7-1.9 ng/dL), and elevated thyroid stimulating immunoglobulin.

During the current admission, HbA1c had risen to 13.6%, C-Peptide 0.6 ng/mL (1.1-4.4 ng/mL) and GAD-65 antibody >250 IU/mL (<5 IU/mL), consistent with a diagnosis of late-onset type 1 diabetes. Repeat thyroid function tests (TSH <0.002 mIU/L, total T3 74 ng/dL, and free T4 1.2 ng/dL), were consistent with subclinical hyperthyroidism. A 21-hydoxylase antibody level was 13 U/mL (<1 U/mL), but cortisol rose appropriately in response to cosyntropin. Based on the patient’s constellation of vitiligo, autoimmune thyroid disease, type 1 diabetes, and elevated 21-hydroxylase antibodies, she was diagnosed with APS2.

Conclusion: We present an unusual case of a patient with APS2, who was diagnosed with type 1 diabetes 5 months after developing GBS and being treated with IVIG. Prior reports demonstrate an association between GBS and other autoimmune diseases, including one case report of GBS in a patient with APS2. HLA DR3 has been associated with APS2, type 1 diabetes, Addison’s disease and Grave’s disease. Its association with GBS is less clear, although HLA DR3 was increased in one Mexican cohort with GBS. This case report adds to the literature suggesting an association with GBS and other autoimmune diseases, specifically, with APS2.

References:

Jin PP, Sun LL, Ding BJ, Qin N, Zhou B, et al. (2015) Human Leukocyte Antigen DQB1 (HLA-DQB1) Polymorphisms and the Risk for Guillain-Barré Syndrome: A Systematic Review and Meta-Analysis. PLOS ONE 10(7): e0131374

Melmed, S., Polonsky, K. S., Larsen, P. R., & Kronenberg, H. (2016). Williams textbook of endocrinology. Philadelphia, PA: Elsevier
SUN-694 Case Study of Nonalcoholic Steatohepatitis Reversibility in Type Two Diabetic Patient with Weight Loss Using Liraglutide
Authors: Shaghouli Amna Ali , Aranky Rola
Published: May 2020

Introduction Nonalcoholic fatty liver disease (NAFLD) is a common form of chronic liver disease.1 NAFLD prevalence is likely to be between 75- 100% in the morbidity obese. Where Nonalcoholic steatohepatitis (NASH) in turns develops in 30% of patients with NAFLD. Obesity prevalence in Kuwait is estimated to be 39% for adults male and 52% for adults females.2 No pharmacotherapy is approved for NAFLD treatment, and the basis treatment is lifestyle modifications focusing on body fat loss.3 A study showed that may take 10% or more weight loss to have an impact on NASH Activity Scores as assessed by liver biopsy. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are approved for the treatment of T2D and obesity and have also been shown to reduce liver inflammation and fibrosis.3

Methods A 54 years old male presented to our clinic with a history of hypothyroidism, diabetes with Hemoglobin A1C (HbA1c) of 7%, hypercholesterolemia and overweight with Body Mass Index (BMI) of 27.6 kg/m2

Patient’s investigations showed high Gamma-glutamyl transferase (GGT) and ferritin level, and due to his abnormal liver function test patient was referred for abdominal ultra sound that showed fatty liver disease. With a high NAFLD score, he was referred for Fibroscan that showed fibrosis score of F3; which indicates a sever liver scarring.

GLP-1 RA was started for weight management and a better glycemic control in a setting of multidisciplinary team, including endocrinologist, diabetes educator, dietitian and a physical trainer.

Results In a six months’ period of time, patient was able to lose 15.3% of his total body weight, with better glycemic control of HbA1c of 5.6% from 7% and his repeated Fibroscan showed improvement in his score from F3 to F0 with other clinically important outcomes.

Conclusion GLP-1 RA seems to be safe to use for patients with NASH, and it might have benefits of reversing fibrosis in addition to other benefits such as weight reduction and HbA1c improvement.

References 1- Babusik P, Bilal M, Duris I. Nonalcoholic fatty liver disease of two ethnic groups in Kuwait: comparison of prevalence and risk factors. Medical Principles and Practice. 2012;21(1):56-62.

2- Jamal MH. The Status of Organ Transplantation in Kuwait.

3- Seghieri M, Christensen AS, Andersen A, Solini A, Knop FK, Vilsbøll T. Future Perspectives on GLP-1 Receptor Agonists and GLP-1/glucagon Receptor Co-agonists in the Treatment of NAFLD. Frontiers in endocrinology. 2018;9.
SAT-076 Hypophosphatemic Rickets Secondary to Elemental Formula Use - Report on Two Cases
Authors: Braz Délia Oliveira , Oliveira Renata Santarem , Lopes Fernanda Sousa Cardoso , Pereira Lara , Domingues Alessandra , de Castro Luiz Claudio Goncalves
Published: May 2020

Background: Hypophosphatemic rickets (HR) is usually an inherited disorder, but it may also occur in several clinical settings as an acquired condition due to phosphate absorption and internal distribution issues. Recently it was described the association between the use of the elemental amino-acid based formula (AAF) and HR. Herein we report two male twins presenting this condition.

Clinical case: Two monozygotic preterm (28 weeks + 5 days) brothers, born with extremely low birth weight (895 and 995 grams, -1,4 SDS and -0.9 SDS, respectively), received total parental nutrition from the 1st to the 7th day of life. Afterwards they started oral diet with milk and human milk fortifier FM85 for preventing metabolic bone disease of prematurity. After some weeks they developed abdominal distension, vomiting and hematochezia. Allergy to cow milk protein was suspected and the infants started receiving extensively hydrolyzed milk formula. So, FM85 was suspended and they were put on tricalcium phosphate (12.9%) supplementation from the 4th week of life on. As the gastrointestinal symptoms persisted, the formula was exchanged for elemental formula Neocate at 2 months of age, with improvement of those symptoms.

After the 5th week of life the patients developed hypophosphatemia (2.8 mg/dL, reference 4.8-7.4 mg/dL), hyperphosphatasemia (1,619 IU/L and 2,173 IU/L; reference 70-350 IU/L) and low urinary phosphate excretion, keeping normal calcium and PTH ser um levels. Radiographic skeletal inventory showed under mineralized bones with irregular metaphyseal margins, but no signs of fractures. Calcium and phosphate supplementation doses were increased in attempt to correct the metabolic disturbances, and calcitriol was also started. Nevertheless, hypophosphatemia, hyperphosphatasemia and hypophosphaturia persisted.

At 4 months of age, Neocate was switched to Alfamino, still an AAF. After that, phosphate serum levels went up until normalization and alkaline phosphatase started to decrease. Calcium and phosphate supplementation were decreased to keep their serum levels at the normal range for age.

The boys were then discharged from hospital when they were 4 months old (45 days of life of corrected age), but the family could not afford Alfamino, switching back to Neocate. After that their phosphate serum levels went below normal range again.

Conclusion: To our knowledge, this is the first report on monozygotic twins presenting AAF Neocate-related HR. The underlying mechanisms of Neocate induced hypophosphatemia is still elusive, since its content of phosphate and calcium:phosphate ratio are similar to other AAFs. These cases reinforce the importance of evaluating phosphate metabolism in infants receiving AAF while the pathophysiology of this condition is not entirely understood.
MON-273 Retrospective Analysis of Gonadotropin-Mediated Pubertal Induction in Male Patients with Congenital Hypogonadotropic Hypogonadism (CHH)
Authors: Cangiano Biagio , Goggi Giovanni , Guizzardi Fabiana , Vezzoli Valeria , Duminuco Paolo , Persani Luca , Bonomi Marco
Published: May 2020

CHH is a rare disease characterized by a failure to enter (complete forms) or to complete (partial forms) pubertal development. It has a strong genetic background and it needs a treatment to allow the puberty to complete. In male this goal could be achieved either by the classic testosterone replacement therapy or by the exogenous gonadotropins (Gn) administration which allows both the endogenous testosterone production and the testicular development. So far, only few studies have explored this latter therapeutic approach in inducing the CHH pubertal development and no internationally recognized protocols are available. Aim of this retrospective analysis is to (i) investigate clinical and biochemical predictors of testicular response to Gn-induced puberty in CHH; (ii) study the non-reproductive outcomes of this treatment (height, body proportions) and their determinants. A total of 19 CHH male patients, undergoing two years of Gn-mediated (FSH and hCG) puberty induction started between the ages of 14 and 23 years, were retrospectively evaluated. For each patient clinical history, physical examination, hormonal evaluation, and genetic analysis using Targeted Next Generation Sequencing for CHH genes was performed; 8 patients accepted to perform a semen analysis (SA) at the end of their treatment.Mann Whitney test and multiple regression analysis showed testicular volume after 24 months of Gn-mediated pubertal induction, to be significantly associated with: (i) the presence of cryptorchidism; (ii) the presence of a completely definable genetic cause for the disease; (iii) the presence of a complete CHH form. No significant association was found with the cumulative dose of hCG administered in 24 months. The statistical analyses regarding SA could not find the same associations. Multiple regression analyses investigating the eunuchoid habitus and a measure of the difference of subject’s final height from his target (deltaSDSth), showed a significant association with: (i) age at the beginning of the induction; (ii) the duration of growth during induction; (iii) and (for deltaSDSth) bone age before the induction. Duration of growth during induction resulted to be associated with previous testosterone priming and with partial CHH.In summary, our study confirms cryptorchidism and complete genetic forms of CHH as negative predictors of testicular response probably because they usually affect early phases of life with a complete GnRH deficiency. We also found that the eunuchoid habitus and deltaSDSth are associated not only with delayed treatment, but also with the duration of stature growth during the induction, apparently related to earlier androgenization.
MON-389 Fracture Risk Assessment Models for Patients With T2DM
Authors: Banica Andreea Maria , Oprea Luciana Mihaela , Ilie Iuliana , Elian Viviana , Caragheorgheopol Andra , Iordachescu Carmen , Poiana Catalina , Musat Madalina
Published: May 2020

Introduction

Bone mineral density (BMD) measurement, a tool used to diagnose osteoporosis (OP) and to predict fracture risk, has not been found very useful in type 2 diabetic (T2DM) patients. They have a 69% higher fracture risk despite having higher hip and lumbar spine BMD than the non-diabetic population. The aim of this study was to examine the impact of 3 different fracture risk assessment (FRAX) models using surrogate adjustments for T2DM in predicting osteoporotic fracture risk over 10 years.

Material and Methods

Observational retrospective study included 98 patients with OP or osteopenia: 94 women and 4 men admitted in the National Institute of Endocrinology between 2011-2019. 50 % (n= 49) of the patients had T2DM, while the other half were non-diabetic patients. BMI, BMD, lipid profile, serum creatinine, calcium, phosphorus, 25(OH)vitamin D, HbA1c were assessed. BMD was measured on a GE Lunar osteodensitometer. The risk of major osteoporotic fracture in 10 years was assessed with FRAX adjusted for Romania. For diabetic patients, FRAX was adjusted by adding 10 years to patients’ age (model 1), by using rheumatoid polyarthritis as a substitute for T2DM (model 2) or by lowering T score with 0.5 DS (model 3).

Results

Non-diabetic patients had a lower BMI (p=0.001) and a lower BMD (p=0.03) than diabetic patients. A higher BMI correlated with a higher hip BMD (p=0.004).

For diabetic patients, FRAX risk without adjustment was statistically significant lower than FRAX risk calculated with model 1 and 2 (p< 0.001) for both major and hip fracture risk. Unadjusted FRAX risk was lower than the one calculated with model 3 only for hip fracture risk (p<0.001).

Model 1 FRAX adjustment led to a statistically significant risk of both major osteoporotic fracture (p= 0.004) and hip fracture (p=0.04) over 10 years in diabetic patients than non-diabetic patients, though diabetic patients had higher BMD. The same observation was made when FRAX was adjusted by model 2 (p=0.001) or by model 3 (p=0.001).

HbA1c correlated inversely with FRAX adjusted with all three models.

Discussion

FRAX calculator does not include T2DM among secondary causes of OP and this precludes a proper risk assessment independent of BMD. Trabecular bone assessment (TBS) captures a larger portion of the diabetes-associated fracture risk than BMD, however TBS it is not fully independent of the BMD. We examined 3 models of adjusted FRAX in T2DM patients that showed an important increase in fracture risk prediction when adding BMD - independent risk factors into FRAX calculator.

Conclusion

T2DM patients have a greater risk of major osteoporotic fracture in 10 years at the same BMD compared with non-diabetic population. New models of FRAX adjusted for T2DM are needed in assessing the intervention threshold for OP/osteopenia of patients with T2DM.
SAT-009 SSRI Use in the Peripartum Period Regulates Mammary Gland Parathyroid Hormone Related Protein (PTHrP) by a Serotonylation-Dependent Mechanism
Authors: Sheftel Celeste , Sartori Luma C , Hernandez Laura L
Published: May 2020

During lactation, a woman experiences a considerable amount of bone loss and recent studies suggest bone deficits persist years postpartum. Furthermore, selective serotonin uptake inhibitors (SSRIs), which are often prescribed to women experiencing peripartum depression, have been linked to osteopenia. Serotonin signaling can increase parathyroid hormone related protein (PTHrP), a bone remodeling protein which liberates calcium for the milk. Additionally, fluoxetine (a common SSRI) results in increased mammary gland serotonin content and PTHrP, and treatment during the peripartal period reduced maternal bone mineral density. One proposed mechanism of serotonin action is by its covalent addition to proteins by transglutaminase (TG2), termed serotonylation. We therefore investigated whether the combination of fluoxetine and lactation can exacerbate maternal bone loss and the underlying mechanism. We hypothesized that SSRI-induced serotonin signaling in the lactating mammary gland increases PTHrP through a serotonylation-dependent mechanism. Treatment of mouse mammary epithelial cells (HC11) with fluoxetine significantly upregulates PTHrP gene expression and the concentration of its downstream effector, cAMP, over control (P < 0.0004). Furthermore, treatment of the HC11 cells with fluoxetine in addition to a TG2 inhibitor, monodansylcadaverine, restores PTHrP mRNA expression to levels observed in the control. Small g-proteins have emerged as a common target protein for serotonylation. Currently, our data suggest that the g-proteins, RhoA and Rab4, are potential serotonylation targets in the mammary gland. Together these data suggest that the molecular process of serotonyation in HC11 cells links serotonin signaling to increased PTHrP expression. Future work is directed at using the cre-lox system to genetically ablate serotonylation using a WAPCre/TG2Flox transgenic mouse to determine whether decreasing serotonylation in vivo in the mammary gland during lactation improves maternal bone mass.
SUN-552 Follistatin-Like 3 (FSTL3), a Transforming Growth Factor β (TGFβ) Ligand Inhibitor, Regulates Placental Development in Mice
Authors: Huntington Josef , Robertson Rachel , Dhoot Gurtej K , McGonnell Imelda M , Wheeler-Jones Caroline , Mukherjee Abir
Published: May 2020

Follistatin-like 3 (FSTL3), a glycoprotein that inhibits transforming growth factor-β (TGFβ) ligands such as activin, is expressed highly in the placenta and other vascular tissues. In addition, FSTL3 is strongly induced in pre-eclamptic placenta. To test the hypothesis that FSTL3 function is required for capillary bed structure and function we studied the placenta in FSTL3 gene deleted mice (FSTL3 KO). We have previously shown that FSTL3 deletion produces striking defects in the placenta when compared to WT. Placental size increases significantly in comparison to WT, at 16.5 and 18.5 dpc, with concurrent reduction in placental efficiency at 18.5 dpc. Histological analyses reveal structural differences in placental junctional zones in FSTL3 KO placenta compared to WT. Morphometric analyses show that the labyrinth area compared to the placenta area is significantly reduced in FSTL3 KO mice. We also found that activin-responsive FSTL3-synexpression genes are upregulated in FSTL3 KO placenta. Of these, EPHB4 protein is induced in the placenta along with its ligand EphrinB2. Here we show that FSTL3 deletion leads to endothelial cell expansion but reduction in blood vessel density along with increased extracellular matrix deposition. Further investigation of the placental phenotype revealed differential expression patterns of desmin and cytokeratin protein, reduced von Willebrand factor (VWF) and increased CD31 and VEGFR2 labelling within FSTL3 KO mice placental labyrinths. To identify mechanisms that might lead to the altered placental development in FSTL3 KO mice qPCR analyses were performed. Our results identified differences in the expression of crucial transcripts, such as Cdh5, Pgf, Fra1and Cited1, that are associated with the regulation of vascular biology. Additionally, we find increased Histone3 and SMAD2 phosphorylation in FSTL3 KO placenta indicating increased proliferation and activin signalling, respectively. These findings suggest that the balance between cellular proliferation and differentiation might be altered in the absence of FSTL3. Thus, we conclude that FSTL3 function, at least partly through the inhibition of activin action, is necessary for normal placental circulation and development.
MON-033 Androgen Increases the Accumulation of Advanced Glycation End Products in Granulosa Cells by Activating ER Stress in PCOS
Authors: Azhary Jerilee Mariam Khong , Harada Miyuki , Takahashi Nozomi , Hirota Yasushi , Koga Kaori , Osuga Yutaka , Hiraike Osamu , Kunitomi Chisato
Published: May 2020

Polycystic ovarian syndrome (PCOS) is associated with hyperandrogenism. Previously we found that androgen activated endoplasmic reticulum (ER) stress in granulosa cells of antral follicles in PCOS, contributing to ovarian fibrosis (1) and growth arrest of antral follicles (2). In addition, recent studies demonstrated the accumulation of advanced glycation end products (AGEs) in granulosa cells from PCOS patients, which contribute to its pathology. Based on these findings, we hypothesized that androgen upregulates the expression of the receptor for AGEs (RAGE) in granulosa cells of antral follicles by activating ER stress. This in turn, increases the accumulation of AGEs in these cells. In the present study, we found that testosterone induced the expression of RAGE and accumulation of AGE in cultured human granulosa-lutein cells (GLCs). These effects were inhibited with the treatment of tauroursodeoxycholic acid (TUDCA), a clinically available ER stress inhibitor agent. Knockdown of the transcription factor C/EBP homologous protein (CHOP), an unfolded protein response (UPR) factor activated by ER stress, inhibited the testosterone-induced RAGE expression and AGE accumulation. Pretreatment with flutamide, as well as knockdown of androgen receptor decreased the testosterone-induced RAGE expression. Expression of RAGE was increased in GLCs obtained from patients with PCOS. Concomitantly, the expression of RAGE and the accumulation of AGE was increased in granulosa cells of antral follicles from PCOS patients and dehydroepiandrosterone (DHEA)-induced PCOS mice. Administration of the RAGE inhibitor, FPS-ZM1 or TUDCA to PCOS mice, reduced the expression of RAGE and the accumulation of AGE in granulosa cells of antral follicles, accompanied by a reduction of atretic follicles and improvement in the estrous cycle. In summary, our findings indicate that hyperandrogenism in PCOS increases the expression of RAGE and accumulation of AGEs in the ovary by activating ER stress. The potential therapeutic benefit of targeting the AGE-RAGE system, either with a RAGE inhibitor or an ER stress inhibitor agents, may serve as a novel approach for the treatment of PCOS. (1) Takahashi et al. Sci Rep. 2017;7(1):10824. (2) Azhary et al. Endocrinol. 2019;160(1):119–132
MON-464 A Rare Case of Hypocalcemia-Induced Intractable Vomiting Requiring PEG Tube Placement
Authors: Mallari Margaret A , Palmeiro Christopher Robert
Published: May 2020

Introduction: Hypoparathyroidism is characterized by hypocalcemia and hyperphosphatemia secondary to inadequate PTH secretion. Clinical manifestations are carpopedal spasm, perioral paresthesia, and seizures. Herein, we present a case of hypoparathyroid-induced hypocalcemia requiring PEG tube placement.

Case Presentation: Patient is a 41-year-old female who presents with intractable nausea, continuous vomiting, abdominal pain, and perioral paresthesia for the past 4 days. Patient has a past medical history significant for hypoparathyroidism, severe hypocalcemia, hypomagnesemia, hyperphosphatemia, and iron deficiency anemia. Patient was diagnosed with hypoparathyroidism at the age of 16 when her son was born with congenital abnormalities due to severe maternal hypocalcemia. She has 4 children, 1 son passed away in infancy from severe hypocalcemia. Out of the remaining 3 children, 2 daughters have hypoparathyroidism. Patient has had multiple recurrent admissions for severe hypocalcemia presenting as angina, syncope, and left-sided weakness. Both cardiology work up and neurology workup have been negative. MRI of the brain shows basal ganglia calcifications. Labs are significant for corrected calcium 6.72 mg/dL (n 8 to 10 mg/dL), magnesium 1.4 mg/dL (n 1.7 to 2.2 mg/dL), phosphorus 7.4 mg/dL (n 2.4 to 4.5 mg/dL), Vitamin D 14.9 ng/mL (n 30 to 100 ng/mL), and PTH level 9.8 pg/mL (n 18.5 to 88 pg/mL). Prior ACTH stimulation test was within normal limits excluding adrenal insufficiency. EGD biopsy on prior admission was positive for H. Pylori, however patient left against medical advice and did not receive triple therapy. Patient was admitted for hypocalcemic crisis and placed on a calcium gluconate drip, oral calcium, magnesium, calcitriol, and Vitamin D, in addition to H. pylori triple therapy. During the hospitalization, she was unable to tolerate oral medications for greater than 2 weeks resulting in PEG placement. The patient’s electrolytes were successfully repleted via PEG tube and she was discharged.

Discussion: Spontaneous hypoparathyroidism is a rare metabolic disorder characterized by parathyroid glands that do not produce or secrete enough PTH to maintain normal levels of calcium and phosphorous in the blood. Though GI consequences such as steatorrhea may occur, to our knowledge, this is the first reported case of hypocalcemia-induced intractable vomiting requiring PEG tube. Before PEG placement, the patient had 12 admissions in 1 year. After PEG placement, the number dropped significantly to 4 admissions in 1 year. Due to the unique presentation of hypoparathyroid hypocalcemia, we would like to raise awareness regarding such a presentation which can be challenging for clinicians.

References: Abboud B, Daher R, Boujaoude J. Digestive manifestations of parathyroid disorders. World J Gastroenterol. 2011;17(36):4063-4066. doi:10.3748/wjg.v17.i36.4063.