bluuebunny/crossref_metadata_2025 huggingface dataset:
MON-101 Costa Rican National Primary Congenital Hypothyroidism Screening Program Evaluation. Retrospective Cohort Trial Between 2015 and 2017
Authors: Cob Alejandro , Aita Fred Cavallo , Rodríguez Agnes
Published: May 2020

Congenital hypothyroidism (CH) is one of the leading causes of intellectual impairment worldwide in infancy. The newborn screening has been able to prevent this mental disability, by a prompt initiation of therapy. Over the last years the incidence of HC has been increasing, mainly by lowering the screening cut-off level that leads to detection of milder cases. There is conflicting evidence if children with mild CH without treatment may develop neurological impairment in the future.

Costa Rican newborn screening program in divided in three stages, measuring serum TSH concentrations from a heel prick aliquot of capillary blood dried onto a filter paper. Each test has different TSH cut-off values to determine if the newborn needs a clinical evaluation by an endocrinologist, needs another screening test or rules out hypothyroidism.

We developed an observational, descriptive, retrospective study, based on medical records, to evaluate our newborn screening program performance. The study included the total national population of screened newborns from 2015 to 2017. Descriptive analysis and analytical analysis of variables were done, and test’s sensitivity and specificity were determined.

The study analyzed 204.241 screened newborns, and 145 children referred to the Endocrinology Department of the National Children Hospital. This population represents 97% of births in these 3 years. The recall rate for a first positive test was 0.3%. Congenital hypothyroidism was confirmed in 73% of children referred to the Endocrinology Department because of a positive screening. Incidence was 1/1926 births. Detection rate was independent of birth weight nor gestational age. 45.3% of children diagnosed with CH were detected after the first screening test, 52.8% after the second screening test and 1.9% after the third screening test. Screening test analysis showed high sensitivity and specificity, with diagnostic accuracy above 90%, except for the third screening test. Free thyroxine measurements alone weren’t useful to predict CH diagnosis.

The coverage of the national neonatal screening program extends almost to the entire population. Our test specificity is within international standards. Incidence of CH in Costa Rica is similar to that reported in medical literature. With current detection cut-off level, there is no need of performing a second mandatory evaluation to preterm and low weight newborns. The third screening test has a low performance rate, does not improve detection of children with CH significantly, and delays clinical evaluation by the endocrinologist. Prognosis of treated children with CH is excellent, with no evidence of severe cognitive deficit.
SAT-208 An Adrenal Incidentaloma with Extramedullary Hematopoiesis
Authors: Zachary Tyler , Lien Lillian
Published: May 2020

Introduction: Adrenal adenomas are incidentally noted during nonadrenal disease imaging at a rate up to 4%. Frequency of incidentalomas increases with age, most being adrenocortical adenomas. This case highlights an uncommon etiology of such an adrenal mass finding. Case Description: A 37-year-old with a history of hypertension, hypothyroidism, and tobacco use was admitted after post-operative complication. Prior to surgery, she had been experiencing right upper quadrant pain along with 70 lb weight loss and diarrhea. She otherwise had frequent palpitations. Patient had undergone cholecystectomy and common hepatic duct injury was noted. Imaging revealed a 5.3 x 3.5 cm right adrenal mass previously unknown prior to surgery. Hormonal workup was negative for overproduction of aldosterone, cortisol, DHEA-S or metanephrines. Discussion: Patient underwent successful resection of adrenal mass, revealing adrenal adenoma with osseous metaplasia and hematopoiesis. Extramedullary hematopoiesis is a usually discovered incidentally as in this case. Typical sites are the spleen and liver. Cases of adrenal gland manifestations have been reported in the presence of hemoglobinopathies (thalassemia, hereditary spherocytosis) or myelofibrosis. At four-month follow-up, laboratory testing on this patient didn’t suggest any erythrocytic or leukocytic disorder. Conclusion: This case highlights an uncommon finding of hematopoiesis in an adrenal incidentaloma without any underlying hematologic defect or disease. References: Motta, I., Boiocchi, L., Delbini, P., Migone De Amicis, M., Cassinerio, E., Dondossola, D., Rossi, G. and Cappellini, M. D. (2016), A giant adrenal myelolipoma in a beta-thalassemia major patient: Does ineffective erythropoiesis play a role?. Am. J. Hematol., 91: 1281-1282. doi:10.1002/ajh.24446. Stewart P, Newell-Price J. (2016). The Adrenal Cortex. In Melmed S, Polonsky K, Larsen P, Kronenberg H, Williams Textbook of Endocrinology. (13th ed., pp 489-555). Philadelphia, PA: Elsevier
MON-601 Obesity Pharmacotherapy Is Effective in the United States Veterans Affairs Patient Population: A Local and Virtual Cohort Study
Authors: Pendse Jay , Vallejo-García Franco , Parziale Andrew , Griffin Megan , Callanan Mae , Tenner Craig , Diaz Jose Orlando Aleman
Published: May 2020

Background: Overweight and obesity are major health burdens, and the military veteran population may be disproportionately affected. Multiple new pharmacologic agents and combinations have been approved by the FDA for use in medical weight management. Using deidentified records from our local interdisciplinary weight management clinic and a national clinical data repository, we assessed obesity pharmacotherapy use and its real-world effectiveness for weight loss and improvement of comorbid metabolic parameters in this vulnerable population.

Methods: During the initial year of the local weight management clinic, we found over 50 records with monthly followup of lifestyle intervention augmented by obesity pharmacotherapy. In the national clinical data repository, we identified over 2 million records for unique individuals prescribed bupropion-naltrexone, liraglutide, lorcaserin, orlistat, or phentermine-topiramate, and metformin considered as a control prescription. We selected records with detailed documentation of weight trends from 1 year before to 1 year after first prescription date for further analysis.

Results: The most commonly prescribed medications in our local weight management clinic were metformin, liraglutide, orlistat, and combination phentermine/topiramate. On average, we observed −4.0 ± 2.1 kg weight loss over the initial 6-month intervention in records that completed at least 3 visits within this period. In the national database, over 800,000 records for an obesity or control metformin prescription provided adequate weight documentation to compare weight slopes during the year before and after the prescription start date. Records for metformin prescriptions showed −0.04 ± 0.008 kg/week difference in weight slope over one year before versus after the prescription start date. The greatest difference in weight slope was seen with phentermine-topiramate (−0.13 ± 0.03 kg/week), followed by lorcaserin, liraglutide, bupropion-naltrexone, and orlistat.

Conclusions: Our data suggests that veterans with obesity experience weight loss at 1 year follow-up when engaged with our interdisciplinary weight management clinic. Nationally, veterans with obesity experience modest weight loss when prescribed pharmacotherapy. Taken together, our two data sources provide complementary perspectives to help guide obesity pharmacotherapy in veterans with obesity.
MON-129 Analysis of Omega3 PUFAs Status Among the Female and Male Population of the Moscow Region
Authors: Vorslov Leonid , Davidyan Ovanes , Avetisyan Artur , Nizhnik Aleksander , Paramonov Sergey , Kalinchenko Svetlana Yurevna
Published: May 2020

INTRODUCTION:

All humans have levels of EPA+DHA that if methodologically correctly assessed in erythrocytes, are optimal more than 8%. Omega-3 polyunsaturated fatty acids (PUFAs), namely eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are permanent subjects of interest not only in relation to the protection of cardiovascular health and the prevention of the incidence of both ventricular and atrial arrhythmias, but also many serious health issues that can be prevented by optimal levels.

OBJECTIVE: The aim of this study was to assess in a retrospective study the omega-3 PUFAs status at Moscow region according age and sex.

SUBJECTS AND METHODS:

In this retrospective study, the records of 1349 patients who presented with various complaints in the period from 2013 to 2017 aged 1 to 91 were examined. Fatty acids within the red blood cell membranes were analyzed as methyl ethers after trans-esterification with sodium methylate using GC-MS followed by omega-3 index calculation.

RESULTS:

Deficiency of omega-3 PUFAs was found in 68.5% of patients. The most severe deficiency was noted in children and adolescents aged 0 to 17 years (in girls to a greater extent). In age groups of 18–44 and 45–59 years, the prevalence of severe (<4%) and moderate (4–8%) deficiency was comparable in males and females: among 18–44-year-old men severe deficiency was noted in 5.6%, moderate – in 29.4%, at the age of 45–59 years – in 7 and 23%, respectively; among women – 6.4, 24.4, 8.4 and 20%, respectively. In the age group of 60-74 years, prevalence of severe deficiency was significantly higher in men, who had severe deficiency in 9.2% of cases, whereas in women of the same age it was found only in 4.8% of cases, the prevalence of moderate deficiency is 23 and 23.8%, respectively.

CONCLUSIONS:

Such high prevalence of severe omega-3 PUFA deficiency in girls under 17 is likely due to girls’ and their parents’ concerns about weight, diet and veganism, and requires the inclusion of omega-3 index analysis in adolescent girls’ screening. Thus, during the most important period – the period of puberty – 25% of girls have metabolic and hypoxic disorders due to deficiency of omega-3 PUFA and are at risk of not only diseases associated with metabolic disorders, but also reproductive disorders (infertility, miscarriage, fetal malformations). The obtained data is indicative of the necessity to choose dosages of omega-3 PUFAs, considering not only the patients age, but also their gender.
SAT-138 Neutrophil Elastase Promotes Proliferative Signals in Prostate Cells Through EGFR and DDR1
Authors: Xiao Zhiguang , Lerman Irina , Hammes Stephen R
Published: May 2020

Studies examining many different cancers have demonstrated that inflammation plays a critical role in tumor progression, in part through the release of proteases from stromal cells that function to either remodel the tumor microenvironment or to directly stimulate cancer cells to grow. One specific protease, neutrophil elastase (NE), has been shown to be a critical regulator of cancer growth in several mouse models. Accordingly, our laboratory demonstrated that NE, most likely from granulocytic myeloid-derived suppressor cells, potentially promotes prostate cancer progression in several different in-vivo and in-vitro models. To date, however, little is known regarding the mechanisms utilized by NE to promote tumor growth. It has been suggested that NE might cleave epidermal growth factor (EGF) or transforming growth factor-α from the cell surface to induce activation of EGFR/ERK signal transduction in an autocrine fashion. Alternatively, NE has been shown to enter into early endosomes to degrade insulin receptor substrate-I, ultimately resulting in phosphoinositol 3-kinase hyperactivity and subsequent tumor cell proliferation. Here we demonstrate that NE triggered proliferative signals in six prostate cell lines representing the spectrum of prostate cell differentiation, including normal prostatic epithelium, benign prostatic hypertrophy, and metastatic prostate cancer. Focusing on ERK signaling, we found that the stimulatory effect of NE on ERK phosphorylation was dose dependent and was abrogated by small interfering RNA induced EGFR knockdown, as well as by pretreatment of cells with irreversible EGFR inhibitor AG1478. Unlike EGF, however, NE-initiated EGFR phosphorylation was minimal. Thus, while EGFR appears to be critical for NE-induced ERK activation, perhaps it is not extensively activated directly by NE. Notably, discoidin domain receptor-1 (DDR1) was strongly expressed in normal prostate epithelium cells, but gradually decreased and had little expression in benign and metastatic prostate cancer cells sequentially. Nevertheless, similar to EGFR knockdown, silencing of DDR1 in all cell types inhibited NE mediated pERK upregulation, suggesting that DDR1 may also be important for NE-induced action. Together, our data suggest that NE, in concert with low level signals from the EGFR and DDR1, play an important role in promoting prostate cell proliferation both in normal and cancerous prostate epithelial cells.
OR31-06 Candidate Gene Variants in a Large Cohort of Women with Primary Ovarian Insufficiency
Authors: Gorsi Bushra , Moriwaki Mika , Moore Marvin B , Rajkovic Aleksandar , Nelson Lawrence M , Yandell Mark , Welt Corrine Kolka
Published: May 2020

Primary ovarian insufficiency (POI) is highly heritable. The majority of cases have no known cause. We hypothesized that mutations in previously identified genes or genes from the same pathways are the cause of POI in a recessive or dominant manner. Subjects included 294 women diagnosed with POI (amenorrhea with an elevated FSH level). All had a 46XX karyotype, and normal FMR1 repeat number. Subjects were recruited in Boston (n=95), at the NIH and Washington University (n=98), and in Pittsburgh (n=98). Controls included subjects recruited for health in old age and disorders unrelated to reproduction or cancer, and subjects from the 1000 Genomes Project (total n=587). Variants were called using the Sentieon software package (https://www.sentieon.com). Case and control samples were stratified on ethnicity, relatedness and heterozygosity. Peddy and XPAT were used to calculate quality control metrics to detect outlier samples for removal from analysis to create a homogenous dataset. The number of cases (227) and controls (458) was adjusted for downstream analysis. XPAT imposed additional quality filters and removed variants. A second filter removed variants that did not pass a Gnomad filter of <0.001 allele frequency. VAAST was used to determine a composite likelihood ratio (CLR) as the test statistic to represent the aggregate burden of variants of affected individuals in each transcript relative to a set of 458 control genomes. The significance of each transcript’s VAAST CLR score was evaluated by 1 million permutations. We screened exomes for variants in previously identified genes causing POI in humans and those demonstrating infertility in a male or female mouse model. We also used the American College of Medical Genetics and Genomics standards for interpretation of pathogenicity of a variant, with priority on null variants in genes with probability of loss of function intolerance based on the observed vs. expected rate in gnomAD, in vivo or in vitro functional evidence of a damaging effect, significantly increased prevalence compared to controls, i.e. not found in any controls or in fewer than 10 in the gnomAD database if the subject had a matching race/ethnicity. Thirty-four subjects were removed for poor quality exomes and relatedness. Fifty-three subjects had at least one variant in a previously identified POI gene or one in which there was a previously identified functional model. Two subjects carried recessive variants and 30 carried at least one novel heterozygous candidate variant for follow up. Analysis of genetic causes of POI in this large cohort identified candidate causal gene variants in over half of the subjects. The data demonstrate that the genetic architecture is heterogeneous. Although recessive mutations have been identified in consanguineous families, the data suggest that a dominant or oligogenic pattern of inheritance may be important.
SAT-295 An Extremely Rare Novel Missense Variant C.912G≫A; P.M304I in SOX3 Gene Is Responsible for X-Linked GH Deficiency in a Brazilian Boy Without Mental Retardation
Authors: Benedetti Anna Flavia Figueredo , Silva Juliana M , Biscotto Isabela Peixoto , Ferreira Nathalia Pereira , Arnhold Ivo J , Mendonca Berenice Bilharinho , Carvalho Luciani Renata Silveira
Published: May 2020

SOX3 (SRY-related HMG-box gene 3), located in the X chromosome, spans only one exon and is expressed in the infundibulum, diencephalon and hypothalamus. Alterations in SOX3, mainly deletions or insertions in the polyalanine tract, were associated with mental retardation, isolated GH deficiency (IGHD) or combined pituitary hormone deficiencies (CPHD). Missense variants are rare and only two were reported. Our aim was to find a molecular cause in patients with pituitary hormone deficiency and determine genotype-phenotype correlation. Twenty-eight patients (15F:13M) 24 CPHD:4 IGHD were selected for the study. Whole blood DNA was extracted using the Salting Out method. Library preparation was performed following Agilent’s SureSelectXT customized gene panel protocol containing 654 genes known to cause endocrine diseases. Illumina NextSeq 500 platform was used for sequencing at SELA. Alignment to genome reference hg19 was performed using BWA-MEM. Variants were called with FreeBayes and annotated by Annovar. Allele frequency ≤1% for exonic regions was considered in 1000 Genomes, gnomAD, ABraOM and SELA populational databases for variant filtering. Family segregation was done using Sanger sequencing. RNA and protein analysis were performed using mfold and YASARA, respectively. Protein models were made by I-Tasser. SOX3 missense variant (c.912G>A/p.M304I) was found in one male patient, without mental retardation, diagnosed with IGHD at the age of 7 years. After GH replacement, he reached final height at the age of 18 within family target height. Pituitary image showed an ectopic posterior pituitary, hypoplastic anterior pituitary and thin pituitary stalk. SOX3 (c.912G>A/p.M304I) variant in hemizygous state was absent in populational data banks. In silico prediction algorithms SIFT, PolyPhen, and Mutation Assessor were predicted as damaging. Family segregation showed normal mother and sister carriers of the variant, while father, brother and uncle (from mother’s side), all phenotypically normal, did not harbor the variant. RNA In silico analysis pointed that the variant causes mRNA structure change. Protein stability dropped from 677.46 kcal/mol in wild type to 666.69 kcal/mol in p.M304I, making it less stable. Protein Interaction analysis with DNA binding motif (PDB 2LE4) required two times less energy in mutant (376.19 kcal/mol) than wild type protein (646.77 kcal/mol), leading to a less stable interaction. We conclude that one among 28 patients presented a rare novel variant in SOX3 associated to IGHD in a patient without mental retardation and compatible with an X-linked inheritance pattern.
OR08-05 Sex and Ethnic Differences in Advanced Lipoprotein Profiles in South Asians, African-Americans, and Caucasians
Authors: Sarcone Camila , Fosam Andin , Armiyaw Abdul-Latif , Grewal Shivraj , Bansal Rashika , Rabel Antoinette , Muniyappa Ranganath
Published: May 2020

Background: African-Americans (AA) and South Asians (SA) are known to have higher risk for T2D and cardiovascular disease (CVD) compared to Caucasians (CA). Advanced analysis of lipoprotein particles with nuclear magnetic resonance (NMR) spectroscopy can offer insights into CVD risk and lipid metabolism beyond a standard lipid panel. Insulin resistance (IR) is known to be associated with atherogenic lipoprotein profile.

Objective: To characterize the lipoprotein profile in AA, CA, and SA men and women.

Design: A cross-sectional study of 182 healthy, non-diabetic SA, AA and CA patients was conducted at NIH. Subjects underwent an intravenous glucose tolerance test from which insulin sensitivity (Si) was derived using the Minimal Model. Lipoprotein profiles were measured by NMR with the LP4 deconvolution algorithm, which reports triglyceride-rich lipoprotein particles (TRLPs), high-density lipoprotein particles (HDLPs), and low-density lipoprotein particles (LDLPs). For group comparisons, Si was adjusted for age and fat free mass. Lipoprotein parameters were adjusted for age and body fat %.

Results: Fifty-nine non-diabetic SA (33 males, 26 females), 49 AA (26 males, 23 females), and 74 CA (29 males, 45 females) were included in the study. Ethnic differences in Si were observed in men (p=0.002) but not in women (p=0.43). SA men had a significantly lower Si than both AA and CA men (p=0.02). TG concentrations and TRL particle number were significantly higher in CA men and women when compared with AA. TRLP size was not different between the ethnic groups in either sex. LDL particle number and ApoB concentration was significantly higher in SA men and women compared to AA and CA. There were no ethnic or sex differences in LDL size. HDL concentration, HDL particle number, and ApoA-I levels were not different between the groups in both sexes. However, in SA, large HDL particle number and HDL particle size was significantly lower than CA. Cholesteryl ester transfer protein (CETP) activity was significantly higher in SA men, but not women, when compared with AA and CA. Ethnic differences in LDLP and L-HDLP number remained even after adjusting for Si.

Conclusions: In SA men and women, the lipoprotein phenotype (higher LDLP and lower L-HDLP) is independent of insulin sensitivity. Increased CETP activity may contribute to the lower large HDL particle number in this group. In AA, TG and TRLP number were lower as previously reported. Further investigation is needed to determine the factors mediating the atherogenic profile in SA.
MON-235 Mycobacterium Fortuitum Infection Mimicking Sellar Chondrosarcoma in a Non-Immunosuppressed Patient: An Unusual Cause of Hypopituitarism and Oculomotor Nerve Palsy
Authors: Mavromati Maria , Fitsiori Aikaterini , Janssens Jean-Paul , Jornayvaz Francois
Published: May 2020

A 32-year old male patient of central African origin presented with diplopia and left eyelid ptosis. He described a 2-month history of fatigue, weight loss (8 Kg), headaches, diffuse myalgia and night sweats. Clinical examination revealed cavernous sinus syndrome with left eyelid ptosis and weakness of eye adduction. Magnetic resonance imaging of the brain demonstrated a 36 mm mass centered on the left petroclival suture, infiltrating the sella and the pituitary gland, the ipsilateral orbital apex as well as the cavernous sinus bilaterally. The mass showed heterogenous enhancement after gadolinium injection, with elements of central necrosis and was associated with an extensive bone destruction. These radiologic features raised the hypothesis of chondrosarcoma. Chest computed tomography demonstrated multiple lung micro-nodules suspect of metastasis. Laboratory testing of the anterior pituitary function revealed low free-T4 (11 pmol/l, n = 12-22) with normal TSH (0.4 mUI/l, n=0.3-4.2), low total testosterone (1.5 ugr/l, n = 3.3-8.1) with normal LH and FSH and slight hyperprolactinemia (27 ugr/l, n = 4-15). IGF-1, 24-h urinary free cortisol, as well as morning serum cortisol and cortisol after 250 mcg ACTH stimulation test were normal. There was no evidence of diabetes insipidus. Levothyroxine was prescribed. Craniotomy was performed, for left optic nerve decompression and biopsy of the mass. Pathologic examination revealed granulomatous, giganto-cellular and necrotizing inflammation, but no evidence of malignancy. PCR for Mycobacterium tuberculosis complex was negative but Mycobacterium fortuitum was detected in sputum and also confirmed in cerebral biopsy latter. Other causes of granuloma were excluded (brucellosis, cat scratch disease, histoplasmosis, syphilis, coccidioidomycosis, tropical germs etc.). Different causes of immunosuppression (including HIV) were excluded. The patient was treated with amikacin, isoniazid and ciprofloxacin for several months and improved gradually. MRI performed one year later demonstrated significant decrease on the size of the sellar mass (more than 50% of its initial size). Central hypogonadism regressed spontaneously with decrease in tumor size, and normal testosterone levels were achieved at one-year follow-up (7 ugr/l, n = 3.3-8.1). Mycobacterium fortuitum infections of the sella turcica are poorly described in literature in non-immunosuppressed individuals. Although usually not pathogenic, histopathological examination, identification in the CNS lesion and the lungs and response to treatment are convincing evidence of a causal relationship. Differential diagnosis from malignant lesions is challenging and biopsy is necessary in order to establish the cause and offer adequate treatment.
SAT-497 Conversion of Hashimoto’s Thyroiditis to Grave’s Disease: A Case Report
Authors: Wahedi Tayba S , Douba Najah Younes
Published: May 2020

Introduction: Hashimoto’s thyroiditis and Grave’s disease are common causes for autoimmune thyroid disease. Conversion from Grave’s disease to hypothyroidism have been previously reported in literature. But development of Grave’s disease after a long standing hypothyroidism rarely occurs.Case report: a 22 -year-old Saudi pregnant female patient, was diagnosed with subclinical hypothyroidism with positive anti -thyroid peroxidase antibodies (Anti-TPO) in 2009. She was started on thyroxin and eventually became euthyroid with normal TSH levels till 2016. During subsequent follow-ups, patient was increasingly complaining of palpitations, weight loss and fine tremors. Thyroid function revealed increasingly suppressed TSH levels and over-replacement was suspected. Thyroxin dose was then gradually reduced and finally stopped for few months. Yet her symptoms persisted. Repeated thyroid function showed suppressed TSH level and elevated T4, T3 levels in keeping with overt hyperthyroidism. Thyroid scan further confirmed the diagnosis with diffuse thyroid uptake suggestive of Grave’s disease.Patient was started on medical treatment initially, then successfully treated with radioactive ablation.Conclusion: Although it rarely occurs, possibility of conversion from hypothyroidism to hyperthyroidism should always be kept in mind while treating hypothyroid patients with persistent clinical or biochemical evidence of hyperthyroidism despite dose reduction.References:[1] McLachlan SM. Rapoport B. Thyrotropin-blocking autoantibodies and thyroid-stimulating autoantibodies: Potential mechanisms involved in the pendulum swinging from hypothyroidism to hyperthyroidism or vice versa. Thyroid. 2013;23(1):14-24.[2] Ohye H, Nishihara E, Sasaki I, et al. Four cases of Graves’ disease which developed after painful Hashimoto’s thyroiditis. Intern Med. 2006;45(6):385-9.
SUN-555 Vitamin E Sequestration by Liver Fat in Vitro and in Women with Hepato-Steatosis
Authors: Violet Pierre-Christian , Ebenuwa Ifechukwude , Wang Yu , Niyyati Mahtab , Padayatty Sebastian , Head Brian , Wilkins Kenneth , Chung Stacey , Thakur Varsha , Ulatowski Lynn , Atkinson Jeffery , Ghelfi Mikel , Smith Smith Sheila , Smith Sheila , Tu Hongbin , Bobe Gerd , Liu Chia-Ying , Herion David , Shamburek Robert , Manor Danny , Traber Maret , Levine Mark Alan
Published: May 2020

BACKGROUND: The global obesity epidemic has sobering consequences to human health. Especially concerning is obesity-associated hepato-steatosis (HS), a common cause of chronic liver disease in the Americas and Western Europe that precedes non-alcoholic steatohepatitis (NASH). Maintenance of normal body weight is the only current means to prevent HS and NASH. We hypothesized that excess liver fat in obesity-associated HS could act as a pathophysiologic chemical depot for fat-soluble vitamins and alter normal physiology. Because clinical trials with Vitamin E (α-T) have shown that NASH partially responds to this supplement, we selected α-T as a model vitamin to test the sequestration hypothesis.

INTERVENTIONS: Under an IND and IRB-approved protocol, two deuterium-labeled α-tocopherols (d3-α-T and d6-α-T) were administered orally and intravenously, respectively, to 10 healthy women and 6 women with HS. Serial blood samples obtained over 72 h were analyzed by LC-MS/MS. In parallel, we performed studies in hepatocytes in cell culture and mouse model.

RESULTS: In healthy women who received oral d3- and intravenous d6-α-T, 85% of the initial plasma peak d6-α-T disappeared within 20 minute and reappeared in the plasma peaking between 6-8 h. Compared to healthy subjects, subjects with HS had similar d6-α-T entry rates into liver, but reduced release rates into plasma (p<0.001). Similarly, pharmacokinetics parameters (AUC and Maximum Concentration [Cmax]), were reduced (AUC0-8,p<0.01;Cmax p<0.02) in HS subjects, indicating reduced hepatic d6-α-T output. Consistently, livers of mice fed with a high fat diet (42% fat) had more vitamin E compared to controls diet (5% fat), with both diets having the same α-T content

CONCLUSION: These findings suggest the unique role of the liver in vitamin E physiology which is dysregulated by excess liver fat (measured by magnetic resonance spectroscopy). Considered together, the findings imply that obesity-associated HS may produce unrecognized hepatic α-T sequestration, which might subsequently drive liver disease. The data here raise the intriguing possibility that timely α-T supplementation might attenuate progression of HS to NASH, perhaps by correcting an unrecognized fat-induced, localized, hepatic vitamin E deficiency prior to onset of inflammation, hepatitis, and fibrosis. Additionally, our findings raise the possibility that HS may similarly alter hepatic physiology of other fat-soluble vitamins.
OR07-05 Is Urinary Calcium the Only Predictor of Nephrolithiasis in Patients with Asymptomatic Primary Hyperparathyroidism?
Authors: Saponaro Federica , Cetani Filomena , Mazoni Laura , Apicella Matteo , Scalese Marco , Pardi Elena , Borsari Simona , Marcocci Claudio
Published: May 2020

The 4th International Workshop for the management of asymptomatic PHPT included, among the criteria for parathyroidectomy, the presence of hypercalciuria (dUCa> 400 mg/day) and increased biochemical stone risk profile.

The aim of the present study was to evaluate the biochemical stone risk profile in 176 consecutive patients (143 females and 33 males) with asymptomatic PHPT. We recorded clinical and biochemical data, including 24 hours urinary measurements of the following parameters: volume and pH, creatinine, calcium, magnesium, sodium, potassium, ammonium, uric acid, oxalate, citrate, phosphate, inorganic sulphate and chloride and kidney ultrasound.

In our cohort dUCa> 400mg/day showed a low sensitivity and positive predictive value (PPV) for nephrolithiasis with high specificity (46.2, 32.7, 73.0% respectively), while hypercalciuria by 4 mg/kg/bw (d-UCa>4mg/kg) had a high sensibility, with low PPV and specificity (79.5, 27.7, 40.1%)

Daily hypomagnesuria (d-HypoMg), but not any other urinary parameter, was an independent predictor of nephrolithiasis in the univariate (OR 2.97 CI 1.27-7.09 P=0.014) and multivariate analyses adjusting for age, sex, BMI, and eGFR (OR 3.13 CI 1.17-8.42 P=0.02). d-HypoMg was relatively lower in the regression analysis with urinary calcium in patients with nephrolithiasis compared with those without. The mean ratio between (dUCa) and (dUMg) was higher in patients with nephrolithiasis compared with those without (4.6±2.0 vs 3.3±4.1; P<0.001). In the univariate and multivariate analyses the dUCa/dUMg ratio was a significant predictor of nephrolithiasis [OR 4.9 (2.3-10.5); P<0.001; OR 5.3 (2.4-11.6), P<0.001, respectively]. The AUC using the dUCa/dUMg ratio as variables was 0.69 (CI 0.60-0.79; P<0.0001). The best cut-off value, set at the highest Youden index, was equal to 4.0, with a sensitivity of 59.0% and a specificity of 77.4%.

In patients with hypercalciuria (>400 mg/24-hour) dUMg was positively correlated with dUCa in those without nephrolithiasis (r=0.50, β=0.2, P=0.002) but not in those with nephrolithiasis (r=0.05, β= 0.014; P=0.8). In patients without hypercalciuria we found that hypomagnesuria remained a predictor of nephrolithiasis using either 400 mg/die (P=0.002, OR 5.12 (1.84-14.24) or 4 mg/kg bw (P=0.014, OR 6.24 (1.45-26.8). Moreover, the OR for nephrolithiasis improved using the combination of d-HypoMg with d-UCa>4mg/kg (OR 8.12, CI 1.92-34.18, P=0.004), but not with dUCa> 400mg/day.

The current urinary calcium threshold of >400 mg/24-hour has a low sensitivity in detecting nephrolithiasis; our data suggest that sensitivity, specificity and positive predictive value could be improved including dUMg, dUCa/dUMg ratio and the combination of d-HypoMg with d-UCa>4mg/kg in the stone risk evaluation.
SUN-542 The Effect of Energy Deprivation on Metabolic Hormone Responses to Meals
Authors: Shekhar Skand , Leka Helen , Kim Anne , Purse Bona , Hersch Katie R , McGee Christopher , McGrath John , Smith-Ryan Abbie E , Hall Janet Elizabeth
Published: May 2020

Background: Intermittent caloric restriction (ICR) has recently gained popularity as a weight-loss strategy; however, fasting metabolic hormones and dynamic meal-related responses, are not well-established in this setting. Methods: We measured metabolic hormone responses to 5-days of neutral or decreased energy availability (NEA, 45 kcal/kg LBM*d vs DEA, 20 kcal/kg LBM*d) in the early follicular phase (EFP) in 19 regularly-cycling, sedentary, women (age 23.36± 2.08 yr; mean±SD). Hunger was assessed using a visual analogue scale on the 5th day of each condition. Scheduled breakfast and lunch were administered according to assigned caloric intake, while an afternoon snack based on NEA was provided on both occasions. Blood was sampled for leptin, insulin, glucose, and GH at 10-min intervals and cortisol was measured at 30-min intervals over eight hours starting at 0800 h, while Orexin A and adiponectin were measured in fasting samples. AUC for each hormone for every meal and diet condition were analyzed using linear mixed models. Insulin and insulin/glucose ratio (I/G) were also adjusted for meal calories. Percentage body fat mass was measured every visit using air displacement plethysmography (BodPod®). Results are presented as least square mean ± sem. Results: There were no differences in body mass index or % fat mass after NEA vs DEA although there was a significant increase in hunger with DEA (p=0.002). Fasting levels of glucose and insulin were unchanged while leptin decreased with DEA (1.27±0.07 and 1.04±0.07 ng/mL, NEA and DEA respectively; p<0.0001), and Orexin A increased (0.55±0.04 and 0.60±0.04 ng/mL; p=0.04). The AUC for glucose was lower with DEA across all meals (p<0.0001). Insulin, I/G and I/G normalized for ingested calories (nI/G) decreased in response to DEA (p<0.005, p<0.05 and p<0.0001). The slope of the increase in leptin across the day was not different between NEA and DEA (p=0.20). Adiponectin, GH and cortisol were unaffected by DEA. Conclusion: These studies indicate that although fasting glucose and insulin are unaffected by short-term caloric restriction, the insulin response to glucose is attenuated even when adjusting for meal-related calories. Orexin A increased and leptin decreased with reduced caloric intake, acting, at least in part, to stimulate appetite. Taken together, these hormonal responses, directed at preserving energy homeostasis, have important implications for understanding the potential efficacy of intermittent caloric restriction.
SUN-515 Use of Plasmapheresis for Treatment of Thyroid Storm Resistant to Antithyroidals
Authors: Vega Myrian Noella Vinan , Mejia Ana Marcella Rivas , Nugent Kenneth
Published: May 2020

Management strategies of thyroid storm include measures to reduce thyroid hormone synthesis, hormone release, conversion from T4 to T3, and inhibition of the peripheral effects of excessive thyroid hormone. Plasmapheresis has been described as a treatment option when traditional therapy is not successful or not feasible.

We present a case of an adult patient who presented in thyroid storm in whom plasmapheresis was used successfully as a bridge to thyroidectomy.

51-year-old female with history of hypertension presented with sudden onset shortness of breath, and palpitations. She had an irregular heart rate of 140BPM, respiratory rate of 40, mean arterial blood pressure 65mmHg. Electrocardiogram confirmed atrial fibrillation with rapid ventricular response and the patient was admitted to the intensive care unit. She was started on diltiazem drip and subsequently received amiodarone and electrical cardioversion due to persistent rapid heart rate. She developed respiratory distress and required endotracheal intubation.

Initial thyroid profile revealed low TSH and normal FreeT4, but her FT4 increased above normal on day 2, treatment for thyroid storm was initiated with potassium iodine, hydrocortisone and propylthiouracil. She was kept on propranolol 80 mg q/4h, intravenous esmolol 50 mcg/kg/min, diltiazem drip 5 mg/hr, and was started on Digoxin 0.25 mg q/4h. TSI and TPO were undetectable, and thyroid ultrasound revealed a right nodule measuring 5 x 2.2 x 3.7cm. Thyroid storm was attributed to a toxic nodule exacerbated by exposure to excess iodine (contrast for imaging and amiodarone). Propylthiouracil, hydrocortisone and beta blocker were maximized, and cholestyramine was added, but their heart rate remained elevated, blood pressure worsened requiring synchronized cardioversion.

Because of persistent hyperthyroid state, refractory to medical treatment, patient was started on plasmapheresis on day 10 of hospitalization, she underwent 5 sessions with significant reduction in Free T3 and Free T4 (Figure 1), and remarkable improvement in her hemodynamic status and resolution of tachycardia. Patient underwent total thyroidectomy on day 16, without complications.

Plasmapheresis has been described as a treatment option for refractory thyroid storm, as a bridge therapy prior thyroidectomy. During plasmapheresis, thyroid-binding globulin, thyroid hormones, cytokines and putative antibodies are removed with the plasma; then the colloid replacement provides new binding sites for circulating free thyroid hormone (2). Although albumin binds thyroid hormone less avidly than TBG, it provides a much larger capacity for low-affinity binding that may contribute to lower free thyroid hormone levels, providing a window for thyroidectomy.

1.

Muller C et al, Role of Plasma Exchange in the Thyroid Storm, Therapeutic Apheresis and Dialysis15 (6): 522–531
SUN-636 Gaps in Quality of Delivery of Post-Partum Care in Preconception Counselling for Pregnant Women with Pre-Existing Diabetes at a Large Academic Tertiary Centre
Authors: Abbas Minan , Feig Denice , Mukerji Geetha
Published: May 2020

BACKGROUND: Women with pre-existing diabetes are at increased risk of serious adverse pregnancy outcomes compared with the general maternity population including congenital anomaly, stillbirth and neonatal death. The 2018 Diabetes Canada Clinical Practice Guidelines (DC CPG) on Diabetes in Pregnancy recommend that women with pre-existing diabetes are provided with postpartum and preconception counseling by their diabetes healthcare team, as this is associated with improved maternal and fetal outcomes.

OBJECTIVE: To evaluate the quality of physican counselling of post-partum management and pre conception advice for women with pre-existing diabetes who receive their intrapartum care at Mount Sinai Hospital Diabetes in Pregnancy Clinic in Toronto Ontario.

METHODS: Eligible patients were pregnant women with pre-existing Type 1 and Type 2 diabetes who were followed in pregnancy until their 6 weeks postpartum clinic visit. Consecutive baseline chart review of patients between June 2018 - June 2019 was performed to audit documentation of physician counselling of DC CPG recommendations at the 6 week post-partum visit. Key components of the recommendations included: 1) targeting an HbA1c of <7% pre-pregnancy, 2) folic acid supplementation and neural tube defect prevention, 3) weight management and optimization of BMI, 4) contraceptive measures and family planning, 5) information regarding outcomes and risks for mother and baby 6) yearly retinal exam.

RESULTS: Results of our chart review found that 42% (n=50) of women with pre-existing diabetes who received their intrapartum care at our clinic returned for their 6 week postpartum visit between June 2018-June 2019. Audit of the 6 week post-partum clinic note found that less than 20% of women had physician documentation of counselling on two or more key components of the DC CPG recommendations (1-6).

CONCLUSION: There is a large gap in women attending postpartum appointments and there are significant gaps in physician documentation of counselling among women with pre-existing diabetes. Further analysis will be conducted in order to determine if there is a patient knowledge gap regarding counselling recommendations and a quality improvement project will be undertaken to close this gap.
SAT-685 Euglycemic Diabetic Ketoacidosis in T1d: The Era of SGLT-2 Inhibitors and Keto-Diet
Authors: Castellanos-Diaz Jessica , Mathews Sherin Elsa , Barsamyan Gayane , Julio Leey-Casellas , Kadiyala Sushma
Published: May 2020

Introduction Euglycemic diabetic ketoacidosis (DKA) is a challenging diagnosis since near normal blood sugar levels can be misleading. In the present case, we describe a patient with Type 1 Diabetes (T1D) on SGLT2 who underwent a strict low carb diet. Case Report A 70-year-old female with past medical history of unspecified diabetes mellitus and primary hypothyroidism presented to emergency room complaining of nausea and dizziness of four days with decreased oral intake. She was alert and oriented, normal weight (52 kg, BMI 20 kg/m2) with stable vital signs, except for mild tachypnea (22/min). Initial labs showed serum glucose 136 mg/dL, bicarbonate 10 mmol/L (normal 20-31), anion gap of 27, venous blood gas pH 7.1, B-hydroxybutyrate 8.8 mmol/L (normal 0.02-0.27), glucosuria > 500 mg/dL, and moderate ketonuria. Screening for ethyl alcohol and ethylene glycol was negative. Lactic acid, cardiac enzymes, renal and liver function tests were normal. She was diagnosed with diabetes mellitus at age 37, on insulin since then. No alcohol use. Her new primary care physician found an A1C of 9.0% for which metformin 1000mg oral twice a day and empagliflozin 12.5 mg oral daily were added and aspart insulin was discontinued. Daily glargine remained at 20 units daily. She was advised to lose weight for which she started a keto-diet 4 weeks prior to this presentation. She had lost 15 pounds since then accompanied by polyuria and polydipsia. Upon admission, she received IV insulin and IV fluids. An endocrinology consultation was requested for euglycemic DKA secondary to SGLT2 complicated by starvation ketosis. Antibodies against glutamic acid decarboxylase were positive at 250 IU/mL (normal < 5). She was discharged on glargine, aspart insulins and oral medications were discontinued. Conclusion This case shows the importance of identifying the specific type of diabetes for appropriate individualization of therapy. Following a keto-diet in unrecognized T1D can trigger ketoacidosis in the setting of SGLT2 inhibitors leading to euglycemic diabetes ketoacidosis.
SUN-925 Carcinoid: A Crisis in the Upside Down
Authors: Arzeno Luis E , Lessard Kimberly Kochersperger , Jabbour Serge A
Published: May 2020

Unrecognized carcinoid tumors can rarely present as a life-threatening condition known as carcinoid ‘crisis’ which typically presents as significant but transient hypotension if there is no appropriate preventive treatment. Somatostatin analogs such as Octreotide are agents of choice to avoid such crises. However, there is minimal literature and a lack of guidelines regarding the management of an active, labile carcinoid crisis in patients exhibiting both hypotension and hypertension, as will be presented here.

Case: A 76-year-old female with end-stage renal disease, status post kidney transplant on immunosuppressants, who was initially admitted for workup of hematuria. Abdominal CT revealed a bladder mass with various features concerning for malignancy and an incidental mesenteric mass, followed by bladder biopsy suggestive of neoplasm. The patient was taken to the OR where she first underwent resection of the bladder mass with subsequent proceeding to the removal of the mesenteric mass. Within minutes of manipulation of the mass, the patient became significantly hypotensive with a mild response to fluid resuscitation, requiring vasopressors. A frozen section suggested the possibility of a neuroendocrine tumor. Given concerns of carcinoid crisis the patient was started on Octreotide infusion achieving some degree of hemodynamic stabilization but soon developed extremely labile blood pressure with rapidly alternating hypotension (SBP <60mmHg) and hypertension (SBP >200mmgHg). During hypotensive episodes, the aid of adjunctive beta-adrenergic agents was required, while the doses for the Octreotide infusion were as high as 200mcg/hr. Initial Endocrinologic workup revealed a Chromogranin A level 1,178 ng/mL (25 - 140 ng/mL), VIP <50 pg/mL (<75 pg/mL), 24 hr 5HIAA 23.5 (<=6.0 mg/24 h), Serotonin 2,334 ng/mL (56 - 244 ng/mL) consistent with carcinoid. Repeat Serotonin levels 5 days after octreotide infusion was 674 ng/mL. The patient was successfully weaned from vasopressors but required continuation of Octreotide for additional 5 days due to intermittent episodes of hypotension.

Carcinoid crisis is a life-threatening condition associated with hypotension, and less commonly hypertension, from the release of vasoactive agents from tumor manipulation. Preparation with Octreotide before any manipulation or anesthesia is recommended to avoid a carcinoid crisis. However, if a crisis develops management is mainly with a continuous Octreotide infusion. The use of beta-adrenergic agents is debated, due to a possible “paradoxical effect” which could further worsen hypotension. Others argue that there is a role in preventing prolonged episodes of hypotension. In this case, it was required high doses and the infusion was needed for 5 days, probably related to the presence of ESRD which could have prolonged the bioavailability of the vasoactive agents.