bluuebunny/crossref_metadata_2025 huggingface dataset:
MON-022 Dissecting the Interplay Between Diet and PCOS Pathology on Gut Microbiota in a PCOS Mouse Model
Authors: Paris Valentina Rodriguez , Kaakoush Nadeem O , Solon-Biet Samantha M , Edwards Melissa C , Ledger William L , Gilchrist Robert B , Simpson Stephen J , Handelsman David J , Walters Kirsty A
Published: May 2020

The gut microbiome has been implicated in the development of metabolic disorders such as obesity and type-2 diabetes, and more recently polycystic ovary syndrome (PCOS). PCOS is a heterogeneous disorder with reproductive, endocrine and metabolic irregularities, and clinical and animal studies have reported that PCOS causes a decrease in microbial diversity and composition. Diet is an important regulator of the gut microbiome, and a recent study identified that alterations in macronutrient balance impact gut microbial communities which correlate with different metabolic health outcomes (1). We have identified that macronutrient balance impacts the development of PCOS traits. Therefore, to investigate the interplay between macronutrient balance and a PCOS environment on the gut microbiome, we analyzed the intestinal microbiome from fecal pellets of control and DHT-induced PCOS mice exposed to 10 different diets that varied systematically in protein (P), carbohydrate (C) and fat (F) content. The amount of dietary P, C and F consumed significantly altered alpha and beta diversity of the gut microbiota of pooled control and PCOS mice (P<0.0001). Alpha diversity between control and PCOS mice on the same diet did not differ significantly, and hence was only affected by diet composition. However, beta diversity was significantly altered between control and PCOS mice (P<0.05). We performed DESeq2 analysis and identified an operational taxonomic unit (OTU) within Bacteroides (OTU3) to be the most differentially abundant OTU between control and PCOS mice, with a significant decrease in PCOS mice compared to controls (control: 7.88 and PCOS: 5.38; fold change = 1.464; P<0.0001). The consensus sequence of Bacteroides OTU3 was found to share 99.2% similarity to Bacteroides acidifaciens. B. acidifaciens is associated with obesity with elevated levels reported to prevent the onset of obesity (2). Thus, we then investigated the influence of P, C and F on the relative abundance of Bacteroides OTU3 and revealed an association with C consumption, with increasing levels of C leading to increased levels of Bacteroides OTU3 (Carb: r= 0.22, p=0.0028, q=0.015). These findings demonstrate that diet exerts a stronger influence over the gut microbiome than PCOS pathology. However, the hyperandrogenic PCOS environment does lead to changes in gut microbiota beta diversity, with a specific decrease in an obesity-associated (2) Bacteroides species in PCOS mice that is also responsive to levels of C consumption. Reference: (1) Holmes et al., Cell Metabolism. 2017; 25(1): 140-151. (2) Yang et al., Mucosal Immunology. 2017, 10 (1), 104-116.
SAT-123 Nuclear Receptor 4A1 (NR4A1) Acts as a Tumor Suppressor in Anaplastic Thyroid Cancer
Authors: Guan Hongyu , Li Hai , Xu lijuan , Li Yanbing
Published: May 2020

The nuclear orphan receptor NR4A1 has been demonstrated to play important roles in development and progression of various cancers. However, the biological roles and its underlying mechanisms of NR4A1 in anaplastic thyroid cancer (ATC) are largely unknown. Here, we showed that the expression level of NR4A1 was robustly down-regulated in ATC cell lines and human ATC tissues as compared to Nthy-ori 3-1 cells and normal thyroid tissues, respectively, using in silico analysis, qRT-PCR and immunohistochemistry analyses. Gain-of-function experiments were carried out to understand the NR4A1’s responsiveness to apoptotic inducers. The results showed that ectopic over-expression of NR4A1 reduced cell viability and promoted cell apoptotic rate induced by UV irradiation or Adriamycin. Moreover, the activities of caspase-3 and PARP were elevated in NR4A1 overexpression cells in response to apoptotic inducers. Furthermore, we found that down-regulation of XIPA was involved in the pro-apoptotic role of NR4A1 in ATC cells. Collectively, these findings suggest that the nuclear orphan receptor NR4A1 acts as a tumor suppressor in ATC via regulating XIPA, providing a potential therapeutic target against ATC.
MON-603 GPR142 Expression Levels Were Correlated with Plasma Ghrelin Levels and Heights in Morbidly Obese Patients
Authors: Ueda Yoko , Iwakura Hiroshi , Doi Asako , Matsutani Norihiko , Morita Shuhei , Inaba Hidefumi , Ariyasu Hiroyuki , Fukuda Naoki , Hayata Keiji , Ojima Toshiyasu , Nishi Masahiro , Yamaue Hiroki , Akamizu Takashi
Published: May 2020

Recently, aromatic amino acids, especially tryptophan were discovered to be the strongest ligands for GPR142, which was previously known as an orphan GPCR. GPR142 is expressed in the digestive tract and pancreas in mice and human. Previously we found that GPR142 is highly expressed in the ghrelin-producing cell line, MGN3-1 cells, and that tryptophan strongly stimulated ghrelin secretion in vitro.

In this study, we measured the mRNA expression levels of GPR142 in the gastric samples of 6 morbid obese patients undergone laparoscopic sleeve gastrectomy and compared its level with their clinical parameters. GPR142 expression levels were negatively correlated with plasma desacyl ghrelin levels (p=0.011) and positively correlated with heights (p=0.08).

The current results that GPR142 expression levels were correlated with plasma desacyl ghrelin levels may confirm the link between GPR142 signal and regulation of ghrelin secretion demonstrated in our in vitro study. Regarding to the correlation with heights, there are some reports that plasma ghrelin levels were inversely correlated with heights in children[1-3], although, as far as we know, there are no reports demonstrating the relationship between plasma ghrelin levels and heights in adults. Considering that ghrelin strongly stimulates growth hormone secretion, GPR142 signaling may have influence on height through regulating ghrelin-growth hormone axis.

Conclusion

GPR142 mRNA expression levels were negatively and positively correlated with plasma desacyl ghrelin levels and heights in morbid obese adults undergone bariatric surgery. Current results may help understanding the pathophysiological role of GPR142 in the regulation of ghrelin secretion and heights.

References

1. MO Camurdan, et al. Endocrine Journal 2006, 53 (4), 479–484

2. HS Park, et al. Metabolism Clinical and Experimental 2005, 54, 925–929

3. Joy C. Bunt,et al. J Clin Endocrinol Metab 2003, 88(8): 3756-3761
MON-592 The Impact of Bariatric Surgery on the Risk of Non-Alcoholic Fatty Liver Disease in Morbidly Obese Patients
Authors: Borges-Canha Marta , Neves João Sérgio , Mendonça Fernando , Silva Maria Manuel , Costa Cláudia , Cabral Pedro M , Gonçalves Vanessa Guerreiro , Lourenço Rita , Patrícia Meira , Salazar Cristina Daniela , Maria Ferreira João Silva , Pedro Jorge Pires , Belo Sandra , Lau Eva , Sande Ana , Viana Sara , Freitas Paula , Carvalho Davide M ,   AMTCO group
Published: May 2020

Introduction: Non-alcoholic fatty liver disease (NAFLD) is strongly associated with obesity, and the prevalence of both diseases is increasing notably. The lack of effective treatment options for NAFLD is leading to a great consideration towards the identification of new approaches.

Aim: We aimed to evaluate the change one year after bariatric surgery of parameters of hepatic function and in the hepatic scores, Fatty Liver Index (FLI, predictor of hepatic steatosis), and BARD, BMI, AST/ALT ratio and DM, (predictor of hepatic fibrosis).

Methods: Observational retrospective cohort study in morbidly obese patients that underwent bariatric surgery between January 2010 and July 2018. We excluded patients missing hepatic function parameters before or one year after the surgical procedure. We used two linear regression models: 1) unadjusted; 2) adjusted for surgery type (gastric sleeve, gastric band and gastric bypass), sex, age, body mass index, diabetes and dyslipidaemia.

Results: The included population (n=1955) had an average age of 43.1±10 years and 85.8% were female. We observed a relevant decrease in transaminases (pre-operative AST and ALT, 24.8±12.4 and 29.5±19.5U/L, vs 22.4 ± 11.1 and 22.2±14.7 post-operatively, respectively, p<0.01) and gamma-glutamyltransferase (36.9±35.4 vs 21.4±22.0U/L, p<0.01), and an increase in alkaline phosphatase (77.8±23.5 vs 80.8±25.4U/L, p<0.01) and total bilirubin (0.56±0.23 vs 0.68±0.24mg/dL, p<0.01). Both FLI and BARD markedly decrease one year after surgery (p<0.01). Comparing the surgical procedures, gastric sleeve was associated with a greater reduction of hepatic enzymes and of both FLI and BARD comparing with gastric band. Comparing with gastric bypass, sleeve was associated with a greater reduction of transaminases and alkaline phosphatase, but a smaller reduction of FLI and BARD.

Conclusion: Bariatric surgery is associated with a reduction of the hepatic enzymes and an improvement of FLI and BARD. Bariatric surgery may represent an effective therapeutic approach to NAFLD.
MON-110 Utilization of GluCEST, a Novel Neuroimaging Technique, to Characterize the Brain Phenotype in Hyperinsulinism/Hyperammonemia Syndrome
Authors: Rosenfeld Elizabeth , Nanga Ravi P R , Reddy Ravinder , Revell Andy , Roalf David R , Davis Kathryn A , De Leon Diva D
Published: May 2020

BACKGROUND: Hyperinsulinism/Hyperammonemia (HI/HA) syndrome is the second most common form of congenital hyperinsulinism. It is caused by gain-of-function mutations in glutamate dehydrogenase (GDH), a mitochondrial enzyme expressed in pancreatic β-cells, liver, kidney, and brain, and is responsible for metabolizing glutamate into α-ketoglutarate and ammonia. In addition to hyperinsulinemic hypoglycemia due to abnormal GDH activity in pancreatic β-cells, ~80% of patients have developmental delays, learning, or behavioral disorders and >60% have atypical absence seizures (Bahi-Buisson, 2008). These neurologic symptoms are not fully explained by hypoglycemia and are hypothesized to result from central nervous system (CNS) glutamate imbalance due to CNS GDH overactivity. Newer magnetic resonance imaging (MRI) techniques have allowed for sensitive estimation of CNS glutamate using Glutamate Chemical Exchange Saturation Transfer (GluCEST). We aimed to comprehensively characterize the biochemical and clinical neurologic phenotype of HI/HA leveraging GluCEST MRI.

Methods: Subjects with confirmed HI/HA diagnosis and without contraindication to MRI had electroencephalogram (EEG), serum ammonia, and the following validated neurodevelopmental assessments: ABAS-3, BRIEF, and ASEBA CBCL (if <18 years) or ASR (if >18 years) completed. GluCEST MRI axial hippocampal and midsagittal slices were acquired on a 7.0T Siemens scanner and reported as GluCEST % contrast. Healthy control GluCEST % contrast data were obtained from a separate study using the same neuroimaging protocol.

Results: 8 HI/HA subjects (4 female; mean age 28 years [range 16-56] years) participated to date. Median serum ammonia was 58 umol/L (IQR 39-89). 50% self-reported learning impairments and 37.5% self-reported prior ADHD diagnosis. Marked unilateral increase in hippocampal GluCEST % contrast was observed in 3/6 subjects (2 L>R; 1 R>L). Overall, median peak GluCEST % contrast level was significantly higher in HI/HA subjects than controls (10.3% [IQR 8.9-11.3] v. 8.0% [IQR 7.8-8.4], p=0.0013, n=6).

Conclusions: This is the first study to evaluate CNS glutamate via GluCEST in HI/HA. Hippocampal glutamate, measured by GluCEST % contrast, was significantly higher in HI/HA subjects than healthy controls. Laterality in hippocampal glutamate was observed in half of subjects. These findings are remarkable given the known role of abnormal glutamate signaling in the development of epilepsy and neurocognitive impairment. Next steps are to complete midsagittal GluCEST image processing, EEG and neurodevelopmental assessment interpretations to explore correlations between CNS phenotype and brain glutamate pattern. GluCEST holds promise for elucidating the pathophysiology of CNS manifestations in HI/HA syndrome.
SUN-311 Adrenal Reserve Testing with the Glucagon Stimulation Test (GST) and Cosyntropin Stimulation Test (CST) in Deployed Veterans with Mild Traumatic Brain Injury
Authors: Nagireddi Rama Priyanka , Win Htet Htet , Wagstaff Sarah , Neal Moira , Friedman Kathryn , Anderson Robert J
Published: May 2020

Introduction: Mild Traumatic Brain Injury (mTBI) is associated with anterior pituitary hormone dysfunction. The potential long-term effect of this injury on pituitary function in Veterans is not clear. We reviewed the utility of the fixed dose Glucagon Stimulation Test (GST) compared with the high dose Cosyntropin Stimulation test (CST) for hypothalamic-pituitary-adrenal (HPA) reserve over time in these patients with mTBI.

Methods: We present an interim report of our 4-year longitudinal prospective pilot study of pituitary function in Veterans diagnosed with mTBI. Of the 34 mTBI Veterans enrolled, we have tested 28 of them (4 female, 24 male; age and BMI, 31.5±7.0 years and 30.4±6.2, mean±SD, respectively) for baseline pituitary hormone levels and cortisol response to the CST. In 22 subjects growth hormone and cortisol responses to GST were tested at baseline (Year 0). Follow-up testing was done for 18 mTBI subjects in Year 1, 13 subjects in Year 2, 10 subjects in Year 3 and 5 subjects in Year 4. The same baseline data were obtained for 14 age-, sex-, deployment- and BMI-matched control subjects without mTBI (2 female,12 male; age and BMI 34.4±6.8 years and 30.5±4.9, mean±SD, respectively). Cortisol cutoffs of <18 mcg/dL with the CST and <9.0 mcg/dL with the GST were used for the diagnosis of adrenal insufficiency.

Results: Secondary adrenal insufficiency (AI), likely partial, was identified during this study on 6 occasions: 3/22 subjects at Year 0, 1/18 at Year 1, 0/13 at Year 2, 1/10 at Year 3 and 1/5 at Year 4. Two baseline subjects with AI reverted to normal in Years 1-3, one relapsed in Year 4 and a third had no further testing. Correlations of the cortisol levels from GST vs the 60-minute cortisol from CST were significant at Year 0 (n=22, r=0.553, p=0.008) and at Year 1 (n=18, r=0.802, p<0.0001). Due to decreased numbers, there were no significant correlations at Years 2 through 4. Similar correlations were obtained using the 30-minute CST values. However, the CST cortisol value predicted the low GST value in only 2/6 subjects. The mean GST cortisol levels and 60-minute CST cortisol levels for subjects at each year were not significantly different over Years 0 through 4 based on ANOVA analyses (CST: F=1.519, p= 0.206; GST: F= 0.796, p=0.532).

Conclusions: Secondary adrenal insufficiency, likely partial, related to mTBI was detected by GST on 6 occasions (twice in one patient) over 4 years of observation. GST can provide useful information about HPA axis reserve, and appears to be more reliable than CST. Identification of potential secondary adrenal insufficiency using the GST in Veterans with mTBI can provide a beneficial combined test for these patients when other testing is not feasible.
SUN-175 Repeat Unstimulated AVS with Aid of Plasma Metanephrines Identifies Unilateral Primary Aldosteronism When Initial AVS and Metomidate PET-CT Fails To
Authors: Tan Ying Tse Sarah , Zhang Meifen , Gani Linsey , Khoo Joan , Tan Colin , Ng Keng Sin , Puar Troy H
Published: May 2020

Introduction

Adrenal venous sampling (AVS) is the reference test for identifying unilateral primary aldosteronism (PA). However, in patients with corticol co-secreting adrenal nodules, elevated cortisol levels may affect the interpretation of aldosterone-cortisol (AC) ratios. ACTH-stimulation may further confound results. In such patients, the use of plasma metanephrines instead of cortisol as a correcting factor may be helpful.

Case Summary

A 54 year old lady presented with 8 years of hypertension and hypokalaemia (nadir 2.2mmol/L) while on amlodipine 10mg and valsartan 80mg daily. PA was confirmed by a post-saline infusion aldosterone 1075pmol/L. CT identified a 2.4cm right lipid rich adrenal adenoma. Serum cortisol post 1mg overnight dexa-suppression test was unsuppressed at 63mmol/L.

First AVS was done sequentially under ACTH stimulation and suggested lateralization to the right, with lateralization ratio (LR) 3.4. However, this was <4, and there were bilaterally low AC ratios compared to peripheral vein. Metomidate PET-CT scan then showed increased uptake over the nodule, but lower than the contralateral gland. In view of these findings, repeat AVS was done simultaneously without ACTH stimulation. Given the possibility of a co-secreting adenoma, plasma metanephrines were also measured. Second AVS showed right-sided lateralization (LR 11.8). Using metanephrines as a correction factor, the LR was even more elevated at 22.3, with contralateral suppression.

She underwent right adrenalectomy and was cured of hypertension and hypokalaemia at 6 months post surgery. Aldosterone renin ratio has normalized: aldosterone <4ng/dL, plasma renin activity 0.6ng/ml/hr.

Clinical Lessons

While ACTH stimulation helps to improve success rates of cannulation by increasing cortisol gradients, most studies show that it lowers LR. Furthermore, this would be concerning in patients with cortisol co-secreting adenomas. In this case, repeat AVS without ACTH demonstrated improved lateralization to the right. The use of metanephrine as a correcting factor appears to be a better indicator of right sided disease. However, while plasma metanephrines have been shown to be useful to indicate correct catheter placement, it has not been adopted as a correction factor for dilution yet. Finally, in addition to affecting AVS results, cortisol-cosecreting tumors may also affect 11C-Metomidate PET-CT imaging.

Conclusion

In patients with suspected cortisol co-secreting adenomas, unstimulated AVS and use of plasma metanephrines may help to identify unilateral PA even when conventional AVS and metomidate scans fail to. Further studies on using metanephrines as a correcting factor for lateralisation would be helpful.
SUN-066 Prenatal Sex Steroid Serum Concentrations in Relation to Sex-Typical Play Behavior at 4 Years of Age
Authors: Sethuram Swathi , Swan Shanna , Wang Christina C L , Barrett Emily , Nguyen Ruby , Raymond Samantha , Evans Sarah , Sathyanarayana Sheela
Published: May 2020

INTRODUCTION: Sex differences in play behavior have been seen in rodents, primates and humans with literature showing some associations with maternal sex steroids. The PreSchool Activities Inventory (PSAI) is a validated tool to assess sexually-dimorphic play behavior. We assessed the associations between prenatal maternal estradiol (E2), free testosterone (fT) and total testosterone (T) and children’s PSAI scores at age 4.

METHODS: Data were collected in The Infant Development and the Environment Study (TIDES), a US-based multi-center pregnancy cohort. The analysis included 399 pregnant women with complete data on sex steroids, PSAI and covariates. Early pregnancy E2 and T were analyzed by liquid chromatography tandem mass spectrometry and fT by equilibrium dialysis using labeled testosterone. PSAI scores (masculine, feminine and composite) were calculated from questionnaires completed by mothers when child was approximately 4 years old. Covariates included: maternal age and education, child age at questionnaire completion, number of older brothers and sisters, infant race and parental attitudes towards sex-atypical play behavior. After demonstrating nonlinear associations between PSAI scores and sex steroids, we used multivariable sex-stratified quadratic regression to model these relationships.

RESULTS: The analysis included 192 boys and 207 girls (mean age: 4.5 years). Sex steroids in serum collected at 6-20 weeks’ gestation (mean: 11 weeks) were similar in mothers of boys and girls. In girls, E2 showed a quadratic relationship with the masculine score (beta (E2) = 0.003, p = 0.002, beta (E22) = -7.3E-7, p <0.001). Masculine scores were lower among girls whose mothers had E2 above the 75th percentile (2160 pg/ml). In boys, we observed a positive linear association of borderline significance (beta (fT) = 9.11, p = 0.06) and a significant negative association for the quadratic term (beta (fT2) = -7.44, p = 0.04). PSAI measures were not associated with E2 in mothers of boys, fT in mothers of girls, or T in either sex.

DISCUSSION: This study did not replicate previously reported associations between T and masculine scores in girls. However, we found that, while most maternal E2 levels were not associated with play behavior in either sex, levels above the 75th percentile were associated with reduced masculine scores in girls at age 4. Our data also suggest a somewhat reduced feminine scores in boys born to mothers with fT above the 75th percentile. These results, based on a small sample using a maternal assessment of play behavior, should be examined in a larger sample using an objective measure of play.
SAT-412 Genetic Susceptibility to Graves’ Disease Conferred by HLA-DQβ1 Position 57
Authors: Badenhoop Klaus , Bee Sarah , med cand , Penna-Martinez Marissa
Published: May 2020

Introduction: Human leukocyte antigen (HLA) locus is the major genetic risk factor for autoimmune endocrine diseases. The amino acid variability at the HLA-DQβ1 position 57 encoded by both DQB1 alleles was identified as critical risk residue for type 1 diabetes. We therefore investigated this amino acid residue at HLA-DQβ1 position 57 in Graves’ disease (GD). Subjects and methods: DNA samples were obtained from 572 healthy controls (HC, 262 females/310 males) and 299 patients with GD (255 females/44 males) and genotyped for HLA-DQB1 using a sequence specific primer (SSP, 13 primer pairs) approach. The PCR amplified products were analyzed by gel electrophoresis. The HLA-DQB1 alleles were defined with their corresponding amino acid residues at the DQß chain positon 57 as follows: Ala57 (DQB1*0201,*0302), Asp57 (DQB1*0301,*0303,*0401,*0402,*0503,*0601,*0602*,0603) Val57 (DQB1*0501,*0604) and Ser57 (DQB1*0502). Finally, the frequencies for amino acid variabilities and their combinations (Ala/Ala, Ala/non-Ala and non-Ala/non-Ala) were calculated and compared by Pearson-Mantel-Haenszel Chi-squared test. Results: The presence of Ala57 was significantly more frequent in patients with GD compared to HC (25% vs. 39%, OR: 1.77; p=7x10-4), whereas Val57 was less frequent (19% vs. 12%, OR: 0.59; p=0.04). In contrast, no difference in the distribution between GD and HC concerning the amino acids Asp57 and Ser57 was observable. Similar results were found in female (Ala57 23% vs. 38%, OR:2.01; p=1.2x10-3 and Val57 19% vs. 13%, OR:0.35; p=1.2x10-4) but not in males (p >0.5). Furthermore, homozygous HLA-DQB1 Ala (8% vs. 15%, OR:1.98; p=5x10-3) as well as heterozygous HLA-DQB1 Ala/non-Ala (34% vs. 45%, OR:1.58; pc=5x10-3) were significantly more prevalent, while non-Ala/non-Ala (58% vs. 40%, OR:0.49 pc=3x5x10-6) was found to be less frequent in patients than in HC. By gender stratification there was a significant difference between female patients with GD and female HC in the distribution of the mentioned amino acid combinations (Ala p=4.5x10-3, Ala/non-Ala pc=0.02, non-Ala/non-Ala p=1x10-5). Conclusion: We identify a strongly predisposing role for HLA-DQβ1 Ala5 7to GD, particularly in women, highlighting the gender specific disease risk. Immunogenetic testing may pave the way towards personalized treatment.
SUN-362 Bone Involvement in Adult Patients Affected with Ehlers-Danlos Syndromes
Authors: Eller-Vainicher Cristina , Grassi Giorgia , Chiodini Iacopo , Cairoli Elisa , Palmieri Serena , Franchetti Sara , Marinelli Barbara , Castronovo Paola , Arosio Maura , Bassotti Alessandra
Published: May 2020

INTRODUCTION: The Ehlers-Danlos syndrome (EDS) is characterized by abnormalities of the connective tissue leading to ligamentous laxity and skin and tissue fragility, bone involvement is an emerging manifestation. We evaluated the bone metabolism, bone mineral density (BMD) and bone quality (measured by trabecular bone score, TBS), and the prevalence of clinical fractures and morphometric vertebral fractures (mVFx) in a large group of adult EDS patients. METHODS: Two-hundred and sixty-six consecutive Caucasian patients, aged ≥18 years (38.3±11.8) (190 females, 76 males) 58% with classical, 34.9% with hypermobility, 4.5% with vascular and 4.8% undefined EDS were enrolled. We had genetic information of 117 patients (74 patients showed no mutations, 2 COL2 mutations, 8 COL3 mutation, 28 COL5 mutations and 5 other genes mutations). In all subjects’ calcium-phosphorous metabolism, bone turnover, BMD at the lumbar spine (LS) and femur (femoral neck, FN and total femur, FT) and radius and TBS by dual-energy X-ray absorptiometry were assessed. Moreover, we evaluated the history of clinical fragility and the mVFx presence by spine radiograph. RESULTS: The 20.6% of patients showed a Z-score BMD ≤-2.0, the 29.8% ≥1 mVFx and the 24.5% ≥1 clinical fractures. Male patients showed a higher prevalence of reduced BMD (31.9 vs 15.6%; p=0.007) and mVFx (41.4% vs 24.8%; p=0.026). Patients with ≥1 mVFx were older (43.2±12 vs 35.6±12; p=0.0001), showed a lower TBS z-score (-1.4±1.7 vs -0.8±1.2; p=0.013) and lower phosphate levels (3.3±0.6 vs 3.5±0.5; p=0.032) with an higher prevalence of hypophosphatemia (24.5% vs 8.8%; p=0.014). No difference was found in prevalence of EDS subtypes or gene mutations. In EDS patients, the VFx presence was significantly associated with TBS and age, even after adjusting for sex and hypophosphatemia. CONCLUSIONS: EDS patients have reduced BMD and bone quality (as measured by TBS) and increased prevalence of clinical and mVFx associated with age and TBS.
OR22-05 Rare Biallelic Variants in Obesity-Related Genes in the Madrid Pediatric Obesity Cohort
Authors: Martos-Moreno Gabriel Á , Moeller Ida Hatoum , Martín-Rivada Álvaro , Pérez-Jurado Luis A , Argente Jesús
Published: May 2020

BACKGROUND: Obesity is a heterogenous disease resulting from environmental and genetic factors and is characterized by disordered energy balance, regulated in part by the hypothalamic melanocortin-4 receptor (MC4R), including neuronal ciliary assembly and trafficking pathways.1 Rare loss-of-function variants in genes encoding components of this pathway are associated with severe obesity and hyperphagia, with or without additional features.2 However, such rare genetic disorders may be underestimated due to a lack of genetic screening in individuals with severe obesity.3 Our objective was to identify and characterize rare genetic variants in a Spanish population from Madrid with childhood obesity. Methods: This analysis was conducted from a prospectively-collected cohort of children with obesity, generally with a BMI>+3DS. Participants were sequenced for 35 obesity-related genes, including 23 genes related to Bardet-Biedl (BBS) and Alström syndromes, plus an additional 12 genes associated with non-syndromic, monogenic causes of obesity, to identify individuals with rare (<1% frequency in gnomAD) potentially biallelic (homozygous and compound heterozygous) non-synonymous variants in protein-coding regions. Results: Of the 1019 Spanish patients with obesity, 493 (48.4%) were female and the mean age and BMI were 10.41 ± 3.38 years and 4.38 ± 1.76 SDS (79.8% above +3 SDS), respectively. We identified 26 rare potentially biallelic variants in 25 unique individuals, including 2 individuals with homozygous variants in POMC, 3 individuals with two variants in SRC1, one individual with two variants in ADCY3, and one individual with a homozygous mutation in LEP. In addition, we identified 18 individuals with biallelic mutations in one of 23 BBS or ALMS1 genes, including two individuals with known pathogenic variants and clinically confirmed BBS. Conclusions: Rare and potentially biallelic sequence variants were identified in 25 individuals with childhood obesity. These results support the use of genetic testing for individuals with severe obesity who may be candidates for specific clinical interventions or additional targeted therapies.
SAT-052 A Novel Oral Testosterone Therapy (TLANDO) Safely Restores Testosterone to Eugonadal Levels with Fixed Dose Treatment
Authors: DelConte Anthony , Patel Mahesh V , Papangkorn Kongnara , Chidambaram Nachiappan , Bruno Benjamin J , Kim Kilyoung , Frank Joel , Khera Mohit , Miner Martin , Kaminetsky Jed , Vignozzi Linda , Goldstein Irwin
Published: May 2020

Most testosterone (T) replacement therapy (TRT) products have relied on dose titration to achieve eugonadal levels. However, dose titration in clinical practice can be time-consuming, expensive, and subject to errors. TLANDO (LPCN 1021) is a novel oral testosterone undecanoate (TU) product absorbed via the intestinal lymphatic pathway. A previous clinical study (NCT02081300) suggested that titration with TLANDO has little to no impact to improve PK profiles. The objective of this study was to assess whether fixed dose of TLANDO can restore testosterone to eugonadal levels. A 24 day, open-label, single-arm, multicenter study with TLANDO in hypogonadal men (NCT03242590) was conducted. Subjects (N=95) received 225 mg testosterone undecanoate orally twice a day (i.e., 30 minutes after morning and evening meals) for 24 days. On Day 24, blood samples were collected over a 24 hour period. The primary endpoint was the percentage of TLANDO-treated subjects who achieved a 24-hour average serum T concentration within the eugonadal range of 300 to 1080 ng/dL after 24 days of treatment. Mean peak serum T concentration was calculated based on daily TLANDO administration at Day 24. Key safety endpoints included incidence of adverse events (AEs), physical examination results, clinical laboratory test results, and changes in HCT, lipids, and PSA. Treatment compliance was calculated as a percentage of the amount of study drug used divided by the amount of study drug expected to be used. 94 subjects completed the study with mean age of 56.0 years, mean BMI 32.8 kg/m2, and baseline T level 202 ± 75 ng/dL. 80% of subjects achieved a 24-hour average serum T concentration within the normal range at Day 24. The lower and upper bounds of the 95% confidence interval was 72% and 88% respectively. Following daily administration of TLANDO at Day 24, the mean peak serum T concentration was 1178 ± 484 ng/dL. The incidence of treatment emergent adverse events (TEAEs) was 21%. The most frequently reported TEAEs were blood prolactin increase (6.3%), weight increase (2.1%), headache (2.1%), and musculoskeletal pain (2.1%). No deaths were reported during the study. Increase in hematocrit (0.9%) and PSA (0.2 μg/L) was observed. Decrease in lipids was observed (-6.9 mg/dL for HDL, -1.5 mg/dL for LDL, -8.9 mg/dL for triglycerides, and -10.6 mg/dL for total cholesterol). Overall mean treatment compliance was 99.7 ± 4.9%. In conclusion, a twice-daily, fixed-dose of TLANDO (450 mg TU total daily dose) successfully achieved target serum T level and achieved a safety profile consistent with that of other approved TRT products.
SUN-924 Functioning Abdominal Paraganglioma Presenting as Acute ST-Elevation Myocardial Infarction
Authors: Kongkit Jaruwan , Leelaprute Meythee , Houngngam Natnicha , Snabboon Thiti
Published: May 2020

Background:

Functioning paraganglioma is a rare catecholamine-producing tumor that arises in the sympathetic nervous system. It usually presents with sustained or paroxysmal hypertension accompanied by episodes of its classic triad of headache, palpitation, and diaphoresis. However, a wide range of signs and symptoms may be present. We report an unusual manifestation as acute myocardial infarction, which accidentally diagnosed by the trigger response from metoclopramide injection.

Case presentation

A 66-year-old woman with medical history of well-control hypertension, dyslipidemia and type 2 diabetes mellitus for 8 years presented with typical angina pain for 1 hour. She denied history of chest pain or triad symptoms of pheochromocytoma/paraganglioma (PCC/PGL). Her physical examination was unremarkable except severe hypertension, 206/89 mmHg, and occasional sinus tachycardia. Acute inferior wall myocardial infarction was proposed by an electrocardiogram study, acute ST elevation in lead II, III and aVF, and highly elevated cardiac enzymes. Echocardiogram and coronary angiography showed preserved left ventricle function (LV ejection fraction 70%) without regional wall motion abnormality. No evidence of coronary artery disease was found. During the catheterization, the cardiologist raised the possibility of the presence of PCC/PGL from her fluctuating blood pressure, 73/42 to 206/113 mmHg, after 10-mg metoclopramide injection to control her vomiting. Computer tomography of the abdomen showed a lobulated heterogeneous enhancing left para-aortic mass with internal necrosis, 6.1x4.9x4.1 cm in size, abutting left anterolateral aortic wall and encasing celiac trunk, superior mesenteric artery, and left renal arterial wall. Her hormonal study showed 24-hour urine fractionated metanephrine/normetanephrine levels of 2,924 nmol (<1,777 nmol)/4,328 nmoL(< 3,279 nmol), respectively, and plasma free metanephrine/normetanephrine levels of 93.66 pg/mL (0-96.6 pg/mL)/233.61 pg/mL (0-163.05 pg/mL). She underwent surgical tumor removal with uneventful outcome and the pathology confirmed the diagnosis of functioning PGL. During 2-years follow-up, the patient remained asymptomatic and her hormonal and functioning imaging study showed no recurrence. The genetic testing for PCC/PGL panel was negative.

Conclusion:

We present an unusual manifestation of PCC/PGL as acute coronary syndrome. The clinician should remind this tumor as the differential diagnosis, especially in a patient with negative coronary angiogram.
SAT-404 Neonatal Hypocalcemic Seizures in Offspring of a Mother with Familial Hypocalciuric Hypercalcemia Type 1 (FHH1)
Authors: Hannan Fadil M , Dharmaraj Poonam , Gorvin Caroline M , Soni Astha , Nelhans Nick D , Olesen Mie Kronborg , Boon Hannah , Cranston Treena , Thakker Rajesh V
Published: May 2020

Background: Familial hypocalciuric hypercalcemia type 1 (FHH1) is caused by loss-of-function mutations of the calcium-sensing receptor (CaSR), and considered to be a benign condition associated with mild-to-moderate hypercalcemia (1). However, the children of parents with FHH1 can develop a variety of disorders of calcium homeostasis in infancy.

Objective: To further characterise the range of calcitropic phenotypes in the children of a mother with FHH1.

Methods: We assessed a three generation FHH kindred by clinical, biochemical and mutational analysis following informed consent.

Results: The kindred comprised a hypercalcemic male, his daughter who had hypercalcemia and hypocalciuria, and her four children, of whom two had asymptomatic hypercalcemia, one was normocalcemic, and one suffered from transient hypocalcemic seizures during infancy. The hypocalcemic infant had a serum calcium of 1.57 mmol/L (normal, 2.0-2.8) and PTH of 2.2 pmol/L (normal, 1.0-9.3) as a consequence of maternal hypercalcemia, and required treatment with I-V calcium gluconate infusions. Mutational analysis identified a novel heterozygous p.Ser448Pro CaSR variant in the hypercalcemic family members, but not in the children with hypocalcemia or normocalcemia. Three-dimensional modelling using a reported crystal structure of the dimeric CaSR showed the mutated Ser448 residue to be located in the CaSR extracellular domain, and predicted the p.Ser448Pro variant to disrupt a hydrogen bond interaction across the extracellular CaSR dimer interface. The variant Pro448 CaSR, when expressed in HEK293 cells, was shown to significantly impair CaSR-mediated intracellular calcium mobilisation and mitogen-activated protein kinase (MAPK) responses following stimulation with extracellular calcium, thereby demonstrating it to represent a loss-of-function mutation.

Conclusion: These studies have identified a novel loss-of-function CaSR mutation which caused asymptomatic hypercalcemia in a mother and her children who had inherited the mutation. However, one child who did not inherit the mutation developed transient neonatal hypocalcemic seizures as a consequence of maternal hypercalcemia. These findings highlight the importance of assessing serum calcium and undertaking CaSR mutational analysis in the newborn offspring of a mother with FHH1.

Reference: (1) Hannan FM, Kallay E, Chang W, Brandi ML, Thakker RV. The calcium-sensing receptor in physiology and in calcitropic and noncalcitropic diseases. Nat Rev Endocrinol. 2018; 15(1): 33-51.
SAT-735 Effects of Androgen Receptor Activation on Angiogenesis
Authors: Huo Yen-Nien
Published: May 2020

The effect of androgen on angiogenesis has been documented. However, its molecular mechanisms underlying has not been well illustrated. Here, we conducted both in vitro migration assay and proliferation assay to investigate whether androgen receptor activation have any impacts on the angiogenesis. Treatment with an androgen receptor (AR) agonist, metribolone (R1881) at a range of concentrations (0.05-5 nM) or dihydrotestosterone (DHT) at a range of concentrations (0.5-2 nM) caused concentration-dependent inhibition of proliferation and migration in human umbilical venous endothelial cells (HUVEC). Blockade of the AR activity by pre-treatment with HF (5 nM), an AR antagonist, or knockdown of AR expression using the lenti-virus shRNA technique abolished the R1881-induced proliferation and migration inhibition in HUVEC, suggesting that AR receptor activation can inhibit endothelial cell proliferation and migration. To further delineate the signaling pathway involved in the AR activation-induced proliferation inhibition, our data indicate that R1881 inhibited proliferation in vascular endothelial cells through activating the AR/cSrc/AKT/p38/ERK/NFκB signaling pathway, which in turn up-regulated the expression of p53, p21 and p27 protein, and finally reduced endothelial cell proliferation. To investigate signaling pathway involved in the AR activation-induced migration inhibition, our data showed that R1881 can reduce the membrane translocation of RhoA and Rac-1, suggesting that inhibition of the RhoA and Rac-1 activity might be involved in the R1881-inhibited endothelial cell migration. Over-expression of RhoA prevented the R1881-inhibited endothelial cell migration and this effect was abolished by pre-treatment with Y27623, a ROCK inhibitor, confirming that inhibiting RhoA activity participated in the R1881-inhibited endothelial cell migration. Using the zebrafish and Matrigel angiogenesis models, we also demonstrated that R1881 inhibited angiogenesis through the AR-mediated pathway in vivo.
SUN-390 Computed Tomography Derived Skeletal Muscle Radiodensity Is Better Predictor of Muscle Power Than Skeletal Muscle Area in Community-Dwelling Older Adults
Authors: Choi Heewon , Hong Namki , Park Narae , Kim Chang Oh , Kim Hyeon Chang , Choi Jin Young , Youm Yoosik , Rhee Yumie
Published: May 2020

Computed tomography (CT) derived skeletal muscle area (SMA) and muscle radiodensity (SMD) reflect distinctive quantitative, qualitative characteristics of skeletal muscle. Peak jump power reflects the ability to exert force within a limited time, which has greater relationship with mobility and risk of falls. CT-based SMA and SMD may have potential as useful surrogates for muscle function. However, the association of CT-based muscle parameters, especially SMD, with peak jump power has not been investigated yet. Community-dwelling older adults enrolled in the Korean Urban Rural Elderly study from 2016 to 2018 underwent abdominal CT scans and countermovement two-legged jumping test on ground reaction force platform. SMA and SMD were measured at CT images at L3 vertebral level. Mean age of 1523 patients was 74.7 years and 65.1% was female. For peak jump force, L3SMA was stronger contributing factor than SMD (standardized beta of SMA vs. SMD = 0.16 vs. 0.08 for men; 0.12 vs. 0.05 for women; p < 0.05 for all). However, SMD was a better indicator of peak jump power compared to SMA in both sexes (standardized beta of SMD vs. SMA = 0.21 vs. 0.17 for men; 0.15 vs. 0.13 for women; p < 0.05 for all). These associations remained robust even after adjustment for age, height, weight, triglyceride, HDL cholesterol, high sensitivity C-reactive protein, and insulin resistance. One standard deviation decrease of SMD was associated with 8% elevated odds of low jump power relative to weight after adjustment for potential confounders (adjusted OR = 1.08, p < 0.001), whereas the association between SMA and low jump power was attenuated. SMD improved discrimination for individuals with low jump power when added to SMA and conventional risk factors (Area under the receiver-operating characteristics curve 0.732 to 0.750, p=0.006). SMD was an independent predictor of jump power with additive discriminatory value to SMA and conventional risk factors. Our findings suggest the potential complimentary role of SMD as muscle quality indicator beyond muscle mass as a surrogate for muscle function.
MON-915 Acute Abdominal Pain and the Pheochromocytoma
Authors: Weiner Yotam , Jameel Omar
Published: May 2020

Background:

Pheochromocytomas are neuroendocrine tumors that release large amounts of metanephrines and catecholamines, resulting in a wide array of symptoms including hypertension, diaphoresis, and headaches. If left unrecognized they can lead to serious morbidity including ischemic or hemorrhagic CVA, encephalopathy, MI, Aortic Dissection, and renal injury.

Clinical Case:

A 62-year-old male began having difficulties with his blood pressure over the past year. He was first hospitalized for an acute ischemic CVA with hypertensive urgency. His blood pressure was generally controlled throughout the admission but he continued to have intermittent elevations. After transferring to an inpatient rehabilitation unit he had an episode of acute nausea, severe lower abdominal pain, and emesis following dinner. He was tachycardic and hypertensive up to 190/115. Acute abdominal imaging revealed constipation but no obstruction. His symptoms resolved, returning a few hours later with another episode of acute nausea, vomiting, and severe lower abdominal pain, with blood pressure 210/126 and tachycardia. IV Metoprolol, Hydralazine and pain medications did not significantly improve his blood pressure, he was subsequently started on a Nitroglycerin drip. Abdominal workup was unremarkable, he was stabilized and discharged back to rehabilitation on increased oral medications. He continued to have blood pressure spikes up to 200/124 with nausea, vomiting, and severe abdominal pain until a Clonidine patch was started, after which his blood pressure was better controlled. He was discharged home with continued outpatient therapies.

A few weeks later he returned to the ER with nausea and severe abdominal pain, blood pressure at home was 254/185. On exam he was diaphoretic, tachycardic, and tachypneic. A CTA scan was obtained without signs of dissection. A Nitro drip with IV push Hydralazine were not effective at controlling his blood pressure, and so Lisinopril, Amlodipine, and a Clonidine patch were added. Over the next few days he had progressively fewer hypertensive elevations and his symptoms were only present during hypertensive episodes. An extensive workup for secondary hypertension was started. 24-hour plasma and urine Metanephrines were within normal limits. Urine Normetanephrine was elevated to 1266 ug/24h (Ref 88-444). Urine Norepinephrine was elevated to 124 ug/24h (Ref 15-80), Urine Dopamine was elevated to 578 ug/24h (Ref 65-400), and total Catecholamines were elevated to 133 ug/24h (Ref 15-100).

Conclusion:

This case illustrates the variance in presentations for Pheochromocytoma and the importance of maintaining a high index of suspicion for secondary causes in patients with intractable hypertension. While commonly reported symptoms include nausea and hypertension, the presentation of acute abdominal pain as the primary complaint is also an important feature of this disease.
SUN-007 Elevated Levothyroxine Requirements Post-Partum as Initial Presentation of Placenta Accreta
Authors: Bao Ginny W , Weinberg Melissa E , Kwan Christina
Published: May 2020

Introduction: It is well known that estrogen plays an important role in thyroid regulation. We report an unusual case of post-partum placenta accreta causing pathologic estrogen secretion leading to increased levothyroxine (LT4) requirements and inability to lactate.

Case: A 36-year-old woman with history of Hashimoto’s hypothyroidism presented post-partum day 11 after a normal vaginal delivery with inability to produce breast milk and mildly elevated TSH levels. Prior to her pregnancy, she required an equivalent dose of 142 mcg of LT4 supplementation daily, which increased appropriately to 171 mcg during pregnancy. After delivery, LT4 was decreased to 150mcg in anticipation of normalization of levothyroxine requirements to pre-pregnancy level. However, she had difficulty lactating and was found to have elevated prolactin, estradiol, and TSH levels. The following day, she presented to her obstetrician for persistent vaginal bleeding and was found to have placenta accreta requiring dilation and curettage (D&C). Her LT4 requirements eventually dropped to 125 mcg with decreasing beta-HCG and estrogen levels after successful D&C treatment. She was also then able to produce sufficient breast milk for lactation.

Discussion: This case highlights the effect of estrogen on LT4 requirements during physiologic pregnancy and postpartum with placenta accreta. It is expected that hypothyroid patients have approximately 25-50% increased thyroid replacement requirements during pregnancy, which normalizes soon after delivery.1 Estrogen increases thyroxine-binding globulin and lowers circulating free thyroxine2,, which causes higher thyroid replacement requirements. Estrogen is also known to inhibit lactation. Our patient demonstrates that this holds true even in a pathologically high estrogen state from placenta accreta. Our case uniquely demonstrates a temporal association between estrogen levels and LT4 requirements in the post-partum hypothyroid patient. Patients with inappropriately high TSH levels after delivery should prompt investigation into pathologic causes of elevated estrogen-states, as levothyroxine requirements are expected to normalize immediately post-partum.

References:

1. Bungard TJ, Hurlburt M. Management of hypothyroidism during pregnancy. CMAJ. 2007;176(8):1077-8.

2. Alexander EK, Marqusee E, Lawrence J, Jarolim P, Fischer GA, Larsen PR. Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med. 2004 Jul 15;351(3):241-9.