bluuebunny/crossref_metadata_2025 huggingface dataset:
OR06-03 Serotonin Regulates Corticotroph Tumor Cell Proliferation and ACTH Secretion
Authors: Zhang Dongyun , Bergsneider Marvin , Wang Marilene B , Kim Won , Heaney Anthony P
Published: May 2020

Serotonin (5-HT) is an important hormonal modulator and neurotransmitter, and 5-HT has been demonstrated in pituitary tissue from several species. Previous responses to 5-HT antagonists have been reported in some patients with Cushing disease although this effect was unsustained, and ACTH and cortisol levels actually increased in some patients. To better understand the role of serotonin in the regulation of corticotroph tumor growth and ACTH secretion, we first measured serotonin levels in supernatants (SNs) derived from murine corticotroph tumor AtT20 cells. We demonstrated that AtT20 cells secrete serotonin (2±0.05ng/105cells/24h) which was ~50% of the levels secreted by the serotonin secreting mid-gut carcinoid BON-1 cell-line (4.2±0.05ng/105cells/24h). In contrast, serotonin secretion was not detected in rat pituitary tumor lactotroph (GH3) or human embryonic kidney (HEK293) cell SNs, or in our Ham’s F12 medium control. Immunocytochemical staining using serotonin specific antibodies demonstrated that serotonin was diffusively present in AtT20 cell cytoplasm, suggesting that serotonin was endogenously generated in the AtT20 cells. Using real-time PCR, we demonstrated that both serotonin synthesis enzymes, tyrosine hydroxylase-1 (THP1) and -2 (THP2) are expressed in AtT20 cells with higher relative THP1 expression, confirming endogenous corticotroph pituitary tumor serotonin production. We further demonstrated that the synthetic glucocorticoid Dexamethasone (100nM x 24h) suppressed TPH1 expression and inhibited corticotroph tumor serotonin secretion. We next evaluated the actions of serotonin and various serotonin antagonists on corticotroph tumor cell proliferation and ACTH secretion. Ritanserin (10-5M) inhibited murine corticotroph tumor proliferation by 5% and inhibited ACTH secretion by ~25%. In contrast, metergoline (10-5M) and the orally administered TPH inhibitor, telotristat etiprate (10-5M for 1-3 days), inhibited ACTH secretion by 50% and 30% respectively but did not reduce cell proliferation, suggesting that Metergoline and telotristat may regulate ACTH secretion independently of their anti-proliferative effect. Addition of serotonin (10-4~10-5M) to corticotroph tumor cells cultured in reduced serum (OptiMEM) or no serum conditions, resulted in an 80% increase in cell proliferation but had little effect on ACTH secretion with a 1-4% increase. In summary, we have demonstrated that serotonin is synthesized in and secreted from corticotroph tumor cells and that serotonin plays a role in regulation of corticotroph tumor proliferation and ACTH secretion in vitro. Our findings using inhibitors of serotonin action indicate potential for targeting this pathway as a novel treatment for patients with CD.
SAT-358 Hypercalcemia-Induced Altered Mental Status as the Primary Manifestation of Classic Hodgkin Lymphoma
Authors: Modarressi Taher , Shah Megha
Published: May 2020

Hodgkin lymphomas (HL) are lymphoid neoplasms formed by a conglomerate of malignant Hodgkin/Reed-Sternberg cells with heterogeneous non-neoplastic inflammatory cells. Classic HL (cHL), one of two major subtypes, comprises 90% of all cases. HL typically presents as asymptomatic adenopathy or mass on chest imaging; constitutional symptoms (unintentional weight loss, night sweats, fever) occur in approximately 40% of cases. Though hypercalcemia is not uncommon in HL due to increased production of 1,25(OH)2D or, less commonly, direct bony involvement, it is unusual for severe hypercalcemia and its related symptoms to be the primary reason for presentation such as in our case below.

An 87-year-old man was admitted to our institution with three days of increasing agitation and confusion in the context of several weeks of forgetfulness and decline in his daily activities. He previously lived robustly independently. His past medical history included atrial fibrillation, hyperlipidemia, and benign prostatic hyperplasia. His home medications included metoprolol, apixaban, atorvastatin, tamsulosin, finasteride and a multivitamin.

Laboratory evaluation revealed serum calcium 17.5 mg/dL and serum creatinine 3.0 mg/dL (eGFR 20 mL/min/1.73m2). Complete blood count, phosphate, magnesium and alkaline phosphatase were normal. Intravenous fluids and later pamidronate improved his calcium to the 11–13 mg/dL range. Endocrinological workup revealed PTH 7 pg/mL (nl 15–65 pg/mL), 25(OH)D 15 ng/mL (nl 20–80 ng/mL), PTHrP 0.8 pmol/L (nl <2.0 pmol/L) and 1,25(OH)2D 57 pg/mL (nl 18–64 pg/mL). Serum protein electrophoresis showed no abnormalities and lactate dehydrogenase was 230 U/L (nl 125–250 U/L)

Computed tomography (CT) of his abdomen revealed non-specific prominent mesenteric lymph nodes. Neck CT did not show any abnormal cervical or supraclavicular lymphadenopathy. Chest CT did not show any mediastinal masses, abnormal lymphadenopathy, or findings consistent with silicosis (he had a 15-year history of masonry and brick-laying). Bone scan showed asymmetric uptake in two areas of his femurs, with xrays revealing subcortical scleroic lesions. Patient declined inpatient bone marrow biopsy, and was empirically started on prednisone, with rapid improvement in calcium to 9.6 mg/dL and return to his baseline mental status. He eventually accepted and underwent bone marrow biopsy as an outpatient, which revealed marrow involvement by classic Hodgkin lymphoma. The patient was started on a regimen of brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine, with excellent clinical response.

This case illustrates an atypical, hypercalcemia-driven initial presentation of Hodgkin’s lymphoma. It also exhibits the hallmark “inappropriate normal” 1,25(OH)2D which, in the context of hypercalcemia and low PTH, suggests extrarenal (i.e. PTH-independent) production of 1,25(OH)2D.
SAT-620 Left Ventricular Myocardial Deformation in T2DM Is Associated with Chronic Hyperglycemia but Not Myocardial Perfusion: A Study Based on Magnetic Resonance Imaging
Authors: Zhou Fangli , Deng Mingyan , Xie Linjun , Guo Yingkun , Ren Yan
Published: May 2020

Background: Diabetic cardiomyopathy is accompanied by left ventricular diastolic dysfunction. Abnormal glucose metabolism plays an important role in the pathogenesis of diabetic cardiomyopathy. However, it’s still not clear whether the influence of hyperglycemia on LV dysfunction is directly affects cardiomyocytes or is related to impaired myocardial perfusion. In this work, we focus on investigating the association between HbA1c and myocardial dysfunction, and if it is independent of myocardial perfusion reserve.

Materials and Methods: 64 type 2 diabetic patients were recruited at the endocrine clinic. They are divided into two group, well blood glucose-controlled group (HbA1c<7) and poor glucose-controlled group (HbA1c≥7) T2DM group, according to their HbA1c level. All of the T2DM patients and age-matched healthy volunteers (normal glucose metabolism group, NGM group) underwent CMR to acquire normal values for myocardial strain and perfusion reserve.

Results: Well blood glucose-controlled group owned lower global circumferential PSSR than NGM group (p=0.037). Global circumferential PS (p=0.011), global longitudinal PS (p=0.004), global radial PDSR (p=0.005), circumferential PDSR (p=0.001), longitudinal PDSR (p=0.001), global circumferential PSSR (p=0.049), longitudinal PSSR (p=0.041) were significantly lower in the poor glucose-controlled group compared to the NGM group. In the multivariable linear regression analysis, HbA1c existed in all equations except the global circumferential PSSR equation and p<0.05, and Slope, Max SI and Tpeak did not show dependent association with longitudinal and circumferential strain parameters.

Conclusion: In subclinical cardiac dysfunction T2DM patients, diastolic dysfunction is more common, but systolic dysfunction is still exist. Poor blood glucose control which is defined as HbA1c ≥ 7% is an independent risk factor for LV deformation for T2DM patients. Subclinical myocardial dysfunction is not triggered by myocardial perfusion reserve.
SAT-209 Treatment-Resistant Hypertension in a Post-Transplant Patient with Cystic Fibrosis: A Rare Case of Pheochromocytoma
Authors: Tansey David Joseph , Hatunic Mensud , Conneely John , Murray Michelle
Published: May 2020

Background: Pheochromocytoma is a rare catecholamine-producing tumor with an estimated incidence of less than 0.1% in the global population. We present the case of a pheochromocytoma in a 25-year-old man with a background history of a double-lung transplant for Cystic Fibrosis, carried out 5 years earlier. Clinical Case: A 25 year old, with a background history of Cystic Fibrosis and a Double Lung transplant in 2012 presented to the emergency department with crampy abdominal pain, nausea and vomiting. He was diagnosed with Distal Intestinal Obstruction syndrome (DIOS) for which he was admitted for rehydration and laxatives. Contrast-enhanced computed tomography (CT) imaging of the abdomen and pelvis which showed a 3.4 cm right adrenal lesion, which was confirmed by a subsequent MRI Adrenals and an Endocrinology review was requested. On review, the patient was noted to be hypertensive with a blood pressure averaging 170/90 despite treatment with 3 different anti-hypertensive medications - namely amlodipine, telmisartan and doxazosin. On review of his medical notes, it was clear that he had been persistently hypertensive over the last 3 years. On further questioning, he noted increasingly frequent sweating episodes over the last number of months but denied any palpitations, headache or back pain. Laboratory analysis showed an elevated plasma normetanephrines (NMN) of 3167 pmol/L (182-867) as well as elevated metanephrines (MN) of 793 pmol/L (61-377) and high 3-MT of 257 pmol/L (<185). His MIBG scan showed only a mild increase in the uptake of tracer to the right adrenal gland compared to the left. The case was discussed at a multidisciplinary meeting and given the suggestive laboratory and radiologic findings, a presumptive diagnosis of pheochromocytoma was made. After controlling blood pressure with an alpha-blocker and beta-blocker for a week, the patient was hydrated and scheduled for an elective right adrenalectomy. The histopathology of the excised adrenal gland was consistent with a 3cm pheochromocytoma with none of the adverse features associated with malignant potential. The patient recovered well post-op, his blood pressure normalised and he was discharged home well for follow-up at the Endocrine and Transplant clinics. Conclusion: We describe a rare case of a right adrenal pheochromocytoma in a young man with multiple co-morbidities, who completely recovered after tumor resection. This case highlights the crucial importance of investigating secondary causes of hypertension, especially in younger patients. This is the first documented case in the literature of a case of pheochromocytoma in a post-transplant patient with Cystic Fibrosis. References: 1. Farrugia FA, Marikos G et al. Pheochromocytoma, diagnosis and treatment: Review of the literature. Endocrine Regulation, Volume 51, Issue 3, 30th August 2017.
OR03-06 NAD+ Availability Modulates 11β-HSD1-Mediated Glucocorticoid Regeneration in Mouse Skeletal Muscle
Authors: Elhassan Yasir S , Kabli Ali , Nielsen Thomas , Fletcher Rachel , Oakey Lucy , Cartwright David , Chubanava Sabina , Garten Antje , Doig Craig , Treebak Jonas Thue , Lavery Gareth Geoffrey
Published: May 2020

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an NADPH-dependant reductase located in the sarcoplasmic reticulum (SR) lumen of skeletal muscle. It generates active glucocorticoids to regulate permissive and adaptive metabolism and contributes to the development of the Cushing’s syndrome phenotype in mice receiving oral corticosterone. The SR enzyme hexose-6-phosphate dehydrogenase (H6PDH) generates NADPH which supports 11β-HSD1 activity. H6PDH depletion disrupts the SR NADPH/NADP ratio leading 11β-HSD1 to assume glucocorticoid-inactivating dehydrogenase activity. Little is understood regarding routes to NAD(P)(H) biosynthesis and metabolism in the SR. Here we asked whether modulating cellular nicotinamide adenine dinucleotide (NAD+) availability (the parent molecule of NAD(P)(H)) would influence muscle 11β-HSD1 activity given its sensitivity to the SR NADPH/NADP ratio. We used FK866 to inhibit nicotinamide phospho-ribosyltransferase (NAMPT, rate-limiting enzyme in NAD+ biosynthesis) to deplete NAD(P)(H) in wild type mouse primary myotubes. FK866 treatment for 48h impaired cellular energetic status, reducing NAD+ (>90%), NADP+ (>50%) and ATP (>30%) without limiting cell viability. 11β-HSD1 reductase activity was decreased to 30% that of untreated cells (152±18 vs. 512±44 pmol/mg protein/h respectively, p<0.005). Employing H6PD knockout myotubes, NADP+-dependent 11β-HSD1 dehydrogenase activity was also impaired following NAMPT inhibition. The NAD+ precursor nicotinamide riboside (NR, 0.5mM), which bypasses NAMPT inhibition through the NR kinase pathway restored NAD+ levels and rapidly rescued 11β-HSD1 reductase activity in wild type and dehydrogenase activity in H6PD knockout myotubes. To assess this in vivo, we examined 11β-HSD1 reductase activity in muscle explants of inducible muscle-specific NAMPT knockout mice in which NAD+ levels are reduced by 90%, and show 40% lower activity compared to wild type explants (114±14 vs. 67±10 pmol/mg protein/h, p=0.04). These data suggest a novel level of redox-regulated 11β-HSD1-mediated glucocorticoid metabolism in skeletal muscle. These data also imply a pathway by which NAD+ status is communicated between the cytosol and the SR, which is contrary to the current belief that the pyridine nucleotide pool in these compartments is separate. NAMPT inhibition is being studied as a potential anti-cancer therapy and these data reveal hitherto unanticipated effects this therapy may have in a range of tissues.
MON-220 Real World Performance of Urinary and Plasma Metanephrine Assays in Diagnosing Phaeochromocytoma/Paraganglioma
Authors: Deyab Eithar , Saleh Dina , Menon Ravi Kumar
Published: May 2020

Introduction:

Diagnosis of pheochromocytoma/paraganglioma (PPGL) can be challenging. Plasma metanephrines have highest sensitivity (96-99%) yet lowest specificity (85%)1 whereas 24-hour urinary metanephrines have 87.5% sensitivity and 99.7% specificity. Diagnostic accuracy depends on factors such as patient positioning and medications, questioning its potential value in a hospital setting.

Methods:

The audit was performed in a hospital which caters to a population of 400,000. Data was collected retrospectively on patients who had a request for plasma or urine metanephrines from March 2018 – September 2018.

Results:

A total of 85 patient order requests (58% male, 42% female) were reviewed; only 2 patients were ultimately diagnosed with a pheochromocytoma.

The mean age of patients was 48 years. The most common indication for requests was hypertension (64 patients).

Locations of order requests included 42% from outpatient clinics, 32% inpatient requests, 18% from Ambulatory Care, 6% by A&E and 2% by GP. Of the 27 (32%) inpatient requests, 10 had positive results: 1 diagnosed with primary aldosteronism, 1 with hypercortisolism and the others had no definite diagnosis. 8/10 patients with positive results did not have a repeat test.

Focusing on plasma metanephrines, 52% plasma metanephrines samples were negative, 22% were positive and 26% were not processed due to laboratory error. From the 19 positive plasma metanephrines, adrenal adenoma was present in 7 patients (from this group, 1 was referred for surgery with confirmed diagnosis of pheochromocytoma), 1 patient’s MIBG scan was negative and 1 diagnosis of stress-related raised metanephrines was made. The remaining 10 patients did not undergo an adrenal scan.

9 out of 18 cases with positive urine metanephrines had an adrenal adenoma. In 7/9, plasma metanephrines were positive, the remaining 2 had negative plasma metanephrines.

34 cases with initial negative test still had another urine/plasma metanephrines performed with similar negative result. Furthermore <50% of the positive urine or plasma metanephrines were referred to and reviewed by the Endocrine team.

Discussion:

This audit highlights the potential pitfalls of investigating PPGL with plasma and urinary metanephrines, and in fact raises the question of its accuracy as an inpatient diagnostic tool as none of the positive inpatient tests resulted in a diagnosis of PPGL. Inappropriate urine and plasma metanephrines requests cause financial burden and patient anxiety. Even with outpatient requests, few positive results led to a PPGL diagnosis. Patient selection and conditions of testing must be more rigorously scrutinised and threshold for positive result must be raised for specificity of the test to be improved in ‘real world’ conditions.

References:

1. Lenders JW al. Biochemical diagnosis of pheochromocytoma: which test is best? JAMA. 2002.
OR23-04 SST5 Expression and USP8 Mutation in Functioning and Silent Corticotroph Pituitary Tumors
Authors: castellnou Solene , Vasiljevic Alexandre , Lapras veronique , Raverot Veronique , Alix Eudeline , Borson-Chazot Francoise , Jouanneau Emmanuel , Lasolle Hélene , Raverot Gerald
Published: May 2020

Context. Somatostatin receptor type 5 (SST5), a target of pasireotide, is inconsistently expressed by corticotroph tumors. Somatic driver mutations in the ubiquitin-specific protease 8 (USP8) gene have been describes in 35% to 60% of corticotropinomas. SST5 expression has been found to be higher in USP8mut corticotropinomas.

Objective. To study the correlation between clinical and biochemical characteristics of a large cohort of functioning and silent corticotroph tumor and SST5 expression or USP8 mutation status. To describe SST5 expression and the response to pasireotide in 5 patients.

Design. Retrospective cohort study.

Setting. University hospitals of Lyon.

Patients. 62 patients operated for a corticotroph tumors between 2013 and 2017.

Intervention. None.

Main Outcome Measure. Clinical, biological, radiological and pathological data were evaluated depending on SST5 expression measured by immunohistochemistry (rabbit monoclonal antibody, clone UMB-4, Abcam). Membrane immune-positivity with an IRS>1 was considered positive. USP8 analysis was performed by Sanger sequencing in 50 tumors.

Results. SST5 expression was positive in 26 (41.9%) pituitary tumors. A moderate or strong IRS was found in 24.2% of the cohort and in 32.5% of the functioning pituitary tumors. Compared to SST5-negative pituitary tumors, those expressing SST5 were more frequent in women (92.3% vs 55.6%; p=0.002), fewer were silent (7.7% vs 58.3%; p<0.001), smaller (7 vs 19mm; p=0.001) and less invasive (15.4% vs 44.4%; p=0.03).

USP8 mutations were identified in 26% of the cohort and more frequent in functioning (n=11/30, 36.7%) compared to silent corticotroph tumors (n=2/20, 10%; p=0.05). SST5 expression was more frequent in USP8mut vs USP8neg tumors (58.8% vs 7.7%; p<0.001).

Among treated patients, normal urinary free cortisol (UFC) levels were obtained in 3 patients (IRS 0, 2, and 6) and a 4-fold decrease of UFC in one patient (IRS 4).

Conclusion. SST5 expression seems to be associated with functioning, well-differentiated pituitary tumors and USP8 mutation. However, a correlation between SST5 expression or USP8mut and response to pasireotide treatment remains to be confirmed.
MON-177 CAH-X Syndrome in a German Cohort of Patients with Congenital Adrenal Hyperplasia
Authors: Sappl Andrea , Lottspeich Christian , Vill Katharina , Morak Monika , Bidlingmaier Martin , Reisch Nicole
Published: May 2020

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) is encoded by the CYP21A2 gene. The CYP21A2 gene is flanked and partially overlapped by the TNXB gene encoding an extracellular matrix protein called Tenascin-X. Deficiency of Tenascin X can cause the Ehlers-Danlos Syndrome (EDS). Deletions of CYP21A2 extending into TNXB rarely cause CAH combined with EDS. Heterozygosity of TNXB mutations causing haploinsufficiency of TNX, however, have been described in about 5-7% in a patient cohort from the US and has been named CAH-X syndrome, CAH associated with mild hypermobility form of EDS.

We genetically investigated a cohort of 81 adult patients (31 males, mean age 37,8 years +/- 9,8) with classic CAH for CAH-X. Patients genetically positive for CAH-X and unaffected CAH control patients matched for sex, age and BMI underwent a thorough clinical investigation including joint examination by Beighton 9-point scale, skin and neurological examination, by a standardised protocol of thransthoracic echocardiography and muscle ultrasound. In addition serum tenascin-X has been measured.

In our cohort we identified one patient with CAH and EDS and 4 patients with CAH-X syndrome. All CAH-X patients had serum concentrations of tenascin-X below the normal range, however, not different from 35 unaffected CAH patients with regard to serum concentration. All 4 patients with CAH-X syndrome showed some associated clinical symptoms. Two had joint hypermobility detected by Beighton 9-point score. Two of four CAH-X patients showed cardiac abnormalities (mild mitral regurgitation in one patient and a surgically corrected common arterial trunk type I A in the other patient). The patient with CAH and EDS showed cardiac abnormalities in addition to typical EDS symptomatology. All 5 affected patients complained about back pain and showed foot malposition. Profound changes in muscle ultrasound were found in 60 % of patients with CAH-X syndrome (3/5) and in none of the controls (0/5).

In conclusion, our data confirm the previously described prevalence of CAH-X. Beighton-score seems to be a quick and cheap screening instrument for CAH-X and should be performed in all patients with classic CAH, since protein level in serum cannot be used for screening for CAH-X-Syndrome. A stronger focus needs to be made on back pain and foot malposition as symptoms of CAH-X and echocardiography should be performed in all CAH-X patients. Therapy should depend on clinical symptoms in patients.
SUN-711 Association of Single Nucleotide Polymorphisms of CYP11B2, CYP11B1 and CYP17A1 with Primary Aldosteronism in a Multi-Ethnic Malaysian Cohort
Authors: Azam Afifah , Shahar Mohammad Arif , Gany Siti Liyana Saud , Sukor Norlela , Kamaruddin Nor Azmi , MacKenzie Scott Mackay , Azizan Elena Aisha
Published: May 2020

Primary aldosteronism (PA), also known as Conn’s syndrome, is a common curable cause of hypertension. Family studies of essential hypertensive patients suggest that heritable genetic factors play a role in blood pressure regulation1. Interestingly, single nucleotide polymorphisms (SNP) in genes encoding enzymes involved with adrenal steroidogenesis, CYP11B2, CYP11B1 and CYP17A1, associate with increased risk of hypertension2. Therefore, we analysed whether selected SNPs in these genes are associated with PA. We performed an association study using genotype imputation for selected SNPs of the steroidogenic enzyme genes CYP11B2 (rs4546, rs1799998, rs13268025), CYP11B1 (rs6410, rs149845727), and CYP17A1 (rs1004467, rs138009835, rs2150927) from a pilot genome wide association study of Malaysian PA patients and healthy controls which was merged with the Singapore Genome Variation Project (SGVP) population dataset3. Genotype imputation for minor and major alleles was validated using PCR sequencing (n>10 for each genotype). Further, one SNP from each steroidogenic enzyme (CYP11B2:rs1799998, CYP11B1:rs6410 and CYP17A1:rs1004467) was validated using commercial TaqMan genotyping assays on the ABI 7000 Sequence Detection System which was performed on 149 PA patients and 78 non-hypertensive healthy individuals. Case-control genetic association analysis was performed at http://www.oege.org/software/orcalc.html and the association between genotypes and phenotypes was done using the independent-samples Kruskal-Wallis test on SPSS (version 25). The Minor Allele Frequencies (MAFs) for rs1004467, rs6410 and rs1799998 were similar to East Asian populations but differed significantly different from European, African, American and South Asian populations (rs1004467 MAF: C=0.258/298, rs6410 MAF: A=0.265/298, rs1799998 MAF: C=0.225/298). In Chinese patients matched by gender, heterozygotes for rs6410 had significantly increased risk of PA compared to common homozygotes (OR: 3.15, 95% CI: 1.01–9.8, p=0.04). Across patients of different ethnicity, the distribution of aldosterone levels was significantly different (p=0.039). In summary, only SNP rs6410 in Chinese patients matched by gender showed association with PA in our South East Asian cohort. More functional experiments need to be done to find out whether this is causal for PA or whether the SNP is in linkage disequilibrium with the actual functional causative SNPs. Once the functional SNP is known, identification of these germline variants in asymptomatic family members would allow early screening of PA to be offered and potentially provide novel drug targets to treat the disease.

References: 1Timberlake et al., Curr Opin Nephrol Hypertens. 2001 Jan;10(1):71-9. 2MacKenzie et al., Int J Mol Sci. 2017 Mar 7;18(3). pii: E579. 3Teo et al., Genome Res. 2009 Nov;19(11):2154-62.
SUN-622 The Risk of Hip and Non-Vertebral Fractures in Diabetes: A Systematic Review and Meta-Analysis Update
Authors: Vilaca Tatiane , Schini Marian , Harnan Susan , Poku Edith , Cummings Steven R , Eastell Richard
Published: May 2020

Background Previous meta-analyses have reported an increase in the risk of hip fractures in diabetes, but the risk of non-vertebral fractures has not been investigated. In addition, it is not known how the risk of fractures is affected by age, body mass index, diabetes duration and insulin use. To investigate these features, we conducted a meta-analysis on the risk of hip and non-vertebral fractures in diabetes. MethodsWe selected a previously published review to be updated. Medline, Embase and Cochrane databases were searched in March 2018 and an update conducted in March 2019 (Pubmed) using relevant MeSH and free text terms such as “diabetes”, “hyperglycaemia” and “fracture”. We selected observational studies with data on the risk of fractures in adults ολδερ τηαν 18 years old with diabetes compared to people without diabetes. Study quality was assessed using the Newcastle Ottawa Scale. We used the random-effects model to calculate the risk estimates and 95% confidence intervals.Results Forty-nine studies were included. Forty-three studies were included in the hip fracture analysis, 40 cohorts and 3 case-control studies, reporting data from 17,575,873 participants, 2,387,899 with diabetes and 321,720 fractures. Eighteen studies reported the risk of fractures in two or more sites and were included in the non-vertebral fracture risk analysis. All but one study were cohorts. These studies reported data from 2,982,622 participants, 414,195 with diabetes and 185,363 fractures. In both analyses, age varies from 20 to 100 years old, including both type 1 and type 2 diabetes. Overall, the study quality was judged to be moderate to good.We found a significant increase in the risk of fracture in diabetes both for hip (RR 1.52, 95% CI 1.42-1.63) and for non-vertebral fracture (RR 1.20, 1.14-1.27). The increase in the risk was greater for insulin users and longer duration of diabetes, at both sites. At the hip, the risk was higher in the younger population, women, and those with T1D. ConclusionThere was an increase in the risk of hip and non-vertebral fractures in diabetes. Although the mechanisms are not established, patients with type 1 diabetes were the population at higher relative risk. The evidence suggest that the skeleton should be considered a site for diabetic complications.
MON-386 Determining Vitamin D Status: Analytical Variability Between Available Assays
Authors: Wahab Azni Lihawa Abdul , Schneider Hans Gerhard
Published: May 2020

Clinical interest to evaluate serum 25-hydroxyvitamin D[25(OH)D] to assess Vitamin D status in health risks continue to increase exponentially over the last decade. Variability of 25(OH)D measurements remains controversial despite the international initiative Vitamin D Standardization Program (VDSP) to standardise the assays. The aim of the present study was to examine the correlation of 25(OH)D concentrations measured by different assays. We measured 25(OH)D using the new Abbott Alinity and DiaSorin LiaisonXL chemiluminescence immunoassays against the National Institute of Standards and Technology (NIST)-traceable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The immunoassay method were compared with the LC-MS/MS using Passing-Bablok regression and Bland-Altman analysis. Common 25(OH)D cut-point for classification of vitamin D deficiency was used to compare the different assays.

125 adult serum samples were randomly selected and measured 25(OH)D levels ranged between <10 nmol/L to 290 nmol/L as determined by LC-MS/MS. Compared to the LC-MS/MS, both immunoassays demonstrated strong positive relationship based on Passing-Bablok regression analysis. The results were as follows: Abbott Alinity = 0.85x + 1.29nmol/L, 95% CI: -2.39 to 5.03 (r=0.94); DiaSorin LiaisonXL= 0.74x + 2.54nmol/L, 95% CI: -2.53 to 6.18 (r=0.91).

Despite apparent good correlation, the overall mean bias was -12.6% for Abbott Alinity and -24.4% for DiaSorin LiaisonXL assays. A higher percentage of patients were classified as vitamin D deficient (25(OH)D <50 nmol/L) using DiaSorin LiaisonXL (53%) followed by Abbott Alinity (49%), when compared with LC-MS/MS (34%). Using 25(OH)D ≥ 50nmol/L as “adequate” determined by LC-MS/MS method, 22% (18/82) and 28% (23/82) of patients were classified as “deficient” when analysed on Abbott Alinity and DiaSorin LiaisonXL respectively.

Clinician should be aware of the inter-method variability among different Vitamin D assays despite standardization efforts. These differences could be due to cross-reactivity with 25(OH)D2 and vitamin D metabolites, such as 24,25(OH)2D and epimeric forms. 3-epi-25(OH)D is not separated chromatographically by the LC-MS/MS method used in this study. Therefore, the negative bias observed might be due to interference from the 3-epi-25(OH)D, whereby clinical significance is uncertain. It is present in low concentrations in adult human serum, 1 but seen in significant amounts in neonatal serum.2 It is advisable to monitor serum 25(OH)D level following treatment in the same laboratory.

1. Lensmeyer G, et al. The C-3 epimer of 25-hydroxyvitamin D3 is present in adult serum. JCEM 2012; 97: 163–8.

2. Singh RJ, et al. C-3 epimers can account for a significant portion of total circulating 25-hydroxyvitamin D in infants, complicating accurate measurement and interpretation of vitamin D status. JCEM 2006; 91: 3055-61.
MON-126 Telemedicine Interventions for Treatment of Diabetes Mellitus in Low- and Middle-Income Countries: A Systematic Review and Meta-Analysis
Authors: Correia Jorge César , Meraj Hafsa , Teoh Soo Huat , Waqas Ahmed , Pataky Zoltan , Golay Alain
Published: May 2020

Diabetes mellitus (DM) is associated with significant morbidity, mortality and poor quality of life. It also has substantial social and financial implications because over 75% of patients with DM live in low- and middle-income countries (LMIC). In this context, it is often opined that diabetes care can be improved by employing telemedicine interventions. The present systematic review and meta-analysis aims to estimate the clinical effectiveness of telemedicine in improving biochemical and treatment adherence outcomes related to DM and provide the certainty of evidence for these interventions. Using a pretested search strategy, nine academic databases were searched from their inception to August 2019: Web of Science, PubMed, Medline, Global Health Library, Cochrane Central Register of Controlled Trials (CENTRAL), New York Academy of Medicine (NYAM) and Popline. We only included RCTs and cluster RCTs testing the effectiveness of tele-medicine-based interventions in type 1, 2 and gestational diabetes in LMIC. Risk of bias in the included RCTs was assessed using the Cochrane tool for assessment of risk of bias in randomized controlled trials. A series of meta-analyses for each individual outcome was run using random effects analyses. Certainty of evidence for these interventions was assessed using the GRADE guidelines. A total of 22 studies describing 23 interventions were included. We identified five modes of interventions delivered using telephone calls (n=6), SMS (n=5), telemetry (n=5) web-based systems (n=3) and smartphone apps (n=3). Major strategies included health record keeping, follow ups, reminders, psychoeducation, glucose monitoring, monitoring prompts, alerts and online consultations Overall, a significant treatment effect was seen among outcomes of HbA1c (SMD=-0.30, 95% CI= -0.42 to -0.17, n=6548, I2= 80.21%) and fasting blood sugar levels (SMD=-0.17, 95% CI= -0.32 to -0.01, n=4709, I2=60.49%), self-efficacy (SMD= 1.94, 95% CI= 1.31 to 2.58, n=626, I2= 95.99) and treatment adherence (SMD= 1.16, 95% CI= 0.78 to 1.54, n=437, I2= 84.8%). A marginally significant effect was seen in improvement of knowledge regarding diabetes (SMD= 0.66, 95% CI= -0.006 to 1.33, n=1345, I2= 93.38%). No significant treatment effect was seen in outcomes of serum triglyceride levels (SMD= -0.02, 95% CI= -0.18 to 0.14, n= 1535, I2=2.98%), serum total cholesterol levels (SMD= -0.05, 95% CI= -0.20 to 0.09, n= 4862, I2=66.45%) and BMI (SMD= -0.03, 95% CI= -0.13 to 0.07, n= 5372, I2=41.78 %). Telephone calls and SMS based telemedicine interventions yielded the highest treatment effects when compared with telemetry and smartphone apps-based services. Although telemedicine was found to be effective in improving several DM related outcomes, the certainty of evidence was downgraded to very low due to substantial heterogeneity, publication bias and risk of bias.
SUN-909 A Unique Presentation of Multiple Endocrine Neoplasia (MEN) Type 1 Mosaicism Caused by a Novel c.124G>A Variant in the MEN1 Gene
Authors: Drummond Russell Sinclair , Harte Rachel , Hilmi Omar , Currie Gemma , Hughes Kate , McManus Frances , Carty David Martin
Published: May 2020

The MEN1 gene is positioned on the long arm of chromosome 11 (11q13) and results in the production of menin. A classical tumour suppressor gene; the spectrum of reported germline MEN1 mutations occur throughout the gene with no strong genotype/phenotype relationship. Mosaicism is extremely rare, a recent report citing only 2 mosaic cases by next generation sequencing1. We describe a 43-year-old female with MEN1 mosaicism associated with parathyroid adenoma and probable gastrinoma.

Our patient initially presented with nephrolithiasis and nephrocalcinosis alongside biochemistry of primary hyperparathyroidism. Imaging confirmed a right lower pole parathyroid adenoma and the lesion was removed, pathology confirming the diagnosis (July 2018). Post operatively she remained hypercalcaemic. Repeat imaging suggested a further right sided culprit lesion.

One year previously (August 2017) she was admitted with a perforated duodenal ulcer within the first part of the duodenum (D1), ascribed to ibuprofen use, requiring surgical repair. Whilst awaiting repeat parathyroid surgery she represented with a further duodenal ulcer and perforation (February 2019) this time in the second part of the duodenum(D2). A second parathyroidectomy was performed and genetic investigations were instigated, given the presence of classical MEN1 phenotype. Again, pathology was consistent with a parathyroid adenoma (March 2019).

DNA was extracted for next generation sequencing which revealed mosaicism with a c.124 G>A variant detected in the MEN1 gene at a level of approximately 15%.

Further investigations have shown normal serum prolactin and pituitary and pancreatic MRI imaging. With no other family members testing positive (parents and 2/3 children) this mutation appears to be a de novo index case. Adjusted Calcium is normal 2.53 mmol/L (2.2-2.6 mmol/L) but serum Chromogranin A is elevated (2620 µg/L (ref range <95 µg/L)).

The c.124 G>A variant predicts an amino acid substitution p.(Gly42Ser) in menin structure, an amino acid change previously associated with MEN12. Given the paucity of MEN1 mosaicism reported within the literature with the presence of the two cell lines and only 15% mosaicism close monitoring will be crucial to determine the genotype/phenotype relationship in our patient.

1 Choppin et al 2019 Eur J Endocrinol 1; 180(2):L1-L3

2 Itoh et al 2017 Clin Pediatr Endocrinol 26;25-28
OR30-01 Real-World Minimed™ 670G System Use and Glycemic Outcomes of Pediatric and Adult Individuals Living with Type 1 Diabetes (T1D) in the United States
Authors: Vigersky Robert Alan , Stone Michael , Agrawal Pratik , Zhong Alex , Velado Kevin , Cordero Toni , Shin John
Published: May 2020

Introduction: The MiniMed™ 670G system was FDA-approved in 2016 for adults and adolescents ≥14yrs, and in 2018 for children ages 7-13yrs with T1D. Since then, use of the system has grown to over 180,000 people in the U.S. The glycemic control benefits of real-world MiniMed™ 670G system Auto Mode use in the U.S. were assessed. Methods: System data (aggregated five-minute instances of sensor glucose [SG]) uploaded from March 2017 to July 2019 by individuals (N=118,737) with T1D and ≥7yrs of age who enabled Auto Mode were analyzed to determine the mean % of overall time spent <54mg/dL/<70mg/dL (TBR); between 70-180mg/dL (TIR); and >180mg/dL/>250mg/dL (TAR). The impact of Auto Mode was further assessed in a sub-group of individuals (N=51,254) with, at least, 7 days of SG data for both Auto Mode turned ON and turned OFF. The % of TIR, TBR and TAR, and the associated glucose management indicator (GMI) were evaluated for the overall OFF (2,524,570 days) and ON (6,308,806 days) periods, and across different age groups. Results: System data TIR was 71.3%; TBR was 0.4% and 1.9%, respectively; and TAR was 26.8% and 6.2%, respectively. User-wise data of Auto Mode OFF versus ON showed a mean of 70.3% of the time spent in Auto Mode, that TIR increased from 60.9% to 69.9%; and that both TBR and TAR decreased. For those 7-13yrs (N=1,417), TIR increased from 48.7% to 61.5%; TBR increased from 0.5% to 0.6% and from 2.0% to 2.2%, respectively; and TAR decreased from 49.3% to 36.3% and from 20.5% to 13.0%, respectively. For those 14-21yrs (N=4,194), TIR increased from 51.0% to 61.5%; TBR decreased from 0.7% to 0.6% and from 2.3% to 2.0%, respectively; and TAR decreased from 46.7% to 36.5% and from 18.5% to 12.5%, respectively. For those ≥22yrs (N=45,643), TIR increased from 62.2% to 70.9%; TBR decreased from 0.7% to 0.5% and from 2.6% to 1.9%, respectively; and TAR decreased from 35.2% to 27.3% and from 9.9% to 6.3%, respectively. The mean GMI decreased by 0.23% (overall), 0.48% (7-13yrs), 0.35% (14-21yrs), and 0.22% (≥22yrs), respectively, with Auto Mode ON versus OFF. Discussion: In over 6 million days of real-world MiniMed™ 670G system Auto Mode use in the U.S., TIR of a large pediatric and adult population with T1D improved by 9% compared to when Auto Mode was OFF, which was comparable to or exceeded the TIR observed in the smaller pivotal trials. These results further support outcomes of the pivotal trials and increased glycemic control with system use.
SAT-439 Thyroid Ultrasound Reports and Thyroid Function Tests in Florida Firefighters: Data from the Firefighter Cancer Initiative
Authors: Casula Sabina , Solle Natasha Schaefer , Caban-Martinez Alberto , Kobetz Erin
Published: May 2020

Background: Several epidemiological studies suggest firefighters are at risk for numerous site-specific malignancies, including thyroid cancer. However, it is not well known if chronic exposure to carcinogenic compounds or radio frequency radiation, increases the rate of thyroid nodules and/or affect the thyroid function in this high-risk occupational group. To gain a better understanding, we examine the rate of thyroid nodules and assess the presence of thyroid dysfunction in a sample of Florida firefighters. Methods: A cross sectional study design was conducted to evaluate 103 firefighters, with not known thyroid disease, who were assessed by a physician-performed, real time ultrasound protocol followed by a blood collection to evaluate TSH, Free T4, T4, T3, TPO and Tg antibodies. Additional data such as gender, age and race were also collected and analyzed. Results: Among the 103 firefighters who completed the study protocol, the sample mean age was 39.4+-7.6 years (range 26 to 60) 88.4% male, 87.6% Caucasian and 65% Hispanic. 8.7% of men and 33% of women were found to have thyroid nodules. Of the 20 participants with thyroid nodules only three nodules were above 1 cm, and only one was classified as high risk and met criteria for fine needle aspiration. 8.7 % of men and 33% of women were found to have +TPO antibodies. 18.6% of men and 25% of women were found to have isolated low T3. Conclusion: The prevalence of thyroid nodules, and of Hashimoto thyroiditis, among Florida firefighters, is comparable with the rate found in the general population based on previous epidemiological data. Surprisingly, we found that a significant number of subjects have isolated low T3. In this study, the level of Free T3 was not assessed, however since T4 was normal, we can conclude that the low T3 was not related to a low level of TBG. Low T3 is usually found in systemic illness and has been postulated as a prognostic factor in cardiovascular disease, chronic fatigue syndrome, survival after stroke, and Alzheimer’s disease. The clinical significance and the prevalence of Low T3 in a healthy population has not been well described. Further research is needed to fully understand the significance of this finding.
SUN-903 Insulinoma - a Tricker Diagnosis When Some Pieces Are Missing
Authors: Silva Maria Manuel
Published: May 2020

Insulinoma is a rare pancreatic neuroendocrine tumour that secretes insulin, causing hypoglycemia. Because of the nonspecific symptoms, the diagnosis could constitute a challenge. Early detection is important to prevent serious consequences.

A 31-year old woman was admitted for prolonged fasting test. She had no relevant past medical or surgical history till eight months before, when she had an episode of generalized tonic-clonic seizure with loss of consciousness. At this time, she was taken to emergency, with identification of a hypoglycaemia of 33 mg/dL. Unfortunately this was undervalued and she was discharged with an appointment on a neurologist. After evaluation, she did an EEG, which was normal, and blood tests that identified a fasting glycemia of 50 mg/dL. By recommendation of her general practitioner, she began to monitor her glycemia during the day, identifying multiple glycemia <50mg/dL – in fasting and post-prandial period. After the first generalized seizure, she had multiple seizures, always associated with hypoglycaemia. During the night she had to wake up every two hours to eat, in order to prevent hypoglycaemia. Moreover, in the last 6 months, she augmented 12 Kg. She also described two episodes of behavioural changes with confusion and speech alteration.

She wasn’t under any medication that could be associated with hypoglycemias. Previous records showed she had a fasting glycemia of 50 mg/dL two years ago. When she was admitted to our department, besides she had eat one hour before, she had glycemia <55 mg/dL. Blood tests showed glucose level=22 mg/dL, insulin=39 μU/mL (normal range 2.6-24.9 μU/mL), C-Pep=0.90 ng/mL (normal range 1.1-4-4 ng/mL). Plasma B-hydroxybutyrate was negative. After Glucagon EV, glucose level increase to 53 mg/dL (>25 mg/dL). We also evaluated cortisol and growth hormone that were normal. Abdominal computed tomography scan with contrast demonstrated a well-defined hypervascular lesion involving pancreas tail. Abdominal MRI was also performed showing a hypervascular lesion involving pancreas tail with 11x21mm. Laparoscopic surgery to enucleate the lesion was made. Pathological evaluation revealed a well-differentiated neuroendocrine tumour (positive staining for synaptophysin, cromogranin and insulin) measuring 0.3 cm. The diagnosis of pancreatic insulinoma was confirmed. After surgery, the glucose level increased to the normal range. The patient is currently in 6 months follow-up with a good evolution.

The diagnosis of insulinoma requires high suspicion. In this case, the patient didn’t have the typical insidious neurogenic symptoms. There is a need to value neuroglycopenic symptoms associated with hypoglycemia, otherwise serious consequences can occur.
SUN-376 A Quality Improvement Project on Identification and Management of Primary Hyperparathyroidism in Patients Who Present with Osteoporosis to Reduce Morbidity from Bone Disease
Authors: Hatta Sharifah Faradila Wan Muhamad , Khine Aye Aye , Chopra Roopa , Chopra Amit , Talapatra Paulomi , Sapkota Hem , Buch Harit
Published: May 2020

Introduction:Individuals with Primary Hyperparathyroidism (PHPT); a common endocrine disorder are at increased risk of both vertebral and peripheral fractures.Meanwhile Normocalcaemic Primary Hyperparathyroidism (NPHPT),a recognised phenotype of PHPT with a prevalence of 0.4-3.1% in community-based cohorts were anticipated to be milder but most case series documented high rates of osteoporosis, fractures and kidney stones.

Objective:We proactively evaluated patients with a new diagnosis of osteoporosis to (a) identify the frequency of hypercalcaemic and normocalcaemic primary hyperparathyroidism in this cohort of patients and (b) to evaluate the benefit of deploying a proactive process for this evaluation as compared to the current arrangement in our Centre of devolving this to the primary care team.

Method:This cross-sectional study evaluated 194 patients whom were referred for dexa scan for newly diagnosed osteoporosis between January 2018 and December 2018. Patients whom had a secondary causes of osteoporosis, eGFR<60mls/min, liver and malabsorptive conditions and taking medications that would interfere with bone metabolism were excluded from the study. A recommendation letter was sent to them and their General Practitioner to undertake the following investigations: serum calcium, PTH, phosphate, vitamin D, magnesium, liver function test, full blood count, coeliac screen and thyroid function test. Abnormal blood tests including new diagnosis of primary hyperparathyroidism and vitamin D deficiency were identified and treated accordingly. A second letter and telephone calls were made as a reminder if no response were received within 12 weeks of the first letter.

Results:After the first letter, only 83 (34.3%) patients complied with the request for the blood tests. After another 3 months a further 86 patients had the test done while 25(12.9%) did not have the test done despite the reminder.Mean age was 69.72 ± 13.01 and 90.2% were females. The commonest indication for bone density assessment was fragility fracture (46.2%). 69 (35.6%) had spinal, 77 (39.7%) femoral and 9 (4.6%%) wrist osteoporosis. 17(8.8%) patients were detected to have hypercalcaemic and 8(4.73%) patients had normocalcaemic primary hyperparathyroidism. 18(10.7%) patients had vitamin D deficiency and secondary PHPT with half of these patients (9(5.3%)) had severe deficiency (<25 nmol/L).

Conclusions:A significant proportion of patients with osteoporosis without prior history of metabolic bone disease had PHPT but the proportion of these having NPHPT is low unlike what is reported in the literature.Proactive assessment of secondary causes is much more effective and should be routinely deployed