bluuebunny/crossref_metadata_2025 huggingface dataset:
6683 The Interrelationship of Baseline Vitamin K and Vitamin D Status on Incident Fractures: Results from the VITamin D and OmegA-3 TriaL (VITAL)
Authors: Chou S H , Booth S L , Ratnarajah D , Cook N , Kotler G , Fu X , Buring J , Manson J E , LeBoff M S
Published: October 2024

Disclosure: S.H. Chou: None. S.L. Booth: None. D. Ratnarajah: None. N. Cook: None. G. Kotler: None. X. Fu: None. J. Buring: None. J.E. Manson: None. M.S. LeBoff: None.

Vitamin D and vitamin K have interdependent roles in bone metabolism. We recently reported that, in the VITamin D and OmegA-3 TriaL (VITAL), daily supplemental vitamin D (2000 IU/d) vs. placebo did not reduce fracture risk in 25,871 U.S. men (aged ≥50) and women (aged ≥55).[1] While vitamin D stimulates transcription and translation of osteocalcin (OC) and matrix Gla protein (MGP), vitamin K is needed to carboxylate and activate these proteins. Older adults tend to have low vitamin K intakes, and low vitamin K status may attenuate effects of vitamin D on bone. In this VITAL ancillary study, we tested in a case-cohort sample of 1,162 participants with fractures and an age-sex-matched subcohort size of 2,652, whether baseline low vitamin K status, alone or in combination with lower 25(OH) vitamin D level, predicts incident total, non-vertebral, and hip fractures. The mean (±SD) age of participants was 68.3±7.2 years, 61.5% were female, and 81.7% was Non-Hispanic White. Fractures were reported on annual questionnaires and adjudicated through medical record review. To assess vitamin K function, percent undercarboxylated OC (%ucOC) and dephosphorylated undercarboxylated MGP ([dp]ucMGP) were measured in fasting baseline blood samples, with %ucOC calculated from measures of ucOC and total OC. Higher levels of %ucOC and (dp)ucMGP indicate lower vitamin K status. Serum 25(OH)D was measured by LC-MS/MS and vitamin K biomarkers by sandwich ELISAs (IDS-iSYS Multi-Discipline Automated System). Participants with incident fracture had higher baseline vitamin K status, as assessed by (dp)ucMGP levels, but this was not corroborated by %ucOC. Compared to participants with low baseline vitamin K status and baseline 25(OH) vitamin D levels below the median (30.0 ng/mL), participants with higher baseline vitamin K and D status had a similar incidence of total and non-vertebral fractures. For the 91 hip fracture cases, baseline status of vitamin K and D did not predict hip fracture incidence. In this ancillary study, low vitamin K status by (dp)ucMGP and %ucOC, alone or in combination with baseline 25(OH) vitamin D levels below the median, was not associated with increased fracture incidence. Ongoing analyses are assessing whether phylloquinone levels as another vitamin K biomarker predict incident fracture risk. Furthermore, we have also previously shown that the effects of supplemental vitamin D on total and hip fractures were not modified by baseline vitamin K status in VITAL, the largest randomized controlled trial of supplemental vitamin D vs. placebo on fractures. From our findings in VITAL, higher vitamin K status does not protect against fractures. 1. LeBoff MS, et al. NEJM. 2022.

Presentation: 6/1/2024
12321 The Neurotransmitter Glutamate Promotes The Endocrine Functions Of Bone
Authors: Delgado I Canal , Romeo-Guitart D , Oury F , Karsenty G
Published: October 2024

Disclosure: I. Canal Delgado: None. G. Karsenty: None.

The osteoblast-derived hormone osteocalcin must be decarboxylated to become active. This can be achieved by neurite-derived glutamate, which once in osteoblasts, inhibits the enzyme responsible of osteocalcin carboxylation. Glutamate enters osteoblasts through the EAAT1/Glast transporter, a gene highly expressed in glial cells but whose functions in peripheral organs has not been systematically investigated. To precisely define the functions of glutamate in osteoblasts, we generated mice lacking Glast only in osteoblasts (Glastosb-/-). We first observed that deleting Glast from osteoblasts decreased circulating levels of the uncarboxylated and active form of osteocalcin. Phenotypic analysis showed that Glastosb-/- mice experience a much weaker acute stress response following exposure to a physical stressor, are hyperglycemic and hypoinsulinemic compared to wild-type (WT) littermates. These abnormalities are the ones seen in mice lacking osteocalcin and were corrected by exogenous osteocalcin. We next used this mutant mouse strain as a tool to ask whether any of the symptoms observed in GLAST-deficient patients might be due, in part, to the absence of glutamate signaling in osteoblasts. We focused on cognition because this central function is impaired in GLAST-deficient subjects, and it is regulated by osteocalcin. We observed that Glastosb-/- mice had a severe cognitive impairment. To define more precisely the contribution of bone to the cognitive defect caused by the absence of GLAST, we relied on both pharmacological and genetic experiments. First, we treated WT mice with a Glast inhibitor that does not cross the blood-brain barrier (BBB) and therefore, does not affect any brain structure, or with another Glast inhibitor that crosses the BBB. In the conditions of this experiment, only the Glast inhibitor that does not cross the BBB impaired cognition in WT mice, further suggesting that glutamate signaling regulates behavior in part by regulating the release of active osteocalcin from bone. To strengthen these results, we are currently comparing cognition functions in mutant mice lacking Glast in glial cells or neurons. Together, our observations illustrate the important functions played by of glutamate in osteoblasts and suggest that some behavioral phenotype caused by the absence of GLAST in humans may originate, at least in part, from the disruption of glutamate signaling in the skeleton.

Presentation: 6/2/2024
8775 The Silent Orchestrator: Tumor Induced Osteomalacia as a Rare Culprit Behind Hypophosphatemia
Authors: Montesinos-Cartagena M , Rivera-Rosa J , Perez-Draper C S , Colon-Castellano J
Published: October 2024

Disclosure: M. Montesinos-Cartagena: None. J. Rivera-Rosa: None. C.S. Perez-Draper: None. J. Colon-Castellano: None.

Tumor induced osteomalacia (TIO) is a rare disorder characterized by the abnormal metabolism of phosphate and active vitamin D due to overproduction of fibroblast growth factor 23 (FGF23). FGF23 is a hormone that regulates phosphate homeostasis by reducing both phosphate renal reabsorption and production of active vitamin D. Here, we present the case of a 92-year-old male with past medical history pertinent for prostate adenocarcinoma with metastasis to bone on palliative therapy with leuprorelin, enzalutamide, and zoledronic acid who was admitted due to persistent watery diarrheas. Biochemical parameters showed mild hypocalcemia of 8.1 mg/dL (Normal Range (NR), 9-11), hypophosphatemia of 0.8 mg/dl (NR, 2.5- 4.5), albumin of 3.7 g/dl (NR, 3.5-5.5), alkaline phosphatase of 122 IU/l (NR,40-150), preserved renal function with creatinine of 0.79 mg/dl (NR, 0.7-1.2), elevated intact parathyroid hormone (PTH) of 134 pg/ml (NR, 9-52) and active vitamin D deficiency of 11 ng/ml (NR, 30-100 ng/ml). Urine electrolytes remarkable for hyperphosphaturia of 266.8mmol/L. Due to the decreased levels of active vitamin D in this patient with hypophosphatemia, FGF23 levels were measured and came back elevated on 3457 RU/mL (NR, <180RU/mL). Thus, diagnosis of tumor induced osteomalacia was made. The patient was initiated on calcitriol, calcium carbonate and electrolyte replacement was provided. Treatment with burosumab was considered, however due to multiple comorbidities and advanced cancer stage, goals of care were discussed with the patient and his family who opted for hospice care. Our case shows the importance of considering TIO as a possible underlying cause of hypophosphatemia. Moreover, measurement of FGF23 levels is key for diagnosis of TIO, especially in patients with multiple factors contributing to low serum phosphate levels. Adequate diagnosis is essential to determine prognosis and subsequent treatment.

Presentation: 6/1/2024
9173 The Use Of The Frax Tool And Its Adjustments In Women Living With Diabetes: A Cohort Study In Primary Care In Brazil
Authors: de Oliveira Fernando M , MC Leal Rafaela , Vasconcellos Comim Fabio , Orlandin Premaor Melissa
Published: October 2024

Disclosure: F.M. de Oliveira: None. R.M. Leal: None. F.V. Comim: None. M.O. Premaor: None.

In recent decades, an increased risk of fractures in people living with diabetes has been described. This risk appears to be independent of bone mineral density (BMD). Therefore, screening instruments for fracture risk have been proposed in this population. The FRAX® algorithm is one of them. However, the initially described FRAX® algorithm has some limitations in PVDM. Some studies suggest that minor modifications to this instrument can improve its performance. These modifications appear to work well in other countries, such as Canada. However, we do not know whether these adjustments work in the Brazilian population. The objective of our study was to evaluate the calibration and accuracy of the FRAX® algorithm with and without adjustments for women living with DM (MLDM). Methods: To this end, a cohort study was carried out that included women receiving primary care in the city of Santa Maria, Rio Grande do Sul. The risk for major and hip fractures was calculated using the FRAX® tool. The FRAX® risk was calculated:

1. Without adjustments (unadjusted FRAX®)

2. Increasing the entered age by ten years in individuals with DM (FRAX® 10 years)

3. Inserting the diagnosis of DM as rheumatoid arthritis (FRAX® AR)

Of the 1,301 women eligible to participate in the study, 1,057 were enrolled, and 854 completed the 5-year follow-up. There were no differences between the area under the ROC curve of the unadjusted calculated FRAX® score and the FRAX® 10-year or FRAX® AR for major and hip fractures. The accuracy for major fracture was 0.948 (unadjusted FRAX®), 0.947 (FRAX® 10 years) and 0.946 (FRAX® AR). Furthermore, for hip fractures, the accuracies were 0.989 (unadjusted FRAX®), 0.988 (FRAX® 10 years) and 0.988 (FRAX® AR). On the other hand, both the FRAX® 10 years and the FRAX® AR were better calibrated, presenting a lower Chi-square. The calibration for major and hip fractures was, respectively, 15.4 (FRAX® unadjusted), 14.4 (FRAX® 10 years) and 14.4 (FRAX® AR), and 0.87 (unadjusted FRAX®), 0.32 (FRAX® 10 years) and 0.69 (FRAX® AR). In conclusion, the FRAX algorithm showed good accuracy in WLDM followed in primary care. The FRAX® 10-year and FRAX® AR settings were better calibrated in this population. These data suggest that using the FRAX® tool with adjustments could help identify the risk of fractures in WLDM in primary care in Brazil.

Presentation: 6/3/2024
6785 Thrombocytopenia: A new adverse effect of Romosozumab
Authors: Dejhansathit Siroj , Akabogu Nwamaka , Stanley Brian , marium fnu , Bazuaye Efosa M , Sophia Krusniak Lara , Zubair Khan Uzma
Published: October 2024

Disclosure: S. Dejhansathit: None. N. Akabogu: None. B. Stanley: None. F. marium: None. E.M. Bazuaye: None. L.S. Krusniak: None. U.Z. Khan: None.

Introduction: Romosozumab, a monoclonal anti-sclerostin antibody, is a new anabolic agent approved by the US FDA in 2019 for treatment of osteoporosis. Osteocytes produce sclerostin which inhibits bone formation. Consequently, suppressing sclerostin enhances osteoblast function leading to improved bone mass and reduction in fractures. Romosozumab therapy has demonstrated efficacy in lowering vertebral and nonvertebral fractures. Despite its effectiveness, cardiovascular events are the main concern and it is contraindicated in individuals with prior history or increased risk of myocardial infarction or stroke. This case marks the first incidence of immune thrombocytopenia (ITP) associated with Romosozumab use. Case Description: A 72-year-old Caucasian woman with a past medical history of chronic kidney disease, GERD, seizure disorder, and asthma was referred to Endocrinology clinic for osteoporosis management. Osteoporosis was diagnosed in 2019 on DXA scan showing T-scores at lumbar spine (LS), femoral neck, and total hip as -3.1, -3.1, and -3.0, respectively. She was treated with Zoledronic acid injections. Workup at this visit showed elevated parathyroid level, while calcium, vitamin D, magnesium, phosphorus levels were within the normal range. Repeat DXA in February 2023 revealed a 4.8% decreased in BMD at LS. Due to severity of osteoporosis, treatment with Romosozumab monthly was initiated. After receiving the third dose of Romosozumab, she experienced epistaxis and easy bruising of her skin. Labs revealed severe thrombocytopenia (platelet count of 12,000/microL). Peripheral blood smear showed no platelet clumping or megakaryocytes. HIV and HCV testing returned negative, prompting a referral to hematology. A presumptive diagnosis of ITP was made. Treatment with prednisone was initiated. A careful history and review of medications was conducted for identification of secondary causes of thrombocytopenia. Romosozumab was the only medication added recently, leading to a suspicion that it might be the causative factor for thrombocytopenia. Consequently, Romosozumab was discontinued. Subsequent complete blood count revealed a return of the normal platelet count. Conclusion: Given the novelty of Romosozumab, limited data exist on its safety profile. This case marks the first reported incidence of thrombocytopenia associated with Romosozumab use underscoring the importance of identifying drugs as a secondary cause of thrombocytopenia. This case emphasizes the need for ongoing pharmacovigilance and monitoring when using novel therapeutic agents like Romosozumab.

Presentation: 6/3/2024
7949 Unraveling a Unique Presentation of Paget’s Disease of Bone
Authors: Puri Sadhana , Bovee Laura , Narla Radhika
Published: October 2024

Disclosure: S. Puri: None. L. Bovee: None. R. Narla: None.

Background: Paget's Disease of Bone (PDB) is a disorder characterized by rapid bone destruction and repair, which results in distortion of bone architecture. PDB occurs most commonly in adults over 55 and of European descent. PDB presents with both lytic and sclerotic lesions, predominantly in the axial skeleton. Serum alkaline phosphatase (ALP) levels and bone turnover markers (BTMs) are typically elevated in PDB. Clinical Case: A 53-year-old African-American woman with a history of breast cancer, PTSD, depression, and obesity (BMI 37) presented with worsening back pain over the past six months. Her pain would start at the center of her back and radiate to her left lower extremity. She endorsed rapid weight loss and night sweats and had lumbar bony tenderness on exam, prompting a spinal MRI. Spinal MRI was significant for diffuse sclerosis of the L3 vertebral body only. The radiology report provided a broad differential for this finding, including metastases, lymphoma, infection, PDB, and hemangioma. Due to progression of the patient’s back pain and concern for possible malignancy, a whole-body SPECT was completed which showed isolated tracer uptake into the L3 vertebral body extending into the pedicles and spinous process. Similar findings were noted on bone scans dating back to 2001. Per the radiology report, the presence of sclerosis with minimal expansion is most suggestive of PDB. Endocrinology was consulted for guidance on treatment and surveillance imaging for this patient. The endocrinology team discussed the case with radiology, who confirmed that the patient’s imaging findings had classic features of PDB. Bone specific ALP (B-ALP) and procollagen type 1 amino-terminal propeptide (P1NP) as bone turnover markers (BTMs) were within normal limits. A DEXA scan is pending to evaluate for concurrent osteoporosis. Clinical Lessons: PDB was favored as the most likely diagnosis primarily due to the sclerotic appearance of the patient’s vertebral lesion on imaging, radicular symptoms, and exam finding of bony point tenderness. Other diagnoses, such as metastatic disease, were considered and were thought to be unlikely given that the vertebral lesion is monostotic and stable. This case highlights the necessity of carefully evaluating radiographic findings and clinical history in the diagnosis of PDB. In this case, the patient was from a demographic group unlikely to have PDB and, unexpectedly, did not have elevated BTMs. It is important to consider PDB on the differential diagnosis in cases such as this because PDB can present in myriad ways and in a variety of patient populations.

Presentation: 6/2/2024
6928 Vitamin D excess in a patient with hypoparathyroidism after parathyroidectomy
Authors: Zavgorodneva Z , Barsegian A , Zhang F
Published: October 2024

Disclosure: Z. Zavgorodneva: None. A. Barsegian: None. F. Zhang: None.

Introduction. We describe a case of a patient with mild persistent hypoparathyroidism after parathyroidectomy with autotransplantation, which was indicated for ESRD-related secondary hyperparathyroidism. The patient presented with nonspecific complaints and was found to have a high Vitamin D level after long-term moderate-dose Vitamin D supplementation. Case report. A 71-year-old male with a past medical history of end-stage renal disease (ESRD) undergoing hemodialysis for the past 18 years, as well as a history of parathyroidectomy with autoimplantation of parathyroid glands in the forearm in 2010 due to severe secondary hyperparathyroidism, presented to the hospital complaining of generalized weakness and lower extremity cramps that had been ongoing for a few weeks. Further investigations did not reveal evidence of infectious processes. A review of medications indicated the absence of statins among his outpatient medications. No focal neurological deficits or objective signs of muscle weakness were identified. Laboratory findings showed no significant metabolic derangements or haematological abnormalities. Inflammatory markers and creatine phosphokinase were within normal ranges. As part of the workup for generalized subjective weakness and ESRD, Vitamin D levels were checked, revealing a result of of120 ng/mL. The patient reported taking over-the-counter 2000 IU of Vitamin D twice daily for the past six years despite having a normal level of Vitamin D checked five years prior to admission. Calcium supplements were initiated in the postoperative period and continue to be administered at a dose of 600 mg daily. Analysis of the PTH-calcium axis demonstrated persistent mild hypoparathyroidism with hypocalcemia since the time of the surgery. However, there was an observed tendency for calcium levels to improve, especially in the last six years. Vitamin D supplement was discontinued, and the patient was subsequently discharged home with the continuation of physical therapy. Discussion. Explaining the origin of the high level of Vitamin D in this patient poses a challenge. There is limited data in the literature regarding the long-term effects of vitamin D use when the initial Vitamin D levels are normal. Additionally, there are numerous abstracts suggesting significantly higher doses of Vitamin D received for up to 6 years without any evident biochemical or clinical consequences. Moreover, the typical consequences of Vitamin D toxicity, such as hypercalcemia, can not be present in patients who underwent parathyroidectomy. Therefore, it is possible to consider that the severe generalized subjective weakness may be a sign of Vitamin D toxicity itself.

Presentation: 6/1/2024
8702 Age-Sex Differences in Global Burden of Ischemic Heart Disease Attributable to High LDL in the Last 3 Decades:Global, Regional, National Variations, Age Dynamics, and Implications for Global Health
Authors: Adedara V , Maddineni K , Dekhne A , Chinthapalli M , Potluri G , Parisapogu A , Markandu K , Desai H
Published: October 2024

Disclosure: V. Adedara: None. K. Maddineni: None. A. Dekhne: None. M. Chinthapalli: None. G. Potluri: None. A. Parisapogu: None. K. Markandu: None. H. Desai: None.

Background: Ischemic Heart Disease (IHD) stands as the foremost cause of mortality globally, contributing to 9.6 million deaths. Elevated levels of low-density lipoprotein cholesterol (LDL-C) consistently feature among the risk factors associated with IHD. Methods: Employing the Global Burden of Disease framework, we computed mortality and DALYs linked to IHD attributable to LDL-C, stratified by age-sex, year, and covering 204 countries and territories during the period from 1990 to 2019. Non-fatal health outcomes were estimated using DISMOD MR 2.1, Bayesian meta-regression tool for epidemiological modelling. Results were expressed in absolute counts and age-standardized rates (ASR) per 100,000 person-years. Results: The total number of deaths attributed to IHD due to elevated LDL-C increased from 2.5 million (95% Uncertainty Interval: 2-3.1 million) in 1990 to 3.7 million (95% UI: 2.8-4.8 million) in 2019. Concurrently, DALYs increased from 60.4 million (95% UI: 50.4-70.7 million) in 1990 to 84.9 million (95% UI: 69.5-101.3 million) in 2019. In terms of ASR, the annual percentage change (APC) in death rates decreased by 36%, and DALY rates decreased by 32% from 1990 to 2019. Regionally, East Asia exhibited the highest increase in APC in death counts by 191%, followed by Commonwealth Low-Income countries at 164%, and Oceania at 160% during the same period. Conversely, the Commonwealth High-Income region experienced the highest decrease at 41%. Males displayed higher APC in death (48% vs. 44%) and DALYs (42% vs. 38%) compared to females over the last three decades. In terms of ASR, males observed a higher decrease compared to females. In 2019, the age group 80-84 years had the highest number of deaths at 534,079 (264,177-813,898), while DALYs were most pronounced in the 55-59 year age group, reaching 10.6 million (8.9-12.3 million). Conclusion: IHD remains a significant global health challenge, with high LDL-C levels being a crucial modifiable risk factor. Age-sex disparities in the burden of IHD are evident, driven by variations in LDL-C metabolism, hormonal changes, and lifestyle factors. Recognizing and addressing these disparities is essential for developing effective prevention and treatment strategies tailored to different populations and age groups.

Presentation: 6/2/2024
8294 Association between gene mutations and DNA methylation of CYP11B2 in aldosterone-producing adenoma
Authors: Kometani Mitsuhiro , Mizoguchi Ren , Demura Masashi , Aiga Ko , Konishi Seigo , Aono Daisuke , Karashima Shigehiro , Takeda Yoshiyu , Yoneda Takashi
Published: October 2024

Disclosure: M. Kometani: None. R. Mizoguchi: None. M. Demura: None. K. Aiga: None. S. Konishi: None. D. Aono: None. S. Karashima: None. Y. Takeda: None. T. Yoneda: None.

Context: Primary aldosteronism (PA) causes hypertension and cardiovascular complications. Recently, in aldosterone producing adenomas (APA), various genetic mutations have been identified. In addition, epigenetic mechanisms, such as DNA methylation, are also involved in excessive aldosterone production. Several studies have shown that aldosterone synthase (CYP11B2) is hypomethylated in APA. On the other hand, the relationship between specific genetic variants identified in APA and DNA methylation has not been fully clarified. Objective: To investigate the relationship between specific genetic mutations in APA and DNA methylation of CYP11B2. Methods: We analyzed 48 patients (female 23 cases) diagnosed with APA and treated between 2001 and 2022. First, Gene mutation analysis using next-generation sequencing was performed. KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CACNA1H, which are known mutations in PA, and PRKACA, PRKA1A, GNAS, CTNNB1, and ARMC5, which are known mutations in Cushing’s syndrome, were evaluated. Next, DNA methylation analysis of the CYP11B2 promoter using pyrosequencing were performed using APA. We targeted three CpG regions near the transcription start site of CYP11B2. Results: The respective mean values for all patients were: age 52 years, systolic blood pressure 138 mmHg, diastolic blood pressure 87 mmHg, ARR 1,326, serum potassium level 3.4 mEq/L, and tumor diameter 15 mm. Genetic mutation analysis revealed KCNJ5 gene mutations in 33 of the 48 patients. Among the other cases, mutations in the CTNNB1 gene were found in three cases, mutations in the ATP1A1 gene in two cases, mutations in the CACNA1D gene in one case, and PRKACA gene mutations in one case. The remaining seven patients had no mutations in any of the analyzed genes. When DNA methylation of the promoter region of CYP11B2 was analyzed in APAs with and without mutations in KCNJ5, we found that in all three CpG regions, DNA methylation rate was significantly reduced in APAs with mutations in KCNJ5 gene (CpG1 22% vs. 30%, CpG2 42% vs. 73%, CpG3 47% vs. 75%, respectively). Conclusions: The most common genetic mutation in APA was the KCNJ5 mutation; APA with the KCNJ5 mutation had significantly lower methylation rates than CYP11B2. This suggests that genetic mutations in APA affect DNA methylation and result in hormone overproduction.

Presentation: 6/3/2024
8418 Association of GLP-1 Receptor Agonists and SGLT-2 Inhibitors with Major Adverse Cardiovascular Events and Serious Liver Events among Patients with Type 2 Diabetes and MASLD
Authors: Kutz Alexander , Wexler Deborah J , Liu Jun , Paik Julie M , Patorno Elisabetta
Published: October 2024

Disclosure: A. Kutz: None. D.J. Wexler: None. J. Liu: None. J.M. Paik: None. E. Patorno: None.

Introduction and study question Little is known about the cardiovascular (CV) and hepatic effectiveness of glucagon-like peptide 1 receptor agonists (GLP-1 RA) and sodium–glucose cotransporter 2 inhibitors (SGLT-2i) in people with type 2 diabetes (T2D) and known metabolic dysfunction-associated steatotic liver disease (MASLD) in clinical practice. We assessed the comparative CV and hepatic effectiveness and the safety of GLP-1 RA and SGLT-2i in people with T2D and prevalent MASLD. Methodology Using pooled data from Medicare fee-for-service (2013–2020) and a large U.S. health insurance database (2013-June 2022), we conducted two propensity-score fine stratification weighted cohort studies including adults with T2D and a diagnosis of MASLD who initiated GLP-1RA, SGLT-2i, or dipeptidyl peptidase 4 inhibitors (DPP-4i, reference). Using Cox proportional hazards models, we assessed the primary CV effectiveness composite outcome of acute myocardial infarction, ischemic stroke, hospitalization for heart failure, or all-cause mortality. The primary hepatic effectiveness outcome was a composite of serious liver events (hospitalization for ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, bleeding esophageal varices, hepatic encephalopathy, or liver transplantation). The safety outcome was a composite of severe adverse events (lower limb amputation, non-vertebral fracture, emergency admission for hypoglycemia, or hospitalization for acute kidney injury, diabetic ketoacidosis [DKA], severe genital or urinary tract infection, acute pancreatitis, or biliary event). Major results Compared with DPP-4i (n=17,084 initiators), the hazard ratio (HR) for the primary CV outcome associated with GLP-1 RA (n=13,666 initiators) was 0.67 (95% CI, 0.56 to 0.81), corresponding to an incidence rate difference (IRD) per 1,000 person-years of -21.6 (95% CI, -26.7 to -16.6). The HR for the primary hepatic outcome was 0.47 (95% CI, 0.25 to 0.90), the IRD -2.1 (95% CI -3.4 to -0.9). Similar CV benefits were observed for SGLT-2i (n=11,108) vs DPP-4i (n=16,979), with a HR for the primary CV outcome of 0.82 (95% CI 0.70–0.96) and an IRD of -11.0 (95% CI -16.2 to -5.8). For the primary hepatic outcome, the HR was 0.81 (95% CI 0.45 to 1.44) and the IRD -1.1 (95% CI -2.4 to 0.3). Severe adverse events were not more frequent with GLP-1RA or SGLT-2i compared with DPP-4i. Interpretation and conclusion Among people with T2D and MASLD, the use of GLP-1 RA or SGLT-2i was associated with fewer CV events, vs DPP-4i, while GLP-1 RA also reduced serious liver events. Compared with DPP-4i, GLP-1RA or SGLT-2i were not associated with higher safety adverse event rates.

Presentation: 6/2/2024
7246 Cardiac Paraganglioma: A Rare Entity
Authors: Javed Laraib , Jonea Lim
Published: October 2024

Disclosure: L. Javed: None. L. Jonea: None.

Cardiac paragangliomas are an exceptionally uncommon subset of neuroendocrine neoplasms. We present a case of a patient presenting with this condition. 70-year-old woman with pertinent past medical history of chronic veinous insufficiency complicated by recurrent abscesses of her right leg since venaseal procedure. The patient had positive IgG lambda on immunofixation that raised concerns for MGUS. Therefore, a F-18 FDG PET-CT scan was performed for further evaluation. PET-CT revealed a hypermetabolic mass in the upper inner right thigh and the right atrium (SUV 17.6) raising concern for septic thrombi. She was admitted in the hospital for initiation of antibiotic therapy. Transesophageal echocardiogram (TEE) revealed a 4.5 cm x 4.0 cm mass in the right atrioventricular (AV) groove region, extending over the root of the main pulmonary artery. Following discharge, despite completing six weeks of IV antibiotic therapy a CT scan on a subsequent clinic visit revealed the same mass as seen on TEE. CT imaging raised suspicion of neuroendocrine tumor. This led to referral to the endocrinology department. Laboratory results showed elevated normetanephrine and dopamine levels increasing likelihood of paraganglioma. Lab Results: 24 hr urine normetaneprhine :7197(N ≤ 376 mcg), 24 hr urinary dopamine :879 (N ≤400 mcg), 24 urinary metanephrine: 84 (N ≤96 mcg) & 24 hr urinary epinephrine <3 (N ≤20 mcg). Her home systolic blood pressure readings varied between 120’s & 170’s. She was initiated on Prazosin 1 mg daily in addition to the existing antihypertensive medications of nebivilol, amlodipine & furosemide. Few months later, this patient successfully underwent cardiac mass resection. Histologic findings of the resected mass were consistent with paraganglioma. Post-surgery, anti-hypertensive medications were discontinued, and blood pressure normalized to systolic readings in the 90s to 120s and diastolic readings in the 60s to 80s. Repeat biochemical tests indicated a normalization of normetanephrine & dopamine levels, validating the success of the resection. This case features an extremely rare entity cardiac paraganglioma that had an atypical clinical manifestation of being asymptomatic. Timely diagnosis and appropriate management are crucial for patient outcomes. Surgical intervention, although fundamental, bears significant risks, necessitating meticulous preoperative management to mitigate potential complications. The medical approach focuses on averting perioperative complications such as hypertensive crisis, cardiac arrhythmias and myocardial infarction. This is achieved by administering alpha and beta adrenoceptor blockers for a minimum of two weeks before the scheduled surgery. Regular follow up is also essential due to the unpredictable malignant potential of these tumors.

Presentation: 6/3/2024
7524 Cholesterol ester storage disease
Authors: Ebrahimi N , Lara R Cardenas , Tariq S
Published: October 2024

Disclosure: N. Ebrahimi: None. R. Cardenas Lara: None. S. Tariq: None.

Introduction: Cholesterol ester storage disease (CESD) is a lysosomal disease that has deficiency of lysosomal acid lipase (LIPA or LAL). This is a rare autosomal recessive disorder of cholesterol metabolism first described by Fredrickson in 1963. As of 1989, approximately 50 cases of CESD had been reported. There's a good chance that more CESD individuals were misdiagnosed for other illnesses.A deficiency in the LIPA enzyme leads to access storage of macrolipids and specific complex carbohydrates called macropolysaccharides in the cells of various tissues. Clinical manifestations include hepatic steatosis, hepatomegaly, and fibrosis, resulting in micronodular cirrhosis of the liver. Patients are often not properly diagnosed with CESD until they are adults. Case presentation:51 years old female presented to my clinic for uncontrolled complicated type 2 diabetes. After reviewing her medical history, she noted, she and her sister have a rare condition called CESD. She was not aware of any treatment available and currently on atorvastatin 80 mg daily, evolocumab 140 mg every 14 days, and ezetimibe 10 mg daily.She follows up with hepatologist and cardiologist for annual imaging and monitoring the progression of her condition. She gets FibroScan annually. Her last scan indicated fibrosis score of 4/ FIB-4 index 1.58, meaning intermediate risk of advanced fibrosis.Lab: AST 46, ALT 52, total cholesterol 137, LDL 59, HDL 57, TG 119Recent abdominal CT showed fatty liver disease with mild hepatomegaly.Physical exam: slightly enlarged liver noted.After reviewing all labs and imaging, I started her on sebelipase alfa 1mg/kg/dose IV every 14 days, and will follow up every 6 months. Discussion: CESD is an autosomal recessive disorder that is inherited affecting male and female sexes equally.Abnormally reduced activity of acid lipase, a lysosomal enzyme that hydrolyzes triglycerides and cholesterol esters, is the hallmark of this condition. About half of the patients have hepatic fibrosis at the time of diagnosis. Hepatic cirrhosis and liver failure, along with portal hypertension and resulting esophageal varices often occur in advanced stages.When distinguishing clinical signs, such hepatomegaly, CESD dx may be suspected. A comprehensive exam, full patient history, and specialized testing that identify low LIPA enzyme activity in specific body cells and tissues can all be used to confirm a diagnosis. Most common gene variant, E8SJM, if negative sequencing of LIPA gene is done.Baseline evaluation of lipid biomarkers, echocardiogram, stress test, liver function tests, liver biopsy, kidney function biomarkers, complete blood count, coagulation tests, and sebelipase antibody testing. Genetic counseling is recommended for close family members.In 2015 FDA approved a new medication which is an enzyme replacement therapy called sebelipase alfa. It is administered by IV infusion every 2 wks.

Presentation: 6/3/2024
8532 Circulating Neprilysin in Pregnancy
Authors: Kulovic-Sissawo Azra , Weiss Elisa , Jantscher-Krenn Evelyn , Hiden Ursula
Published: October 2024

Disclosure: A. Kulovic-Sissawo: None. E. Weiss: None. E. Jantscher-Krenn: None. U. Hiden: None.

Background: In the complex nature of pregnancy, the female organism undergoes pivotal vascular and metabolic changes orchestrated by a tightly regulated interplay of bioactive regulatory molecules. The neutral endopeptidase, neprilysin, exists both in a membrane-bound and a soluble form (sNEP), of with the latter present in the circulatory system. Neprilysin degrades an exciting range of bioactive peptides involved in glycemic control (insulin B chain, GLP-1) and vascular tone regulation (angiotensin I and II, bradykinin, ANP, BNP), and both of them are altered in pregnancy. Objective: Due to the substrate-specificity of neprilysin and its multifaceted role we hypothesize that neprilysin may be involved in metabolic and vascular adaptions during pregnancy. However, the link between sNEP and maternal metabolism in pregnancy has not yet been investigated. Methodology: Serum sNEP concentration (n=102), longitudinally collected from metabolically healthy women (trial number NTC05496712), was measured at three visits throughout gestation (gestational age: 12.5±0.7; 20±0.8; 33±1.6 weeks) and post-partum (2±1.2 days after delivery) using commercially available sandwich ELISA. In addition, sNEP levels in pregnancy were compared to a cohort of non-pregnant women within reproductive age (n=50). Clinical and anthropometric measurements were determined and the association of sNEP and metabolic characteristics elucidated. Results: Circulating sNEP levels were non-normally distributed (median ± IQR: 2334±232624 pg/ml, n=82, gestational age 12.5±0.7 weeks) and showed high biological variability, with individual levels remaining constant over gestation. After delivery, however, sNEP concentration decreased (median± IQR: 1968±171060 pg/ml n=82, p=0.0001). sNEP showed a positive correlation with systolic blood pressure (Spearman, n=56, r=0.321, p=0.02) at early stages of pregnancy and non-fasting GLP-1 (Spearman, n=98, r=0.309, p=0.002) throughout gestation, but not with blood glucose, insulin resistance or BMI. In the non-pregnant state sNEP concentration (median±IQR: 4322±392152 pg/ml, n=38) positively correlated with body fat percentage (Pearson, n=38, r=0.405, p=0.01), fasting glucose (Pearson, n=43, r=0.301, p=0.05) and body mass index (Spearman, n=38, r=0.369, p=0.02) but did not correlate with systolic blood pressure (Pearson, n=36, r=-0.120, p=0.48). Conclusion: For the first time, the link between sNEP, metabolism and blood pressure during uncomplicated pregnancy was investigated. The decrease in post-partum circulating sNEP as compared to levels throughout pregnancy suggests a particular way of sNEP regulation and release during gestation. Our data indicate that in both, pregnant and non-pregnant state, sNEP may be involved in metabolic and cardiovascular regulation, with circulating sNEP levels showing massive individual differences.

Presentation: 6/3/2024
8571 Co existence of aldosterone excess in adrenal myelolipomas
Authors: Mishra I , Baliarsinha A
Published: October 2024

Disclosure: I. Mishra: None. A. Baliarsinha: None.

Co existence of aldosterone excess in adrenal myelolipomas Abstract: Adrenal myelolipomas are benign, lipomatous tumours, most of which present as adrenal incidentalomas.Co existence of cortisol excess states and aldosterone producing carcinomas is reported with adrenal myelolipomas,however isolated aldosterone excess without imaging features of adrenal malignancy is rare.We describe 3 cases presenting for evaluation of hyperaldosteronism but with imaging features consistent with myelolipomas. Case 1;58 year female presented with hypertension and spontaneous hypokalemia.On evaluation BMI was 25.3kg/m2,Gr 2 hypertensive retinopathy with systemic examination within normal limits.Biochemical evaluation revealed; Pl.Aldo(ng/dl)32.5; PRA(ng/ml/hr)0.54; ARR 60.5; SIT Pl.Aldo(ng/ml)27.8; AVS- not done; IMAGING(CT) Left adrenal fat attenuating 16×13mm lesion baseline HU < - 20 ?adrenal myelolipoma; Mx Left adrenalectomy H/P Adrenocortical hyperplasia;post op-resolution of hypokalemia with persistence of hypertension controlled with decreased number of drugs. Case 2;38 year male presented with resistant hypertension ,cerebro vascular accident,right hemiparesis and diuretic induced hypokalemia.On evaluation BMI was 31 kg/m2,Gr 1 hypertensive retinopathy with right hemiparesis.Biochemical evaluation revealed; Pl.Aldo(ng/dl)12.3; PRA(ng/ml/hr) 0.82; ARR 15; SIT Pl.Aldo(ng/ml)7.79; AVS- not done; IMAGING(CT) Left adrenal fat attenuating 28×30mmlesion baseline HU < -20? adrenal myelolipoma; Mx Left adrenalectomy H/P adrenal myelolipoma;post op-resolution of hypokalemia ,recovery of weakness and normalization of hypertension without drugs. Case 3;49 year male presented with hypertension ,incidental detection of adrenal lesion on ultrasound for pain abdomen and normokalemia.On evaluation BMI was 27 kg/m2,no significant findings on general examination with systemic examination within normal limits. Biochemical evaluation revealed; Pl.Aldo(ng/dl)12.2; PRA(ng/ml/hr) 0.58; ARR 20.2; SIT Pl.Aldo(ng/ml)11; AVS- not done; IMAGING(CT) Left adrenal fat attenuating 22x 26 mm lesion baseline HU < -20? adrenal myelolipoma; Mx drug therapy for hypertension due to refusal for surgical therapy with monitoring of blood pressure. In surgically treated adrenal myelolipomas, adrenal hormone excess is reported in 5-6% of cases, with autonomous cortisol secretion being most common .Even on the background of CT findings consistent with myelolipomas, patients fulfilling the screening and confirmatory criterias of primary hyperaldosteronism must be subjected to apt therapeutic modality.The presence of aldosterone clusters with excessive aldosterone synthase activity in these lesions could be reason for occurrence of primary hyperaldosteronism in myelolipomas.

Presentation: 6/3/2024
7496 Differences in seasonality's influence on individual lipid parameters: A time series analysis
Authors: Edo N , Sawa T , Terakawa A , Uchino T , Yamazaki H , Uno K , Uno K , Morita K , Ishikawa T , Teramoto T , Tsukamoto K
Published: October 2024

Disclosure: N. Edo: None. T. Sawa: None. A. Terakawa: None. T. Uchino: None. H. Yamazaki: None. K. Uno: None. K. Uno: None. K. Morita: None. T. Ishikawa: None. T. Teramoto: None. K. Tsukamoto: None.

Introduction: Many studies have reported seasonal changes in serum lipid levels. However, how much the seasonality affects the individual lipid parameters is still undetermined. Therefore, this study aimed to evaluate the differences in seasonality's influence on lipid parameters. Participants and Methods: We retrospectively collected data on TC, HDL-C, LDL-C, and TG levels measured between March 2016 and February 2021. All participants were over 18 years old and were included in this study regardless of underlying disease or treatment status. Next, we made two datasets: one with simultaneous TC, HDL-C, and TG measurements (Group A, n = 137,964) and the other with simultaneous HDL-C, LDL-C, and TG measurements (Group B, n = 119,614). Non-HDL-C and LDL-C (Friedewald: F) levels were calculated in Group A. Using the monthly median levels, we made monthly time series data for each sex. Upon adjusting for the monthly mean age, the data were decomposed into seasonal component (St), trend component, and remainder component (Rt), using seasonal and Trend decomposition using Loess method, which was performed by the "forecast::stl()" function of R software. Finally, the degree of seasonality's influence was evaluated by calculating the following parameters using the dispersions of each component: St/(St + Rt). Results: In Group A, the parameters calculated were as follows: TC; 0.78, HDL-C; 0.79, non HDL-C; 0.49, LDL-C (F); 0.63, and TG; 0.35 for male individuals, and TC; 0.76, HDL-C; 0.81, non HDL-C; 0.37, LDL-C (F); 0.51, and TG; 0.44 for female individuals. In Group B, these were as follows: HDL-C; 0.81, LDL-C; 0.28, and TG; 0.32 for male individuals, and HDL-C; 0.84, LDL-C; 0.28, and TG; 0.33 for female individuals. Discussion: Our results suggest that the effects of seasonality were more evident in TC and HDL-C levels and that they were more subtle in non-HDL-C, measured LDL-C, and TG levels. Therefore, considering in which season they are measured would be preferable when evaluating the HDL-C level. On the contrary, non-HDL-C and directly measured LDL-C levels might be able to be assessed, regardless of the season.

Presentation: 6/3/2024
5109 Evaluation of an educational intervention to primary care providers to increase screening for primary aldosteronism
Authors: Figueiredo Maria Gabriela de Faria , Wagoner Jill , Young William F , Fishbein Lauren Michelle , McDermott Michael T
Published: October 2024

Disclosure: M.D. Figueiredo: None. J. Wagoner: None. W.F. Young: None. L.M. Fishbein: None. M.T. McDermott: None.

Introduction: Primary aldosteronism (PA) accounts for at least 5% of hypertension cases and up to 20% of resistant hypertension. Underdiagnosis leads to delayed treatment and increases cardiovascular morbidity and mortality. Our objective was to assess the impact of an educational series for primary care providers (PCPs) on increasing screening rates for PA. Methods: Educational intervention consisted of a 5-day, 2-minute email series for 111 PCPs on PA screening, confirmation, and treatment (trained group). Following the training, EMR data were extracted for patients with PAC (plasma aldosterone concentration) or PRA (plasma renin activity), new hypertension diagnosis code, or a new MRA prescription within 1 year pre- or post-intervention and data pre- and post- intervention were compared. A proper screen included sending both PAC and PRA simultaneously. IRB approval was obtained. Results: In the pre-intervention year, 57 patients were properly screened for PA by the 111 PCPs. Post-intervention, 151 patients were screened for PA showing a 2.65-fold increase in screening with the educational intervention. Using a paired T-test across quartiles pre- and post-intervention, this increase was statistically significant (P=0.0148). We further demonstrated a sustained effect throughout the 12 months post-intervention per quartile (Q+1 n=29, Q+2 n=45, Q+3 n=33, Q+4 n=42). Of the total cohort screened (both pre- and post-intervention), 28% had a positive screen for PA (defined liberally as PAC >5 ng/dL with PRA <1 ng/mL/h). Discussion: The educational intervention drove an increase in PCP screening for PA in the year post-intervention and this increase was sustained across all quartiles of the year. Of the screened cohort (pre- and post-intervention), 28% screened positive for PA, and those patients were more frequently referred to specialists post-intervention. Our study has some limitations, including the relatively small sample size of PCPs educated and patients screened, and the 2020 start to the COVID-19 pandemic impact during the post-intervention period. Conclusion: Our findings advocate for continued education to reinforce PA screening criteria using an easy, not time consuming and effective educational tool. Continuous education is crucial to reinforce next steps in confirmation and treatment.

Presentation: 6/3/2024
6478 Loss of TSPO Inhibits Autophagy and Exacerbates Steatosis via Fatty Acid Uptake
Authors: Li Yuchang , Chen Liting , Sottas Chantal , Patel Nrupa D , Raul Mahima C , Garza Samuel , Papadopoulos Vassilios
Published: October 2024

Disclosure: Y. Li: None. L. Chen: None. C. Sottas: None. N.D. Patel: None. M.C. Raul: None. S. Garza: None. V. Papadopoulos: None.

Nonalcoholic fatty liver disease (NAFLD) is a chronic clinicopathological condition characterized by substantial lipid accumulation in hepatocytes, posing an increased risk of liver injury. Previous research suggested that the depletion of translocator protein (TSPO, 18kDa), a ubiquitously distributed high-affinity cholesterol- and drug-binding protein located in the outer mitochondrial membrane, triggers simple steatosis (SS) in hepatocytes. However, the precise role of TSPO in SS remains elusive. In this study, we investigated the impact of Tspo deletion in rats fed with an 8-week high-fat-fructose-cholesterol (GAN) diet. Feeding TSPO knockout (KO) rats with the GAN diet led to the development of insulin and glucose resistance, accompanied by elevated plasma cholesterol and hepatic triacylglycerol levels. Fatty acid synthase, responsible for de novo lipogenesis, was upregulated in the livers of these rats. Furthermore, livers from GAN diet-fed TSPO KO rats showed increased CD36 expression, a fatty acid translocase facilitating the transport of long-chain free fatty acids into cells. In vitro experiments on Huh7 cells with stably overexpressed CD36 (CD36_OE) demonstrated impaired mitochondrial membrane potential and mitochondrial function, manifested by reduced oxygen consumption rate and ATP production. Acetyl-CoA (AcCoA), a precursor for fatty acid synthesis, exhibited significant upregulation in CD36_OE compared to control in Huh7, regardless of fatty acid treatment. This pattern of elevated AcCoA was consistent with observations in the livers of TSPO KO rats fed with GAN diet. The elevated AcCoA stimulated the acetylation of the regulatory-associated protein of mTOR (Raptor), activating mTORC1 and hindering autophagy. These results were corroborated by immunoprecipitation studies conducted on liver samples from both wild-type (WT) and TSPO KO rats fed with GAN diet. Additionally, the inhibition of autophagy in response to TSPO loss in livers from rats fed with GAN diet was mediated by unc-51-like autophagy-activating kinase 1 (ULK1) phosphorylation. In summary, our study underscores that TSPO deficiency intensifies the progression of NAFLD by amplifying CD36-mediated free fatty acid uptake, compromising mitochondrial function, increasing AcCoA levels, and impairing autophagy during the initial stages of steatosis (SS).

Presentation: 6/2/2024