bluuebunny/crossref_metadata_2025 huggingface dataset:
6976 Early-Onset Paget's Disease- A Unique Presentation In A Young Female With Elevated Alkaline Phosphatase And Low Back Pain
Authors: El Sayed F
Published: October 2024

Disclosure: F. El Sayed: None.

Background Paget disease of bone is an age-related disorder characterized by abnormal growth in certain bones, leading to changes in size and shape. Commonly affecting the skull, spine, pelvis, and long bones, it is more prevalent in men, those over 55, with a family history, and of European ancestry. The prevalence of Paget's disease of bone is approximately 2-3% in individuals over 55 in the United States and Europe, with higher rates in those of European descent. Symptoms, such as pain and deformities, may arise from the condition itself or complications like arthritis. While Paget disease can cause visible abnormalities and fractures in affected bones, most individuals remain asymptomatic. Diagnosis often involves blood tests measuring alkaline phosphatase levels, bone scans, and x-rays. Case Presentation We present the case of a 34-year-old woman who sought evaluation due to persistently elevated alkaline phosphatase (ALP) levels in the thousands. The abnormality was discovered during routine blood work conducted during her pregnancy in 2020, and subsequent investigation revealed a chronic elevation for over three years. The patient reported chronic lower back pain but denied other neurological symptoms. Quantification of ALP Bone showed elevated levels at 629, with normal aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, as well as within-range calcium and gamma-glutamyl transferase (GGT). A whole-body bone scan revealed marked radio tracer uptake in the calvarium, raising concerns for Paget's disease. The patient received a one-time infusion of Zoledronic acid (5 mg), leading to a significant decrease in ALP levels to 182 after three months. Subsequent examination by an Ear, Nose, and Throat (ENT) specialist unveiled bilateral extra bone deposition and mild hearing loss in the right ear, adding a unique dimension to the patient's presentation. This case highlights the importance of a comprehensive approach to diagnose and manage Paget's disease, even in younger individuals with atypical symptoms. Discussion and conclusion Paget's disease presenting in young adults with back pain can be a diagnostic challenge due to its atypical occurrence in this age group. Although back pain is a common symptom, the underlying cause might not immediately be linked to Paget's disease, which typically affects older individuals. However, when encountering persistent back pain in young adults, especially when accompanied by elevated alkaline phosphatase levels, clinicians should consider Paget's disease as a potential differential diagnosis. Further investigation, including imaging studies and bone scans, becomes crucial to confirm the presence of Paget's disease and initiate appropriate management strategies to mitigate its impact on the patient's health and quality of life.

Presentation: 6/2/2024
12609 Navigating The Therapeutic Challenge Of Post-surgical Hypoparathyroidism And Refractory Hypocalcemia
Authors: Fawcett D , Domingo A
Published: October 2024

Disclosure: D. Fawcett: None. A. Domingo: None.

Introduction: Post-surgical hypoparathyroidism poses a challenge due to calcium metabolism disturbances, ranging from mild to life-threatening complications. Despite advancements, vigilant monitoring and tailored interventions are vital for optimizing outcomes. Refractory hypocalcemia, resistant to standard therapies, underscores the need for specialized care to prevent prolonged hospitalization and morbidity. Case description: A 68-year-old woman with a history of Graves' disease and parathyroid carcinoma underwent total thyroidectomy and parathyroidectomy in January 2024. She presented to the emergency department for the second time with a recurrence of bilateral hand and perioral paresthesias, along with numbness, tingling, and weakness throughout her body. Notably, she had a prior hospital admission with similar symptoms and was discharged on calcium carbonate, magnesium, calcitriol, and vitamin D3. Vital signs were not provided. Initial laboratory workup revealed a calcium level of 4.3, with corrected calcium at 5.8, and magnesium levels at 1.8, supplemented with magnesium oxide. A 24-hour urine calcium test, vitamin D, and malabsorptive workup for celiac disease were unremarkable. Immunoglobulin A was low; however, tissue transglutaminase IgA and anti-gliadin antibodies were negative. An electrocardiogram showed a normal sinus rhythm with QT prolongation to 570 ms. Despite resuming her home regimen, her calcium level remained low, prompting initiation of calcium infusion. Consultations with endocrinology and nephrology were made, necessitating close monitoring and uptitration of calcium and vitamin D supplements for achievement and maintenance of low normal calcium levels. High doses of 3g TID of calcium and calcitriol 2mcg PO TID allowed for symptom control and discharge with outpatient follow-up with endocrinology and nephrology. Conclusion: Supplemental therapy with calcium and vitamin D analogues is standard for managing post-surgical hypoparathyroidism. Early identification and adequate management prevent hypocalcemia-related complications, including tetany, seizures, and cardiovascular anomalies such as QTc prolongation, as seen in our patient, which can result in torsade de pointes. Multidisciplinary care alongside nephrology was paramount. Serum calcium should be maintained in the low normal range, and 24-hour urine calcium excretion should also be closely monitored. Daily hydrochlorothiazide can be used to prevent hypercalciuria. In recurrent cases, as in our patient, titration of calcium and vitamin D analogues is imperative. Long-term consequences, including renal dysfunction, osteoporosis, and increased cardiovascular risk, underscore the necessity for timely diagnosis and management.

Presentation: 6/2/2024
8387 PTH Analogs in the Management of Osteoporosis in Patients with HIV: An Under-Investigated Treatment Option
Authors: Cappetta K , Erenler F
Published: October 2024

Disclosure: K. Cappetta: None. F. Erenler: None.

Background: Several studies evaluating the fracture risk in individuals with HIV suggest that their fracture burden is elevated compared to the general population due to a multitude of factors.[1] For example, highly active antiretroviral therapy (HAART) is associated with decreased bone mineral density (BMD).[1] Certain agents such as tenofovir disoproxil fumarate (TDF) are particularly associated with reduced BMD, whereas tenofovir alafenamide (TAF) tends to cause fewer deleterious effects.[1] Bisphosphonates are considered first-line options for the treatment of osteoporosis in HIV-infected adults.[1] PTH analogs such as abaloparatide are not well-studied in this population, but case reports with teriparatide have shown promising results.2 To the best of our knowledge, we present the first case in which abaloparatide was initiated in a patient with osteoporosis and HIV with subsequent significant BMD gains. Case: A 64 year-old Indian woman with well-controlled HIV (CD4+ cell count 370 cells/µL; undetectable viral load) on HAART and no history of fractures or hypercalciuria was diagnosed with osteoporosis in 2013 by dual-energy X-ray absorptiometry (DXA) scan. Her most significant risk factors are postmenopausal state, HIV, and HAART, including TDF until 2015; in 2015, she was transitioned to a combination therapy that includes TAF. She was treated with alendronate weekly from 2013-2018. DXA in Sept. 2021 showed T-scores of -2.7 (BMD 0.738 g/cm2) at the spine, -2.3 (0.592 g/cm2) at the femoral neck, and -1.7 (0.732 g/cm2) at the total hip. Given her history of prolonged bisphosphonate exposure, young age, and worst T-score at the spine, the decision was made to start the patient on anabolic therapy with abaloparatide in July 2022. Repeat DXA in Aug. 2023 showed T-scores of -2.4 (0.777 g/cm2) at the spine (a statistically significant 5.3% gain in BMD vs. 2021), -2.4 (0.583 g/cm2) at the femoral neck, and -1.7 (0.733 g/cm2) at the total hip (stable BMD). Discussion: Bone microarchitecture, especially trabecular bone (such as is found at the spine), and the balance of bone resorption and formation is negatively altered by the host immune response and viral proteins in HIV-infected adults, leading to a high prevalence of osteopenia and osteoporosis in this population.[1] Abaloparatide increases BMD—preferentially at the spine—by stimulating osteoblast function.2 Although data on these agents in individuals with HIV are limited, PTH analogs can be efficacious in the treatment of osteoporosis in this population, especially for low BMD at the spine, and warrants further investigation. References: 1.Ahmed M, et al. Bone Health in People Living with HIV/AIDS: An Update of Where We Are and Potential Future Strategies. Microorganisms. 2023; 11(3):789. 2.Wheeler AL, et al. Teriparatide treatment of osteoporosis in an HIV-infected man: a case report and literature review. AIDS. 2015 Jan 14;29(2):245-6.

Presentation: 6/3/2024
6761 PTH-independent Hypercalcemia Secondary to Severe Tophaceous Gout Bone Erosion
Authors: MacLeod R S , Cassetta M A , Majumdar S K
Published: October 2024

Disclosure: R.S. MacLeod: None. M.A. Cassetta: None. S.K. Majumdar: None.

Introduction: Severe hypercalcemia associated with chronic tophaceous gout is extremely rare and usually related to elevated calcitriol secretion by inflammatory granulomatous lesions. Herein is a case where hypercalcemia appears to be mediated by excessive bone erosion in several gout lesions. Case: A 61-year-old man with history of advanced gouty arthropathy presented to the hospital with progressive weakness, lethargy and back pain. For the 3 months prior to presentation, he was noted to have worsening hypercalcemia of unknown etiology. He was not taking calcium or vitamin D supplements and had relatively low dietary calcium intake. He had a recent decrease in mobility and reduced fluid intake due to weakness and back pain in the past 6 months. On presentation, his corrected calcium was 16 mg/dL (8.8-10.2) with suppressed intact PTH of 10.4 pg/mL (16-77) and elevated uric acid at 9.0 mg/dL (2.7-7.3). Further evaluation revealed vitamin D25-OH was 28 ng/mL (30-100), PTH-rp was 21 pg/mL (14-27), and calcitriol was 49 pg/mL (18-72). Due to high normal ranges of PTH-rp and calcitriol, the differential included malignancy and sarcoidosis as possible drivers of hypercalcemia. Serum and urine protein electrophoreses showed no evidence for myeloma, and CT scans of the head, chest, abdomen and pelvis did not reveal malignancy but noted extensive arthropathy with soft tissue masses in the lumbar spine. Skeletal metastatic series showed erosive changes of the axial and appendicular skeleton consistent with inflammatory arthropathy. Two sets of biopsies performed of the L5 right pedicle mass revealed findings consistent with gouty tophus with some granulomas noted at the periphery. Serum CTx measurements were 2403 and 2802 pg/mL (87-345) on consecutive days indicating high bone turnover. Due to reduced renal function at the time, he was given 60 mg denosumab subcutaneously to treat his hypercalcemia. As his gout appeared to be the driver of his hypercalcemia, rheumatology was consulted and recommended uricase infusions for treatment. He had subsequent improvement of his corrected calcium to 10.8 mg/dL on the day of discharge. His calcium and uric acid later normalized and he experienced resolution of his gouty tophi with chronic uricase infusions, later transitioned to maintenance allopurinol. He has yet to receive other anti-resorptive treatments after the single dose of denosumab, now 3 years post treatment. Conclusion: Inappropriately high normal calcitriol in PTH-independent hypercalcemia should raise suspicion for granulomatous lesions or lymphoma facilitating extra-renal vitamin D conversion. In this case hypercalcemia appeared due to severe gouty arthropathy that resolved after treatment with uricase. It is likely that inflammation and granulomatous changes at the tophus-bone interface stimulated osteoclast activity and calcitriol production resulting in hypercalcemia.

Presentation: 6/2/2024
6859 Recurrent Hypercalcemia Due to Prolonged Immobilization After a Profound Vascular Event
Authors: Azocar Villalobos Jorge L , Godasi Bramara , Duro Teodor , Lovato Christina
Published: October 2024

Disclosure: J.L. Azocar Villalobos: None. B. Godasi: None. T. Duro: None. C. Lovato: None.

Background: Hypercalcemia from immobility is rare, typically seen in young men with spinal cord injuries, but it has also been reported in elderly patients with co-morbidities after sustaining a vascular event. The condition is characterized by increased bone resorption after skeletal unloading, which leads to hypercalcemia and decreased levels of parathyroid hormone and 1,25(OH)2 vitamin D. This, in turn, results in decreased bone formation and a significant renal calcium leak. Clinical Case: A 56-year-old woman with a history of cirrhosis due to alcohol abuse and hypertension was admitted after sustaining a left middle cerebral artery infarction, which was complicated by cerebral edema with brain compression and herniation that resulted in profound neurologic deficits. The patient underwent craniotomy, subdural evacuation, and partial temporal lobectomy. During the course of her hospitalization, she developed recurrent episodes of hypercalcemia. The first episode occurred about 6 weeks after her admission. Serum calcium, corrected for albumin, was as high as 16.2 mg/dL (n 8.4-10.4 mg/dL) and PTH <6 pg/mL (n 18-84 pg/mL). The patient was given IV fluids and calcitonin subcutaneously for 48 hours. She also required continuous renal replacement therapy for 3 days due to oliguria. Another episode occurred 2 months later and was managed with IV fluids, calcitonin for 48 hours, and 4 mg IV zoledronic acid. The patient developed hypercalcemia again 4 months later, which required another dose of 4 mg IV zoledronic acid and IV fluids. The patient remained normocalcemic for the following 3 months until she was transferred to a long-term care facility. Additional workup excluded other causes, including hypercalcemia of malignancy with PTHrp <2.0, normal calcitriol, SPEP, UPEP and kappa lambda ratio, and negative CT scans. The diagnosis of hypercalcemia due to immobilization was confirmed by her history. Supporting lab work revealed marked bone resorption with a c-telopeptide 3,277 pg/mL (n 177-1015 pg/mL postmenopausal female). Bone-specific alkaline phosphatase was 22.6 ug/L (7.0-22.4 ug/L postmenopausal female). Clinical Lessons: The diagnosis of hypercalcemia due to immobilization should include patient history, supporting lab work, and must exclude other causes. Skeletal loading is the preferred treatment. However, as this case illustrates, other treatment modalities must be pursued if skeletal loading is not feasible and there is persistent hypercalcemia.

Presentation: 6/2/2024
6396 Recurrent hyperparathyroidism due to parathyromatosis
Authors: Valenciaga A , Rayan M N , Ing S W
Published: October 2024

Disclosure: A. Valenciaga: None. M.N. Rayan: None. S.W. Ing: None.

Background: Parathyromatosis is a rare cause of hyperparathyroidism. It refers to numerous parathyroid tissue foci within the neck and mediastinum, arising from the expansion of embryologic parathyroid tissue or due to the dissemination of parathyroid cells during surgical resection of abnormal parathyroid glands. Here, we describe the case of a patient who underwent multiple medical and surgical interventions to manage recurrent hyperparathyroidism secondary to parathyromatosis. Clinical Case: A 28-year-old male with no significant past medical or family history presented to the ED in 2012 after experiencing malaise for months and a syncopal episode. Labs showed serum calcium (Ca) of 18.1 mg/dL and parathyroid hormone (PTH) of 1199 pg/mL. Sestamibi scan was non-localizing, but ultrasound and CT scan identified a 1.5 cm nodule posterior to the right thyroid lobe, concerning for a parathyroid adenoma. He underwent surgical excision of this nodule which revealed benign parathyroid tissue on final pathology. He felt well for a few years, but symptoms recurred in 2017 with hypercalcemia, elevated PTH, and nephrolithiasis. Sestamibi scan was again non-localizing. He underwent a more extensive neck surgery where the right thyroid and a left central neck soft tissue specimen showed atypical parathyroid tissue on final pathology, favoring the diagnosis of parathyromatosis. He underwent a third surgery in 2019 after symptoms recurred, with more hypercellular parathyroid tissue identified in the neck. He remained asymptomatic again until 2021, when his Ca rose to 18.2 mg/dL with PTH of 2159 pg/mL while Sestamibi showed uptake in the left thyroid. He then underwent a fourth, very extensive neck surgery. Pathology revealed at least 36 nodules of parathyroid tissue embedded in skeletal muscle and fibroadipose tissue. No significant cytological atypia was found favoring a diagnosis of parathyromatosis rather than a carcinoma. Post-op PTH improved to 667 pg/mL and calcium levels dropped to 6.2 mg/dL. PTH dropped to 132 pg/mL later that year. A few months later, his levels started to rise, with Ca peaking at 13.3 mg/dL and PTH at 1260 pg/mL in 2023. Sestamibi scan was non-localizing. He had taken cinacalcet but was dose-limited due to nausea. Zometa was also given without good response. We then initiated monthly denosumab 120 mg with improvement in Ca and PTH levels. Conclusions: This is a rare and challenging case, both to diagnose and treat. Due to the scarcity of cases, there are no well-defined clinical guidelines for diagnosis and management. While a great tool, Sestamibi scans in his case have been negative or not completely inclusive of foci that were later found in surgical pathology. Surgery is a key part of management, but patients may not achieve permanent remission, making medical therapy also essential in controlling Ca and PTH levels, and a multidisciplinary approach key in management of these cases.

Presentation: 6/2/2024
6633 Romosozumab Use in a Patient With Osteogenesis Imperfecta Type 3
Authors: Kumar Babu Vedesh , Phatak Sonal
Published: October 2024

Disclosure: V.K. Babu: None. S. Phatak: None.

Introduction: Osteogenesis Imperfecta (OI) is a rare genetic condition with qualitative and/or quantitative abnormalities in type 1 collagen. Its estimated prevalence ranges from 10,000 - 20,000 live births. Fractures are a hallmark feature of this condition. Biphosphosphonates have been widely studied in this patient population. Parathyroid Hormone (PTH) Analogues have also been used. Data from Sclerostin inhibitors is sparse and data from Denosumab is limited to children and pre-menopausal women. We present a post-menopausal female with Osteogenesis Imperfecta Type 3 who failed therapy with oral bisphosphonates, intravenous bisphosphonates, and eventually responded to Romosozumab followed by Denosumab. Clinical Case: This is a post-menopausal female with Osteogenesis Imperfecta Type 3 diagnosed at the age of 20 years. She has no similar family history, denied hearing issues, and reached menopause at 46 years of age. She received a combination of Alendronate, Risedronate and Zoledronic acid from 2004 (44 years old) to 2019 with the last dose of Zoledronic acid 5 mg in September 2019. She sustained multiple fragility fractures throughout that period, with the last one being a pelvis fracture in 2020. Her Serum PTH, Vitamin D, Albumin adjusted Calcium, Serum Phosphorus, Serum Protein Electrophoresis, and Celiac Panel were unremarkable. She was offered the option of continuing with bisphosphonate therapy, or switching to Romosozumab, PTH analogues, or Denosumab. She declined PTH analogues due to need for daily administration. The Sclerostin inhibitor (Scl-Ab), Romosozumab was started on July, 2021 for a duration of 12 months and switched to Denosumab, which is her current therapy. Her Bone Mineral Density (BMD) on Dual Energy Absorptiometry one year following the completion of Romosozumab therapy showed an increase at the Antero-Posterior Lumbar Spine of 20.7%, Left Femoral Neck of 35.0%, and Left Total Hip of 16.2% compared to two years prior with no reported fragility fractures since. Conclusion: Bisphosphonate therapy has been well-studied in patients with OI, especially type 1. Data on patients with OI type 3 is scarce. Our patient continued to sustain fractures despite therapy with oral and intravenous bisphosphonates prompting us to use Romosozumab, off-label. One case has been reported of Romosozumab use in a 65 year old man with OI type 1, with drastic (more than 20%) improvements noted in spine and hip BMD. Our patient with type 3 OI had comparable improvements in BMD with no fractures sustained since. In mouse models of OI, Scl-Ab improved the density, biomechanical strength, and osteoblastic apposition of long bones. A clinical trial with another Scl-Ab, Sertrusumab, for patients with OI types 1, 3, and 4 has been performed and results are awaited. Romosozumab can be considered off-label for patients with OI type 3 not responding to Bisphosphonate and/or PTH analogue therapy.

Presentation: 6/2/2024
6500 Screening Rates in Emerging Adults With Cystic Fibrosis for Cystic Fibrosis-Related Bone Disease: A Retrospective Cohort Study
Authors: Cobb Crystal , Stecenko Arlene , Hunt William R , Linnemann Rachel , Daley Tanicia , Tangpricha Vin
Published: October 2024

Disclosure: C. Cobb: None. A. Stecenko: None. W.R. Hunt: None. R. Linnemann: None. T. Daley: None. V. Tangpricha: None.

INTRODUCTION Cystic fibrosis bone disease (CFBD) is a common endocrinopathy in patients with cystic fibrosis (CF). Poor bone health is associated with increased risk of fractures, potentially leading to decreased pulmonary function and worse health outcomes. The transition period from adolescent to adult care is a particularly vulnerable period in terms of bone health. It is recommended that patients with CF have bone density screening starting at age 18 and every 1-2 years. The purpose of this study was to examine the frequency of bone density screening in adolescents and young adults with CF followed at a single accredited CF center. Methods This was a retrospective chart review of patients with CF between ages 18 and 30 who had transitioned to adult care between 2013 and 2023 at our CF clinic. Frequency of bone density screening was assessed by completion of dual-energy x-ray absorptiometry (DXA) and included the last pediatric Z-scores, if available, and adult Z-scores up to 10 years after transition. Height adjusted Z-scores were used when appropriate for pediatric values. Transplant patients and patients who did not attend at least one year of adult clinic were excluded. Results Ninety-five patients were identified. Seven patients did not have documentation of a DXA scan, while 88 had at least one DXA scan as emerging adults. Ten out of 88 adults received a repeat DXA within 2 years of their prior scan. 42 out of 88 (48%) of patients were at risk for CFBD with at least one Z-score ≤ -1. Of these at risk patients only 5 got a repeat DXA within two years. None of the patients undertook routine DXA exams consistently every 2 years regardless of risk. CONCLUSION Our study suggests that emerging adults with CF and decreased bone mineral density are being under screened for progression of CFBD. Evaluating the barriers to bone density screening will be important to optimize bone health and improve outcomes. In the era of CFTR modulator therapies, more attention to bone health is required especially with the increased life expectancy of people living with CF. Strategies focused on increased bone density screening, promotion of healthy lifestyle, optimizing nutritional status, and addressing hypogonadism appear to be critical in this transition period for young adults with CF.

Presentation: 6/3/2024
8224 Vitamin D Supplementation for Healthy Elderly People and the Incidence of Fracture: A Systematic Review and Meta-Analysis
Authors: de Souza M d , Moraes Dantas R L , Duraes V L , Renganathan G , Mendes T B
Published: October 2024

Disclosure: M.D. de Souza: None. R.L. Moraes Dantas: None. V.L. Duraes: None. G. Renganathan: None. T.B. Mendes: None.

Background: The impact of vitamin D supplementation on the incidence of fracture in healthy elderly individuals remains uncertain. Objectives: We performed a systematic review and meta-analysis of studies investigating the incidence of fracture in healthy elderly patients with supplementation of vitamin D at doses exceeding 800 IU per day in comparison to placebo. Methods: We systematically searched PubMed, Embase and Cochrane Central Register of Controlled Trials in November 2023 with the main following search terms: ‘Vitamin D’, ‘supplementation’, ‘elderly’, ‘fracture’ and ‘randomized trial’. The initial search revealed 2,160 articles that were screened and assessed according to inclusion and exclusion criteria. Risk ratio (RR) and Hazard ratio (HR) with 95% confidence intervals were used to compare treatment effects for categorical endpoints. Heterogeneity was evaluated with Cochran Q test and I2 statistics; p values inferior to 0.10 and I2>25% were considered significant for heterogeneity. Results: A total of seven randomized controlled trials with 71,899 patients were included, of whom 36,822 (51.2%) were women. A total of 25,916 (78.2%) participants received a daily dose of vitamin D higher than 1,500 UI. The incidence of total fractures was not significantly different between participants who received vitamin D or placebo (RR 1.01; 95% CI 0.81-1.09; p=0.92; I2=57%) / HR 1.03; 95% CI 0.97-1.27; p=0.5; I2=45%). There was no difference in regards vitamin D dosage analysis (< 1500 UI/day RR 1.06; 95% CI 0.81-1.39; p=0.67; I2=82%/ ≥ 1500 UI/day RR 0.97; 95% CI 0.90-1.04; p=0.38; I2=0%).There was a significant 34% relative risk increase of hip fractures among women treated with vitamin D compared to placebo (121 events in 14033 participants) (RR 1.34; 95% CI 1.06-1.70; p=0.01; I2=0%). In the subgroup of men, there was no significant difference in hip fractures with supplementation of vitamin D compared to placebo (RR 0.86; 95% CI 0.65-1.13; p=0.28; I2=0%) / HR 0.87; 95% CI 0.65-1.18; p=0.37; I2=0%). Conclusion: In this meta-analysis of 71,899 healthy elderly individuals, the supplementation of vitamin D significantly increased the risk of hip fractures compared to placebo among women.

Presentation: 6/2/2024
9305 Circulating MicroRNA-based Biomarker Combinations for Differentiating Uni- and Bilateral Primary Aldosteronism Using a Machine Learning Approach
Authors: Vekony Balint , Nyiro Gabor , Herold Zoltan , Fekete Janos , Ceccato Filippo , Gruber Sven , Kurzinger Lydia , Parasiliti-Caprino Mirko , Szeredas Balint , Nazri Siti Khadijah Syed Mohammed , Fell Vanessa , Bassiony Mohamed , Azizan Elena A B , Bancos Irina , Beuschlein Felix , Igaz Peter
Published: October 2024

Disclosure: B. Vekony: None. G. Nyiro: None. Z. Herold: None. J. Fekete: None. F. Ceccato: None. S. Gruber: None. L. Kurzinger: None. M. Parasiliti-Caprino: None. B. Szeredas: None. S. Syed Mohammed Nazri: None. V. Fell: None. M. Bassiony: None. E.A. Azizan: None. I. Bancos: None. F. Beuschlein: None. P. Igaz: None.

Background: The differentiation of uni- and bilateral forms of primary aldosteronism (PA) is of pivotal clinical relevance. Whereas unilateral PA warrants surgical treatment, bilateral PA is treated by aldosterone antagonists. The most reliable way to differentiate these two entities is adrenal venous sampling (AVS) that is an invasive method with limited availability and requiring great expertise. Aim: To develop a circulating blood-borne microRNA-based approach using machine learning for the differentiation of uni- and bilateral PA. Methods: Circulating microRNA profiling on an Illumina MiSeq platform was performed on total RNA samples isolated from EDTA-anticoagulated blood specimens taken by AVS from 18 pairs of right and left suprarenal veins (10 uni-, 8 bilateral PA). Significantly differentially expressed microRNAs were analyzed by a neural network (90-10% learner-tester cross-validation simulation). From the top 29 significantly differentially expressed microRNAs, 9 were selected for validation by Taqman RT-qPCR on a separate cohort of 30 AVS-confirmed samples (15-15 uni- and bilateral forms) both on plasma samples from adrenal as well as from peripheral veins. The method was finally tested on another independent cohort of peripheral blood samples from 80 patients (40 uni- and 40 bilateral PA). Results: Regarding the 9 microRNAs selected for validation, microRNA abundance was non-significantly lower in peripheral samples compared to AVS samples. By analyzing peripheral plasma samples, ten combinations of 4-8 microRNAs from the pool of 9 microRNAs turned out to have maximal sensitivity and specificity values over 85 %. The best combination included 6 microRNAs with a sensitivity of 86.3 % and a specificity of 87.91 % (AUC = 0.871). The inclusion of further parameters such as imaging, potassium and renin levels did not improve the model’s performance. Conclusion: The analysis of circulating blood-borne microRNAs represents a minimally invasive and potentially reliable way of differentiating uni- and bilateral PA. If bilateral PA is confirmed by the model, no more localization efforts would be necessary thus simplifying the management of PA patients. This would be relevant both from the patient’s and a public health perspective.

Presentation: 6/3/2024
9169 Evaluation Of Screening Practices For Primary Aldosteronism In Patients With Treatment Resistant Hypertension
Authors: Markovic N , Brankovic M , Smith A P , Mittal A , Matassa D
Published: October 2024

Disclosure: N. Markovic: None. M. Brankovic: None. A.P. Smith: None. A. Mittal: None. D. Matassa: None.

Background: Despite the recognized high prevalence of primary aldosteronism (PA) in patients with treatment resistant hypertension (TRH), PA remains underdiagnosed. Our aim was to investigate the appliance of screening recommendations for secondary causes of TRH in the largest inner-city population in New Jersey. Method: The retrospective chart review analysis included all patients with TRH evaluated in the internal medicine clinic from July 2020 to July 2021. Initial patient charts were obtained based on the number of antihypertensive medications used for treatment. All patients on 3 or more antihypertensives, including one diuretic, were evaluated. Subsequently of 242 charts evaluated, 102 were excluded due to either patient noncompliance with medications or being controlled on 3 antihypertensive medications including diuretic. All patients who did not have BP at goal (>140/90 mmHg) while on 3 antihypertensives or BP at goal while on 4 antihypertensives were included in the study. Result: Of 140 patient charts included, 66.4 % were female and 33.6% male. Most of our population based on race and ethnicity were African American (66.8%) and Latin American (14.3%), Asian and White represented 2.1% and 1.4%, respectively, and 13.6% declared themselves as other. In patients with TRH microalbumin/creatinine ratio was checked in 95.7%, CMP in all patients, HbA1C in 98.6%, TSH in 93.6%, PTH in 29.3% and uric acid in 28.6%. Plasma renin was ordered by providers in 32 patients (22.9%) and plasma aldosterone in 33 patients (23.6%) out of which plasma aldosterone to plasma renin ratio was completed in 10.7% of patients at least one time, 5.7% two times and 2.9% three or more times. Renal artery ultrasound was completed in 17.1% out of which 0.7% (1 patient) was found to have renal artery stenosis. CT abdomen/pelvis was performed in almost half of our patients (49.3%) and majority (92.9%) had ophthalmology referral. There were no differences in the screening for PA based on patient race, ethnicity, and insurance. Conclusion: This data shows that in patients with TRH only less than one third had appropriate work-up ordered that included plasma aldosterone to plasma renin ratio with an even smaller percentage of patients completing the test. Our next step is to increase the number of charts reviewed and to develop tools that will be available in the clinical settings to increase the frequency of screening for PA in patients with TRH.

Presentation: 6/1/2024
7974 Expression of C-X-C Motif Chemokine Receptor 4 (CXCR4) in Aldosterone-Producing Adenomas and Adjacent Non-Functional Adenomas
Authors: Wu Chun-Yi , Nanba Kazutaka , Blinder Amy , Luther James M , Turcu Adina , Giordano Thomas J , Udager Aaron , Rainey William E
Published: October 2024

Disclosure: C. Wu: None. K. Nanba: Grant Recipient; Self; AstraZeneca. A. Blinder: None. J.M. Luther: None. A. Turcu: None. T.J. Giordano: None. A. Udager: None. W.E. Rainey: None.

Background: Primary aldosteronism (PA) is the leading cause of endocrine hypertension, and when unilateral, it can be cured with adrenalectomy. Subtyping into unilateral or bilateral disease can be costly, invasive and clinically challenging. Aldosterone-producing adenoma (APA)-targeted positron emission tomography/computed tomography (PET/CT) has emerged as a potential non-invasive imaging technique that could circumvent the need for adrenal venous sampling (AVS) for subtype determination. Radiolabeled probes have been developed that bind the enzyme aldosterone synthase (CYP11B2) and chemokine receptor 4 (CXCR4). However, the expression of CXCR4 in APA and non-functional adenomas (NFA) has not been extensively studied. Objective: To evaluate the differential expression of CXCR4 in APA versus NFA, thereby assessing its utility as a reliable biomarker in PET/CT imaging for PA subtyping. Methods: A cohort of twenty-one patients with PA who underwent unilateral adrenalectomy and were found to have an APA and an adjacent NFA were included in this study. Formalin-fixed, paraffin-embedded (FFPE) sections of resected adrenal tissue were used for the analysis. Aldosterone synthase (CYP11B2) immunohistochemistry (IHC) was performed to identify APA (CYP11B2-positive) and NFA (CYP11B2-negative). APA and NFA RNA was isolated followed by quantitative RT-PCR (qPCR) for ACTB (β-actin), CYP11B2, and CXCR4. Results: Compared to the adjacent NFA, APA expressed 1108 ±370-fold more CYP11B2 (P=0.007). For CXCR4 the average fold increase of APA relative to the adjacent NFA was 2.41 ±0.72 (P=0.059). Not only did APA CXCR4 mRNA expression not reach statistical significance compared to NFA, 8 of 21 patients had higher CXCR4 transcript levels in the adjacent NFA than in APA. Conclusions: Our findings confirm CYP11B2 expression as a robust and specific APA marker with low levels observed in NFA. The transcript analysis of CXCR4, however, questions its utility as a selective marker for APA over NFA. Additional studies are needed to examine the CXCR4 protein expression in APA versus other adrenal tumors to ensure specificity of CXCR4 as an APA marker in PET/CT imaging modalities.

Presentation: 6/3/2024
7042 From NAFLD to MASLD: Assessing the Impact of Changing the Definition of Fatty Liver Disease
Authors: McPhaul M J , Louie J Z , Shiffman D , Bril F
Published: October 2024

Disclosure: M.J. McPhaul: Consulting Fee; Self; Quest Diagnostics. J.Z. Louie: Employee; Self; Quest Diagnostics. D. Shiffman: Consulting Fee; Self; Quest Diagnostics. F. Bril: None.

Nonalcoholic fatty liver disease (NAFLD) has been renamed metabolic dysfunction-associated steatotic liver disease (MASLD), and its definition has also been updated to include the presence of at least one cardiometabolic (CM) risk factor. The aim of this study was to assess the demographic and biochemical characteristics of patients with NAFLD, who do not meet criteria for MASLD, and to assess the effect of cumulative number of CM risk factors on liver disease severity. Methods: The study population included 33,674 participants in the 2020 annual wellness program of a nation-wide employer that included laboratory tests and anthropometric measurements, after excluding those with incomplete data and BMI <18.5 kg/m2. Hepatic steatosis was defined as intact insulin (II)*ALT ≥290 (Bril et al, JCEM 2021). CM risk factors were defined according to MASLD definition. Differences between groups were assessed using t-tests or Chi-square tests. The association between number of CM risk factors and hepatic steatosis was assessed by a trend test. Association with II, AST, and ALT was assessed by linear regression models. Results: A total of 7,059 (27%) participants had hepatic steatosis. However, 61 (1%) of these participants did not have any CM risk factors, and thus had NAFLD, but not MASLD. Compared with participants with no steatosis, they were younger (-8 [95% CI: -10 to -5] years), had a lower fraction of women (54 vs. 67%, p=0.04), higher fraction of Hispanic patients (28 vs. 13%, p=0.0007). Despite absence of CM risk factors, 39% were insulin resistant (II>10.5 uIU/mL). This group of patients with no CM risk factors had plasma AST and ALT levels that were higher than MASLD patients (p <0.002). Among patients with hepatic steatosis and only 1 CM risk factor, the most common CM risk factors were overweight, obesity, or increased waist circumference. Less than 15% had any glucose, lipid, or BP abnormality. Higher number of CM risk factors was associated with a higher prevalence of hepatic steatosis (p<0.0001). Among patients with MASLD, higher number of CM risk factors was associated with higher levels of II (p<0.0001), but not with higher AST or ALT (both p>0.15). Conclusion: Changes in NAFLD definition resulted in a new subgroup of patients that were previously defined as NAFLD, but do not have MASLD. Our results showed that this group of patients are likely to have insulin resistance and may be at risk of liver fibrosis, despite their lack of CM risk factors.

Presentation: 6/2/2024
8562 Mineralocorticoid Receptor Antagonist Do Not Prevent Primary Aldosteronism Subtyping by Adrenal Vein Sampling
Authors: Pintus Giovanni , Seccia Teresa M , Rossitto Giacomo , Caroccia Brasilina , Ceolotto Giulio , Lenzini Livia , Rossi Gian Paolo
Published: October 2024

Disclosure: G. Pintus: None. T.M. Seccia: None. G. Rossitto: None. B. Caroccia: None. G. Ceolotto: None. L. Lenzini: None. G. Rossi: None.

Background. Current guidelines suggest withdrawal of mineralocorticoid receptor antagonists (MRA) before subtyping primary aldosteronism (PA) by adrenal venous sampling (AVS), but this practice can cause severe hypokalemia and/or uncontrolled high blood pressure (BP) values. Aims. To investigate the feasibility of unilateral PA (uPA) identification by AVS in patients on MRA treatment. Methods. We compared the rate of uPA identification between patients with and without MRA treatment, using two large datasets of patients who were submitted to AVS from 2000 to 2023 in absence of interfering drugs. The rate of uPA identification was also compared between patients with suppressed renin levels (DRC < 2 mUI/L) and unsuppressed renin levels (DRC > 2 mUI/L or DRC > 8.2 mUI/L). Results. Compared to non-MRA PA patients (n = 779), those with MRA (n = 61) showed a higher daily drug dose (2.25 vs 1.5, p = 0.001), a higher rate of adrenal nodules at imaging (82 vs 67, p = 0.022) and of adrenalectomy (72 vs 54%, p = 0.01). The AUROC of lateralization index (LI) did not show significant differences between groups, neither under unstimulated conditions (0.960 vs 0.937, p = 0.590) nor after cosyntropin (0.923 vs 0.917, p = 0.938). Sensitivity analyses confirmed these results 1) after propensity score matching in several adjusted models and 2) in patients with undetectable, suppressed or unsuppressed renin levels. Conclusions. MRAs, at doses that controlled blood pressure and potassium levels in PA patients, did not preclude the identification of uPA at AVS. Moreover, unsuppressed renin levels were not associated with lower rate of uPA identification.

Presentation: 6/3/2024
9307 Significance of Assessing QTc Interval in Chronic Hypoparathyroidism and its Clinical and Biochemical Correlates
Authors: Namjoshi Preeti Vijay , Saha Soma , Sharma Vibhav , Goswami Ravinder , Narang Rajiv , Mani Kalaivani
Published: October 2024

Disclosure: P.V. Namjoshi: None. S. Saha: None. V. Sharma: None. R. Goswami: None. R. Narang: None. K. Mani: None.

Background: Patients with chronic hypoparathyroidism (cHypoPT) and hypocalcemia are at risk of QTc prolongation and life-threatening arrhythmias. Information on clinical and biochemical correlates of QTc in cHypoPT is limited. Design: Observational study in cHypoPT cohort, tertiary-care-center.Materials and methods: Eighty-eight nonsurgical cHypoPT patients (age 44.1±15.4 years, 45 males) were assessed for QTc interval and its possible correlates including arrhythmic symptoms (palpitations/giddiness/syncope), and serum total calcium, phosphorus, 25(OH)D, and iPTH. Results: The mean QTc was 428±34 ms and showed a significant inverse correlation with serum total calcium measured on the same day (r=-0.43, p<0.001). 13.6% of cHypoPT had prolonged QTc. The mean serum total calcium (7.05±1.94 vs. 8.49±1.01 mg/dL, p=0.02) was significantly lower in patients with prolonged QTc. Patients with arrhythmic symptoms had significantly higher mean QTc (p=0.02) and tended to have lower average serum total calcium during follow-up (p=0.06). Multivariable regression showed female gender, higher current age, BMI, and low serum calcium as the significant independent determinants of QTc. For every mg/dL decrease in serum total calcium, QTc increased by 13 ms. Receiver operating characteristic (ROC) analysis revealed serum total calcium at cut-off 8.27 mg/dL discriminated prolonged QTc with area-under-curve being 0.72 [95% CI: 0.51, 0.93]. Conclusion: cHypoPT patients have an increased risk of QTc prolongation which was associated with arrhythmic symptoms, female sex, higher age, BMI, and low serum total calcium. ROC analysis indicated maintaining serum total calcium level of at least 8.27 mg/dL to minimize the risk of prolonged QTc. The study indicates the need for close monitoring of arrhythmic symptoms as well as ECG in cHypoPT patients.

Presentation: 6/2/2024
7722 Temporal mineralocorticoid receptor activation regulates the molecular clock and transcription of cardiovascular disease modulators in myeloid cells
Authors: Young M J , Heanue S , Kanki M , Ray D W , Morgan J , Cole T J
Published: October 2024

Disclosure: M.J. Young: None. S. Heanue: None. M. Kanki: None. D.W. Ray: None. J. Morgan: None. T.J. Cole: None.

The mineralocorticoid receptor (MR) is an established target in the treatment of heart failure, as a mediator of cardiac inflammation and fibrosis. We recently identified a bidirectional regulatory role for the MR and the peripheral molecular clock in cardiac cells. We have also demonstrated a novel role for the MR in macrophages/monocytes in the progression of cardiac inflammation and fibrosis. Given that immune cells are implicated in cardiac pathology, we investigated whether the MR modulates temporal transcription of the molecular circadian clock and inflammatory mediators in the spleen from myeloid MR null mice (MyMRKO), and in immortalised bone marrow derived cells (BMDCs) RNAseq and RT-qPCR analysis of whole spleen from wild type (WT) or MyMRKO revealed differential expression of the clock genes Per2, Cry1, REV-ERBα, and Dbp predominantly at ZT0 and ZT4 compared to ZT12 and ZT16. 10nM aldosterone or corticosterone modulated the 24hr pattern of expression of Per2, REV-ERBα and other clock components in cultured BMDCs, supporting a direct role of MR in timekeeping. MR modulation of genes involved in the proinflammatory response in macrophages such as iNOS, IL-1β, Arg-1, IL-10, CCL2 and Spp1 was more evident at the start of the ‘lights on’ phase in mice, suggesting that low circulating corticosterone at these times allows for a more dominant MR response as a result of preferential binding. Genes related to PPARγ signalling, a key pathway in the development of cardiovascular disease, also demonstrated MR-dependent regulation in a temporal manner. Significant differences in temporal MR modulation were evident between males and females, implying a role for sex hormones in the modulation of circadian signalling and myeloid inflammatory responses in the context of MR-regulated transcription. Our findings underscore the dynamic influence of MR signalling on circadian rhythms and inflammatory pathways in myeloid cells, highlighting potential sex-based differences and offering insights into its pivotal role in cardiovascular disease pathogenesis.

Presentation: 6/3/2024
12517 The Condition Of The Heart And Myocardial Changes In Patients With Type 2 Diabetes
Authors: Alieva Anna , Li Victoria
Published: October 2024

Disclosure: A. Alieva: None. V. Li: None.

Relevance: Type 2 diabetes is associated with serious complications, including cardiovascular diseases, among which is diabetic autonomic cardiomyopathy (DAC), significantly increasing the risk of heart failure and cardiovascular mortality. The mechanisms of myocardial changes in type 2 diabetes (T2D) are not fully understood, which limits the possibilities for prevention and treatment of DAC in such patients. A deeper understanding of myocardial changes in type 2 diabetes may help improve the prognosis and treatment outcomes in patients with this condition. Research objective: To study the condition of the heart muscle in patients with T2D without concomitant arterial hypertension and signs of DAC. Materials and methods: Evaluation of the thickness of the interventricular septum (IVS) and the posterior wall of the left ventricle (PWLV) based on echocardiography examination of the heart. Results: Two groups of 5 patients each were examined. Diabetes duration of more than 5 years, without concomitant arterial hypertension (AH), without significant changes on the electrocardiogram, without complaints from the cardiovascular system, aged 35-42 years. In the first group, glycated hemoglobin ≤ 8.5%, no significant myocardial changes were observed on echocardiography; in the second group with uncontrolled T2D, hypertrophy of the IVS and PWLV was detected. Also, a disturbance of the diastolic function of the left ventricle, directly proportional to the duration of T2D in the group with uncontrolled glycemia, was noted. Conclusions: Analysis of the data obtained shows that an elevated level of glucose in the blood, regardless of the presence of AH, leads to myocardial hypertrophy and remodeling.

Presentation: 6/2/2024