bluuebunny/crossref_metadata_2025 huggingface dataset:
8136 Using High-Resolution Peripheral Quantitative Computed Tomography to Assess Bone Microarchitecture and Guide Osteoporosis Treatment
Authors: Rupani Sawan V , Sfeir Jad , Graeff-Armas Laura
Published: October 2024

Disclosure: S.V. Rupani: None. J. Sfeir: None. L. Graeff-Armas: None.

Bone microarchitecture is an important factor that impacts bone strength. Unlike other factors that affect bone strength, such as bone mineral density and bone turnover, assessment of bone microarchitecture is not yet widely accessible in clinical practice. Computed tomography is the primary method of non-invasively assessing bone microarchitecture. High-resolution peripheral quantitative CT (HR-pQCT) is an emerging imaging modality that provides a three-dimensional assessment of bone densitometry, morphometry, and microarchitecture with a low effective radiation dose. It provides a quantitative and qualitative assessment of cortical and trabecular structural and mechanical properties. We present two similar cases of osteoporosis in males, where knowledge of bone microarchitecture through HR-pQCT helped formulate two distinct and targeted therapeutic approaches. The first case is of a 46-year-old male with a history of idiopathic osteoporosis with multiple nontraumatic vertebral fractures. Given his presentation and age, anabolic therapy such as teriparatide was being considered. He underwent HR-pQCT scanning, which showed average radial trabecular parameters, but his cortical porosity was significantly above average, with similar findings in his tibial parameters. Since teriparatide has been shown to increase cortical porosity, this would not be the best option for our patient, given the risk of further weakening of the microarchitecture of his cortical bone. Therefore, denosumab, which has been shown to decrease cortical porosity, was chosen. Our second patient is a 52-year-old male with idiopathic osteoporosis with multiple nontraumatic vertebral fractures, whose HR-pQCT showed average cortical parameters at both the radius and tibia but low trabecular number and increased trabecular separation at both sites. Since teriparatide increases trabecular thickness and mass, we could confidently choose teriparatide for this patient, with less concern for significant deleterious effects on his cortical bone parameters. These case reports highlight the impact that the assessment of qualitative properties of bone, such as microarchitecture, can have in the management of osteoporosis. Currently, the lack of sufficient validated normative data for HR-pQCT limits its widespread use in the diagnosis of osteoporosis and fracture prediction. However, given that HR-pQCT can characterize the properties of trabecular and cortical bone, it may have a role in helping guide osteoporosis treatment, especially in challenging and atypical cases.

Presentation: 6/3/2024
6724 A Broken Heart Due to Excess Thyroid
Authors: Subramani Rashmi , Subramani Raaghul , Zeykan Violeta
Published: October 2024

Disclosure: R. Subramani: None. R. Subramani: None. V. Zeykan: None.

Introduction: Tachycardia-induced cardiomyopathy related to thyrotoxicosis is an uncommon yet serious complication affecting fewer than 1% of individuals with hyperthyroidism. Restoring a euthyroid state can potentially reverse the abnormal cardiac structure and function. Here we report a case of tachycardia-induced cardiomyopathy secondary to thyrotoxicosis Case Summary: A 52-year-old woman with a history of hypertension presented with recent-onset exertional dyspnea, a nonproductive cough, and paroxysmal nocturnal dyspnea. On examination, she exhibited tachycardia (heart rate: 150/min), tachypnea, hypertension, and was afebrile. Physical findings included a mildly enlarged, firm, non-tender thyroid gland bilaterally, without exophthalmos or tremors. Auscultation revealed bilateral crackles in the left lower lung fields. Laboratory analysis revealed undetectable TSH (<0.02 uIU/mL), elevated free T4 (5.3 ng/dL), free T3 (16.30 pg/mL), thyroid stimulating immunoglobulin (TSI) at 216%, and NT proBNP at 8528 pg/mL. Neck ultrasound and CT confirmed diffuse enlargement of the thyroid gland. Transthoracic echocardiography (TTE) displayed severely depressed left ventricular systolic function, estimating an ejection fraction (EF) of 25-30%. Initial management involved intravenous beta-blockers for heart rate control, IV Lasix, and IV hydrocortisone. Subsequently, the patient received propylthiouracil, propranolol, and prednisone, resulting in symptomatic improvement. A follow-up TTE after 6 months revealed an improved EF of 50%. Discussion: The pathophysiologic mechanisms underlying thyrotoxic cardiomyopathy encompass several factors, including tachycardia-induced cardiomyopathy, direct myopathic effects induced by the T3 hormone, and concurrent autoimmune myocarditis associated with Graves' disease. Thyroid hormone exerts a comprehensive impact on nearly all tissue and organ systems, heightening basal metabolic rate and subsequently increasing preload, myocardial contractility, and cardiac output. While thyrotoxicosis-related congestive heart failure (CHF) is relatively uncommon among patients hospitalized for acute CHF, addressing hyperthyroidism and CHF through definitive treatment yields a more favorable prognosis compared to cases of acute CHF stemming from other etiologies. The intricate interplay of these mechanisms highlights the importance of a comprehensive approach in managing thyrotoxic cardiomyopathy, emphasizing the need for targeted interventions to address both the underlying thyroid dysfunction and associated cardiac manifestations.

Presentation: 6/3/2024
6664 A Case of Undistinguished Congenital Adrenal Hyperplasiain a Patient with Hypertensive Emergency and Hypokalemia
Authors: Signore V L Del , Kaufman S T
Published: October 2024

Disclosure: V.L. Del Signore: None. S.T. Kaufman: None.

CAH is a group of autosomal recessive disorders resulting in alterations of adrenal steroid biosynthesis. With 95% of CAH cases due to 21-hydroxylase deficiency; other causes are rare. The metabolic, phenotypic, and physiologic derangements are specific to the altered enzymatic pathways, most of which are life threatening. Identifying the enzymatic defect is crucial to treat the patient. We present a case of undifferentiated CAH in an adult resulting in significant systemic illness. A 26-year-old well virilized male presented with chief complaint of shortness of breath, lower extremity swelling, and abdominal distension for 3 weeks. He was found to have acute decompensated heart failure with LVEF 20-25%, NSTEMI, atrial fibrillation, hypertensive emergency with BP of 224/102, and potassium (K+) of 2.7 (3.5-5mmol/L). PMH included hypertension and CAH diagnosed at birth. Patient was unsure of his CAH defect. Pediatric endocrinology prescribed glucocorticoids until age 17 at which point he was told steroids were no longer required. He had been lost to follow up for 9 years. Pediatric records were unattainable. Patient remained hypokalemic and hypertensive despite aggressive K+ repletion and multiple IV antihypertensives. Endocrine work up revealed renin 0.19 (0.25- 5.82ng/mL/hr), aldosterone 4 (< or = 21ng/dL), DHEAs 97 (74-617ug/dL), FSH <0.3 (1.4 - 18.1 m[IU]/mL), LH <0.3 (1.5 - 9.3 m[IU]/mL), total testosterone 306 (250-1,100 ng/dL), SHBG 32 (10-50nmol/L), progesterone 7 (0.2-1.4 ng/mL), ACTH 345 (6-50 pg/mL), AM cortisol 4.4 (5-23 ug/dL), 17 hydroxyprogesterone 311 (32-307 ng/dL), androstenedione 1,926 (50-220 ng/dL), 11-deoxycortisol >10,000 (< or = 119 ng/dL). Cosyntropin stimulation test: 30-minute cortisol 11.1 (>18 ug/dL) and 60-minute cortisol 10.4 (>18 ug/dL). Based on clinical and lab findings a diagnosis of 11-beta hydroxylase deficiency was made. Spironolactone was started to counteract the excessive mineralocorticoid effects of deoxycorticosterone and hydrocortisone to decrease ACTH production. With this treatment, patient’s potassium and blood pressure gradually improved. IV antihypertensives were weaned as he transitioned to oral agents. This case demonstrates the importance of understanding and identifying the underlying pathophysiology of CAH to treat patients appropriately. This patient had a mineralocorticoid excess state, but adequate cortisol precursors to prevent adrenal crisis. He requires glucocorticoid therapy to prevent excessive ACTH from driving their BP and metabolic derangements. With appropriate diagnosis of 11-beta hydroxylase deficiency, patient’s excess risk of morbidity and mortality due to the downstream effects of uncontrolled CAH can be minimized.

Presentation: 6/3/2024
8226 A Diagnostic Challenge: Factitious Hypobicarbonatemia in Severe Hypertriglyceridemia
Authors: Rafat Ummara , Azmat Shazia , Siddiqui Mahrukh , Alshantti Raeda , Kircheva Diana , Trendafilova Victoria
Published: October 2024

Disclosure: U. Rafat: None. S. Azmat: None. M. Siddiqui: None. R. Alshantti: None. D. Kircheva: None. V. Trendafilova: None.

Background: Serum CO2 levels measured by a chemistry analyzer usually correlate with calculated bicarbonate levels on an ABG. There are some instances however, when this is not the case. Severe hypertriglyceridemia can cause serum bicarbonate levels to appear falsely low on metabolic panel. Clinical Case: A 48-year-old man was referred to Endocrinology Clinic for evaluation of hypogonadism and severe hypertriglyceridemia. Routine labs revealed a plasma CO2 of 11 mmol/L (20-31). Na was 133 mmol/L (136-145), K was 4.4 mmol/L (3.5-4.7), Chloride was 101 mmol/L (98-109) and anion gap was 25 (8-20) measured using a Siemens Vista enzymatic chemistry analyzer. His triglycerides were > 1100 mg/dL (0-150), above upper detection limits of the analyzer. The patient reported fatigue and mild abdominal pain. He was admitted to the hospital for further evaluation. His lipase was 41 U/L (12-73), lactic acid 1.2 mmol/L (0.50-2.20). ABG showed pH of 7.41, HCO3 of 26.6 mmol/L (22-29), and anion gap of 7 (10-20). The patient was well-appearing with normal vital signs and normal physical exam. He was made NPO and started on pravastatin, fenofibrate and fish oil. Once his triglycerides were < 1000 mg/dL, he was started on a very low-fat, low-carbohydrate diet. The CO2 level on BMP normalized on day 3 of hospitalization, when triglycerides measured 1010 mg/dL. No other treatment was given for the low CO2 levels. It does not appear that other lab indices were significantly affected by the hypertriglyceridemia. Review of Literature: A BMP measures serum total carbon dioxide using a chemistry analyzer using either an enzymatic/spectro-photometric method, or an electrode-based method; an ABG sample calculates plasma bicarbonate with the Henderson-Hasselbach equation, using the pH and partial pressure of pCO2 in the sample. Enzymatic analyzers measure CO2 using spectrophotometry and decrease in light absorbance is proportional to the sample’s CO2 levels. It is postulated that severely high triglycerides can interfere with this reaction and cause spuriously low CO2 levels, a phenomenon called pseudohypobicarbonatemia. One proposed mechanism for interference with the enzymatic assay method is turbidity causing a falsely low measured CO2 level. Verghese et al found that the severity of the CO2 measurement error positively correlates with the severity of triglyceride elevation. Conclusion: Awareness of the phenomenon of hypertriglyceridemia-induced pseudohypobicarbonatemia can prevent misdiagnosis or delays in diagnosis, as well as unwarranted testing and treatment.

Presentation: 6/3/2024
12618 A Rare Case Of Diabetic Ketoacidosis Leading To Severe Hypertriglyceridemia-induced Necrotizing Pancreatitis
Authors: Perez Roman Elizabeth Rhonda , Lopez Rodriguez David A , Ramirez Gorbea Kyrsha , Sanchez Cordero Milaris , Garcia Cruz Yaniris
Published: October 2024

Disclosure: E.R. Perez Roman: None. D.A. Lopez Rodriguez: None. K. Ramirez Gorbea: None. M. Sanchez Cordero: None. Y. Garcia Cruz: None.

Acute pancreatitis is an acute inflammatory process of the pancreas that if left untreated can become complicated resulting in multiple organ damage and a fatal outcome in approximately 10%-40% of patients. There are well-known causes that can lead to pancreatitis such as alcohol, hereditary disorders, cholelithiasis, prior pancreatitis, and medications. Less frequently, it can be related to poorly controlled diabetes mellitus and diabetic ketoacidosis (DKA), given that in a state of low or deprived insulin, there is a breakdown of triglycerides into toxic fatty acids by pancreatic lipases; this lipotoxicity can result in the development of acute pancreatitis. We present a case of a 50-year-old woman with a past medical history of untreated hyperlipidemia and previous pancreatitis who was transferred to our institution with acute epigastric pain radiating to the back, nausea, and persistent vomiting. Upon arrival, blood glucose was 299 mg/dL, HbgA1c of 11.4%, lactic acid of 3.6 mmol/L, hypocalcemia of 6.0 mg/dl, hypoalbuminemia, and elevated pancreatic enzymes, amylase 869 U/L and lipase 2,493 U/L. The lipid panel was remarkable for total cholesterol of 1,085 mg/dL and triglycerides of 4,369mg/dL. Abdominopelvic CT scan confirmed acute pancreatitis with extensive peripancreatic and regional mesenteric edema. This patient was treated with aggressive IV fluid resuscitation and treated for DKA as per protocol. Despite prompt treatment, the patient rapidly deteriorated, developing pulmonary effusions and impending respiratory failure requiring mechanical ventilation. Her hyperglycemia was challenging to control and in the setting of severe hypertriglyceridemia, insulin requirements were higher, as intravenous insulin is useful in patients with concomitant findings, in the absence of plasmapheresis availability. Despite the marked reduction of triglyceride to 978 mg/dL and a decrease in pancreatic enzymes, multiorgan failure developed. Unfortunately, the patient died. Repeated abdominopelvic CT imaging revealed the progression of the disease to necrotizing pancreatitis involving the pancreatic head, uncinate process, and neck of the pancreas with evidence of a small hypodense lesion at the level of the tail of the pancreas. This case emphasizes the importance of prompt recognition of acute pancreatitis secondary to uncontrolled hyperglycemia with concomitant severe hypertriglyceridemia since it can lead to a worse clinical outcome as seen in our patient who developed rapid progression to necrotizing pancreatitis. It is paramount not to delay treatment with aggressive fluid resuscitation, continuous insulin infusion, and if available, plasmapheresis; as these treatment strategies in conjunction can be life-saving.

Presentation: 6/3/2024
6966 A Rhythmic Life-Threatening Enigma Unveiled: KCNH2 Mutation-Associated Torsades de Points Unmasking Primary Hyperaldosteronism in Cardiological Realm
Authors: Dejprapasorn Saran , Nopparatana Napawadee , Soonthornpun Supamai , Leelawattana Rattana , Kietsiriroje Noppadol , Limumpornpetch Sunti , Nilmoje Thanapon , Lohawijarn Watchara , Wongsuttipakorn Tanate , Choochuen Pongsakorn , Limumpornpetch Padiporn
Published: October 2024

Disclosure: S. Dejprapasorn: None. N. Nopparatana: None. S. Soonthornpun: None. R. Leelawattana: None. N. Kietsiriroje: None. S. Limumpornpetch: None. T. Nilmoje: None. W. Lohawijarn: None. T. Wongsuttipakorn: None. P. Choochuen: None. P. Limumpornpetch: None.

Introduction: Primary hyperaldosteronism (PA) is characterized by hypertension and hypokalemia. However, its ability to masquerade life-threatening Torsades de Pointes makes it an unusual and dismissed diagnosis, revealing the link between PA and serious arrythmia. Clinical Case A 30-year-old female experienced three episodes of palpitations, followed by syncope. Upon admission, her blood pressure was 147/87 mmHg. ECG showed prolonged QT intervals with potassium level was 2.6 mmol/L (3.5-5.0 mmol/L). Continuous cardiac monitoring captured Torsades de Pointes. Despite potassium replacement, long QT still persisted. Pathogenic variant, c.2592+1G>A, within KCNH2 was discovered. Aldosterone concentration showed 69.65 ng/dL (9.70-62.60 ng/dL) and plasma renin activity was 0.12 ng/mL/h (1.50-5.70 ng/mL/h). Aldosterone-to-renin ratio was 580. Aldosterone post 4-h saline infusion test was 31.71 ng/dL which were consistent with PA. Adrenal unenhanced CT scan identified bilateral adrenal nodules (right 1.3 cm, left 1.1 cm). After receiving a cardioverter-defibrillator and spironolactone, the patient has had no palpitations, and their potassium level has remained normal. Clinical lessons: PA rarely presents ventricular arrhythmia. KCNH2 mutation may link between long QT syndrome (LQTS) and PA arises. LQTS type 2 is attributable to KCNH2 mutations, impacting potassium channel subunits crucial for adjusting currents during sympathetic activation. This is essential for shortening the QT interval with increasing heart rate. KCNH2 mutations disrupt this process, prolonging the QT interval and heightening the risk of arrhythmias. Aldosterone synthesis relies on calcium signaling triggered by potassium currents. Adrenal cortex hosts approximately 90 potassium channels genes, including KCNJ5 and KCNH2. Mutations in gene can disrupt the calcium signaling cascade, leading to excessive aldosterone production. While KCNJ5 mutation is well-documented in PA, the potential correlation between KCNH2 mutations and a similar mechanism remains unexplored in clinical reports to date. This case highlights the importance of a thorough comprehension of genetic cause contributing to pathogenesis of PA with complex clinical presentations.

Presentation: 6/1/2024
8399 Adherens Junctions Regulate Aldosterone Production and Zona Glomerulosa Morphogenesis
Authors: Berber M , Guagliardo N A , Barrett P Q , Haykir B , Chortis V , Borges K S , Carlone D L , Breault D T
Published: October 2024

Disclosure: M. Berber: None. N.A. Guagliardo: None. P.Q. Barrett: None. B. Haykir: None. V. Chortis: None. K.S. Borges: None. D.L. Carlone: None. D.T. Breault: None.

Primary aldosteronism (PA) caused by the autonomous production of aldosterone by zona Glomerulosa (zG) cells of the adrenal gland is the most common cause of endocrine hypertension, which increases the risk of cardiovascular and renal disease, independent of blood pressure. Current treatments with mineralocorticoid receptor antagonists do not fully mitigate these risks. Thus, a better understanding of the mechanisms underlying PA pathogenesis is important for the development of new therapeutic strategies. zG cells are organized in multicellular rosette structures, which are the functional aldosterone-producing units. Rosettes are stabilized by intercellular adherens junctions (AJs) comprised of cadherins, beta-catenin (βCat) and alpha-catenin (αCat), which link to the actin non-muscle myosin II (NMII) network. Recent data implicate AJs and rosettes in aldosterone-producing cell clusters and an unbiased proteomic analysis of aldosterone-producing adenomas detected an upregulation of the GTPase RhoC, an important regulator of AJ stability.We hypothesized that AJs are potent modulators of aldosterone production and zG morphogenesis with important implications for PA. Using the NCI-H295R cell line with confocal microscopic and co-immunoprecipitation assays, we found that potassium (K+) and angiotensin II (AngII) stimulation markedly enhanced the formation and maintenance of AJs. In addition, treatment with inhibitors of Rho-associated kinase (ROCK) (Y-27632) and NMII (blebbistatin) largely abrogated the effects of K+ and AngII stimulation on AJs, suggesting the Rho-ROCK-NMII pathway regulates AJ stability in the zG. Moreover, disruption of AJs, using either blebbistatin or deletion of αCat using CRISPR, blunted the aldosterone response to K+ stimulation (100% and 50%, respectively). Furthermore, zG-specific deletion of αCat (αCat-LOF) in mice led to disruption of AJs, impaired rosette formation and decreased 24-hour urinary aldosterone excretion on standard (Control 5.6±1.7 ng/mg; αCat-LOF 2.9±0.7 ng/mg (aldosterone/creatinine)) or high K+ (Control: 34.7±13.7 ng/mg; αCat-LOF 19.4±9.5 ng/mg (aldosterone/creatinine)) diets. Finally, mice with zG-specific βcat-GOF demonstrated enhanced AJ stability, increased rosette size and zG hyperplasia, which was abrogated in zG-specific bigenic βCat-GOF::αCat-LOF mice, without affecting gene expression of canonical βcat targets. These data indicate that AJs modulate aldosterone production and zG morphology, revealing AJs as a novel molecular target for the treatment of high-risk patients with PA.

Presentation: 6/3/2024
7551 Association of Remnant Cholesterol with Sarcopenia in Korean Adults: A Nationwide Population-Based Study using Data from the KNHANES
Authors: Jang S , Hwang S Y , Jang A , Kim K , Yu J , Kim N , Yoo H , Seo J , Kim S , Kim N , Baik S , Choi K
Published: October 2024

Disclosure: S. Jang: None. S. Hwang: None. A. Jang: None. K. Kim: None. J. Yu: None. N. Kim: None. H. Yoo: None. J. Seo: None. S. Kim: None. N. Kim: None. S. Baik: None. K. Choi: None.

Objectives: Mounting evidences indicate the importance of interplay between skeletal muscle and lipid metabolism. Remnant cholesterol (remnant-C) is considered as one of the principal residual risk factors for atherosclerotic cardiovascular disease (ASCVD) as well as metabolic disorders, but there is limited study about the impact of remnant-C on sarcopenia. Research design and Methods: Data from the Korea National Health and Nutrition Examination Surveys (KNHANES) between 2008 and 2011 was used in this nationwide population-based study. A total of 17,408 participants were enrolled. Subjects were categorized into 4 groups according to the quartile of remnant-C values. We conducted multivariable logistic regression analysis to evaluate the association between remnant-C and muscle mass measured using dual-energy X-ray absorptiometry (DXA). Results: 1,989 participants (11.4%) presented low muscle mass, and there was a sequential increase in the percentage of low muscle mass across remnant-C quartiles (Q1, 5.8%; Q2, 9.9%; Q3, 12.9%; Q4, 17.1%). In the full adjusted model, those in the highest remnant-C quartile group showed the highest odds ratio for low muscle mass after adjusting for various confounding factors (Q2, 1.18 [0.95-1.47]; Q3, 1.12 [0.9-1.39]; Q4, 1.37 [1.1-1.71], P <0.05). A wide range of subgroup and sensitivity analyses showed consistent results, which may support the robustness of the present findings. Conclusions: Increased remnant-C value is related to high risk of low muscle mass in Korean population. Remnant-C may be a novel marker to predict and manage sarcopenia in the aging society. There should be future research to verify its clinical usefulness.

Presentation: 6/2/2024
7093 Atherogenic Index of Plasma Is Strongly Correlated With Cardiovascular Disease Independent of LDL level in the US Population
Authors: Ayesh Hazem , Dean Niswender Kevin , Carranza Leon Barbara Gisella
Published: October 2024

Disclosure: H. Ayesh: None. K.D. Niswender: None. B.G. Carranza Leon: None.

Introduction: Cardiovascular disease (CVD) poses a global health challenge, prompting exploration of risk factors. The Atherogenic Index of Plasma (AIP), calculated as the readily available TG/HDL-C ratio, stands out as a promising avenue for investigation. Previous studies have reported an independent association between AIP and cardiovascular disease across diverse populations. Despite this recognized significance, there exists a gap in understanding its relevance in the US. This research aims to bridge this gap by examining the AIP-CVD relationship within the US population, utilizing data from the National Health and Nutrition Examination Survey (NHANES). Methods: The study included 4,784 NHANES subjects, with AIP values calculated using the established formula. The outcome was assessed using a combined variable (stroke, myocardial infarction, and CAD). Statistical analysis employed logistic regression to evaluate the AIP-CVD relationship, controlling for age, BMI, hemoglobin A1c, blood pressure, smoking, and LDL levels. Results/Discussion: We observed a significant correlation between AIP and CVD (odds ratio: 1.77, P = 0.026, 95% CI: 1.07-2.94), which persisted after controlling for common risk factors, including HbA1c, BMI, blood pressure, smoking, and LDL levels. Importantly, our findings highlighted the independence of this association from LDL levels—a pivotal observation with implications for healthcare strategies. Our study suggests that even with optimized LDL levels, AIP maintains an independent association with CVD. Existing literature supports the notion that AIP levels are strongly correlated with small dense LDL and remnant cholesterol levels. The pragmatic utility of AIP as a cardiovascular risk marker is evident due to the impracticality and costliness of testing for small dense LDL and remnant cholesterol. Given AIP is based on routine lipid profiles, our data underscores the potential integration of AIP into clinical practice, streamlining risk assessment. As we delve into our findings, the optimization of cardiovascular risk beyond LDL levels emerges as a tangible goal, with AIP emerging as a valuable tool. Larger studies are needed to validate and generalize these findings in the US population.

Presentation: 6/2/2024
6824 Bile Acid Elevation in Nonalcoholic Steatohepatitis Correlates With Fibrogenesis and Mitochondrial Dysfunction In Vitro
Authors: Dinesh Patel Nrupa , Li Yuchang , Chandrakant Raul Mahima , Sottas Chantal , Papadopoulos Vassilios
Published: October 2024

Disclosure: N. Patel: None. Y. Li: None. M. Raul: None. C. Sottas: None. V. Papadopoulos: None.

Nonalcoholic steatohepatitis (NASH) is the most severe form of nonalcoholic fatty liver disease. It is estimated that over 115 million adults are affected by NASH worldwide. The causes of NASH are unclear, and no treatment is yet available. Bile acids (BAs) are steroids synthesized in the liver, promoting lipid absorption. The levels of BAs are tightly regulated in the body. Patients diagnosed with NASH frequently exhibit increased levels of BAs in both liver tissue and plasma, indicating a potential association between elevated BA concentrations and the pathogenesis of NASH. In an in vivo study using a high-fat diet rat model of NASH, we measured plasma BA composition and levels. The results obtained indicated substantial increases in the concentrations of glycocholic acid (GCA), glycochenodeoxycholic acid (GCDCA), glycodeoxycholic acid (GDCA), and taurodeoxycholic acid (TDCA) in NASH compared to controls. These findings suggested their potential implication in the development of NASH. To elucidate the mechanistic link between changes in BA synthesis and fibrogenesis, in vitro experiments were conducted using the LX-2 humane hepatic stellate and Huh7 human hepatocellular carcinoma cells. First, the concentrations of the selected bile acids (GCA, GCDCA, GDCA, and TDCA) used in our studies were found to be non-toxic to the cells using the MTT assay. Subsequent qPCR analyses demonstrated the upregulation of key fibrotic genes (TGFβ, COL1A1, ACTA2) in LX-2 cells following exposure to individual bile acids GCA, GCDCA, GDCA, and TDCA. Immunocytochemistry (ICC) studies further demonstrated fibrogenesis by revealing increased expression of COL1A1 following treatment with each of the four bile acids. These data suggest that changes in BA formation are linked to fibrogenesis. We subsequently explored the impact of BAs on mitochondrial function using the Seahorse XF Cell Mito Stress Test in Huh7 cells. The results obtained revealed a reduction in the oxygen consumption rate and ATP production in response to BA treatment. This observation suggests a potential role for modified BAs in disrupting mitochondrial homeostasis, a recognized contributor to the progression of NASH. In summary, the data presented provide valuable insights into the complex effects of modified BAs on NASH pathogenesis, establishing connections between changes in BA composition and fibrogenesis, mitochondrial dysfunction.

Presentation: 6/2/2024
12369 Clinical Experience With Inclisiran At An Academic Center
Authors: Marin L Chavez , Gonzalez M , Linton M F , Leon B G Carranza
Published: October 2024

Disclosure: L. Chavez Marin: None. M. Gonzalez: None. M.F. Linton: None. B.G. Carranza Leon: None.

Background: Inclisiran, a small interfering RNA (siRNA) molecule designed to inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9), is the only siRNA approved for management of elevated low-density lipoprotein cholesterol (LDL-C) in both primary (for patients with familial hypercholesterolemia) and secondary prevention of cardiovascular disease. In clinical trials, Inclisiran has been shown to reduce LDL-C by more than 50% in populations at high cardiovascular risk. However, real world data about its tolerability and efficacy is still limited. Methods: We conducted an electronic medical record search to identify subjects who were prescribed Inclisiran at a lipid clinic within Vanderbilt University Medical Center (Nashville, USA). Subjects were included if they received at least one dose of Inclisiran and had pre- and post- LDL-C levels. Subjects taking other LDL-C lowering medications like statins, ezetimibe, bempedoic acid, and PCSK-9 inhibitors were included. Pre- and post- LDL-C averages were calculated and analyzed with 95% confidence intervals. The reasons for medication discontinuation were also examined. Results: Out of 69 subjects identified, only 19 met criteria for inclusion, while 32 never received a dose due to cost burden and insurance denial. The other 18 subjects were not included due to inadequate lab results at the time of data collection. In subjects who received at least one dose of Inclisiran, average pre-LDL-C was 142 mg/dL [CI: 34.7] while post-LDL-C was 77 mg/dL [CI: 24.0], notable for a 46% decrease in LDL-C levels. These subjects were also receiving another lipid lowering agent, like a statin, or had previously used a monoclonal antibody-PCSK-9 inhibitor. Those without prior use of PCSK-9 inhibitors were also analyzed. Average pre-LDL-C was 109.5 mg/dL [CI: 15.8] while post-LDL-C was 39.8 mg/dL [CI: 17.2], which revealed a 64% decrease in LDL-C levels. The main reason for discontinuation of Inclisiran was insurance denial followed by individual preference. Only one subject discontinued Inclisiran due to experiencing a generalized rash. Conclusions: Inclisiran is an effective and overall well-tolerated medication indicated for the management of elevated LDL cholesterol. Our study revealed that for individuals with above goal LDL-C, despite maximum tolerated therapy with a statin, additional LDL-C lowering benefits can be seen with Inclisiran use. However, insurance approval and cost burden seem to be the main barriers for access.

Presentation: 6/3/2024
12463 Effect Of Multiple Blood Sampling In A Single Session On Adrenal Vein Sampling For Identification Of Primary Aldosteronism
Authors: Yagishita Nobuyuki , Kometani Mitsuhiro , Aiga Ko , Mizoguchi Ren , Yoneda Takashi
Published: October 2024

Disclosure: N. Yagishita: None. M. Kometani: None. K. Aiga: None. R. Mizoguchi: None. T. Yoneda: None.

Context: Adrenal vein sampling (AVS) is recognized as the gold standard method to distinguish subtypes of primary aldosteronism (PA), helps differentiating the pathogenic side and determining the appropriate treatment strategies. The Selectively Index (SI) and Lateralization Index (LI), which are based on aldosterone and cortisol levels, are used to determine the success rate of AVS and to diagnose PA subtypes. On the other hand, determining the success of adrenal vein insertion and disease type remains controversial, and various methods to improve its accuracy are still being reported. Objective: Evaluate the impact of performing multiple blood samplings from the inferior vena cava (IVC) and each adrenal vein (AV) during a single AVS session and its impact on the success rate of said AVS and the consequent accuracy of PA subtype diagnosis. Patients: A total of 48 patients who were diagnosed as PA and underwent multiple AVS procedures at Kanazawa University Hospital or Houju Memorial Hospital. Protocol: This study involved 48 patients diagnosed with PA. AVS was performed using the following procedure. A catheter is inserted into the IVC through the right or left femoral vein. A sample is first taken from the IVC (IVC-1). AVS was then performed in the order of right adrenal vein and left adrenal vein or vice versa. After cannulation of each adrenal vein, samples were taken three times before switching to the other adrenal vein. After the collection of each adrenal vein was completed, samples were taken again from the IVC (IVC-2). Results: Of the 48 patients, 44 patients were included in the study, for whom all sets of AVS samples were available. For each patient, six SI's were calculated per AV. Multiple AV samples did not affect the success rate of AVS. Regardless of the cortisol level in the AV, the SI calculated using the cortisol level in IVC -2 was significantly higher in most patients (P < 0.0001). Only patients in whom AVS was successful in all cases were selected to determine lateralization. Since nine different LI’s could be calculated, there were nine chances to determine subtypes for each patient. 18 patients in IVC-1 (left: 2, right: 4, bilateral: 12), 17 patients in IVC-2 (left: 3, right 2, bilateral: 12) all exhibited consistencies in lateralization. Except four patients which in both cases exhibited inconsistencies in lateralization. Conclusions: These results revealed that multiple blood samplings resulted in lateralization discrepancies that could not be determined with a single blood sampling. Although it was not possible to confirm that multiple blood samplings influence the success rate of AVS, it was newly confirmed that the timing of blood sampling from IVC impacts it.

Presentation: 6/1/2024
8697 Effects of Fibrate Combination Therapy on the Prevention and Progression of Non-Alcoholic Fatty Liver Disease in Patients with Dyslipidemia Undergoing Statin Treatment: A Retrospective Cohort Study Using Dada from the Korean National Health Insurance Service
Authors: Choi Jong Han , Kim Suk Kyeong , Lim Dong-Lim , Song Kee-Ho
Published: October 2024

Disclosure: J. Choi: None. S. Kim: None. D. Lim: None. K. Song: None.

Background and Hypothesis: Non-alcoholic fatty liver disease (NAFLD), recognized as part of the metabolic syndrome, has become a significant public health issue. However, there has been no suitable pharmacological treatment beyond lifestyle management due to the lack of appropriate modalities for early diagnosis and treatment response assessment. Fibrates, potent drugs for treating hypertriglyceridemia, have been considered potential therapeutic candidates for hepatic steatosis due to their capacity to reduce liver lipid accumulation. However, they have failed to demonstrate histopathological improvement and lack large-scale randomized controlled trials showing radiological improvement. Purpose: We aimed to evaluate the effectiveness of fibrates in improving hepatic steatosis using the fatty liver index (FLI) and hepatic steatosis index (HSI). These are presented as predictive panels for hepatic steatosis by the Korean Association for the Study of the Liver, having been well validated in large-scale epidemiological studies for Koreans through radiological examinations. They are also independently valuable as they utilize different serological and clinical indicators. The analysis was feasible using claim data and health examination records from the Korean National Health Insurance Service. Research Method: This study was conducted on individuals with dyslipidemia receiving statin treatment, who had undergone consecutive health examinations provided by the KNHIS. Among these, patients newly starting fibrates treatment for moderate hypertriglyceridemia (triglyceride levels 150-500 mg/dl) were selected as the treatment group (n=10,616). A control group (n=10,616) was established using 1:1 propensity score matching. The odds ratios (ORs) for the hepatic steatosis were analyzed by the FLI and HSI between these two groups, respectively. Additionally, the fibrates treatment group was categorized based on medication possession ratio (MPR), and the ORs were evaluated accordingly. Results: The fibrate treatment group reduced hepatic steatosis by 10.8% according to the FLI and 17.6% according to the HSI, compared to the control group. Notably, in the subgroup with a high MPR of over 80%, there was a substantial decrease in hepatic steatosis, with a 69.8% reduction observed for FLI and a 66.3% reduction for HSI. Conclusion: Fibrate treatment in patients with hypertriglyceridemia who are already on statin therapy can significantly reduce the prevalence of hepatic steatosis.

Presentation: 6/3/2024
12607 Female Mice Exhibit Sex-specific Steatosis Patterns With Aging
Authors: Landgraf A , Okada J , Xiaoli A , Qiu Y , Eliscovich C , Viswanathan P , Schuster V , Kurland I J , Shinoda K , Pessin J E
Published: October 2024

Disclosure: A. Landgraf: None. J. Okada: None. A. Xiaoli: None. Y. Qiu: None. C. Eliscovich: None. P. Viswanathan: None. V. Schuster: None. I.J. Kurland: None. K. Shinoda: None. J.E. Pessin: None.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects 38% of the global population and is becoming a leading cause of liver transplant and hepatocellular carcinoma (HCC). MASLD affects adult men at higher rates than adult women, but during aging, women lose their protection from MASLD. Declines in serum estrogen during menopause are the suspected cause of this aging-associated loss of protection, but the molecular effects of estrogen loss on the liver have not been fully characterized. Here, we modeled the effect of menopause on MASLD using young and aged female mice on high fat diet and characterized the liver steatosis profile associated with menopause. Male and female C57BL/6J mice were placed on high fat diet (HFD) or low fat chow diet (NCD) for 15 weeks from 6-21 wks/old (young cohort) or 64-79 wks/old (aged cohort). Body weight and fat composition were tracked throughout the experiment. Extracted livers were used to perform hepatic triglyceride (TG) analysis, liver H&E staining, whole liver RT-qPCR, proteomics, and lipidomics. Liver TG analysis showed young female mice had almost no HFD-induced liver steatosis after 15wks while aged female mice develop extensive steatosis. Additionally, aged female mice on HFD gained weight at significantly faster rate than young female mice. Liver H&E staining demonstrated that the steatosis type in aged female mice was exclusively macro-vesicular and located in zone II (mid-zone) of the hepatic lobule compared to combined micro-vesicular and macro-vesicular patterns originating from zone III (pericentral) in male mice. In humans, micro-vesicular steatosis is more severe and associated with disruptions in mitochondrial fatty acid oxidation while macro-vesicular steatosis is more benign1. Proteomic and lipidomic analysis clustered samples according to their steatosis type (macro, micro, or combined) and identified distinct lipid and protein signatures of each steatosis type. These findings suggest there may be two distinct, sex-specific mechanisms by which mammals accumulate fat in the liver: an estrogen-mediated mechanism controlling macro-steatosis and an alternative mechanism regulating micro-vesicular steatosis possibly through impairments in pericentral fatty acid oxidation. This model would have broad implications for MASLD therapeutic strategy. (1) Fromenty, B. & Roden, M. Mitochondrial alterations in fatty liver diseases. J Hepatol78, 415-429, doi:10.1016/j.jhep.2022.09.020 (2023).

Presentation: 6/3/2024
8504 Germline VHL-gene Alterations Are Associated With An Increased Risk Of Cardiovascular Disease - A Large Population Study
Authors: Halperin Reut , Tirosh Amit
Published: October 2024

Disclosure: R. Halperin: None. A. Tirosh: None.

Introduction: Von Hippel-Lindau (VHL) is an autosomal dominant disease associated with increased risk for developing hemangioblastomas of the central nervous system and retina, renal cell carcinoma (RCC), pancreatic neuroendocrine tumors (PNET), adrenal pheochromocytomas and paraganglioma (PPGL). Loss of function VHL alterations lead to pseudohypoxia and, consequently, to angiogenesis and metabolic derangements (e.g., increased glucose uptake). Little is known about the systemic effects of VHL alterations on the cardiometabolic system. Aim Study whether VHL gene variants are associated with increased cardiometabolic risk. Methods: Data were extracted from the UK Biobank database, including demographic and anthropometric parameters, medical history, and lab testing. Whole exome sequencing data were available for all patients, and a focused variant calling and annotation of the VHL gene region was performed on the DNA-nexus platform. A composite of major adverse cardiovascular events (MACE) per patient consisted of ischemic heart disease (IHD), cerebrovascular accident (CVA), and peripheral artery disease (PVD). VHL variant severity was sub-categorized into low (silent or missense), intermediate (in-frame insertion or deletion and 5’ UTR variants), and high-risk (nonsense or frameshift). Results: Data from 460,430 participants were analyzed (45.8% males, age at inclusion 73.6±8.1 years). IHD, CVA, and PVD rates were 11.5%, 3.0%, and 1.8%, respectively. Germline VHL variants were detected in 2594 participants (0.45%), with 2073 low- (242 silent, 1830 missense), 505 intermediate- (18 in-frame deletion and 23 in-frame insertion and 464 5' UTR variants), and 16 high-risk (3 frameshift insertions, one frameshift deletion, and 12 nonsense) VHL variants. In the multivariable logistic regression analysis, harboring a high-risk VHL variant was associated with an 11-fold increased risk of MACE (odds ratio [OR] 11.1, 95% confidence interval 1.5-54.1, p=0.006), after adjustment for age at inclusion, age at diagnosis with cancer, sex, kidney function, c-reactive protein plasma levels, and diagnosis status with diabetes mellitus, hypertension, dyslipidemia, obesity, and RCC. Conclusions and discussionVHL gene alterations are associated with an increased cardiometabolic risk. Metabolic changes or enhanced drive for angiogenesis might contribute to this association. Further research is needed to verify these results and to assess a possible benefit from early intervention in this population.

Presentation: 6/3/2024
6772 Graves' Wrath on the Heart: A Focus on Pericardial Effusion
Authors: Subramani Rashmi , Zahra Sundas , Manas F N U
Published: October 2024

Disclosure: R. Subramani: None. S. Zahra: None. F. Manas: None.

Introduction: Hyperthyroidism, marked by an overproduction of thyroid hormones, is linked to various cardiovascular issues like high or normal output heart failure, arrhythmias, and tachycardia-related cardiomyopathy. Pericardial effusion is less common in hyperthyroidism compared to hypothyroidism. Here we report a 20 year old with pericardial effusion, later diagnosed with Grave’s disease. Case Summary: A 20-year-old female with a past medical history of anxiety, depression, and seizure disorder presented to the emergency department with chief complaints of dizziness, shortness of breath, palpitations, and chest pain. She complained of tremors, generalized weakness, and weight loss for the last two months. She denied any personal or family history of hypo- or hyper-thyroidism. No history of head or neck irradiation, anterior neck tenderness or pain, dysphagia or hoarseness. No history of recent viral infection. Examination revealed tachycardia with thyromegaly and pericardial friction rub but there was no neck tenderness, exophthalmos or lid lag. Blood work was remarkable for low TSH (<0.02 uIu/ml, normal: 0.27-4.2 uIu/ml) and elevated free T4 (>7.7nd/dl, normal:0.9-1.7ng/dl) and total T3 (>651 ng/dl, normal 80-200 ng/dl). Rest of the blood work, including blood cultures and immunologic workup (antinuclear antibody, anti-neutrophil cytoplasmic antibody, and rheumatoid factor) was negative. EKG showed sinus tachycardia. CT chest confirmed thyromegaly and showed pericardial effusion. Ultrasound neck showed enlarged heterogeneous thyroid gland with relative increased vascularity. Echocardiography showed mild to moderate pericardial effusion with no tamponade physiology and normal ejection fraction. Anti thyroid peroxidase antibodies, thyroid stimulating immunoglobulin, and TSH receptor antibodies were markedly elevated. The patient was diagnosed with Grave’s thyrotoxicosis with thyromegaly and pericardial effusion. Endocrinology was consulted and the patient was started on beta blockers for symptom control and anti-thyroid medication (methimazole). Discussion: Fabowale MO et al highlighted the potential role of immunological mechanisms in causing pericardial effusion, while Fonseca et al focused on pathophysiological changes involving both extravascular and intravascular proteins, coupled with reduced lymphatic drainage. Cardiac complications in Graves' disease tend to occur more frequently when the condition has been poorly managed for an extended period before seeking medical help. If symptoms persist despite achieving proper control, clinicians need to be watchful for potential cardiac complications.

Presentation: 6/3/2024
8521 Increased Blood Pressure SDS in Boys With Early Onset Hypogonadism
Authors: Lucas-Herald A K , McNeilly J D , Ahmed S F
Published: October 2024

Disclosure: A.K. Lucas-Herald: None. J.D. McNeilly: None. S.F. Ahmed: None.

Introduction: Androgens are essential for normal vascular function. As such, early onset hypogonadism may be associated with an increased risk of accelerated vascular ageing and early vascular dysfunction. Methods: Boys aged 12-18 years were recruited from a tertiary paediatric endocrine clinic for non-invasive vascular phenotyping. Cases were boys who had proximal hypospadias and had undergone surgical repair for this or boys with genetically confirmed Klinefelter Syndrome. Controls were either healthy volunteers or boys who had undergone review for constitutional delay of puberty but had not required intervention. Vascular assessment was undertaken to assess blood pressure (BP), arterial stiffness (pulse wave velocity), subclinical atherosclerosis (carotid artery intima media thickness (CIMT)) and endothelial function (brachial artery flow mediated dilatation (FMD)). Where appropriate, standard deviation scores (SDS) were used for comparisons adjusting for sex, age and height. Statistical analysis was done by Graphpad Prism v 8.0. Comparisons between groups were via ANOVA or Mann-Whitney U tests with p<0.05 representing statistical significance. Results: Twenty-two boys with conditions that may have been associated with a period of intra-uterine hypogonadism(hypospadias (n=11), Klinefelter Syndrome (n=11) (median age (range) 14.3 yrs (6.2, 16.9) and 11 healthy controls were recruited (median age 15.5 (6.8, 16.5)). There were no differences between the groups in terms of birthweight SDS, gestation at birth or presence of co-existing conditions. Systolic BP SDS was higher in boys with early onset hypogonadism (median (range) 1.25 vs. 0.5, p=0.01) compared to controls. There was no difference in SBP SDS between those with Klinefelter Syndrome and those with hypospadias (median (range) 1.0 vs. 1.5, p=0.6). CIMT SDS (1.75 vs. 0.0, p=0.02) and pulse pressure (34 vs. 30 mmHg, p=0.03) were increased in boys with early onset hypogonadism compared to controls but there were no differences in body mass index SDS, pulse wave velocity, FMD or mean arterial pressure. Conclusions: Adolescents with potential early onset hypogonadism have higher systolic BP SDS compared to healthy controls. There is a need to consider regular monitoring and early intervention in boys with early onset hypogonadism for risk stratification to prevent the development of cardiovascular disease later in life

Presentation: 6/3/2024