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1.
EClinicalMedicine ; 71: 102576, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38618204

RESUMEN

Background: Primary aldosteronism (PA) is caused by autonomous aldosterone overproduction and characterised by uncontrolled hypertension. There are currently no treatments that target aldosterone synthesis. We evaluated the safety and efficacy of a novel aldosterone synthase inhibitor, dexfadrostat phosphate, in patients with PA. Methods: This multi-centre, randomised, phase 2 trial was conducted between November 2019 and May 2022 (NCT04007406; EudraCT code 2019-000919-85). Adults with PA and an office systolic blood pressure of 145-190 mmHg were included. After a 2-week single-blind placebo run-in period, participants were randomised 1:1:1 to receive oral dexfadrostat phosphate 4, 8, or 12 mg once daily for an 8-week double-blind treatment period, followed by a 2-week single-blind placebo withdrawal period. Randomisation was conducted centrally and stratified by centre and sex. At the beginning and end of the treatment period, 24 h ambulatory systolic blood pressure (aSBP) was recorded. Blood samples were taken every 2 weeks. Primary endpoints were the change in aldosterone-to-renin ratio (ARR) and mean 24 h aSBP from baseline to the end of the treatment period in the combined dose group of all participants receiving any dose of dexfadrostat phosphate. Safety endpoints were the occurrence of treatment-emergent adverse events (TEAEs) and serious adverse events over the entire study in all randomised participants who received at least one dose of dexfadrostat phosphate. Findings: In total, 35 participants received dexfadrostat phosphate and all participants completed the study. Twenty-six participants (74.3%) were male, the mean age was 51.9 years (SD 8.7), and most were White (n = 32, 91.4%). The median ARR and the mean 24 h aSBP significantly decreased from the beginning to the end of the treatment period in the combined dose group (ARR: 15.3 vs 0.6, least-squares mean [LSM] change in log-normal values -2.5, p < 0.0001; aSBP: 142.6 vs 131.9 mmHg, LSM change -10.7 mmHg, p < 0.0001). There were no safety concerns; all TEAEs were mild or moderate and there were no serious TEAEs. Interpretation: Dexfadrostat phosphate corrected the ARR and aSBP and was well tolerated in patients with PA, demonstrating the benefit of pharmacologically targeting the source of hyperaldosteronism. Funding: DAMIAN Pharma AG.

2.
J Clin Endocrinol Metab ; 108(9): e720-e725, 2023 08 18.
Artículo en Inglés | MEDLINE | ID: mdl-36974473

RESUMEN

CONTEXT: Adrenal venous sampling (AVS) is the gold standard procedure for subtype diagnosis in patients with primary aldosteronism (PA). Cortisol is usually adopted for the normalization of aldosterone levels in peripheral and adrenal samples. However, asymmetrical cortisol secretion can potentially affect the lateralization index, leading to subtype misdiagnosis. OBJECTIVE: We aimed to assess the prevalence of asymmetrical cortisol secretion in patients undergoing AVS and whether variations in adrenal vein cortisol might influence AVS interpretations. We then evaluated the use of metanephrines for the normalization of aldosterone levels for lateralization index. METHODS: We retrospectively included 101 patients with PA who underwent AVS: 49 patients underwent unstimulated AVS, while 52 patients underwent both unstimulated and cosyntropin-stimulated AVS. Eighty-eight patients had bilateral successful AVS according to metanephrine ratio. We assessed the prevalence of asymmetrical cortisol secretion through the cortisol to metanephrine (C/M) lateralization index (LI). We then evaluated whether the use of aldosterone to metanephrine (A/M) LI can improve the diagnostic accuracy of AVS compared with aldosterone to cortisol (A/C) LI. RESULTS: Asymmetrical cortisol secretion is present in 18% of patients with PA. Diagnosis with A/M LI and A/C LI is discordant in 14% of patients: 9% had a diagnosis of unilateral PA with A/M LI instead of bilateral PA with A/C LI and 5% had a diagnosis of bilateral PA with A/M LI instead of unilateral PA. CONCLUSION: The assessment of metanephrine levels in AVS is useful for the determination of selectivity and lateralization, allowing an accurate diagnosis, especially in patients with asymmetrical cortisol secretion.


Asunto(s)
Aldosterona , Hiperaldosteronismo , Humanos , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/epidemiología , Hidrocortisona , Metanefrina , Estudios Retrospectivos , Prevalencia , Venas , Glándulas Suprarrenales/irrigación sanguínea
3.
J Clin Endocrinol Metab ; 108(7): 1813-1823, 2023 06 16.
Artículo en Inglés | MEDLINE | ID: mdl-36718682

RESUMEN

CONTEXT: Adrenal hyperfunction is associated with an increased risk of cardiometabolic complications in subjects with adrenal incidentaloma (AI). Reliable prevalence estimates of functioning AIs are important to direct resources allocations. OBJECTIVE: To assess the prevalence of autonomous/possible autonomous cortisol secretion (ACS), primary aldosteronism (PA), pheochromocytoma (PHEO), and Cushing syndrome (CS) in patients with AI. METHODS: We performed a comprehensive search of multiple databases (PubMed, Ovid MEDLINE, Web of Science) for potentially relevant studies without language restriction, up to February 2022. Of the 1661 publications evaluated at title and abstract levels, 161 were examined as full text and 36 were included. Study level clinical data were extracted by 3 independent reviewers. RESULTS: The overall prevalence of functioning AIs was 27.5% (95% CI 23.0, 32.5). ACS/possible ACS, with a prevalence of 11.7% (95% CI 8.6, 15.7), was the most frequent hormonal alteration, while PA occurred in 4.4% of the patients (95% CI 3.1, 6.2). Subgroup analysis showed that PA was more prevalent in patients from Asia than in patients from Europe/America; in contrast, ACS/possible ACS had a lower prevalence in Asian countries. At meta-regression analysis, the prevalence of ACS/possible ACS was influenced by the proportion of female patients, while the prevalence of PA was positively associated with the proportion of patients with hypertension and the publication year. Finally, PHEO and CS prevalence were 3.8% (95% CI 2.8, 5.0) and 3.1% (95% CI 2.3, 4.3) respectively. CONCLUSION: This meta-analysis provides extensive data on the prevalence of functioning AIs and the factors affecting heterogeneity in prevalence estimates.


Asunto(s)
Neoplasias de las Glándulas Suprarrenales , Síndrome de Cushing , Hipertensión , Feocromocitoma , Humanos , Femenino , Neoplasias de las Glándulas Suprarrenales/epidemiología , Neoplasias de las Glándulas Suprarrenales/complicaciones , Prevalencia , Síndrome de Cushing/epidemiología , Síndrome de Cushing/complicaciones , Hipertensión/epidemiología , Hipertensión/complicaciones , Feocromocitoma/complicaciones , Hidrocortisona
4.
Rev Endocr Metab Disord ; 24(1): 39-48, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-35536535

RESUMEN

Primary aldosteronism (PA) is the most common form of secondary hypertension. Although hypertensive disorders seem to affect around 5-10% of pregnancies worldwide, literature counts less than 80 cases of PA diagnosed during the peri-partum period. In this review we discuss about current knowledge on pathophysiology, natural history, diagnosis and treatment of PA in pregnancy. Because of the physiologic changes in the renin-angiotensin-aldosterone system (RAAS) and the contraindication to both confirmatory test and subtype differentiation, diagnosis of PA during pregnancy is challenging and relies mostly on detection of low/suppressed renin and high aldosterone levels. The course of pregnancy in patients with PA is highly variable, ranging from progesterone-induced amelioration of blood pressure (BP) control to severe and resistant hypertension with potential maternal and fetal complications. Mineralcorticoid receptor antagonists (MRA) are the recommended and most effective drugs for treatment of PA. As the anti-androgenic effect of spironolactone can potentially interfere with sexual development, their prescription is not recommended during pregnancy. On the other side, eplerenone, has proven to be safe and effective in 6 pregnant women and may be added to conventional first line drug regimen in presence of resistant hypertension or persistent hypokalemia. Ideally, patients with unilateral forms of PA should undergo adrenalectomy prior to conception, however, when PA is diagnosed during pregnancy and medical therapy fails to adequately control hypertension or its complications, adrenalectomy can be considered during the second trimester in case of unilateral adrenal mass at MRI-scan.


Asunto(s)
Hiperaldosteronismo , Hipertensión , Humanos , Femenino , Embarazo , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/terapia , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Espironolactona/uso terapéutico , Hipertensión/tratamiento farmacológico , Eplerenona/uso terapéutico
7.
J Clin Endocrinol Metab ; 106(4): e1708-e1716, 2021 03 25.
Artículo en Inglés | MEDLINE | ID: mdl-33377974

RESUMEN

CONTEXT: The diagnostic work-up of primary aldosteronism (PA) includes screening and confirmation steps. Case confirmation is time-consuming, expensive, and there is no consensus on tests and thresholds to be used. Diagnostic algorithms to avoid confirmatory testing may be useful for the management of patients with PA. OBJECTIVE: Development and validation of diagnostic models to confirm or exclude PA diagnosis in patients with a positive screening test. DESIGN, PATIENTS, AND SETTING: We evaluated 1024 patients who underwent confirmatory testing for PA. The diagnostic models were developed in a training cohort (n = 522), and then tested on an internal validation cohort (n = 174) and on an independent external prospective cohort (n = 328). MAIN OUTCOME MEASURE: Different diagnostic models and a 16-point score were developed by machine learning and regression analysis to discriminate patients with a confirmed diagnosis of PA. RESULTS: Male sex, antihypertensive medication, plasma renin activity, aldosterone, potassium levels, and the presence of organ damage were associated with a confirmed diagnosis of PA. Machine learning-based models displayed an accuracy of 72.9%-83.9%. The Primary Aldosteronism Confirmatory Testing (PACT) score correctly classified 84.1% at training and 83.9% or 81.1% at internal and external validation, respectively. A flow chart employing the PACT score to select patients for confirmatory testing correctly managed all patients and resulted in a 22.8% reduction in the number of confirmatory tests. CONCLUSIONS: The integration of diagnostic modeling algorithms in clinical practice may improve the management of patients with PA by circumventing unnecessary confirmatory testing.


Asunto(s)
Hiperaldosteronismo/diagnóstico , Femenino , Humanos , Aprendizaje Automático , Masculino , Tamizaje Masivo/métodos , Persona de Mediana Edad , Sensibilidad y Especificidad
8.
Eur J Endocrinol ; 183(6): 657-667, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33112264

RESUMEN

OBJECTIVE: Adrenal venous sampling (AVS) is the gold standard to discriminate patients with unilateral primary aldosteronism (UPA) from bilateral disease (BPA). AVS is technically demanding and in cases of unsuccessful cannulation of adrenal veins, the results may not always be interpreted. The aim of our study was to develop diagnostic models to distinguish UPA from BPA, in cases of unilateral successful AVS and the presence of contralateral suppression of aldosterone secretion. DESIGN: Retrospective evaluation of 158 patients referred to a tertiary hypertension unit who underwent AVS. We randomly assigned 110 patients to a training cohort and 48 patients to a validation cohort to develop and test the diagnostic models. METHODS: Supervised machine learning algorithms and regression models were used to develop and validate two prediction models and a simple 19-point score system to stratify patients according to their subtype diagnosis. RESULTS: Aldosterone levels at screening and after confirmatory testing, lowest potassium, ipsilateral and contralateral imaging findings at CT scanning, and contralateral ratio at AVS, were associated with a diagnosis of UPA and were included in the diagnostic models. Machine learning algorithms correctly classified the majority of patients both at training and validation (accuracy: 82.9-95.7%). The score system displayed a sensitivity/specificity of 95.2/96.9%, with an AUC of 0.971. A flow-chart integrating our score correctly managed all patients except 3 (98.1% accuracy), avoiding the potential repetition of 77.2% of AVS procedures. CONCLUSIONS: Our score could be integrated in clinical practice and guide surgical decision-making in patients with unilateral successful AVS and contralateral suppression.


Asunto(s)
Glándulas Suprarrenales/irrigación sanguínea , Aldosterona/sangre , Recolección de Muestras de Sangre/estadística & datos numéricos , Hiperaldosteronismo/diagnóstico , Adulto , Recolección de Muestras de Sangre/métodos , Diagnóstico Diferencial , Femenino , Humanos , Aprendizaje Automático , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Análisis de Regresión , Reproducibilidad de los Resultados , Estudios Retrospectivos , Sensibilidad y Especificidad , Venas
9.
J Clin Endocrinol Metab ; 105(10)2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-32561919

RESUMEN

CONTEXT: Primary aldosteronism (PA) comprises unilateral (lateralized [LPA]) and bilateral disease (BPA). The identification of LPA is important to recommend potentially curative adrenalectomy. Adrenal venous sampling (AVS) is considered the gold standard for PA subtyping, but the procedure is available in few referral centers. OBJECTIVE: To develop prediction models for subtype diagnosis of PA using patient clinical and biochemical characteristics. DESIGN, PATIENTS AND SETTING: Patients referred to a tertiary hypertension unit. Diagnostic algorithms were built and tested in a training (N = 150) and in an internal validation cohort (N = 65), respectively. The models were validated in an external independent cohort (N = 118). MAIN OUTCOME MEASURE: Regression analyses and supervised machine learning algorithms were used to develop and validate 2 diagnostic models and a 20-point score to classify patients with PA according to subtype diagnosis. RESULTS: Six parameters were associated with a diagnosis of LPA (aldosterone at screening and after confirmatory testing, lowest potassium value, presence/absence of nodules, nodule diameter, and computed tomography results) and were included in the diagnostic models. Machine learning algorithms displayed high accuracy at training and internal validation (79.1%-93%), whereas a 20-point score reached an area under the curve of 0.896, and a sensitivity/specificity of 91.7/79.3%. An integrated flowchart correctly addressed 96.3% of patients to surgery and would have avoided AVS in 43.7% of patients. The external validation on an independent cohort confirmed a similar diagnostic performance. CONCLUSIONS: Diagnostic modelling techniques can be used for subtype diagnosis and guide surgical decision in patients with PA in centers where AVS is unavailable.


Asunto(s)
Técnicas de Apoyo para la Decisión , Hiperaldosteronismo/diagnóstico , Pruebas de Función de la Corteza Suprarrenal , Glándulas Suprarrenales/diagnóstico por imagen , Glándulas Suprarrenales/cirugía , Adrenalectomía , Adulto , Aldosterona/sangre , Toma de Decisiones Clínicas/métodos , Femenino , Humanos , Hiperaldosteronismo/sangre , Hiperaldosteronismo/cirugía , Masculino , Persona de Mediana Edad , Potasio/sangre , Curva ROC , Análisis de Regresión , Estudios Retrospectivos , Aprendizaje Automático Supervisado , Tomografía Computarizada por Rayos X
10.
Horm Metab Res ; 52(6): 366-372, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32219799

RESUMEN

The coexistence of aldosterone oversecretion and obstructive sleep apnea is frequently observed, especially in patients with resistant hypertension, obesity, and metabolic syndrome. Since aldosterone excess and sleep apnea are both independently associated with an increased risk of cardiovascular disease, to investigate whether their coexistence might be attributed to common predisposing conditions, such as metabolic disorders, or to an actual pathophysiological interconnection appears of great importance. Fluid overload and metabolic abnormalities relating to aldosterone oversecretion may be implicated in obstructive sleep apnea development. Nocturnal intermittent hypoxia may in turn exacerbate renin-angiotensin-aldosterone system activity, thus leading to hyperaldosteronism. Furthermore, fat tissue excess and adipocyte secretory products might predispose to both sleep apnea and aldosterone oversecretion in subjects with obesity. Consistent with these evidences, obstructive sleep apnea frequently affects patients with primary aldosteronism. Conversely, whether primary aldosteronism is more prevalent in individuals affected by obstructive sleep apnea compared to the general population remains controversial.


Asunto(s)
Hiperaldosteronismo , Apnea Obstructiva del Sueño , Causalidad , Comorbilidad , Susceptibilidad a Enfermedades , Humanos , Hiperaldosteronismo/complicaciones , Hiperaldosteronismo/epidemiología , Prevalencia , Factores de Riesgo , Apnea Obstructiva del Sueño/complicaciones , Apnea Obstructiva del Sueño/epidemiología
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