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1.
Artigo em Inglês | MEDLINE | ID: mdl-32609829

RESUMO

CONTEXT: Catecholamines and adrenocortical steroids are important regulators of blood pressure. Bidirectional relationships between adrenal steroids and catecholamines have been established but whether this is relevant to patients with pheochromocytoma is unclear. OBJECTIVE: This study addresses the hypothesis that patients with pheochromocytoma and paraganglioma (PPGL) have altered steroid production compared to primary hypertensives. DESIGN: Multicenter cross-sectional study. SETTING: Twelve European referral centers. PATIENTS: Subjects included 182 patients with pheochromocytoma, 36 with paraganglioma and 270 primary hypertensives. Patients with primary aldosteronism (n=461) and Cushing syndrome (n=124) were included for additional comparisons. INTERVENTION: In patients with PPGLs, surgical resection of tumors. OUTCOME MEASURES: Differences in mass spectrometry-based profiles of 15 adrenal steroids between groups and after surgical resection of PPGLs. Relationships of steroids to plasma and urinary metanephrines and urinary catecholamines. RESULTS: Patients with pheochromocytoma had higher (P<0.05) circulating concentrations of cortisol, 11-deoxycortisol, 11-deoxycorticosterone and corticosterone than primary hypertensives. Concentrations of cortisol, 11-deoxycortisol and corticosterone were also higher (P<0.05) in patients with pheochromocytoma than with paraganglioma. These steroids correlated positively with plasma and urinary metanephrines and catecholamines in patients with pheochromocytoma, but not paraganglioma. After adrenalectomy, there were significant decreases in cortisol, 11-deoxycortisol, corticosterone, 11-deoxycorticosterone, aldosterone and 18-oxocortisol. CONCLUSIONS: This is the first large study in patients with PPGLs that supports in a clinical setting the concept of adrenal cortical-medullary interactions involving an influence of catecholamines on adrenal steroids. These findings could have implications for the cardiovascular complications of PPGLs and the clinical management of patients with the tumors.

2.
J Hypertens ; 2020 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-32618889

RESUMO

: Autonomous aldosterone overproduction represents the underlying condition of 5-10% of patients with arterial hypertension and carries a significant burden of mortality and morbidity. The diagnostic algorithm for primary aldosteronism is sequentially based on hormonal tests (screening and confirmation tests), followed by lateralization studies (adrenal CT scanning and adrenal venous sampling) to distinguish between unilateral and bilateral disease. Despite the recommendations of the Endocrine Society guideline, primary aldosteronism is largely underdiagnosed and undertreated with high between-centre heterogeneity. Experts from the European Society of Hypertension have critically reviewed the available literature and prepared a consensus document constituting two articles to summarize current knowledge on the epidemiology, diagnosis, treatment, and complications of primary aldosteronism.

3.
J Hypertens ; 2020 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-32618890

RESUMO

: Primary aldosteronism is a frequent cause of secondary hypertension requiring a specific pharmacological treatment with mineralocorticoid receptor antagonist or with unilateral adrenalectomy. These treatments have shown to reduce the excess of cardiovascular risk characteristically associated with this disease. In part I of this consensus, we discussed the procedures for the diagnosis of primary aldosteronism. In the present part II, we address the strategies for the differential diagnosis of primary aldosteronism subtypes and therapy. We also discuss the evaluation of outcomes and provide suggestions for follow-up as well as cardiovascular and metabolic complications specifically associated with primary aldosteronism. Finally, we analyse the principal gaps of knowledge and future challenges for research in this field.

4.
Artigo em Inglês | MEDLINE | ID: mdl-32561919

RESUMO

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 two 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% to 93%), whereas a 20-point score reached an AUC of 0.896, and a sensitivity/specificity of 91.7/79.3%. An integrated flow-chart 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.

5.
High Blood Press Cardiovasc Prev ; 27(2): 105-108, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32266708

RESUMO

Cardiovascular diseases, in particular hypertension, as well as the cardiovascular treatment with Renin-Angiotensin System inhibitors such as Angiotensin Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs), are claimed once again as mechanisms of Severe Acute Respiratory Syndrome (SARS) during the COVID-19 outbreak due to Cov-2 epidemics. In vitro studies are available to support the eventual role of ACE inhibitors and ARBs in both the promotion and antagonism of the disease. The available literature, indeed, presents contrasting results, all concentrated in experimental models. Evidence in humans is lacking that those mechanisms are actually occurring in the present COVID-19 outbreak. Here we present the reasoned statement of the Italian Society of Hypertension to maintain ongoing antihypertensive treatments. Furthermore, the Italian Society of Hypertension presents its own initiative to investigate the issue using an online questionnaire to collect relevant data in human disease.


Assuntos
Antagonistas de Receptores de Angiotensina , Inibidores da Enzima Conversora de Angiotensina , Anti-Hipertensivos , Infecções por Coronavirus , Hipertensão/tratamento farmacológico , Pandemias , Pneumonia Viral , Sistema Renina-Angiotensina , Antagonistas de Receptores de Angiotensina/efeitos adversos , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/uso terapêutico , Betacoronavirus , Doenças Cardiovasculares/complicações , Infecções por Coronavirus/complicações , Humanos , Hipertensão/complicações , Itália , Pneumonia Viral/complicações , Sistema Renina-Angiotensina/efeitos dos fármacos
6.
J Clin Endocrinol Metab ; 105(7)2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32303754

RESUMO

CONTEXT: The clinical spectrum and knowledge of the molecular mechanisms underlying primary aldosteronism (PA), the most frequent form of endocrine hypertension, has evolved over recent years. In accordance with the Endocrine Society guidelines and in light of the growing evidence showing adverse cardiovascular outcomes, it is expected that a progressively wider population of patients affected by hypertension will be screened for PA, including the elderly. EVIDENCE ACQUISITION: A systematic search of PubMed was undertaken for studies related to the renin-angiotensin-aldosterone system (RAAS), PA, and adrenal histopathology in the elderly population. EVIDENCE SYNTHESIS: Several studies showed an age-dependent decrease in the activity of RAAS, together with a progressive decrease of the aldosterone response to sodium intake, particularly after the sixth decade of life. The positive correlation between age and serum aldosterone during liberal sodium intake over serum aldosterone during sodium restriction is paralleled by histological changes in adrenal aldosterone synthase (CYP11B2) expression patterns. Immunohistochemical studies showed a progressive loss of the continuous expression of CYP11B2 in the adrenal zona glomerulosa with aging and a concomitant increase of aldosterone-producing cell clusters, which might be responsible for relatively autonomous aldosterone production. Additionally, following PA confirmation and subtype diagnosis, older age is correlated with a lower benefit after adrenalectomy for unilateral PA. CONCLUSIONS: Accumulating evidence suggests that RAAS physiology and regulation show age-related changes. Further studies may investigate to what extent these variations might affect the diagnostic workup of patients affected by PA.

7.
Artigo em Inglês | MEDLINE | ID: mdl-32147420

RESUMO

Low-renin hypertension (LRH) is a frequent condition in patients with arterial hypertension, accounting for 30% of patients. Monogenic forms can cause LRH in a minority of cases. However, in the large majority of patients, LRH is caused by the combined effects of congenital and acquired factors, comprising dietary habits. Several genetic variants have been proposed as co-factors in the pathogenesis of LRH with normal-low serum aldosterone. Emerging evidences support the hypothesis that a large proportion of LRH with normal-high serum aldosterone is associated with subclinical primary aldosteronism (PA). The recent identification of aldosterone-producing cell clusters (APCCs) as the possible cause of subclinical PA, further supported the concept of a continuous spectrum of autonomous aldosterone secretion, from subclinical forms towards overt PA. In this review we describe the main aspects of LRH, focusing on molecular basis, clinical risk profile and patients' management.

8.
Hypertension ; 75(4): 1025-1033, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32114853

RESUMO

Primary aldosteronism (PA) was considered a rare disorder almost always associated with hypokalemia. The widespread screening of patients with hypertension unveiled an increased prevalence of PA with normokalemic hypertension the prevailing phenotype. Many studies have reported the prevalence of hypokalemia in patients with PA; conversely, the prevalence of PA in patients with hypokalemia is unknown. In this retrospective observational study, we define the prevalence of hypokalemia in referred patients with hypertension and the prevalence of PA in patients with hypokalemia and hypertension. Hypokalemia was present in 15.8% of 5100 patients with hypertension, whereas 76.9% were normokalemic, and 7.3% hyperkalemic. The prevalence of PA in patients with hypokalemia was 28.1% and increased with decreasing potassium concentrations up to 88.5% of patients with spontaneous hypokalemia and potassium concentrations <2.5 mmol/L. A multivariate regression analysis demonstrated the association of hypokalemia with the occurrence of cardiovascular events independent of PA diagnosis. An association of PA with the occurrence of cardiovascular events and target organ damage independent of hypokalemia was also demonstrated. In conclusion, our results confirm that PA is a frequent cause of secondary hypertension in patients with hypokalemia, and the presence of hypertension and spontaneous hypokalemia are strong indications for PA diagnosis. Finally, we show that PA and hypokalemia are associated with an increased risk of cardiovascular events.

9.
Horm Metab Res ; 52(6): 366-372, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32219799

RESUMO

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.

10.
Horm Cancer ; 11(1): 52-62, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32002807

RESUMO

Primary aldosteronism (PA) is the most common cause of secondary hypertension with a high prevalence among patients with resistant hypertension. Despite the recent discovery of somatic variants in aldosterone-producing adenoma (APA)-associated PA, causes for PA due to bilateral aldosterone production (bilateral hyperaldosteronism; BHA) remain unknown. Herein, we identified rare gene variants in ATP2B4, in a cohort of patients with BHA. ATP2B4 belongs to the same family of Ca-ATPases as ATP2B3, which is involved in the pathogenesis of APA. Endogenous ATP2B4 expression was characterized in adrenal tissue, and the gene variants were functionally analyzed for effects on aldosterone synthase (CYP11B2) expression, steroid production in basal and agonist-stimulated conditions, and for changes in biophysical properties of channel properties. Knockdown of ATP2B4 in HAC15 exhibited reduced angiotensin II stimulation in one of four shRNA clones. Stable HAC15 cell lines with doxycycline (dox) - inducible wild-type and variant forms of ATP2B4 - were generated, and dox-induced upregulation of ATP2B4 mRNA and protein was confirmed. However, ATP2B4 variants did not alter basal or agonist-stimulated CYP11B2 expression. Whole-cell recordings in HAC15 cells indicated robust endogenous ATP2B4 conductance in native cells but reduced conductance with overexpressed WT and variant ATP2B4. The previously defined PA-causing ATP2B3 variant served as a positive control and exhibited elevated CYP11B2 mRNA. In conclusion, while this study did not confirm a pathogenic role for ATP2B4 variants in BHA, we describe the sequencing analysis for familial and sporadic BHA and outline a template for the thorough in vitro characterization of gene variants.

11.
J Clin Endocrinol Metab ; 105(3)2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31789380

RESUMO

CONTEXT: Aldosterone-producing adrenocortical adenomas (APAs) are mainly composed of clear (lipid rich) and compact (eosinophilic) tumor cells. The detailed association between these histological features and somatic mutations (KCNJ5, ATP1A1, ATP2B3, and CACNA1D) in APAs is unknown. OBJECTIVE: To examine the association between histological features and individual genotypes in APAs. METHODS: Examination of 39 APAs subjected to targeted next-generation sequencing (11 KCNJ5, 10 ATP1A1, 10 ATP2B3, and 8 CACNA1D) and quantitative morphological and immunohistochemical (CYP11B2 and CYP17A1) analyses using digital imaging software. RESULTS: KCNJ5- and ATP2B3-mutated APAs had clear cell dominant features (KCNJ5: clear 59.8% [54.4-64.6%] vs compact 40.2% (35.4-45.6%), P = .0022; ATP2B3: clear 54.3% [48.2-62.4 %] vs compact 45.7% (37.6-51.8 %), P = .0696). ATP1A1- and CACNA1D-mutated APAs presented with marked intratumoral heterogeneity. A significantly positive correlation of immunoreactivity was detected between CYP11B2 and CYP17A1 in tumor cells of KCNJ5-mutated APAs (P = .0112; ρ = 0.7237), in contrast, significantly inverse correlation was detected in ATP1A1-mutated APAs (P = .0025; ρ = -0.8667). CONCLUSION: KCNJ5-mutated APAs, coexpressing CYP11B2 and CYP17A1, were more deviated in terms of zonation-specific differentiation of adrenocortical cells than ATP1A1- and ATP2B3-mutated APAs.

12.
J Hypertens ; 38(1): 3-12, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31385870

RESUMO

OBJECTIVES: In experimental animal models, exogenous aldosterone excess has been linked to the progression of renal disease. However, the evidence of an increased risk of renal damage in patients affected by primary aldosteronism remains controversial. We aimed at evaluating the association between primary aldosteronism and renal damage through a meta-analysis. METHODS: We performed a quantitative review of studies evaluating parameters of renal function in patients affected by primary aldosteronism compared with hypertensive patients without primary aldosteronism and in patients affected by primary aldosteronism before and after treatment. We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from January 1960 up to April 2019. RESULTS: Forty-six studies including 6056 patients with primary aldosteronism and 9733 patients affected by arterial hypertension without primary aldosteronism were included. After 8.5 years from hypertension diagnosis, patients with primary aldosteronism had an increased estimated glomerular filtration rate (eGFR) compared with hypertensive patients without primary aldosteronism [by 3.37 ml/min IQR (0.82-5.93)] and a more severe albuminuria [standard mean difference 0.55 (0.19-0.91)], resulting into an association with microalbuminuria [odds ratio (OR) 2.09 (1.40; 3.12)] and proteinuria [OR 2.68 (1.89;3.79)]. Following primary aldosteronism treatment, after a median follow-up of 12 months, a reduction in eGFR was observed [by -10.69 ml/min (-13.23; -8.16)], consistent in both medically and surgically treated patients. Similarly, a reduction in albumin excretion and an increase in serum creatinine were observed after treatment. CONCLUSION: Patients affected by primary aldosteronism, compared with patients affected by arterial hypertension without primary aldosteronism, display a more pronounced target organ damage, which can be mitigated by the specific treatment.

13.
Hypertension ; 75(1): 163-172, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31760886

RESUMO

Primary aldosteronism is recognized as the most frequent cause of secondary hypertension, and its screening is expected to become a routine evaluation in most patients with hypertension. The interference of antihypertensive therapies with the aldosterone-to-renin ratio during screening process is a major confounder. Renin-angiotensin-aldosterone system Triple-A analysis is a novel liquid chromatography/tandem mass spectrometry diagnostic assay that allows simultaneous quantification of aldosterone, equilibrium Ang I (angiotensin I), and Equilibrium Ang II in a single sample of serum. We performed a comparative evaluation of the diagnostic performance of the aldosterone-to-Ang II ratio and 5 renin-based diagnostic ratios, differing in methods to determine aldosterone levels and renin activity in a cohort of 110 patients with hypertension (33 patients with confirmed primary aldosteronism and 77 with essential hypertension). All ratios showed comparable areas under the curves ranging between 0.924 and 0.970 without significant differences between each other. The evaluation of the Ang II-to-Ang I ratio revealed persistent drug intake in some patients as cause for suppressed renin-based diagnostic ratios, while aldosterone-to-Ang II ratio remained unaffected. The Youden index optimal cutoff value for the aldosterone-to-Ang II ratio was 6.6 ([pmol/L]/[pmol/L]) with a sensitivity of 90% and a specificity of 93%, proving noninferiority compared with the aldosterone-to-renin ratio while pointing to the potential for an interference-free application in patients under ACE (angiotensin-converting enzyme) inhibitor therapy. This study shows for the first time the accuracy and reliability of renin-angiotensin-aldosterone system triple-A analysis for the screening of primary aldosteronism that can be applied in clinical routine.

14.
Hypertension ; 74(6): 1532-1540, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31679423

RESUMO

The association between primary aldosteronism (PA) and obstructive sleep apnea (OSA) has been a matter of debate. 2016 Endocrine Society guideline recommends screening for PA all hypertensive patients with OSA. We designed a multicenter, multiethnic, cross-sectional study to evaluate the prevalence of PA in patients with OSA and the prevalence of OSA in unselected patients with PA. Two hundred and three patients with OSA (102 whites and 101 Chinese) were screened for PA, and 207 patients with PA (104 whites, 100 Chinese, and 3 of African descent) were screened for OSA by cardiorespiratory polygraphy. Eighteen patients with OSA (8.9%) had PA (11.8% of white and 5.9% of Chinese ethnicity). In patients without other indications for PA screening, the prevalence of PA dropped to 1.5%. The prevalence of OSA in patients with PA was 67.6%, consistent in both white and Chinese patients. A correlation between aldosterone levels and apnea/hypopnea index was observed in white patients with PA (R2=0.225, P=0.016) but not in Chinese patients. Multinomial logistic regression confirmed a significant and independent association between plasma aldosterone levels and moderate to severe OSA diagnosis in white patients (odds ratio, 1.002; P=0.002). In conclusion, aldosterone levels may contribute to the severity of OSA in white patients with hyperaldosteronism, but patients with OSA are not at high risk of PA. Results of the present study challenge the current recommendation of the Endocrine Society guideline that all patients with OSA should be screened for PA, irrespective of the grade of hypertension.

15.
Hypertens Res ; 2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31586159

RESUMO

The available data on the natural history of pheochromocytomas and paragangliomas after radical surgery are heterogeneous and discordant. The aim of our retrospective multicenter study was to find predictors of recurrence in patients with pheochromocytomas and sympathetic paragangliomas submitted to radical surgery in Piedmont (a region in northwest Italy). We collected data from 242 patients diagnosed between 1990 and 2016. Forty-two patients (17.4%) had disease recurrence. Multivariate analysis showed that genetic mutation (HR = 3.62; 95% CI 1.44-9.13; p = 0.006), younger age (HR = 0.97; 95% CI 0.95-0.99; p = 0.031) and larger tumor size (HR = 1.01; 95% CI 1.00-1.02; p = 0.015) were independently associated with a higher recurrence risk of pheochromocytoma and paraganglioma; in pheochromocytomas, genetic mutation (HR = 3.4; 95% CI 1.00-11.48; p = 0.049), younger age (HR = 0.97; 95% CI 0.94-0.99; p = 0.02), higher tumor size (HR = 1.01; 95% CI 1.00-1.03; p = 0.043) and PASS value (HR = 1.16; 95% CI 1.03-1.3; p = 0.011) were associated with recurrence. Moreover, tumor size was the only predictor of metastatic pheochromocytoma and paraganglioma (HR = 4.6; 95% CI 1.4-15.0; p = 0.012); tumor size (HR = 3.93; 95% CI 1.2-16.4; p = 0.026) and PASS value (HR = 1.27; 95% CI 1.06-1.53; p = 0.007) were predictors of metastatic pheochromocytoma. In conclusion, our findings suggest that the recurrence of pheochromocytoma and sympathetic paraganglioma develops more frequently in younger subjects, patients with a family history of chromaffin tissue neoplasms, mutations in susceptibility genes, larger tumors and higher values of PASS. We recommend genetic testing in all patients with PPGL and strict follow-up at least on an annual basis.

16.
Hypertension ; 74(2): 359-367, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31230554

RESUMO

Patients affected by primary aldosteronism (PA) display an increased risk of cardiovascular events compared with essential hypertension (EH). Endothelial dysfunction favors initiation and progression of atherosclerosis and circulating extracellular vesicles (EVs), reflecting endothelial cell activity, could represent one of the mediators of endothelial dysfunction in these patients. The aim of this study was to characterize circulating EVs from patients diagnosed with PA and to explore their functional significance. Serum EVs were isolated from 12 patients with PA and 12 with EH, matched by sex, age, and blood pressure, and compared with 8 normotensive controls. At nanoparticle tracking analysis, EVs concentration was 2.2× higher in patients with PA ( P=0.033) compared with EH and a significant correlation between EV number and serum aldosterone and potassium levels was identified. Fluorescence-activated cell sorting analysis demonstrated that patients with PA presented a higher absolute number of endothelial-derived EVs compared with both patients with EH and normotensive controls. Through EV mRNA profiling, 15 up-regulated and 4 down-regulated genes in patients with PA compared with EH were identified; moreover, EDN1 was expressed only in patients with PA. Microarray platform was validated by quantative real-time polymerase chain reaction on 4 genes ( CASP1, EDN1, F2R, and HMOX1) involved in apoptosis, inflammation, and endothelial dysfunction. After unilateral adrenalectomy, EVs number and expression of CASP1 and EDN1 significantly decreased in patients with PA ( P<0.05). Additionally, the incubation with PA-derived EVs reduced angiogenesis and induced apoptosis in vitro. Circulating EVs might not only represent a marker of endothelial dysfunction but also contribute themselves to vascular dysfunction in patients with PA.


Assuntos
Hipertensão Essencial/fisiopatologia , Vesículas Extracelulares/genética , Regulação da Expressão Gênica/genética , Hiperaldosteronismo/genética , Neovascularização Patológica/genética , Adulto , Apoptose/genética , Estudos de Casos e Controles , Células Cultivadas , Hipertensão Essencial/genética , Feminino , Humanos , Hiperaldosteronismo/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Valores de Referência
17.
J Steroid Biochem Mol Biol ; 189: 274-282, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30654107

RESUMO

In primary aldosteronism (PA) the differentiation of unilateral aldosterone-producing adenomas (APA) from bilateral adrenal hyperplasia (BAH) is usually performed by adrenal venous sampling (AVS) and/or computed tomography (CT). CT alone often lacks the sensitivity to identify micro-APAs. Our objectives were to establish if steroid profiling could be useful for the identification of patients with micro-APAs and for the development of an online tool to differentiate micro-APAs, macro-APAs and BAH. The study included patients with PA (n = 197) from Munich (n = 124) and Torino (n = 73) and comprised 33 patients with micro-APAs, 95 with macro-APAs, and 69 with BAH. Subtype differentiation was by AVS, and micro- and macro-APAs were selected according to pathology reports. Steroid concentrations in peripheral venous plasma were measured by liquid chromatography-tandem mass spectrometry. An online tool using a random forest model was built for the classification of micro-APA, macro-APA and BAH. Micro-APA were classified with low specificity (33%) but macro-APA and BAH were correctly classified with high specificity (93%). Improved classification of micro-APAs was achieved using a diagnostic algorithm integrating steroid profiling, CT scanning and AVS procedures limited to patients with discordant steroid and CT results. This would have increased the correct classification of micro-APAs to 68% and improved the overall classification to 92%. Such an approach could be useful to select patients with CT-undetectable micro-APAs in whom AVS should be considered mandatory.


Assuntos
Adenoma/diagnóstico , Neoplasias das Glândulas Suprarrenais/diagnóstico , Glândulas Suprarrenais/patologia , Hiperaldosteronismo/diagnóstico , Esteroides/análise , Diagnóstico Diferencial , Feminino , Humanos , Hiperplasia/diagnóstico , Masculino
18.
Ann Surg ; 2019 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-30672800

RESUMO

MINI: Clinical remission after unilateral adrenalectomy to treat unilateral primary aldosteronism is achieved in less than half of patients. A linear discriminant model with 6 presurgical predictors of clinical remission was used to build a 25-point prediction score of postsurgical clinical outcomes. The prediction score was integrated into a user-friendly online tool which can be used in a clinical setting to differentiate patients who are likely to be clinically cured after surgery from those who will need continuous surveillance after surgery due to remnant hypertension. OBJECTIVE: To develop a prediction model for clinical outcomes after unilateral adrenalectomy for unilateral primary aldosteronism. SUMMARY BACKGROUND DATA: Unilateral primary aldosteronism is the most common surgically curable form of endocrine hypertension. Surgical resection of the dominant overactive adrenal in unilateral primary aldosteronism results in complete clinical success with resolution of hypertension without antihypertensive medication in less than half of patients with a wide between-center variability. METHODS: A linear discriminant analysis model was built using data of 380 patients treated by adrenalectomy for unilateral primary aldosteronism to classify postsurgical clinical outcomes. The total cohort was then randomly divided into training (280 patients) and test (100 patients) datasets to create and validate a score system to predict clinical outcomes. An online tool (Primary Aldosteronism Surgical Outcome predictor) was developed to facilitate the use of the predictive score. RESULTS: Six presurgical factors associated with complete clinical success (known duration of hypertension, sex, antihypertensive medication dosage, body mass index, target organ damage, and size of largest nodule at imaging) were selected based on classification performance in the linear discriminant analysis model. A 25-point predictive score was built with an optimal cut-off of greater than 16 points (accuracy of prediction = 79.2%; specificity = 84.4%; sensitivity = 71.3%) with an area under the curve of 0.839. CONCLUSIONS: The predictive score and the primary aldosteronism surgical outcome predictor can be used in a clinical setting to differentiate patients who are likely to be clinically cured after surgery from those who will need continuous surveillance after surgery due to persistent hypertension.

19.
Proteomics Clin Appl ; 13(4): e1800049, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30580498

RESUMO

PURPOSE: The current clinical investigation for primary aldosteronism (PA) diagnosis requires complex expensive tests from the initial suspicion to the final subtype classification, including invasive approaches; therefore, appropriate markers for subtype definition are greatly desirable. The present study performs a metabolomics analysis to further examine specific molecular signatures of PA urines EXPERIMENTAL DESIGN: The study considered PA subtype and gender-related differences using two orthogonal advanced UHPLC-MS metabolomics approaches. Patients with essential hypertension (n = 36) and PA (n = 50) who were referred to the outpatient hypertension clinic and matched healthy subjects (n = 10) are investigated. RESULTS: Statistically significant changes (p < 0.05 ANOVA, Fc > 1.5) of metabolites involved in central carbon, energy, and nitrogen metabolism are identified, especially purine and pyrimidine nucleosides and precursors, and free amino acids. PLS-DA interpretation provides strong evidence of a disease-specific metabolic pattern with dAMP, diiodothyronine, and 5-methoxytryptophan as leading factors, and a sex-specific metabolic pattern associated with orotidine 5-phosphate, N-acetylalanine, hydroxyproline, and cysteine. The results are verified using an independent sample set, which confirms the identification of specific signatures. CONCLUSIONS AND CLINICAL RELEVANCE: Metabolomics is used to identify low molecular weight molecular markers of PA, which paves the way for follow-up validation studies in larger cohorts.


Assuntos
Hipertensão Essencial/urina , Hiperaldosteronismo/urina , Caracteres Sexuais , Biomarcadores/urina , Feminino , Humanos , Masculino , Metabolômica , Pessoa de Meia-Idade
20.
J Hypertens ; 37(3): 603-611, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30431526

RESUMO

: Nowadays most patients diagnosed with surgically curable primary aldosteronism have small or micro aldosterone-producing adenoma or unilateral micronodular hyperplasia, which are undetectable with available imaging technologies. Therefore, a negative imaging test by no means excludes unilateral primary aldosteronism. Moreover, about 10% of the subjects above the age of 35 years have nonfunctioning adrenal tumors, regardless of being hypertensive or not, with a prevalence that raises with aging. Hence, the finding of an adrenal mass at imaging does not reliably detect the culprit of primary aldosteronism. On the other hand, when primary aldosteronism patients are selected for adrenalectomy on the basis of demonstration of lateralized aldosterone excess at adrenal vein sampling (AVS), close to 100% are biochemically cured from the hyperaldosteronism, about 45% are cured of arterial hypertension and an additional 52% are markedly improved in terms of blood pressure control. By contrast, patients referred for surgery based on imaging alone often fail to reach these successful outcomes, indicating that surgery was unnecessary or, even worse, performed on the wrong side. For these reasons, and because of the lack of accurate and widely available alternative methods, all current guidelines recommend that AVS be offered to all primary aldosteronism patients with only few exceptions, mainly in patients unable or unwilling to undergo surgery and those with germ-line mutations causing familial primary aldosteronism. The main argument against systematic use of AVS entails its suboptimal performance, partly justified by its intrinsic technical difficulty, and its limited availability. This led to propose skipping AVS strategies for predicting surgically curable primary aldosteronism, but success has been inconsistent. The most urgent standing issue is, therefore, not to find loopholes to avoid AVS, but rather to improve its use, which means improving the rate of AVS success, through formal training of interventionists, selection of appropriate cutoffs and exploitation of a standardized procedure.


Assuntos
Glândulas Suprarrenais/irrigação sanguínea , Adrenalectomia , Coleta de Amostras Sanguíneas/métodos , Hiperaldosteronismo , Humanos , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/cirurgia , Encaminhamento e Consulta
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