RESUMO
BACKGROUND: While clinical features of KCNJ5-mutated aldosterone-producing adenoma (APA) have been reported, evidence of its clinical outcomes is lacking. We aimed to synthesize available literature about the associations between KCNJ5 mutation with cardiovascular and metabolic outcomes among patients with APA. METHODS: In this systematic review of observational studies, MEDLINE and Embase were searched through August 2022. Two independent authors screened the search results and extracted data from eligible observational studies investigating cardiovascular or metabolic outcomes between KCNJ5-mutated APAs and KCNJ5-non-mutated APAs. Risk of Bias In Non-randomized Studies of Interventions was used to assess the quality of the included studies. RESULTS: A total of 573 titles/abstracts were screened and after the expert opinion of the literature, full text was read in 20 titles/abstracts, of which 12 studies were included. Across 3 studies comparing the baseline or change in the cardiac function between KCNJ5-mutated APAs and KCNJ5-non-mutated APAs, all studies reported the association between impaired cardiac functions and KCNJ5 mutation status. Among 6 studies evaluating the cure of hypertension after surgery, all studies showed that KCNJ5 mutation was significantly associated with the cure of hypertension. In quality assessment, 7 studies were at serious risk of bias, while the remaining studies were at moderate risk of bias. CONCLUSIONS: This systematic review provided evidence of the significant association between KCNJ5 mutation and unfavorable cardiovascular outcomes in patients with primary aldosteronism. Further research is needed to improve the quality of evidence on this topic and elucidate the underlying mechanisms of the potential burden of KCNJ5 mutation.
Assuntos
Aldosterona , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G , Mutação , Humanos , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Aldosterona/metabolismo , Aldosterona/biossíntese , Doenças Cardiovasculares/genética , Neoplasias do Córtex Suprarrenal/genética , Hiperaldosteronismo/genética , Adenoma Adrenocortical/genética , Adenoma Adrenocortical/metabolismo , Adenoma/genética , Adenoma/metabolismoRESUMO
BACKGROUND: You Only Look Once version 5 (YOLOv5), a one-stage deep-learning (DL) algorithm for object detection and classification, offers high speed and accuracy for identifying targets. PURPOSE: To investigate the feasibility of using the YOLOv5 algorithm to non-invasively distinguish between aldosterone-producing adenomas (APAs) and non-functional adrenocortical adenomas (NF-ACAs) on computed tomography (CT) images. MATERIAL AND METHODS: A total of 235 patients who were diagnosed with ACAs between January 2011 and July 2022 were included in this study. Of the 215 patients, 81 (37.7%) had APAs and 134 (62.3%) had NF-ACAs' they were randomly divided into either the training set or the validation set at a ratio of 9:1. Another 20 patients, including 8 (40.0%) with APA and 12 (60.0%) with NF-ACA, were collected for the testing set. Five submodels (YOLOv5n, YOLOv5s, YOLOv5m, YOLOv5l, and YOLOv5x) of YOLOv5 were trained and evaluated on the datasets. RESULTS: In the testing set, the mAP_0.5 value for YOLOv5x (0.988) was higher than the values for YOLOv5n (0.969), YOLOv5s (0.965), YOLOv5m (0.974), and YOLOv5l (0.983). The mAP_0.5:0.95 value for YOLOv5x (0.711) was also higher than the values for YOLOv5n (0.587), YOLOv5s (0.674), YOLOv5m (0.671), and YOLOv5l (0.698) in the testing set. The inference speed of YOLOv5n was 2.4â ms in the testing set, which was the fastest among the five submodels. CONCLUSION: The YOLOv5 algorithm can accurately and efficiently distinguish between APAs and NF-ACAs on CT images, especially YOLOv5x has the best identification performance.
Assuntos
Neoplasias do Córtex Suprarrenal , Adenoma Adrenocortical , Aldosterona , Tomografia Computadorizada por Raios X , Humanos , Masculino , Feminino , Neoplasias do Córtex Suprarrenal/diagnóstico por imagem , Neoplasias do Córtex Suprarrenal/metabolismo , Adenoma Adrenocortical/diagnóstico por imagem , Adenoma Adrenocortical/metabolismo , Pessoa de Meia-Idade , Aldosterona/metabolismo , Tomografia Computadorizada por Raios X/métodos , Adulto , Diagnóstico Diferencial , Estudos de Viabilidade , Idoso , Aprendizado Profundo , Algoritmos , Estudos RetrospectivosRESUMO
Unilateral primary aldosteronism is thought to be a surgically curable disease, and unilateral adrenalectomy is the mainstay treatment. The Primary Aldosteronism Surgical Outcome (PASO) consensus was developed to assess clinical and biochemical outcomes to standardize the classification of surgical outcomes. However, fewer than half of patients are cured of hypertension after adrenalectomy; therefore, preoperative patient counseling and evaluation might be necessary. Moreover, current studies show that genetic mutations and histopathology classification are associated with the treatment outcome. The Task Force of Taiwan PA recommends using a specific scoring system, including the PASO score and nomogram-based preoperative score, to predict the clinical outcome before adrenalectomy. Herein, we discuss the associations of current histopathological classification and specific somatic gene mutations with clinical outcomes after surgery.
Assuntos
Hiperaldosteronismo , Hipertensão , Humanos , Estudos Retrospectivos , Hiperaldosteronismo/genética , Hiperaldosteronismo/cirurgia , Resultado do Tratamento , Adrenalectomia , Hipertensão/complicaçõesRESUMO
Complete resolution of hypertension (CRH) after adrenalectomy for primary aldosteronism is far from a certainty. Although several prognostic models have been proposed to predict outcome after adrenalectomy, studies have not clarified which of the available models can be used reliably in clinical practice. To identify, describe and appraise all prognostic models developed to predict CRH, and meta-analyse their predictive performances. We searched MEDLINE, Embase and Web of Science for development and validation studies of prognostic models. After selection, we extracted descriptive statistics and aggregated area under the receiver operator curve (AUC) using meta-analysis. From 25 eligible studies, we identified 12 prognostic models used for predicting CRH after total adrenalectomy in primary aldosteronism. We report the results for 3 models that had available data from at least 3 external validation studies: the primary aldosteronism surgical outcome (PASO) score (AUC: 0.81; 95% confidence interval [CI]: 0.74-0.86; 95% predictive interval [PI]: 0.04-1.00), Utsumi nomogram (AUC: 0.79; 95% CI: 0.72-0.85; 95% PI: 0.03-1.00) and the aldosteronoma resolution score (ARS) model (AUC: 0.77; 95% CI: 0.74-0.80; 95% PI: 0.59-0.86 for all studies and AUC: 0.80; 95% CI: 0.75-0.85; 95% PI: 0.57-0.93 for the studies with the same adrenal vein sampling-guided adrenalectomy rate compared to the models meta-analysed). The PASO score, Utsumi nomogram and ARS model showed comparable discrimination performance to predict CRH in primary aldosteronism. Unlike the ARS model, the number of external validation studies for the PASO score and the Utsumi nomogram was relatively low to draw definite conclusions.
Assuntos
Adenoma Adrenocortical , Hiperaldosteronismo , Hipertensão , Humanos , Prognóstico , Adrenalectomia , Hipertensão/cirurgia , Hiperaldosteronismo/cirurgia , Estudos Retrospectivos , AldosteronaRESUMO
Hyperkalemia is developed in a part of patients with aldosterone-producing adenoma (APA) after adrenalectomy, suspected to be due to the insufficiency of aldosterone secretion. The purpose of this study is to determine the frequency and characteristics of prolonged postoperative hypoaldosteronism (PPHA) using chemiluminescent enzyme immunoassay (CLEIA). We studied 58 patients with APA with long time after adrenalectomy and whose PAC was measured using a CLEIA kit. The PAC value measured using CLEIA was significantly lower than that of using RIA between two consecutive visits before and after the shift of measuring method of PAC (median [interquantile range], 123.0 [99.8-164.0] vs. 39.5 [15.8-64.2] pg/mL, p < 0.01). PAC was below the minimum limit of quantification (4.0 pg/mL) of the CLEIA kit at least once in nine patients (15.5%) who had PPHA. The PPHA group were older (mean ± standard deviation, 61.3 ± 8.5 vs. 50.5 ± 10.1 years, p < 0.01) and had lower eGFR (60.3 ± 14.0 vs. 82.3 ± 22.8 mL/min/1.73 m2, p < 0.01) than the non-PPHA group. The frequency of postoperative hyperkalemia (maximum serum potassium >5.5 mEq/L) was higher in the PPHA group than in the non-PPHA group (55.6% vs. 8.2%, p < 0.01). In conclusion, a few patients with APA long time after adrenalectomy had unmeasurable PAC using CLEIA. PPHA is likely to develop in patients with APA after adrenalectomy who are older and have impaired renal function. Additionally, PPHA is related to the occurrence of postoperative hyperkalemia.
Assuntos
Adenoma , Adenoma Adrenocortical , Hiperaldosteronismo , Hiperpotassemia , Hipertensão , Hipoaldosteronismo , Humanos , Hiperpotassemia/etiologia , Hiperpotassemia/epidemiologia , Aldosterona , Hiperaldosteronismo/complicações , Hiperaldosteronismo/cirurgia , Adenoma Adrenocortical/complicações , Adenoma Adrenocortical/cirurgia , Adrenalectomia/efeitos adversos , Adenoma/complicações , Adenoma/cirurgiaRESUMO
Laparoscopic adrenalectomy is currently the standard treatment modality for unilateral aldosterone-producing adenoma (APA); however, a less-invasive treatment is needed for its treatment. A new bipolar ablation system that poses a lower risk of complications has been recently developed. This study aimed to evaluate the safety and performance of a novel bipolar radiofrequency ablation (RFA) system for the treatment of APAs. Ablations were performed in an ex vivo study using bovine adrenal glands [group A: n = 6, single-probe; group B: n = 6, two probes, interprobe distance (ID) = 12 mm; group C: n = 6, two probes, ID = 20 mm]. The in vivo study was conducted in groups A and B (n = 2 each) using porcine adrenal glands. For the ex vivo study, the mean vertical diameter (Dv) of the coagulative necrosis area and the mean transverse diameter (Dt) values were 11.99 mm and 10.96 mm for group A, 12.66 mm and 10.0 mm for group B, and 23.37 mm and 22.10 mm for group C, respectively. For the in vivo study, the mean Dv and Dt values were 12.23 mm and 9.03 mm for group A, and 16.38 mm and 9.52 mm for group B, respectively. No heat-induced damage to the adjacent organs was observed. To our best knowledge, this is the first study to evaluate the performance of the bipolar system in RFA of the adrenal gland. RFA using the new bipolar ablation system is safe and produces a sufficient coagulation area to treat APAs.
Assuntos
Ablação por Cateter , Ablação por Radiofrequência , Animais , Bovinos , Suínos , Fígado/cirurgia , Necrose/cirurgia , Glândulas Suprarrenais/cirurgiaRESUMO
PURPOSE: Mineralocorticoid receptor antagonists are the first-line treatment for bilateral adrenal hyperplasia (BAH) with primary aldosteronism (PA), while unilateral adrenalectomy is the standard treatment for aldosterone-producing adenoma (APA). In this study, we investigated the outcomes of patients with BAH after unilateral adrenalectomy and compared them with those of patients with APA. METHODS: From January 2010 to November 2018, 102 patients with a diagnosis of PA confirmed by adrenal vein sampling (AVS) and available NP-59 scans were enrolled. All patients underwent unilateral adrenalectomy based on the lateralization test results. We prospectively collected the clinical parameters over 12 months and compared the outcomes of BAH and APA. RESULTS: A total of 102 patients were enrolled in this study: 20 (19.6%) had BAH and 82 (80.4%) had APA. Significant improvements in serum aldosterone-renin ratio (ARR), potassium level, and reduction of antihypertensive drugs were observed in both groups at 12 months after surgery (all p < 0.05). Patients with APA showed a significant decrease in blood pressure after surgery (p < 0.001) than those with BAH. Additionally, multivariate logistic regression analysis indicated that APA was associated with biochemical success (odds ratio: 4.32, p = 0.024) compared to BAH. CONCLUSION: Patients with BAH had a higher failure rate in clinical outcomes, and APA was associated with biochemical success after unilateral adrenalectomy. However, significant improvements in ARR, hypokalemia, and a decreased use of antihypertensive drugs were noted in patients with BAH after surgery. Unilateral adrenalectomy is feasible and beneficial in selected patients, and could potentially serve as a treatment option.
Assuntos
Adrenalectomia , Hiperaldosteronismo , Humanos , Hiperaldosteronismo/etiologia , Hiperaldosteronismo/cirurgia , Aldosterona , Hiperplasia , Anti-Hipertensivos/uso terapêuticoRESUMO
Primary aldosteronism (PA) is a typical example of low renin hypertension, whereas renal artery stenosis (RAS) is a classic form of high renin hypertension. PA and RAS occurring simultaneously in a patient is challenging to diagnose. We report a 32-year-old woman with a 12-year history of resistant hypertension. She was identified to have elevated plasma aldosterone and renin levels with normal aldosterone/renin ratio (ARR). Imaging examinations identified bilateral adrenal thickening and subtotal occlusion of the anterior segment of the left renal artery. Adrenal venous sampling was performed and indicated the existence of unilateral aldosterone over-secretion. It may suggest that even though RAS led to non-suppressed renin, adrenal venous sampling remains to be an applicable approach to establish the diagnosis of aldosterone-producing adenomas, although the diagnostic value of ARR may be compromised due to non-suppressed renin level. The patient underwent a two-stage treatment. First, stenosis of the left renal artery was dilated by percutaneous transluminal renal balloon angioplasty. Two months later, laparoscopic complete left adrenalectomy was performed. Hematoxylin-eosin staining and CYP11B2 immunostaining suggested that this tumor was an aldosterone-producing adenoma. After the two-stage treatment, her blood pressure decreased to a normal level without antihypertensive drugs. This case report raises our awareness of the simultaneous occurrence of RAS and PA. Under this condition, ARR could lead to a false-negative PA. Adrenal venous sampling is warranted to achieve a confirmed diagnosis. For subjects with complex etiologies of secondary hypertension, multi-stage treatment may be required.
Assuntos
Hiperaldosteronismo , Hipertensão , Obstrução da Artéria Renal , Humanos , Feminino , Adulto , Aldosterona/uso terapêutico , Renina , Obstrução da Artéria Renal/complicações , Obstrução da Artéria Renal/diagnóstico , Hiperaldosteronismo/complicações , Hiperaldosteronismo/diagnóstico , Hipertensão/tratamento farmacológicoRESUMO
Aldosterone-producing adenoma (APA) is a common cause of secondary hypertension. This study aimed to explore the lncRNA-miRNA-mRNA competitive endogenous RNA (ceRNA) network to uncover molecular mechanism underlying APA. The mRNA and lncRNA expression data of APA and adjacent adrenal gland (AAG) from GSE60044, GSE64957 and GSE101894 were obtained from the Gene Expression Omnibus (GEO) database to analyse differentially expressed genes (DEGs) and lncRNAs (DElncs). Hub genes were identified by robust rank aggregation (RRA) and protein-protein interaction (PPI) network analysis. The miRcode and miRWalk network tools were used to construct the ceRNA network. 1526 upregulated and 1512 downregulated DEGs were identified, which are mainly enriched in extracellular matrix and Ca2 + -related GO terms. In the KEGG pathway analysis, Ca2+ signalling and the aldosterone synthesis and secretion pathways were enriched. ceRNA network included 2 lncRNAs, 9 miRNAs, and 13 mRNAs. The lncRNAs are MEG3 and LINC00115. The mRNAs included CCND1, TP53, GPRC5B, BMI1, COMMD3-BMI1, ADAMTS15, STAT3, MMP2, SCN2B, CXCL12, HGF, FOS, and THBS1. Overall, this study conducted a ceRNA regulatory network analysis and identified that 2 lncRNAs and 13 mRNAs may contribute to the development of APA. These findings may provide novel diagnostic and intervention targets for APA.
Assuntos
Adenoma , MicroRNAs , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Aldosterona , Redes Reguladoras de Genes , Receptores Acoplados a Proteínas G/genéticaRESUMO
OBJECTIVE: We examined if measurement of adrenal androgens adds to subtype diagnostics of primary aldosteronism (PA) under cosyntropin-stimulated adrenal venous sampling (AVS). DESIGN: A prospective pre-specified secondary endpoint analysis of 49 patients with confirmed PA, of whom 29 underwent unilateral adrenalectomy with long-term follow-up. METHODS: Concentrations of androstenedione, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate (DHEAS) were measured during AVS in addition to aldosterone and cortisol. Subjects with lateralisation index (LI) of ≥4 were treated with unilateral adrenalectomy, and the immunohistochemical subtype was determined with CYP11B2 and CYP11B1 stains. The performance of adrenal androgens was evaluated by receiver operating characteristics (ROC) curve analyses in adrenalectomy and medical therapy groups. RESULTS: During AVS, the correlations between cortisol and androstenedione, DHEA and DHEAS for LI and selectivity index (SI) were highly significant. The right and left side SIs for androstenedione and DHEA were higher (p < .001) than for cortisol. In ROC analysis, the optimal LI cut-off values for androstenedione, DHEA and DHEAS were 4.2, 4.5 and 4.6, respectively. The performance of these LIs for adrenal androgens did not differ from that of cortisol. CONCLUSIONS: Under cosyntropin-stimulated AVS, the measurement of androstenedione and DHEA did not improve the cannulation selectivity. The performance of cortisol and adrenal androgens are confirmatory but not superior to cortisol-based results in lateralisation diagnostics of PA.
Assuntos
Hiperaldosteronismo , Glândulas Suprarrenais , Aldosterona , Androgênios , Androstenodiona , Cosintropina , Desidroepiandrosterona , Humanos , Hidrocortisona , Hiperaldosteronismo/diagnóstico , Estudos Prospectivos , Estudos RetrospectivosRESUMO
PURPOSE OF THE REVIEW: Primary aldosteronism (PA) is the leading cause of secondary hypertension, accounting for over 10% of patients with high blood pressure. It is characterized by autonomous production of aldosterone from the adrenal glands leading to low-renin levels. The two most common forms arise from bilateral adrenocortical hyperplasia (BAH) and aldosterone-producing adenoma (APA). We discuss recent discoveries in the genetics of PA. RECENT FINDINGS: Most APAs harbor variants in the KCNJ5, CACNA1D, ATP1A1, ATP2B3, and CTNNB1 genes. With the exception of ß-catenin (CTNNB1), all other causative genes encode ion channels; pathogenic variants found in PA lead to altered ion transportation, cell membrane depolarization, and consequently aldosterone overproduction. Some of these genes are found mutated in the germline state (CYP11B2, CLCN2, KCNJ5, CACNA1H, and CACNA1D), leading then to familial hyperaldosteronism, and often BAH rather than single APAs. Several genetic defects in the germline or somatic state have been identified in PA. Understanding how these molecular abnormalities lead to excess aldosterone contributes significantly to the elucidation of the pathophysiology of low-renin hypertension. It may also lead to new and more effective therapies for this disease acting at the molecular level.
Assuntos
Adenoma , Neoplasias do Córtex Suprarrenal , Neoplasias das Glândulas Suprarrenais , Adenoma Adrenocortical , Hiperaldosteronismo , Hipertensão , Adenoma/complicações , Adenoma/genética , Adenoma/metabolismo , Neoplasias do Córtex Suprarrenal/complicações , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias das Glândulas Suprarrenais/complicações , Adenoma Adrenocortical/complicações , Adenoma Adrenocortical/genética , Adenoma Adrenocortical/metabolismo , Aldosterona/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Humanos , Hiperaldosteronismo/complicações , Hiperaldosteronismo/genética , Hipertensão/genética , Mutação , Renina , ATPase Trocadora de Sódio-Potássio/genética , ATPase Trocadora de Sódio-Potássio/metabolismoRESUMO
Hypertension due to primary aldosteronism poses a risk of severe cardiovascular complications compared to essential hypertension. The discovery of the KCNJ5 somatic mutation in aldosteroene producing adenoma (APA) in 2011 and the development of specific CYP11B2 antibodies in 2012 have greatly advanced our understanding of the pathophysiology of primary aldosteronism. In particular, the presence of CYP11B2-positive aldosterone-producing micronodules (APMs) in the adrenal glands of normotensive individuals and the presence of renin-independent aldosterone excess in normotensive subjects demonstrated the continuum of the pathogenesis of PA. Furthermore, among the aldosterone driver mutations which incur excessive aldosterone secretion, KCNJ5 was a major somatic mutation in APA, while CACNA1D is a leading somatic mutation in APMs and idiopathic hyperaldosteronism (IHA), suggesting a distinctive pathogenesis between APA and IHA. Although the functional detail of APMs has not been still uncovered, its impact on the pathogenesis of PA is gradually being revealed. In this review, we summarize the integrated findings regarding APA, APM or diffuse hyperplasia defined by novel CYP11B2, and aldosterone driver mutations. Following this, we discuss the clinical implications of KCNJ5 mutations to support better cardiovascular outcomes of primary aldosteronism.
Assuntos
Adenoma , Adenoma Adrenocortical , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G , Hiperaldosteronismo , Adenoma/genética , Adenoma/patologia , Adenoma Adrenocortical/complicações , Adenoma Adrenocortical/genética , Aldosterona/genética , Citocromo P-450 CYP11B2/genética , Citocromo P-450 CYP11B2/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Humanos , Hiperaldosteronismo/etiologia , MutaçãoRESUMO
Primary aldosteronism (PA) is the most common cause of secondary hypertension, and a simpler non-invasive method for identification of aldosterone-producing adenoma (APA) is required to improve the standard of medical treatment for PA patients. We retrospectively analyzed the clinical data of hypertensive patients with an aldosterone/renin ratio (ARR) ≥30 (ng/dL)/(ng/mL/h), and surgical and/or adrenal venous sampling (AVS) results served as the gold standard for APA diagnosis. The study aimed to determine whether positive CCT and SIT results plus a unilateral adrenal nodule found by CT allow unambiguous identification of an APA with high diagnostic specificity. Clinical data from 71 APA and 47 non-APA patients were collected, and logistic regression analysis was performed to construct models. Receiver operating characteristic (ROC) curves were used to analyze the efficacy of diagnostic tests. The areas under the ROC curves (AUCs) were similar between the post-SIT plasma aldosterone concentration (PAC) and post-CCT PAC (p > 0.05). The optimal post-SIT and post-CCT PAC cutoff values were 17.2 and 21.2 ng/dL, respectively. Positive CT findings combined with a post-SIT PAC >17.2 ng/dL or post-CCT PAC >21.2 ng/dL provided specificities of 97.8% and 95.7% for predicting APA, respectively. Logistic diagnostic models 1 (M1, CT finding + post-SIT PAC) and 2 (M2, CT finding + post-CCT PAC) were built, which showed equivalent diagnostic value (AUC = 0.959 and 0.932, respectively) (p > 0.05). The models combining CT findings with post-SIT PACs or post-CCT PACs represent an easier method to distinguish APA patients from other hypertensive patients with positive upright ARR results, especially in primary care where AVS may be unavailable.
Assuntos
Testes de Função do Córtex Suprarrenal/métodos , Neoplasias do Córtex Suprarrenal/diagnóstico , Adenoma Adrenocortical/diagnóstico , Hiperaldosteronismo/diagnóstico , Tomografia Computadorizada por Raios X/métodos , Neoplasias do Córtex Suprarrenal/complicações , Glândulas Suprarrenais/diagnóstico por imagem , Adenoma Adrenocortical/complicações , Adulto , Inibidores da Enzima Conversora de Angiotensina , Captopril , Feminino , Humanos , Hiperaldosteronismo/complicações , Hipertensão/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Solução Salina , Sensibilidade e EspecificidadeRESUMO
The molecular mechanisms by which ATP1A1 mutation-mediated cell proliferation or tumorigenesis in aldosterone-producing adenomas (APAs) have not been elucidated. First, we investigated whether the APA-associated ATP1A1 L104R mutation stimulated cell proliferation. Second, we aimed to clarify the molecular mechanisms by which the ATP1A1 mutation-mediated cell proliferated. We performed transcriptome analysis in APAs with ATP1A1 mutation. ATP1A1 L104R mutation were modulated in human adrenocortical carcinoma (HAC15) cells (ATP1A1-mutant cells), and we evaluated cell proliferation and molecular signaling events. Transcriptome and immunohistochemical analysis showed that Na/K-ATPase (NKA) expressions in ATP1A1 mutated APA were more abundant than those in non-functioning adrenocortical adenoma or KCNJ5 mutated APAs. The significant increase of number of cells, amount of DNA and S-phase population were shown in ATP1A1-mutant cells. Fluo-4 in ATP1A1-mutant cells were significantly increased. Low concentration of ouabain stimulated cell proliferation in ATP1A1-mutant cells. ATP1A1-mutant cells induced Src phosphorylation, and low concentration of ouabain supplementation showed further Src phosphorylation. We demonstrated that NKAs were highly expressed in ATP1A1 mutant APA, and the mutant stimulated cell proliferation and Src phosphorylation in ATP1A1-mutant cells. NKA stimulations would be a risk factor for the progression and development to an ATP1A1 mutant APA.
Assuntos
Adenoma/patologia , Aldosterona/metabolismo , Proliferação de Células , ATPase Trocadora de Sódio-Potássio/genética , Adenoma/metabolismo , Adenoma Adrenocortical/metabolismo , Adenoma Adrenocortical/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citocromo P-450 CYP11B2/genética , Citocromo P-450 CYP11B2/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Humanos , Mutação , Ouabaína/farmacologia , Fosforilação/efeitos dos fármacos , Pontos de Checagem da Fase S do Ciclo Celular , ATPase Trocadora de Sódio-Potássio/metabolismo , Transcriptoma , Quinases da Família src/metabolismoRESUMO
The aim of this study was to reveal clear epidemiologic and clinical characteristics of incidentally discovered adrenal masses, termed adrenal incidentalomas (AIs), and to establish appropriate managemental and therapeutic regimens in Japan. This study had been originally carried out as a project of a research proposed on behalf of the Japanese Ministry of Health, Labour and Welfare, from 1999 to 2004. This nationwide multicenter study on AIs included 3,672 cases with clinically diagnosed AIs, involving 1,874 males and 1,738 females, with mean age 58.1 ± 13.0 years (mean ± SD). In the present study, we focused on the investigation of the real prevalence of various adrenal disorders with AI. The mean nodule size of AI based on computed tomography was 3.0 ± 2.0 cm. Compared to non-functioning adenomas (NFAs), tumor diameters were significantly larger in adrenocortical carcinomas (ACCs), pheochromocytomas, cortisol-producing adenomas (CPAs), myelolipomas, metastatic tumors, cysts, and ganglioneuromas (p < 0.01). Endocrinological evaluations demonstrated that 50.8% of total AIs were non-functioning adenomas, while 10.5%, including 3.6% with subclinical Cushing's syndrome, were reported as CPAs, 8.5% as pheochromocytomas, and 5.1% as aldosterone-producing adenomas. ACCs were accounted for 1.4% (50 cases) among our series of AIs. In conclusion, while almost 50 % of AIs are non-functional adenomas, we must be particularly careful as AIs include pheochromocytomas or adrenal carcinomas, because they may be asymptomatic. To our knowledge, this is the first and the largest investigation of AI, thus providing basic information for the establishment of clinical guidelines for the management of AI.
Assuntos
Neoplasias do Córtex Suprarrenal/epidemiologia , Neoplasias das Glândulas Suprarrenais/epidemiologia , Adenoma Adrenocortical/epidemiologia , Carcinoma Adrenocortical/epidemiologia , Feocromocitoma/epidemiologia , Adolescente , Neoplasias do Córtex Suprarrenal/diagnóstico , Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/patologia , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/metabolismo , Neoplasias das Glândulas Suprarrenais/patologia , Adenoma Adrenocortical/diagnóstico , Adenoma Adrenocortical/metabolismo , Adenoma Adrenocortical/patologia , Carcinoma Adrenocortical/diagnóstico , Carcinoma Adrenocortical/metabolismo , Carcinoma Adrenocortical/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Aldosterona/metabolismo , Catecolaminas/metabolismo , Criança , Pré-Escolar , Síndrome de Cushing/metabolismo , Feminino , Ganglioneuroma/diagnóstico , Ganglioneuroma/epidemiologia , Ganglioneuroma/patologia , Humanos , Hidrocortisona/metabolismo , Lactente , Recém-Nascido , Japão/epidemiologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mielolipoma/diagnóstico , Mielolipoma/epidemiologia , Mielolipoma/patologia , Feocromocitoma/diagnóstico , Feocromocitoma/metabolismo , Feocromocitoma/patologia , Tomografia Computadorizada por Raios X , Carga Tumoral , Ultrassonografia , Adulto JovemRESUMO
Primary aldosteronism is the most common form of secondary hypertension with a prevalence of 5-10% in hypertensive patients. Aldosterone-producing adenoma (APA) is a subtype of primary aldosteronism, and somatic mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, CLCN2, or CTNNB1 were identified and recognized to drive aldosterone production and/or contribute to tumorigenesis in APA. Mutations of KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CLCN2 are known to activate calcium signaling, and its activation potentiate CYP11B2 (aldosterone synthesis) transcription in adrenal cells. Transcriptome analyses combined with bioinformatics using APA samples were conductive for each gene mutation mediated pivotal pathway, gene ontology, and clustering. Several important intracellular molecules in increase aldosterone production were detected by transcriptome analysis, and additional functional analyses demonstrated intracellular molecular mechanisms of aldosterone production which focused on calcium signal, CYP11B2 transcription and translation. Furthermore, DNA methylation analysis revealed that promoter region of CYP11B2 was entirely hypomethylated, but that of other steroidogenic enzymes were not in APA. Integration of transcriptome and DNA methylome analysis clarified some DNA methylation associated gene expression, and the transcripts have a role for aldosterone production. In this article, we reviewed the intracellular molecular mechanisms of aldosterone production in APA, and discussed future challenges for basic studies leading to clinical practice.
Assuntos
Neoplasias do Córtex Suprarrenal/genética , Adenoma Adrenocortical/genética , Aldosterona/metabolismo , Hiperaldosteronismo/genética , Neoplasias do Córtex Suprarrenal/metabolismo , Adenoma Adrenocortical/metabolismo , Canais de Cloro CLC-2 , Canais de Cálcio Tipo L/genética , Sinalização do Cálcio , Canais de Cloreto/genética , Citocromo P-450 CYP11B2/genética , Metilação de DNA/genética , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Perfilação da Expressão Gênica , Humanos , Hiperaldosteronismo/metabolismo , ATPases Transportadoras de Cálcio da Membrana Plasmática/genética , Regiões Promotoras Genéticas , ATPase Trocadora de Sódio-Potássio/genéticaRESUMO
OBJECTIVE: Adrenal vein sampling (AVS) and pathological report were selected as gold standard to assess the value of adrenal CT scan combined with postural stimulation test in diagnosing aldosterone-producing adenoma. METHODS: The clinical data of primary aldosteronism (PA) patients including aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA) were retrospectively collected in the West China Hospital of Sichuan University. The sensitivity and specificity of adrenal CT scan combined with postural stimulation test in diagnosing APA were studied. RESULTS: A total of 83 APA patients and 42 IHA patients were enrolled in this study. ROC curve was plotted with increase percentage of serum aldosterone in upright position compared with recumbent position. The optimal cutoff point for APA diagnosis by postural stimulation test was 11%, and the percentage less than 11% was taken as a positive result. The patients were diagnosed by postural stimulation test, with 60 cases positive and 23 cases negative in APA patients and 12 cases positive and 30 cases negative in IHA patients. When AVS and pathological report were selected as the gold standard, the sensitivity and specificity of postural stimulation test in diagnosing APA were 72.3% and 71.4% respectively. Among the 83 APA patients, 65 patients with unilateral nodules and 18 patients with bilateral nodules were diagnosed by CT scan. The coincidence rate in APA diagnosis between CT scan and AVS or pathological report was 78.3% (65/83). Among the 60 patients with positive result in postural stimulation test, who were diagnosed bilateral nodules by CT scan, 51 patients were diagnosed as APA by AVS or pathological report (51/60). CONCLUSION: Adrenal CT combined with postural test can increase the diagnostic accuracy of APA patients.
Assuntos
Adenoma , Aldosterona , Tomografia Computadorizada por Raios X , Adenoma/diagnóstico por imagem , Glândulas Suprarrenais/diagnóstico por imagem , Aldosterona/metabolismo , China , Diagnóstico Diferencial , Humanos , Estudos RetrospectivosRESUMO
OBJECTIVE: To investigate the clinical characteristics of aldosterone producing adenoma (APA) and idiopathic hyperaldosteronism (IHA) complicated with obstructive sleep apnea hypopnea syndrome (OSAHS) and the effect of OSAHS on renin-angiotensin-aldosterone system (RAAS) in APA and IHA patients. METHODS: The clinical data of 127 patients with primary aldosteronism (PA) diagnosed from May 2010 to Aug. 2019 were retrospectively analyzed. There were 70 cases of APA, 53 cases of IHA. Another 4 cases were primary adrenal hyperplasia (PAH), so not included into further analysis. According to the results of polysomnography, the 123 patients of APA or IHA were divided into OSAHS group (96 cases) and non-OSAHS group (27 cases ). The patients with OSAHS were divided into mild, moderate and severe subgroups based on apnea hypopnea index (AHI).The clinical characteristics, biochemical parameters, plasma renin activity, aldosterone levels, and the ratio of aldosterone to renin activity (ARR) in the patients of APA and IHA complicated with OSAHS were compared with those of the patients without OSAHS. RESULTS: There were 49 OSAHS cases (49/70, 70.0%) in APA patients. and 47 OSAHS cases (47/53, 88.7%) in IHA patients. The age, male ratio, body mass index (BMI), waist circumference, triglyceride, blood uric acid, and blood creatinine in APA patients with OSAHS were higher than those in APA patients without OSAHS ( P<0.05), while high-density lipoprotein and estimated glomerular filtration rate (eGFR) were lower ( P<0.05). Compared to the patients without OSAHS, IHA-OSAHS patients had higher BMI and waist circumference ( P<0.05). Moderate/severe OSAHS-APA patients exhibited higher plasma renin activity levels and lower ARR values than the APA patients with no/mild OSAHS ( P<0.05). There were no significant differences in plasma renin activity, aldosterone levels, and ARR values between moderate/severe OSAHS-IHA group and no/mild OSAHS-IHA group. CONCLUSION: The prevalence of OSAHS is significantly higher in the patients with PA than normal population, and OSAHS may aggravate glycose, lipid and uric acid metabolism in PA patients. Moderate/severe OSAHS can increase renin levels and decrease ARR values in APA patients, but has no significant effect on RAAS in IHA patients.
Assuntos
Adenoma , Hiperaldosteronismo , Hipertensão , Apneia Obstrutiva do Sono , Aldosterona , Feminino , Humanos , Hiperaldosteronismo/complicações , Hiperaldosteronismo/diagnóstico , Hipertensão/complicações , Masculino , Estudos Retrospectivos , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/diagnósticoRESUMO
Primary aldosteronism is one of the most common causes of secondary hypertension. This condition is characterized by autonomous hypersecretion of aldosterone which produces sodium retention and potassium excretion, resulting in high blood pressure and potential hypokalemia. Transient postoperative hyporeninemic hypoaldosteronism with an increased risk of hyperkalemia may occur in some patients. We report the case of a 63-year-old patient with persistent hypokalemia, periodic paralysis, and refractory hypertension who was diagnosed with primary hyperaldosteronism due to elevated aldosterone, undetectable plasmatic renin concentration, and the presence of a left adrenal mass. One month after the surgery, the patient was admitted with signs of severe hyperkalemia (8 mmol/L) and worsened renal function, thus requiring hemodialysis. Fluid resuscitation, loop diuretic, and sodium bicarbonate treatment decreased his potassium. Zona glomerulosa insufficiency was confirmed by hormonal tests which exposed low aldosterone-renin axis. The fludrocortisone treatment was initiated and maintained, with consequent potassium and creatinine stabilization. Old age, long duration of hypertension, impaired renal function, severe hypokalemia before surgery, and large size of the aldosterone-producing adenoma are important risk factors for serious potassium imbalance after removal of the adenoma. We have to consider monitoring the patients after surgery for primary hyperaldosteronism in order to prevent severe hyperkalemia; therefore, postoperative immediate follow-up (arterial pressure, potassium, and renal function) is mandatory.
RESUMO
BACKGROUND: Primary aldosteronism, the excessive production of the steroid hormone aldosterone, is the most common cause of secondary hypertension. Common subforms include bilateral adrenal hyperplasia and aldosterone-producing adenoma. OBJECTIVES: The goal of this review is to summarize important publications on the genetic basis of primary aldosteronism. RESULTS: Somatic mutations in the KCNJ5, CACNA1D, ATP1A1, and ATP2B3 genes have been described as causes of aldosterone-producing adenomas. They eventually all lead to increased cellular calcium influx and aldosterone production. The mechanisms of rare CTNNB1 mutations are less defined. Correlations between mutations and different histologic characteristics as well as gender and ethnicity remain unexplained. Recent publications suggest that bilateral hyperplasia is at least partially due to so-called aldosterone-producing cell clusters, often with mutations in CACNA1D. Rare familial forms show mutations in the CYP11B2, CLCN2, KCNJ5, CACNA1H, or CACNA1D genes. CONCLUSIONS: These results suggest that a significant fraction of primary aldosteronism is due to somatic mutations in single genes.