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The aim of this study was to analyze the differences in the distribution of abdominal adipose tissue between the two subtypes of primary aldosteronism (PA) using abdominal computed tomography. We retrospectively analyzed patients diagnosed as having essential hypertension (EH) or PA from the prospectively collected Taiwan Primary Aldosteronism Investigation (TAIPAI) database. Patients with PA were divided into the subgroups of idiopathic hyperaldosteronism (IHA) and unilateral aldosterone-producing adenoma (APA). Patients’ basic clinicodemographic data were collected, and a self-developed CT-based software program was used to quantify the abdominal adiposity indexes, including visceral adipose tissue (VAT) area, VAT ratio, waist circumference (WC), subcutaneous adipose tissue (SAT) area, and SAT ratio. We included 190 patients with EH and 436 patients with PA (238 with IHA and 198 with APA). The APA group had significantly lower abdominal adiposity indexes than the other groups. We also found negative correlations of aldosterone-to-renin ratio (ARR) with VAT area, VAT ratio, WC, and body mass index (BMI) in the APA group. After propensity score matching (which left 184 patients each in the IHA and APA groups), patients in the APA group still had significantly lower WC, SAT area, SAT ratio, and VAT ratio than those in the IHA group. Furthermore, logistic regression analysis indicated that lower probability of abdominal obesity was significantly related to patients with APA. Our data revealed that the distribution of abdominal adipose tissue was similar in patients with IHA and those with EH, but the abdominal adiposity indexes were significantly lower in patients with APA than in those with IHA and EH.

Radiofrequency ablation (RFA) has emerged as a new treatment for primary aldosteronism owing to aldosterone-producing adenoma (APA). We aimed to compare the perioperative outcomes and safety of RFA and laparoscopic adrenalectomy (LA) for patients with APA. We searched PubMed, EMBASE, and the Cochrane Library for all literatures published from January 2001 to September 2020 to compare RFA with LA for APA. After data extraction and quality assessments, we used Review Manager 5.4.1 and STATA 14.0 to pool the data. Four retrospective studies consisting of 170 patients were obtained. Patients who underwent RFA were associated with shorter operative time (standard mean difference (SMD): −1.98, 95% confidence interval (CI): −3.86 to 0.11, P = 0.04), less intraoperative blood loss (SMD: −0.61, 95% CI: −0.96 to −0.26, P = 0.0007), and shorter hospital stay (weight mean difference (WMD): −1.40, 95% CI: −1.71 to −1.10, P < 0.00001) than those who underwent LA. No significant differences were found in the complication rate (odds ratio (OR): 0.67, 95% CI: 0.27–1.68, P = 0.39), the incidence of hypertensive crisis (OR: 3.16, 95% CI: 0.36–27.94, P = 0.30), the conversion rate (OR: 0.44, 95% CI: 0.04–4.32, P = 0.48) or the treatment success rate (OR: 0.72, 95% CI: 0.22–2.39, P = 0.59) between the two groups. RFA could achieve clinical outcomes that approach LA for patients with APA but result in shorter operative time, less intraoperative blood loss, and shorter hospital stay. However, RFA does not appear to be able to replace the LA. Future prospective randomized trials are needed to validate these results. [ABSTRACT FROM AUTHOR]

The aim of this study was to analyze the differences in the distribution of abdominal adipose tissue between the two subtypes of primary aldosteronism (PA) using abdominal computed tomography. We retrospectively analyzed patients diagnosed as having essential hypertension (EH) or PA from the prospectively collected Taiwan Primary Aldosteronism Investigation (TAIPAI) database. Patients with PA were divided into the subgroups of idiopathic hyperaldosteronism (IHA) and unilateral aldosterone-producing adenoma (APA). Patients' basic clinicodemographic data were collected, and a self-developed CT-based software program was used to quantify the abdominal adiposity indexes, including visceral adipose tissue (VAT) area, VAT ratio, waist circumference (WC), subcutaneous adipose tissue (SAT) area, and SAT ratio. We included 190 patients with EH and 436 patients with PA (238 with IHA and 198 with APA). The APA group had significantly lower abdominal adiposity indexes than the other groups. We also found negative correlations of aldosterone-to-renin ratio (ARR) with VAT area, VAT ratio, WC, and body mass index (BMI) in the APA group. After propensity score matching (which left 184 patients each in the IHA and APA groups), patients in the APA group still had significantly lower WC, SAT area, SAT ratio, and VAT ratio than those in the IHA group. Furthermore, logistic regression analysis indicated that lower probability of abdominal obesity was significantly related to patients with APA. Our data revealed that the distribution of abdominal adipose tissue was similar in patients with IHA and those with EH, but the abdominal adiposity indexes were significantly lower in patients with APA than in those with IHA and EH. [ABSTRACT FROM AUTHOR]

Purpose: To assess the relative clinical efficacy and safety of ablation and laparoscopic adrenalectomy (LA) for the treatment of adrenal aldosterone-producing adenoma (APA). Materials and methods: Pubmed, Embase, and Cochrane Library databases were searched for relevant studies, while the meta-analysis was performed with RevMan v5.3. Results: After initially identifying 496 potentially relevant studies, five were ultimately included in the final meta-analysis. In total, these studies contained 128 patients that underwent LA and 91 patients that underwent ablation to treat APA. Clinical success rates were comparable between these two groups (OR: 0.55, P = 0.20), whereas the pooled decreases of systolic and diastolic blood pressure were significantly larger in the ablation group (P = 0.01 and 0.002, respectively). Pooled changes in the aldosterone-to-renin ratio (ARR), serum potassium levels, and medication use were similar in both groups (P = 0.62, 0.24, and 0.96, respectively). The average operative duration in the ablation group was somewhat shorter, but the difference was not significant (MD: − 57.99; P = 0.05), whereas the average blood loss and postoperative hospital stay duration of patients in the ablation group were decreased for patients in the ablation group compared to the LA group (P < 0.00001 and 0.00001, respectively). Major complication, minor complication, and hypertension crisis rates were comparable between these groups (P = 0.35, 0.69, and 0.09, respectively). Conclusions: Ablation offers comparable efficacy to LA when treating patients with APA, but is associated with a reduced operative duration, decreased intraoperative blood loss, and faster postoperative recovery. [ABSTRACT FROM AUTHOR]

The aim of this study was to explore the long‐term clinical results of Renal denervation (RDN) from the adventitia of the renal artery plus unilateral laparoscopic adrenalectomy to treat patients with resistant hypertension caused by unilateral aldosterone‐producing adenoma (APA). Sixty patients with resistant hypertension caused by APA who were treated at Henan Provincial People's Hospital from December 2016 to March 2018 were selected and randomly assigned to undergo RDN from the adventitia of the renal artery plus adrenalectomy (RDN group, n = 30) or adrenalectomy alone (control group, n = 30). Office blood pressure (BP), antihypertensive medication usage and other laboratory characteristics were followed every 6 months through 36 months. Follow‐up data were available at 36 months for 23 of 30 subjects in the RDN group and for 21 of 30 subjects who were in the control group. At 36 months postprocedure, the reduction in the RDN group was 42.2 ± 21.6 mmHg and that in the control group was 29.8 ± 13.5 mmHg (p =.029 between the groups). During the follow‐up to 36 months postprocedure, no patients in either the RDN group or the control group died due to surgical complications, and the RDN group had no procedural complications, including renal artery dissection, perforation, and renal artery stenosis. There was no change in the mean eGFR of the two groups, and no serious adverse events were reported. In conclusion, RDN from the adventitia of the renal artery plus unilateral laparoscopic adrenalectomy resulted in sustained lowering of BP at 3 years in a selected population of subjects with resistant hypertension caused by unilateral APA without serious safety concerns. [ABSTRACT FROM AUTHOR]

Many cases of primary aldosteronism (PA) in patients who developed hypokalemia-induced rhabdomyolysis and underwent adrenalectomy for aldosterone-producing adenoma (APA) have been reported; however, the immunohistopathological and molecular features remain unknown. We herein report the case of a 28-year-old woman with PA who presented with hypokalemia-induced rhabdomyolysis and underwent adrenalectomy for unilateral APA. An immunohistochemical analysis revealed that most adenoma cells were positive for steroidogenic enzymes, including CYP11B2. A genetic analysis revealed a somatic mutation in the KCNJ5. These findings suggest a strong aldosterone production capacity in our patient's adenoma, which was presumably related to her severe hyperaldosteronism and the resultant hypokalemia-induced rhabdomyolysis.

Purpose: The aim of this study is to examine the effects of different kinds of calcium channel blockers (CCBs) on primary aldosterone-producing adenoma (APA) mainly with KCNJ5 mutations. Primary cultured APA cells were treated with different calcium channel blockers (L/T type CCB benidipine, T-type CCB mibefradil and L-type CCB nifedipine), and aldosterone secretagogues with or without nifedipine. Aldosterone level, aldosterone synthase (CYP11B2) mRNA expression and cell proliferation were detected. The results showed that all three CCBs significantly inhibit aldosterone secretion and CYP11B2 mRNA expression. Benidipine was relatively more effective than mibefradil or nifedipine. In addition, only mibefradil marginally inhibited cell proliferation. Adrenocorticotropin (ACTH) had a much stronger effect in stimulating aldosterone secretion and promoting cell proliferation from APA's than angiotensin II (ATII). Different from ACTH and ATII, potassium had no effect. Nifedipine inhibited the basal and ACTH-, ATII-elicited aldosterone secretion. Twenty three of 24 APAs had somatic KCNJ5 mutation. In conclusion, benidipine, mibefradil and nifedipine significantly inhibit aldosterone secretion in primary cultured APA cells.

Purpose: Aldosterone-producing adenoma (APA) is the main curable cause of endocrine hypertension cause of primary aldosteronism (PA) and it is in up to 66% of all cases investigated with adrenal vein sampling (AVS). Mutations in the KCNJ5 potassium channel involve up to 70% of APA and cause the most florid PA phenotypes. The recent finding that macrolide antibiotics specifically inhibit in vitro the altered function of mutated KCNJ5 channels has opened new horizons for the diagnosis and treatment of APA with KCNJ5 mutations in that it can allow identification and target treatment of PA patients harbouring a mutated APA. Thus, we aimed at investigating if clarithromycin and roxithromycin, two macrolides that potently blunt mutated Kir3.4 channel function in vitro, affect plasma aldosterone concentration in adrenal vein blood during AVS and in peripheral blood, respectively, in PA patients with a mutated APA. Methods and design: We designed two proof of concept studies. In study A: consecutive patients with an unambiguous biochemical evidence of PA will be exposed to a single dose of 250 mg clarithromycin during AVS, to assess its effect on the relative aldosterone secretion index in adrenal vein blood from the gland with and without APA. In study B: consecutive hypertensive patients submitted to the work-up for hypertension will receive a single oral dose of 150 mg roxithromycin. The experimental endpoints will be the change induced by roxithromycin of plasma aldosterone concentration and other steroids, direct active renin concentration, serum K+, systolic and diastolic blood pressure. Discussion: We expect to prove that: (i) clarithromycin allows identification of mutated APA before adrenalectomy and sequencing of tumour DNA; (ii) the acute changes of plasma aldosterone concentration, direct active renin concentration, and blood pressure in peripheral venous blood after roxithromycin can be a proxy for the presence of an APA with somatic mutations.

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. [ABSTRACT FROM AUTHOR]

Context: Results of previous studies demonstrated clear racial differences in the prevalence of somatic mutations among patients with aldosterone-producing adenoma (APA). For instance, those in East Asian countries have a high prevalence of somatic mutations in KCNJ5, whereas somatic mutations in other aldosterone-driving genes are rare.Objectives: To determine somatic mutation prevalence in Japanese APA patients using an aldosterone synthase (CYP11B2) immunohistochemistry (IHC)-guided sequencing approach.Method: Patients with a unilateral form of primary aldosteronism who underwent adrenalectomy at the Tohoku University Hospital were studied. Based on CYP11B2 immunolocalization of resected adrenals, genomic DNA was isolated from the relevant positive area of 10% formalin-fixed, paraffin-embedded tissue of the APAs. Somatic mutations in aldosterone-driving genes were studied in APAs by direct Sanger sequencing and targeted next-generation sequencing.Results: CYP11B2 IHC-guided sequencing determined APA-related somatic mutations in 102 out of 106 APAs (96%). Somatic KCNJ5 mutation was the most frequent genetic alteration (73%) in this cohort of Japanese patients. Somatic mutations in other aldosterone-driving genes were also identified: CACNA1D (14%), ATP1A1 (5%), ATP2B3 (4%), and CACNA1H (1%), including 2 previously unreported mutations. KCNJ5 mutations were more often detected in APAs from female patients compared with those from male patients [95% (36/38) vs 60% (41/68); P < 0.0001].Conclusion: IHC-guided sequencing defined somatic mutations in over 95% of Japanese APAs. While the dominance of KCNJ5 mutations in this particular cohort was confirmed, a significantly higher KCNJ5 prevalence was detected in female patients. This study provides a better understanding of genetic spectrum of Japanese APA patients. [ABSTRACT FROM AUTHOR]

Context: It remains unclear whether adrenalectomy has more beneficial effects than treatment with a mineralocorticoid receptor antagonist on vascular function in patients with aldosterone-producing adenoma (APA).Objective: The aim of this study was to compare the effects of adrenalectomy and treatment with eplerenone on vascular function in patients with APA.Design, Setting, and Patients: Flow-mediated vasodilation (FMD), as an index of endothelium-dependent vasodilation, and nitroglycerine-induced vasodilation (NID), as an index of endothelium-independent vasodilation, were measured to assess vascular function before and after a 3-month treatment with eplerenone and at 3 months after adrenalectomy in 23 patients with APA.Results: Flow-mediated vasodilation and NID after adrenalectomy were significantly higher than those before treatment with eplerenone (5.4 ± 2.6% vs 2.7 ± 1.9% and 14.8 ± 4.7% vs 9.6 ± 4.6%, P < 0.01, respectively) and those after treatment with eplerenone (5.4 ± 2.6% vs 3.1 ± 2.3% and 14.8 ± 4.7% vs 11.0 ± 5.3%, P < 0.01 and P = 0.03, respectively), while treatment with eplerenone did not alter FMD and NID compared with those before treatment with eplerenone. After adrenalectomy, the increase in FMD and NID were significantly correlated with a decrease in plasma aldosterone concentration and a decrease in the aldosterone-renin ratio. There were no significant relationships between FMD and changes in other parameters or between NID and changes in other parameters.Conclusions: Adrenalectomy, but not treatment with eplerenone, improved vascular function in patients with APA. Adrenalectomy may be more effective than treatment with eplerenone for reducing the incidence of future cardiovascular events in patients with APA. Clinical Trial Information: URL for the clinical trial: http://UMIN; Registration Number for the clinical trial: UMIN000003409. [ABSTRACT FROM AUTHOR]

Somatic mutations driving aldosterone production have been identified in approximately 90% of aldosterone-producing adenomas (APAs) using an aldosterone synthase (CYP11B2) immunohistochemistry (IHC)-guided DNA sequencing approach. In the present study, using CYP11B2-guided whole-exome sequencing (WES) and targeted amplicon sequencing, we detected 2 somatic variants in CLCN2 in 2 APAs that were negative for currently known aldosterone-driver mutations. The CLCN2 gene encodes the voltage-gated chloride channel ClC-2. CLCN2 germline variants have previously been shown to cause familial hyperaldosteronism type II. Somatic mutations in CLCN2 were identified in 2 of 115 APAs, resulting in a prevalence of 1.74%. One of the CLCN2 somatic mutations (c.G71A,p.G24D) was identical to a previously described germline variant causing early-onset PA, but was present only as a somatic mutation. The second CLCN2 mutation, which affects the same region of the gene, has not been reported previously (c.64-2_74del). These findings prove that WES of CYP11B2-guided mutation-negative APAs can help determine rarer genetic causes of sporadic PA. [ABSTRACT FROM AUTHOR]

Previous studies describing renal denervation (RDN) from the intima of the renal artery for the treatment of resistant hypertension have reported variable efficacies, and RDN triggers renal intimal injury and atherosclerosis. This study aimed to evaluate the efficacy and safety of RDN from the adventitia of renal artery plus unilateral laparoscopic adrenalectomy to treat patients with resistant hypertension caused by unilateral aldosterone‐producing adenoma (APA). A total of 60 consecutive patients with resistant hypertension caused by unilateral APA were enrolled in this study. Patients were randomly assigned to undergo RDN from the adventitia of the renal artery plus adrenalectomy (RDN group, n = 30) or adrenalectomy alone (control group, n = 30) and were followed up for 12 months. The primary efficacy end point was the change in 24‐hours mean ambulatory systolic blood pressure (SBP) from baseline to 12 months. At the 12‐month follow‐up, the mean reduction of 24‐hours average SBP and office SBP in the RDN group was 20.7 ± 15.2 and 37.1 ± 26.0 mm Hg, respectively, which was significantly higher than the mean reduction of 24‐hours average SBP (11.9 ± 11.1 mm Hg, P =.017) and the office SBP (25.9 ± 16.8 mm Hg, P =.035) in the control group. Serum potassium levels returned to normal 12 months post‐procedure. Patients in the RDN group had higher proportion of cured clinical and biochemical outcomes than those in the control group (35.7% vs 17.9% in clinical outcome; 96.4% vs 89.3% in biochemical outcome, respectively). There were no procedural‐, device‐, or treatment‐related safety events during the 12‐month follow‐up period between the groups. In conclusion, RDN from the adventitia of the renal artery plus unilateral laparoscopic adrenalectomy is more effective than adrenalectomy alone for treating resistant hypertension caused by unilateral APA. [ABSTRACT FROM AUTHOR]

Context and Objective: Posture-responsive and posture-unresponsive aldosterone-producing adenomas (APAs) account for approximately 40% and 60% of APAs, respectively. Somatic gene mutations have been recently reported to exist in approximately 90% of APAs. This study was designed to characterize the biochemical, histopathologic, and genetic properties of these 2 types of APA.Methods: Plasma levels of aldosterone and hybrid steroids (18-oxocortisol and 18-hydroxycortisol) were measured by liquid chromatography-tandem mass spectrometry. Immunohistochemistry for CYP11B2 (aldosterone synthase) and CYP17A1 (17α-hydroxylase) and deoxyribonucleic acid sequencing (Sanger and next-generation sequencing) were performed on APA tissue collected from 23 posture-unresponsive and 17 posture-responsive APA patients.Results: Patients with posture-unresponsive APA displayed higher (P < 0.01) levels of hybrid steroids, recumbent aldosterone and cortisol, larger (P < 0.01) zona fasciculata (ZF)-like tumors with higher (P < 0.01) expression of CYP17A1 (but not of CYP11B2) than patients with posture-responsive APA (most of which were not ZF-like). Of 40 studied APAs, 37 (92.5%) were found to harbor aldosterone-driving somatic mutations (KCNJ5 = 14 [35.0%], CACNA1D = 13 [32.5%], ATP1A1 = 8 [20.0%], and ATP2B3 = 2 [5.0%]), including 5 previously unreported mutations (3 in CACNA1D and 2 in ATP1A1). Notably, 64.7% (11/17) of posture-responsive APAs carried CACNA1D mutations, whereas 56.5% (13/23) of posture-unresponsive APAs harbored KCNJ5 mutations.Conclusions: The elevated production of hybrid steroids by posture-unresponsive APAs may relate to their ZF-like tumor cell composition, resulting in expression of CYP17A1 (in addition to somatic gene mutation-driven CYP11B2 expression), thereby allowing production of cortisol, which acts as the substrate for CYP11B2-generated hybrid steroids. [ABSTRACT FROM AUTHOR]

Mast cells are immune cells present in adrenals from various species. Proliferation and activation of adrenal mast cells seem to be influenced by environment, since they increase during summer and in response to sodium restriction in frogs and mouse, respectively. Although the physiological factors regulating adrenal mast cell activity have not been identified, they might involve neurotransmitters and the renin-angiotensin system. Some data indicate that adrenal mast cells stimulate proliferation of steroidogenic cells in the zona glomerulosa and activate the mineralocorticoid production. In human, mast cell degranulation stimulates aldosterone synthesis through the release of serotonin (5-HT) and activation of 5-HT4 receptors. Increase in mast cell population and upregulation of the 5-HT signaling pathway occur in aldosterone-producing adenomas. In particular, aldosterone-producing adenoma cells overexpress 5-HT4 receptors and are hyper-responsive to 5-HT4 receptor agonists. These data suggest that the intra-adrenal serotonergic regulatory system represents a potential target for development of both adrenal imaging methods to evaluate the lateralization of aldosterone production, and pharmacological treatments of primary aldosteronism. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study is to examine the effects of different kinds of calcium channel blockers (CCBs) on primary aldosterone-producing adenoma (APA) mainly with KCNJ5 mutations. Primary cultured APA cells were treated with different calcium channel blockers (L/T type CCB benidipine, T-type CCB mibefradil and L-type CCB nifedipine), and aldosterone secretagogues with or without nifedipine. Aldosterone level, aldosterone synthase (CYP11B2) mRNA expression and cell proliferation were detected. The results showed that all three CCBs significantly inhibit aldosterone secretion and CYP11B2 mRNA expression. Benidipine was relatively more effective than mibefradil or nifedipine. In addition, only mibefradil marginally inhibited cell proliferation. Adrenocorticotropin (ACTH) had a much stronger effect in stimulating aldosterone secretion and promoting cell proliferation from APA's than angiotensin II (ATII). Different from ACTH and ATII, potassium had no effect. Nifedipine inhibited the basal and ACTH-, ATII-elicited aldosterone secretion. Twenty three of 24 APAs had somatic KCNJ5 mutation. In conclusion, benidipine, mibefradil and nifedipine significantly inhibit aldosterone secretion in primary cultured APA cells. [ABSTRACT FROM AUTHOR]

Introduction: Adrenal venous sampling is useful for discriminating unilateral and bilateral hypersecretion in patients with primary aldosteronism, but it is relatively invasive. To determine the site of hypersecretion more non-invasively, we evaluated predictors of unilateral hypersecretion.Materials and Methods: We evaluated the baseline characteristics and the results of confirmatory tests of 123 patients with primary aldosteronism who underwent adrenal venous sampling.Results: Unilateral hypersecretion was identified in 22.0%. The plasma aldosterone concentration and aldosterone-renin ratio were significantly higher and serum potassium concentration and plasma renin activity were significantly lower in patients with unilateral hypersecretion. Plasma aldosterone concentrations after captopril challenge test, saline infusion test and rapid adrenocorticotropic hormone stimulation test were significantly higher among patients with unilateral hypersecretion. The plasma aldosterone concentration reduction ratio in saline infusion test and plasma aldosterone concentration elevation ratio during rapid adrenocorticotropic hormone stimulation test were significantly higher in patients with unilateral hypersecretion. However, areas under the curve for these parameters were not superior to the values after confirmatory tests.Conclusions: The plasma aldosterone concentration values after captopril challenge test, saline infusion test and rapid adrenocorticotropic hormone stimulation test were useful for identifying patients with unilateral hypersecretion. However, value changes or ratios during confirmatory tests are less useful for this aim. [ABSTRACT FROM AUTHOR]

Driver somatic mutations for aldosterone excess have been found in ≈90% of aldosterone-producing adenomas (APAs) using an aldosterone synthase (CYP11B2)-guided sequencing approach. In the present study, we identified a novel somatic CACNA1H mutation (c.T4289C, p.I1430T) in an APA without any currently known aldosterone-driver mutations using CYP11B2 immunohistochemistry-guided whole exome sequencing. The CACNA1H gene encodes a voltage-dependent T-type calcium channel alpha-1H subunit. Germline variants in this gene are known as a cause of familial hyperaldosteronism IV. Targeted next-generation sequencing detected identical CACNA1H variants in 2 additional APAs in a cohort of the University of Michigan, resulting in a prevalence of 4% (3/75) in APAs. We tested the functional effect of the variant on adrenal cell aldosterone production and CYP11B2 mRNA expression using the human adrenocortical HAC15 cell line with a doxycycline-inducible CACNA1HI1430T mutation. Doxycycline treatment increased CYP11B2 mRNA levels as well as aldosterone production, supporting a pathological role of the CACNA1H p.I1430T mutation on the development of primary aldosteronism. In conclusion, somatic CACNA1H mutation is a genetic cause of APAs. Although the prevalence of this mutation is low, this study will provide better understanding of molecular mechanism of inappropriate aldosterone production in APAs. [ABSTRACT FROM AUTHOR]

Primary aldosteronism (PA) causes 5–10% of hypertension cases, but only a minority of patients are currently diagnosed and treated because of a complex, stepwise, and partly invasive workup. We tested the performance of urine steroid metabolomics, the computational analysis of 24-hour urine steroid metabolome data by machine learning, for the identification and subtyping of PA. Mass spectrometry-based multi-steroid profiling was used to quantify the excretion of 34 steroid metabolites in 24-hour urine samples from 158 adults with PA (88 with unilateral PA [UPA] due to aldosterone-producing adenomas [APAs]; 70 with bilateral PA [BPA]) and 65 sex- and age-matched healthy controls. All APAs were resected and underwent targeted gene sequencing to detect somatic mutations associated with UPA. Patients with PA had increased urinary metabolite excretion of mineralocorticoids, glucocorticoids, and glucocorticoid precursors. Urine steroid metabolomics identified patients with PA with high accuracy, both when applied to all 34 or only the three most discriminative steroid metabolites (average areas under the receiver-operating characteristics curve [AUCs-ROC] 0.95–0.97). Whilst machine learning was suboptimal in differentiating UPA from BPA (average AUCs-ROC 0.65–0.73), it readily identified APA cases harbouring somatic KCNJ5 mutations (average AUCs-ROC 0.79–85). These patients showed a distinctly increased urine excretion of the hybrid steroid 18-hydroxycortisol and its metabolite 18-oxo-tetrahydrocortisol, the latter identified by machine learning as by far the most discriminative steroid. In conclusion, urine steroid metabolomics is a non-invasive candidate test for the accurate identification of PA cases and KCNJ5 -mutated APAs. • We measured 34 steroid metabolites in 24-hour urine samples of patients with primary aldosteronism and healthy controls. • Machine learning applied to the urinary steroid metabolome was highly accurate in identifying primary aldosteronism cases. • Aldosterone-producing adenomas harbouring mutations of the KCNJ5 gene had specific urine steroid fingerprints. • Urine steroid metabolome analysis is a non-invasive candidate test for diagnosing and subtyping primary aldosteronism. [ABSTRACT FROM AUTHOR]

Primary aldosteronism (PA) is a heterogeneous group of disorders caused by the autonomous overproduction of aldosterone with simultaneous suppression of plasma renin activity (PRA). It is considered to be the most common endocrine cause of secondary arterial hypertension (HT) and is associated with a high rate of cardiovascular complications. PA is most often caused by a bilateral adrenal hyperplasia (BAH) or aldosterone-producing adenoma (APA); rarer causes of PA include genetic disorders of steroidogenesis (familial hyperaldosteronism (FA) type I, II, III and IV), aldosterone-producing adrenocortical carcinoma, and ectopic aldosterone-producing tumors. Over the last few years, significant progress has been made towards understanding the genetic basis of PA, classifying it as a channelopathy. Recently, a growing body of clinical evidence suggests that mutations in ion channels appear to be the major cause of aldosterone-producing adenomas, and several mutations within the ion channel encoding genes have been identified. Somatic mutations in four genes (KCNJ5, ATP1A1, ATP2B3 and CACNA1D) have been identified in nearly 60% of the sporadic APAs, while germline mutations in KCNJ5 and CACNA1H have been reported in different subtypes of familial hyperaldosteronism. These new insights into the molecular mechanisms underlying PA may be associated with potential implications for diagnosis and therapy.

Objective: Primary aldosteronism is a major cause of secondary hypertension. Its two principal forms are bilateral adrenal hyperplasia (BAH) and aldosterone-producing adenoma (APA) whose differentiation is clinically pivotal. There is a major clinical need for a reliable and easily accessible diagnostic biomarker for case identification and subtyping. Circulating microRNAs were shown to be useful as minimally invasive diagnostic markers. Our aim was to determine and compare the circulating microRNA expression profiles of adenoma and hyperplasia plasma samples, and to evaluate their applicability as minimally invasive markers.Methods: One hundred and twenty-three samples from primary aldosteronism patients were included. Next-generation sequencing was performed on 30 EDTA-anticoagulated plasma samples (discovery cohort). Significantly differently expressed miRNAs were validated by real-time reverse transcription-qPCR in an independent validation cohort (93 samples).Results: We have found relative overexpression of miR-30e-5p, miR-30d-5p, miR-223-3p, and miR-7-5p in hyperplasia compared to adenoma by next-generation sequencing. Validation by qRT-PCR confirmed significant overexpression of hsa-miR-30e-5p, hsa-miR-30d-5p, and hsa-miR-7-5p in hyperplasia samples. Regarding the microRNA expressional variations, adenoma is more heterogeneous at the miRNA level compared to hyperplasia.Conclusion: Three microRNAs were significantly overexpressed in hyperplasia samples compared to adenoma samples, but their sensitivity and specificity values are not good enough for introduction to clinical practice.

Primary aldosteronism (PA) is the leading cause of secondary hypertension. The source of aldosterone hypersecretion is often due to a unilateral aldosterone-producing adenoma, and unilateral laparoscopic adrenalectomy is recommended in such patients. Before surgery, confirmation of unilateral hypersecretion is necessary. This is optimally performed by adrenal venous sampling (AVS). However, AVS is not always successful e.g., due to difficulties in the cannulation of the right adrenal vein. Here we present the case of a 53-year-old female patient with primary aldosteronism, a left-sided adrenal mass and an inconspicuous right adrenal. AVS was performed, but cannulation of the right adrenal vein failed. Therefore, aldosterone hypersecretion also of the right adrenal could not be excluded despite higher aldosterone concentrations in the left renal and adrenal vein. To increase the certainty that the left sided adrenal mass was the source of aldosterone hypersecretion, steroid profiling was performed in a sample from the inferior vena cava. This revealed markedly elevated levels of 18-oxocortisol, 18-hydroxycortisol, 11-deoxycorticosterone, and 11-deoxycortisol, a steroid profile that strongly suggested that the left sided adrenal mass was an aldosterone producing adenoma, most likely due to a somatic KCNJ5 mutation. Following unilateral adrenalectomy, CYP11B2 immunohistochemistry, and genetics analysis of the resected adrenal confirmed a solitary aldosterone-producing adenoma with intense aldosterone synthase expression, which harbored a previously described KCNJ5 Phe154Cys mutation. Biochemical and clinical cure was confirmed 6 months postoperatively.

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. [ABSTRACT FROM AUTHOR]

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Objective: Primary aldosteronism is a major cause of secondary hypertension. Its two principal forms are bilateral adrenal hyperplasia (BAH) and aldosterone-producing adenoma (APA) whose differentiation is clinically pivotal. There is a major clinical need for a reliable and easily accessible diagnostic biomarker for case identification and subtyping. Circulating microRNAs were shown to be useful as minimally invasive diagnostic markers. Our aim was to determine and compare the circulating microRNA expression profiles of adenoma and hyperplasia plasma samples, and to evaluate their applicability as minimally invasive markers. Methods: One hundred and twenty-three samples from primary aldosteronism patients were included. Next-generation sequencing was performed on 30 EDTA-anticoagulated plasma samples (discovery cohort). Significantly differently expressed miRNAs were validated by real-time reverse transcription-qPCR in an independent validation cohort (93 samples). Results: We have found relative overexpression of miR-30e-5p, miR-30d-5p, miR-223-3p , and miR-7-5p in hyperplasia compared to adenoma by next-generation sequencing. Validation by qRT-PCR confirmed significant overexpression of hsa-miR-30e-5p, hsa-miR-30d-5p , and hsa-miR-7-5p in hyperplasia samples. Regarding the microRNA expressional variations, adenoma is more heterogeneous at the miRNA level compared to hyperplasia. Conclusion: Three microRNAs were significantly overexpressed in hyperplasia samples compared to adenoma samples, but their sensitivity and specificity values are not good enough for introduction to clinical practice. [ABSTRACT FROM AUTHOR]

To investigate the association of DNA polymorphisms in CYP11B2 and CYP11Bl loci with the risk of aldosterone-producing adenoma (APA). Methods We used the real-time PCR TaqMan-MGB probe to detect the single nucleotide polymorphism ( SNP) of CYP11B2 gene rs5301, rs6471570 and CYP11B2 gene rs3802228, rs3802230, rs4545, rs4546, and rs6433 loci in the peripheral blood of 80 patients with APA (APA group) and 101 healthy controls (control group). SNPassoc 1. 9-2 and Haplo stats 2. 17. 0 software were performed to analyse the correlation of the CYP11B2 and CYP11B1 haplotype and genotype with the risk of APA. Results The frequencies of the A allele of rs5301, A allele of rs3802228, and Gallele of rs6433 were higher in the APA group than in the control group (all P < 0. 05). After we adjusted the sex, age and BMI, the frequency of the AG genotype of rs4545 in the APA group was less than that of the control group (P < 0. 05). The haplotype analysis showed that frequencies of GAACAAC and GCGAAGT were lower than those of the control group (OR= 0. 73, 95% CI= 0. 57-0. 93; OR= 0. 81, 95% CI 0. 69-0. 95). Conclusions CYP11B2 and CYP1B1 gene polymorphisms are associated with the risk of APA. The polymorphism rs4545 locus of the CYP11B2 gene is associated with APA population, and APA is negatively correlated with haplotype GAACAAC and GCGAAGT. [ABSTRACT FROM AUTHOR]

Primary aldosteronism (PA) is the leading cause of secondary hypertension. The source of aldosterone hypersecretion is often due to a unilateral aldosterone-producing adenoma, and unilateral laparoscopic adrenalectomy is recommended in such patients. Before surgery, confirmation of unilateral hypersecretion is necessary. This is optimally performed by adrenal venous sampling (AVS). However, AVS is not always successful e.g., due to difficulties in the cannulation of the right adrenal vein. Here we present the case of a 53-year-old female patient with primary aldosteronism, a left-sided adrenal mass and an inconspicuous right adrenal. AVS was performed, but cannulation of the right adrenal vein failed. Therefore, aldosterone hypersecretion also of the right adrenal could not be excluded despite higher aldosterone concentrations in the left renal and adrenal vein. To increase the certainty that the left sided adrenal mass was the source of aldosterone hypersecretion, steroid profiling was performed in a sample from the inferior vena cava. This revealed markedly elevated levels of 18-oxocortisol, 18-hydroxycortisol, 11-deoxycorticosterone, and 11-deoxycortisol, a steroid profile that strongly suggested that the left sided adrenal mass was an aldosterone producing adenoma, most likely due to a somatic KCNJ5 mutation. Following unilateral adrenalectomy, CYP11B2 immunohistochemistry, and genetics analysis of the resected adrenal confirmed a solitary aldosterone-producing adenoma with intense aldosterone synthase expression, which harbored a previously described KCNJ5 Phe154Cys mutation. Biochemical and clinical cure was confirmed 6 months postoperatively. [ABSTRACT FROM AUTHOR]

• Steroid profiling used for random forest modelling of micro-APA, macro-APA and BAH. • High accuracy for macro-APA and BAH, low accuracy for micro-APA classification. • Micro-APA classification improved using novel diagnostic algorithm. • Potential use to select patients with micro-APA for mandatory AVS. 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. [ABSTRACT FROM AUTHOR]

Primary aldosteronism (PA) is the most common form of secondary hypertension, with a prevalence of 5–10% among patients with hypertension. PA is mainly classified into two subtypes: aldosterone-producing adenoma (APA) and bilateral idiopathic hyperaldosteronism. Recent developments in genetic analysis have facilitated the discovery of mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, CACNA1H, CLCN2, and CTNNB1 in sporadic or familial forms of PA in the last decade. These findings have greatly advanced our understanding of the mechanism of excess aldosterone synthesis, particularly in APA. Most of the causative genes encode ion channels or pumps, and their mutations lead to depolarization of the cell membrane due to impairment of ion transport. Depolarization activates voltage-gated Ca2+ channels and intracellular calcium signaling and promotes the transcription of aldosterone synthase, resulting in overproduction of aldosterone. In this article, we review recent findings on the genetic and molecular mechanisms of PA.

For the last seven decades, primary aldosteronism (PA) has been gradually recognized as a leading cause of secondary hypertension harboring increased risks of cardiovascular incidents compared to essential hypertension. Clinically, PA consists of two major subtypes, surgically curable and uncurable phenotypes, determined as unilateral or bilateral PA by adrenal venous sampling. In order to further optimize the treatment, surgery or medications, diagnostic procedures from screening to subtype differentiation is indispensable, while in the general clinical practice, the work-up rate is extremely low even in the patients with refractory hypertension because of the time-consuming and labor-intensive nature of the procedures. Therefore, a novel tool to simplify the diagnostic flow has been recently in enormous demand. In this review, we focus on recent progress in the following clinically important topics of PA: prevalence of PA and its subtypes, newly revealed histopathological classification of aldosterone-producing lesions, novel diagnostic biomarkers and prediction scores. More effective strategy to diagnose PA based on better understanding of its epidemiology and pathology should lead to early detection of PA and could decrease the cardiovascular and renal complications of the patients.

A 56-year-old man presented with a history of hypertension; clinically, the patient had primary aldosteronism (PA) and a 4-cm left adrenal tumor. The left adrenal glands, resected by adrenalectomy, also contained ectopic thyroid tissue (ETT). An immunohistochemical analysis of steroid-converting enzymes revealed an aldosterone-producing adenoma (APA). Among 19 previously reported cases of adrenal ETT, 4 had adrenal hormonal abnormalities, all of which were PA. This is the first case of adrenal ETT coexisting with APA, confirmed by steroid-converting enzyme expression. Further analyses using cumulative case data are required to clarify the correlation between adrenal ETT and APA.

Simultaneous occurrence of pheochromocytoma and aldosterone-producing adrenocortical tumor has been rarely reported in patients with symptoms or findings suggestive for both neoplasms. Herein, we report and discuss on a challenging case of synchronous pheochromocytoma and aldosterone-producing adenoma incidentally detected in the same adrenal gland and documented by biochemical studies and pathological examination.

The importance of an early diagnosis and appropriate management of patients with primary aldosteronism (PA) has become increasingly clear because of the adverse impact of the disorder on cardiovascular and cerebrovascular events and target organ damage. Adrenalectomy potentially cures patients with unilateral PA resulting in normalisation of blood pressure or significant clinical improvements in the majority of patients. Different criteria have been used to evaluate outcomes of unilateral adrenalectomy. Clinical remission (cure of hypertension) is observed in 6% to 86% of patients and clinical benefits from surgery are seen in the majority. Several factors have been identified that predict clinical success after surgery such as age, sex, anti-hypertensive medication dosage and known duration of hypertension. Biochemical remission of PA after unilateral adrenalectomy, characterised by the resolution of hyperaldosteronism and correction of pre-surgical hypokalaemia, is observed in 67% to 100% of patients with unilateral PA. In only a small proportion of patients, adrenalectomy fails to resolve hyperaldosteronism and inappropriate aldosterone production persists after surgery. In this review we discuss the potential reasons for failing to cure hyperaldosteronism after unilateral adrenalectomy for unilateral primary aldosteronism. [ABSTRACT FROM AUTHOR]

Purpose: Aldosterone-producing adenoma (APA) is the main curable cause of endocrine hypertension cause of primary aldosteronism (PA) and it is in up to 66% of all cases investigated with adrenal vein sampling (AVS). Mutations in the KCNJ5 potassium channel involve up to 70% of APA and cause the most florid PA phenotypes. The recent finding that macrolide antibiotics specifically inhibit in vitro the altered function of mutated KCNJ5 channels has opened new horizons for the diagnosis and treatment of APA with KCNJ5 mutations in that it can allow identification and target treatment of PA patients harbouring a mutated APA. Thus, we aimed at investigating if clarithromycin and roxithromycin, two macrolides that potently blunt mutated Kir3.4 channel function in vitro, affect plasma aldosterone concentration in adrenal vein blood during AVS and in peripheral blood, respectively, in PA patients with a mutated APA. Methods and design: We designed two proof of concept studies. In study A: consecutive patients with an unambiguous biochemical evidence of PA will be exposed to a single dose of 250 mg clarithromycin during AVS, to assess its effect on the relative aldosterone secretion index in adrenal vein blood from the gland with and without APA. In study B: consecutive hypertensive patients submitted to the work-up for hypertension will receive a single oral dose of 150 mg roxithromycin. The experimental endpoints will be the change induced by roxithromycin of plasma aldosterone concentration and other steroids, direct active renin concentration, serum K+, systolic and diastolic blood pressure. Discussion: We expect to prove that: (i) clarithromycin allows identification of mutated APA before adrenalectomy and sequencing of tumour DNA; (ii) the acute changes of plasma aldosterone concentration, direct active renin concentration, and blood pressure in peripheral venous blood after roxithromycin can be a proxy for the presence of an APA with somatic mutations. [ABSTRACT FROM AUTHOR]

Primary aldosteronism is the most common form of endocrine hypertension with a prevalence of 6% in the general population with hypertension. The genetic basis of the four familial forms of primary aldosteronism (familial hyperaldosteronism FH types I-IV) and the majority of sporadic unilateral aldosterone-producing adenomas has now been resolved. Familial forms of hyperaldosteronism are, however, rare. The sporadic forms of the disease prevail and these are usually caused by either a unilateral aldosterone-producing adenoma or bilateral adrenal hyperplasia. Aldosterone-producing adenomas frequently carry a causative somatic mutation in either of a number of genes with the KCNJ5 gene, encoding an inwardly rectifying potassium channel, a recurrent target harboring mutations at a prevalence of more than 40% worldwide. Other than genetic variations, gene expression profiling of aldosterone-producing adenomas has shed light on the genes and intracellular signalling pathways that may play a role in the pathogenesis and pathophysiology of these tumors. [ABSTRACT FROM AUTHOR]

BackgroundCurrent guidelines recommend use of the aldosterone‐renin ratio (ARR) for the case detection of primary aldosteronism followed by confirmatory tests to exclude false‐positive results from further diagnostic workup. We investigated the hypothesis that this could be unnecessary in patients with a high ARR value if the quantitative information carried by the ARR is taken into due consideration. Methods and ResultsWe interrogated 2 large data sets of prospectively collected patients studied with the same predefined protocol, which included the captopril challenge test. We used an unambiguous diagnosis of aldosterone‐producing adenoma as reference index. We also assessed whether the post‐captopril ARR and plasma aldosterone concentration fall furnished a diagnostic gain over baseline ARR values. We found that the false‐positive rate fell exponentially, and, conversely, the specificity increased with rising ARR values. At receiver operating characteristics curves and diagnostic odds ratio analysis, the high baseline ARR values implied very high positive likelihood ratio and diagnostic odds ratio values. The baseline and post‐captopril ARR showed similar diagnostic accuracy (area under the receiver operating characteristics curve) in both the exploratory and validation cohorts, indicating lack of diagnostic gain with this confirmatory test (between‐area under the curve difference, 0.005; 95% CI, −0.031 to 0.040; P=0.7 for comparison, and 0.05; 95% CI, −0.061 to 0.064; P=0.051 for comparison, respectively). ConclusionsThese results indicate that the ARR conveys key quantitative information that, if properly used, can simplify the diagnostic workup, resulting in saving of money and resources. This can offer the chance of diagnosis and ensuing adrenalectomy to a larger number of hypertensive patients, ultimately resulting in better control of blood pressure.

Background: The differential diagnosis of the pathogenetic causes of hirsutism in combination with hypertension is a challenge for clinicians. Methods and Results: This case report demonstrates a patient suffering from two hormonally active tumors - an adrenal adenoma with primary aldosteronism and a Leydig cell ovarian tumor with hyperandrogenism. The task of the authors was easier due to the perimenopausal age of the proband. Adrenal selective venous sampling was very helpful in the diagnosis of these active endocrine tumors. Both were resolved by a single laparoscopic surgery. Conclusion: The combination of the two described tumors is a unique clinical finding. The resolution using laparoscopy in a single procedure provided an elegant and efficient therapeutic approach.

This study aimed to evaluate the methylation levels of G protein-coupled receptor (GPCR) related genes and the effects of methylation on mRNA expression levels in aldosterone-producing adenoma (APA). DNA methylation array and transcriptome analysis were applied in non-functioning adrenocortical adenoma (NFA) and APA. We investigated 192 GPCR-related genes and found hypo-methylation in the promoter region of 66 of these genes in APA. An integration study between microarray and methylation analysis revealed that HTR4 , MC2R , TACR1 , GRM3 , and PTGER1 showed hypo-methylation and up-regulation of mRNA in APA. qPCR analysis showed that HTR4 and PTGER1 expression was 9.3-fold and 6.6-fold higher in APAs than in NFAs, respectively, whereas expression of the other genes was not different between the groups. Methylation of HTR4 and PTGER1 at positions −229 and −666 from the transcription start site, respectively, showed a significant inverse correlation with their mRNA levels. Methylation levels were not associated with KCNJ5 or ATP1A1 mutations in human adrenal samples. We demonstrated an increased incidence of CpG island demethylation of GPCR-related gene in APA. The expression of two receptors, HTR4 and PTGER1 , showed a strong association with DNA methylation. [ABSTRACT FROM AUTHOR]

Purpose: To test the efficacy of a strategy based on CT imaging and clinical characteristics on lateralizing origin of excess aldosterone secretion in primary aldosteronism. Patients and methods: Consecutive patients with diagnosed primary hyperaldosteronism from June 2006 to July 2012 in our center underwent adrenal surgeries without pre-operational adrenal venous sampling (AVS) if all the three criteria were met: (1) round- or oval-shaped occupational lesion of low density after contrast enhancement with diameter >1 cm on CT scan was located in one adrenal gland; (2) unequivocally normal contralateral adrenal gland; (3) serum potassium level lower than 3.5 mmol/L. Subjects who had received operation were taken into analysis and follow-ups. Results: One hundred and twenty-five patients fulfilled the criteria and were recruited into our research. One hundred and twenty-two operated patients (97.6%) experienced complete resolution of hypokalemia as well as resolution or improvement in hypertension with reduction in antihypertensive medication, while 3 patients (2.4%) failed to obtain normal kalemia and continued on spironolactone therapy. At a median of 65-month (range 21-93) follow-up of these 122 subjects, 27 patients dropped out (22.1%). The 95 responding patients reported no episodes of paralysis or confirmed hypokalemia or any supplementation of potassium. Multivariate linear correlation analysis showed that plasma potassium level was correlated inversely with tumor diameter ( r = −0.258, 95% CI −0.076, −0.514, p = 0.037) and basal plasma aldosterone level ( r = −0.251, 95% CI −0.040, −0.464, p = 0.042). Conclusions: Most patients with typical unilateral adrenal macroadenomas, normal contralateral glands and hypokalemia could attain favorable surgical therapeutic outcomes without pre-operational AVS lateralization. [ABSTRACT FROM AUTHOR]

Purpose: Aldosterone-producing adenomas with concurrent subclinical cortisol hypersecretion are reported in an increasing number of patients. Five aldosterone-producing adenomas from patients with primary aldosteronism and subclinical hypercortisolism were examined. The aims of our study were: (1) to analyze pathological features and immunohistochemical expression of CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase) in these tumors; (2) to investigate somatic mutations involved in adrenal steroid hypersecretion and/or tumor growth. Methods: Archival micro-dissected paraffin-embedded slides from tumor specimens were used for histological and molecular studies. Immunohistochemistry was performed using monoclonal anti-CYP11B1 and anti-CYP11B2 antibodies. Cellular composition was determined by examining for known features of zona fasciculata and zona glomerulosa, and immunoreactivity for CYP11B1 and CYP11B2 by McCarty H-score. Spot regions for mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, PRKACA, and CTNNB1 gene sequences were evaluated. Results: Four APAs showed a predominant (≥50%) zona fasciculata-like cell pattern: one tumor had CYP11B1 H-score = 150, no detectable CYP11B2 expression, and harbored a PRKACA p.Leu206Arg mutation (that we have reported previously elsewhere), one had no CYP11B1 expression, CYP11B2 H-score = 40, and no mutations; the remaining two adenomas had high CYP11B1 H-score (160 and 240, respectively) and low CYP11B2 H-score (30 and 15, respectively), with the latter harboring a CTNNB1 p.Ser45Phe activating mutation. One of five aldosterone-producing adenomas had a predominant zona glomerulosa-like pattern, CYP11B1 H-score = 15, CYP11B2 H-score = 180, and no mutations. Conclusions: The majority of aldosterone-producing adenomas with concurrent subclinical cortisol hypersecretion were composed mainly of zona fasciculata-like cells, while CYP11B1 and CYP11B2 immunostaining demonstrated clear heterogeneity. In a subset of cases, different somatic mutations may be involved in hormone excess and tumor formation. [ABSTRACT FROM AUTHOR]

Rhabdomyolysis is a condition with a broad spectrum of presentation that can range from mild asymptomatic disease to fatal complications due to electrolyte imbalance, arrhythmias and/or acute renal injury. We report the case of a 35-year-old woman, hypertensive, who was admitted for muscle weakness following a gastrointestinal condition. Biochemically with severe hypokalemia, elevated creatinekinase, conserved renal function, hypocalcemia and metabolic alkalosis. Their comprehensive evaluation culminated in the diagnosis of primary hyperaldosteronism secondary to an aldosterone-producing adenoma which was surgically removed without complications. The presentation of Conn's syndrome with hypokalemia rhabdomyolysis is exceptional since most cases are diagnosed with normokalemia or mild hypokalemia from the secondary hypertension protocol. A high level of suspicion and integral evaluation are necessary to arrive at the correct diagnosis. [ABSTRACT FROM AUTHOR]

Over the past six years, the genetic basis of a significant fraction of primary aldosteronism (PA) cases has been solved. Breakthrough discoveries include the role of somatic variants in the KCNJ5, CACNA1D, ATP1A1, and ATP2B3 genes as causes of aldosterone-producing adenomas (APAs), and the recognition of three novel hyperaldosteronism syndromes with germline variants in the KCNJ5, CACNA1D, and CACNA1H genes. The description of somatic variants in CACNA1D and ATP1A1 in aldosterone-producing cell clusters (APCCs) suggests that these clusters are precursors of some aldosterone-producing adenomas. Yet, a number of questions remain unanswered. These include the genetic basis of about 40 % of APAs without somatic variants in known genes. Do technical issues explain this finding, or are the unexplained APAs due to somatic copy number variation or rare variants in thus-far undiscovered genes? Similarly, the role of CTNNB1 (beta catenin) variants in APA pathogenesis is still unclear. The major question to be solved is the genetic basis of bilateral adrenal hyperplasia (BAH). Is BAH due to the bilateral occurrence of APCCs, to germline variants, or perhaps due to unknown serum factors? Lastly, the etiology of unsolved cases of apparently familial hyperaldosteronism remains to be discovered. It is expected that genetic studies over the next few years will lead to answers to at least some of the questions raised. [ABSTRACT FROM AUTHOR]

Environmental pollutants may act as endocrine disruptors in animals. Organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) enter the food chain and may accumulate in the fatty animal tissues, including adrenals. To our knowledge, no previous study has investigated their presence in the human normal adrenal (NA) cortex and aldosterone-producing adenomas (APA). Surgical fragments of APA from 11 patients and NA from 8 kidney donors were analyzed for 16 PCBs congeners and 10 OCPs. A Matrix Solid-Phase Dispersion (MSPD) method for simultaneous determination of the target compounds in cortex homogenates was developed. A gas-chromatography triple quadrupole mass spectrometry (Triple Quad GC-MS) system was used for the analysis. Data were analyzed using Random Forest and Wilcoxon's rank-sum test. OCPs and PCBs were found in specimens from both types. A subset of pollutants characterized APA more than NA. Higher concentrations (μg g−1) in APA were observed for α-, β-, and γ- Hexachlorocyclohexane (HCH) (1.48 ± 3.32 vs. 0.17 ± 0.19, P = 0.028; 2.81 ± 2.10 vs. 0.96 ± 0.98, P = 0.011; 2.16 ± 4.85 vs. 0.17 ± 0.26, P = 0.004, respectively), as well as for Hexachlorobenzene (HCB) and for PCBs 28, 52 and 101 (3.41 ± 3.11 vs. 0.97 ± 1.06, P = 0.021; 2.34 ± 4.68 vs. 0.25 ± 0.22, P = 0.039; 0.58 ± 1.19 vs. 0.06 ± 0.02, P = 0.002; 0.26 ± 0.43 vs. 0.05 ± 0.00, P = 0.001, respectively). Environmental organochlorine pollutants were shown to be present in the human normal and abnormal adrenal cortex, deserving future investigation on their possible role as adrenal endocrine disruptors in human disease. Copyright © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The mineralocorticoid aldosterone is a major factor controlling the salt and water balance and thereby also the arterial blood pressure. Accordingly, primary aldosteronism ( PA) characterized by an inappropriately high aldosterone secretion is the most common form of secondary hypertension. The physiological stimulation of aldosterone synthesis in adrenocortical glomerulosa cells by angiotensin II and an increased plasma K+ concentration depends on a membrane depolarization and an increase in the cytosolic Ca2+ activity. Recurrent gain-of-function mutations of ion channels and transporters have been identified in a majority of cases of aldosterone-producing adenomas and in familial forms of PA. In this review, the physiological role of these genes in the regulation of aldosterone synthesis and the altered function of the mutant proteins as well are described. The specific changes of the membrane potential and the cellular ion homoeostasis in adrenal cells expressing the different mutants are compared, and their impact on autonomous aldosterone production and proliferation is discussed. [ABSTRACT FROM AUTHOR]

The current pathological diagnosis of aldosterone-producing adenoma (APA) is challenging because no histological markers of aldosterone production are available in routine practice. A previous study demonstrated that Disabled-2 (DAB2) is a specific marker of the zona glomerulosa (ZG) in rodents. The aim of the present study was to investigate the significance of immunohistochemical staining to detect DAB2 in the adrenal tissue of patients with APA. We investigated the expression of DAB2 in 36 adrenal glands with APA, 23 adrenal glands with cortisol-producing adenoma (CPA), and 33 adrenal glands with non-functioning adenoma (NFA). Immunohistochemical staining was performed using anti-DAB2 antibodies on paraffinembedded sections. We analysed the expression of DAB2 semiquantitatively by scoring staining intensity, and assessed the correlation of this information with the clinical findings. DAB2 mRNA expression in adenoma tissues was evaluated by RT-PCR. DAB2 was highly expressed in the ZG in normal human adrenal glands. DAB2 expression was heterogeneous in APA, with spotted, strong staining noted in most samples (25 of 36 APA). CPA and NFA also exhibited extensive low or moderate DAB2 expression. DAB2 mRNA was significantly increased and positively correlated with CYP11B2 in APA (p < 0.05). In APA, the DAB2 score adjusted for tumour volume was positively correlated with plasma aldosterone (p < 0.05). Patients with low or moderate DAB2 staining more frequently exhibited high blood pressure and were diagnosed at a younger age compared with patients with high DAB2 staining. The present study clearly demonstrates that DAB2 is a specific marker of the ZG in normal human adrenal glands but that DAB2 immunostaining is not sufficiently powerful for histopathological diagnosis of APA. DAB2 might be involved in excessive aldosterone biosynthesis and correlate with specific clinical characteristics of APA patients. [ABSTRACT FROM AUTHOR]