Andrea Viola

Long-Term Cardio- and Cerebrovascular Events in Patients With Primary Aldosteronism

BACKGROUND Aldosterone plays a detrimental role on the cardiovascular system and PA patients display a higher risk of events compared with EH. OBJECTIVES The objectives of the study were to compare cardio- and cerebrovascular events in patients with primary aldosteronism (PA) and matched essential hypertension (EH). METHODS We retrospectively compared the percentage of patients experiencing events at baseline and during a median follow-up of 12 years in 270 PA patients case-control matched 1:3 with EH patients and in PA subtypes [aldosterone-producing adenoma (n = 57); bilateral adrenal hyperplasia (n = 213)] vs matched EH. RESULTS A significantly higher number of PA patients experienced cardiovascular events over the entire period of the study (22.6% vs 12.7%, P < .001). At the diagnosis of PA, a higher number of patients had experienced total events (14.1% vs 8.4% EH, P = .007); furthermore, during the follow-up period, PA patients had a higher rate of events (8.5% vs 4.3% EH, P = .008). In particular, stroke and arrhythmias were more frequent in PA patients. During the follow-up, a higher percentage of PA patients developed type 2 diabetes. Parameters that were independently associated with the occurrence of all events were age, duration of hypertension, systolic blood pressure, presence of diabetes mellitus, and PA diagnosis. After division into PA subtypes, patients with either aldosterone-producing adenoma or bilateral adrenal hyperplasia displayed a higher rate of events compared with the matched EH patients. CONCLUSIONS This study demonstrates in a large population of patients the pathogenetic role of aldosterone excess in the cardiovascular system and thus the importance of early diagnosis and targeted PA treatment.

KCNJ5 Mutations in European Families With Nonglucocorticoid Remediable Familial Hyperaldosteronism

Primary aldosteronism is the most frequent cause of endocrine hypertension. Three forms of familial hyperaldosteronism (FH) have been described, named FH-I to -III. Recently, a mutation of KCNJ5 has been shown to be associated with FH-III, whereas the cause of FH-II is still unknown. In this study we searched for mutations in KCNJ5 in 46 patients from 21 families with FH, in which FH-I was excluded. We identified a new germline G151E mutation in 2 primary aldosteronism–affected subjects from an Italian family and 3 somatic mutations in aldosterone-producing adenomas, T158A described previously as a germline mutation associated with FH-III, and G151R and L168R both described as somatic mutations in aldosterone-producing adenoma. The phenotype of the family with the G151E mutation was remarkably milder compared with the previously described American family, in terms of both clinical and biochemical parameters. Furthermore, patients with somatic KCNJ5 mutations displayed a phenotype indistinguishable from that of sporadic primary aldosteronism. The functional characterization of the effects of the G151E mutation in vitro showed a profound alteration of the channel function, with loss of K+ selectivity, Na+ influx, and membrane depolarization. These alterations have been postulated to be responsible for voltage gate Ca2+ channel activation, increase in cytosolic calcium, and stimulation of aldosterone production and adrenal cell proliferation. In conclusion, we describe herein a new mutation in the KCNJ5 potassium channel associated with FH-III, responsible for marked alterations of channel function but associated with a mild clinical and hormonal phenotype.

Prevalence and Characteristics of Familial Hyperaldosteronism: The PATOGEN Study (Primary Aldosteronism in TOrino-GENetic forms)

Primary aldosteronism (PA) is the most frequent cause of secondary hypertension, and patients display an increased prevalence of cardiovascular events compared with essential hypertensives. To date, 3 familial forms of PA have been described and termed familial hyperaldosteronism types I, II, and III (FH-I to -III). The aim of this study was to investigate the prevalence and clinical characteristics of the 3 forms of FH in a large population of PA patients. Three-hundred consecutive PA patients diagnosed in our unit were tested by long-PCR of the CYP11B1/CYP11B2 hybrid gene that causes FH-I, and all of the available relatives of PA patients were screened to confirm or exclude PA and, thus, FH-II. Urinary 18-hydroxycortisol and 18-oxocortisol were measured in all of the familial PA patients. Two patients were diagnosed with FH-I (prevalence: 0.66%), as well as 21 of their relatives, and clinical phenotypes of the 2 affected families varied markedly. After exclusion of families who refused testing and those who were not informative, 199 families were investigated, of which 12 were diagnosed with FH-II (6%) and an additional 15 individuals had confirmed PA; clinical and biochemical phenotypes of FH-II families were not significantly different from sporadic PA patients. None of the families displayed a phenotype compatible with FH-III diagnosis. Our study demonstrates that familial forms of hyperaldosteronism are more frequent than previously expected and reinforces the recommendation of the Endocrine Society Guidelines to screen all first-degree hypertensive relatives of PA patients.

Effect of adrenocorticotropic hormone stimulation during adrenal vein sampling in primary aldosteronism.

Adrenal vein sampling (AVS) is fundamental for subtype diagnosis in patients with primary aldosteronism. AVS protocols vary between centers, especially for diagnostic indices and for use of adrenocorticotropic hormone (ACTH) stimulation. We investigated the role of both continuous ACTH infusion and bolus on the performance and interpretation of AVS in a sample of 76 patients with confirmed primary aldosteronism. In 36 primary aldosteronism patients, AVS was performed both under basal conditions and after continuous ACTH infusion, and in 40 primary aldosteronism patients, AVS was performed both under basal conditions and after ACTH IV bolus. Both ACTH protocols determined an increase in the rate of successful cannulation of the adrenal veins. Both ACTH infusion and bolus determined a significant increase in selectivity index for the right adrenal vein and ACTH bolus for the left adrenal vein. Lateralization index was not significantly different after continuous ACTH infusion and IV bolus. In 88% and 78% of the patients, the diagnosis obtained was the same before and after ACTH infusion and IV bolus, respectively. However, the reproducibility of the diagnosis was reduced using less stringent criteria for successful cannulation of the adrenal veins. This study shows that ACTH use during AVS may be of help for centers with lower success rates, because a successful adrenal cannulation is more easily obtained with this protocol; moreover, this technique performs at least as well as the unstimulated strategy and in some cases may be even better. Stringent criteria for cannulation should be used to have a high consistency of the diagnosis.

Adrenal vein sampling in primary aldosteronism: towards a standardised protocol

Primary aldosteronism comprises subtypes that need different therapeutic strategies. Adrenal vein sampling is recognised by Endocrine Society guidelines as the only reliable way to correctly diagnose the subtype of primary aldosteronism. Unfortunately, despite being the gold-standard procedure, no standardised procedure exists either in terms of performance or interpretation criteria. In this Personal View, we address several questions that clinicians are presented with when considering adrenal vein sampling. For each of these questions we provide responses based on the available evidence, and opinions based on our experience. In particular, we discuss the most appropriate way to prepare the patient, whether adrenal vein sampling can be avoided for some subgroups of patients, the use of ACTH (1-24) during the procedure, the most appropriate criteria for interpretation of adrenal vein cannulation and lateralisation, the use of contralateral suppression, and strategies to improve success rates of adrenal vein sampling in centres with little experience.

Aldosterone Suppression on Contralateral Adrenal During Adrenal Vein Sampling Does Not Predict Blood Pressure Response After Adrenalectomy

CONTEXT Adrenal vein sampling (AVS) is the only reliable means to distinguish between aldosterone-producing adenoma and bilateral adrenal hyperplasia, the two most common subtypes of primary aldosteronism (PA). AVS protocols are not standardized and vary widely between centers. OBJECTIVE The objective of the study was to retrospectively investigate whether the presence of contralateral adrenal (CL) suppression of aldosterone secretion was associated with improved postoperative outcomes in patients who underwent unilateral adrenalectomy for PA. SETTING The study was carried out in eight different referral centers in Italy, Germany, and Japan. PATIENTS From 585 consecutive AVS in patients with confirmed PA, 234 procedures met the inclusion criteria and were used for the subsequent analyses. RESULTS Overall, 82% of patients displayed contralateral suppression. This percentage was significantly higher in ACTH stimulated compared with basal procedures (90% vs 77%). The CL ratio was inversely correlated with the aldosterone level at diagnosis and, among AVS parameters, with the lateralization index (P = .02 and P = .01, respectively). The absence of contralateral suppression was not associated with a lower rate of response to adrenalectomy in terms of both clinical and biochemical parameters, and patients with CL suppression underwent a significantly larger reduction in the aldosterone levels after adrenalectomy. CONCLUSIONS For patients with lateralizing indices of greater than 4 (which comprised the great majority of subjects in this study), CL suppression should not be required to refer patients to adrenalectomy because it is not associated with a larger blood pressure reduction after surgery and might exclude patients from curative surgery.

Concurrent primary aldosteronism and subclinical cortisol hypersecretion: a prospective study.

Background Primary aldosteronism is the most frequent cause of secondary hypertension and is responsible for an increased risk of cardiometabolic complications. A concomitant subtle cortisol hyperproduction could enhance cardiovascular risk. We prospectively estimated the occurrence of subclinical hypercortisolism in primary aldosteronism patients. Methods In a large population of hypertensive patients without clinical signs of hypercortisolism, 76 consecutive patients with primary aldosteronism were investigated. Differential diagnosis between unilateral and bilateral aldosterone hypersecretion was made by computed tomography/MRI and/or adrenal venous sampling (AVS). Subclinical hypercortisolism was defined as failure to suppress plasma cortisol to less than 50 nmol/l after 1 mg-overnight dexamethasone, used as screening test, and at least one of two other abnormal hormonal parameters, that is, adrenocorticotrophin (ACTH) less than 2 pmol/l and urinary cortisol more than 694 nmol/24 h. Results Three out of 76 patients had postdexamethasone plasma cortisol more than 50 nmol/l. Only one also showed low-normal ACTH and mildly elevated urinary cortisol. The patient had a right 4 cm adrenal mass. Laparoscopic adrenalectomy was followed by short-term steroid replacement to prevent adrenal insufficiency. In-situ hybridization showed CYP11B1 expression exclusively in tumoral tissue, whereas CYP11B2 was expressed only in a peritumoral region composed of zona glomerulosa-like cells, suggesting the co-existence of a cortisol-producing adenoma and an aldosterone-producing hyperplasia in the same adrenal. The restoration of hormone abnormalities to normal levels was confirmed at 12 months of follow-up. Conclusion Concurrent aldosterone and subclinical cortisol hypersecretion seems to be a rare event in primary aldosteronism patients; however, its detection by appropriate testing is important to avoid AVS misinterpretation.

Primary aldosteronism: who should be screened?

Primary aldosteronism (PA) has a prevalence in the general hypertensive population from 5 to 10%, and is widely recognized as the most frequent form of secondary hypertension. The 2 main PA subtypes are aldosterone producing adenoma (APA) and bilateral adrenal hyperplasia (BAH) that account for 95% of all PA cases. The diagnosis of PA is a 3-step process that comprises screening, confirmatory testing, and subtype differentiation. The different categories of patients at an increased risk of PA who should thus undergo a screening test were described in the first Endocrine Society (ES) Practice Guidelines for diagnosis and treatment of PA published in 2008. These categories include patients with Joint National Committee Stage 2, Stage 3, or drug-resistant hypertension; hypertension, and spontaneous or diuretic-induced hypokalemia; hypertension with adrenal incidentaloma; hypertension and a family history of early-onset hypertension or cerebrovascular accident at a young age and all hypertensive first degree relatives of patients with PA. Recently, a growing number of studies have linked PA with the metabolic syndrome, diabetes, and obstructive sleep apnea that may be partly responsible for the higher rate of cardio and cerobrovascular accidents in PA patients. The aim of this review is to discuss, which patients should be screened for PA, focusing not only on the well-established categories of the ES Guidelines, but also on additional other group of patients with a potentially high prevalence of PA that has emerged from recent research.

Diagnosis and treatment of unilateral forms of primary aldosteronism.

Primary aldosteronism (PA) is now recognized as the most frequent form of secondary arterial hypertension. The importance of a correct and prompt diagnosis of PA is determined by its relevant prevalence, its increased cardiovascular risk compared to essential hypertension and by the possibility of reversing this increased risk with a targeted therapy. Surgical treatment of unilateral forms of PA (mainly aldosterone-producing adenomas) is at present recommended in well-selected patients because of its cost-effectiveness. Therefore, subtype differentiation of PA forms is of fundamental importance, and available guidelines recommend contrast-enhanced CT-scanning and adrenal venous sampling (AVS) as the main diagnostic tests for this purpose. In this review, we discuss the value of adrenal non-invasive imaging and AVS, the recent advances in complementary tests and, finally, the available data on the outcome of surgical treatment for PA.

9B.06: COMPARISON BETWEEN ALDOSTERONE AND RENIN MEASUREMENT BY CHEMILUMINESCENT IMMUNOASSAY AND RADIOIMMUNOASSAY FOR THE DIAGNOSIS OF PRIMARY ALDOSTERONISM.

Objective: Primary aldosteronism (PA) is the most frequent cause of secondary hypertension responsible for an increased rate of cardiovascular events. According to the Endocrine Society Guidelines, up to 50% of hypertensive patients should be screened for PA, using the aldosterone to renin (or plasma renin activity, PRA) ratio (AARR and ARR, respectively). The automated Diasorin LIAISON® chemiluminescent immunoassay for renin and aldosterone measurement became available and in many laboratories is currently used instead of the classical radioimmunometric PRA and aldosterone assay. Aim of the study was to prospectively compare the diagnostic accuracy of AARR and ARR as screening test for PA and the two aldosterone assays also during confirmatory test in patients with a positive screening test. Design and method: One hundred patients were screened for PA and 44 patients underwent confirmatory test (either by intravenous saline load or by captopril challenge test). We considered as cut off for the AARR 2.7 (ng/dL/mU/L) and for the ARR 30 (ng/dL/ng/mL/h). All patients positive to one of the two screening test underwent confirmatory test; patients with positive confirmatory test underwent subtype diagnosis by CT scanning and adrenal vein sampling. Results: Seventy three patients were diagnosed as essential hypertensives, 22 had bilateral adrenal hyperplasia and 5 had an aldosterone producing adenomas (APA). The AARR displayed a sensitivity of 78% and a specificity of 100%, whereas the ARR had a sensitivity of 96% and a specificity of 90%. Of the 6/27 PA patients missed by AARR, none resulted to be affected by APA. All PA patients were correctly diagnosed by chemiluminescence at confirmatory test. In the overall sample of 181 measurements available both the correlation for the PRA with renin and for aldosterone in chemiluminescence and radioimmunoassay were highly significant (Rho = 0.66, p < 0.0001 and Rho = 0.80, p < 0.0001, respectively). On ROC curves, the AUC for AARR was 0.905 (95% CI 0.821-0.988) and for ARR 0.947 (95% CI 0.903–0.991) and they were not significantly different. Conclusions: The automated aldosterone and renin chemiluminescent assay is a reliable alternative to the well-established radioimmunometric method, especially for the detection of APA.