Primary aldosteronism (PA) is the most common form of secondary hypertension (HTN), with an estimated prevalence of 4% of hypertensive patients in primary care and around 10% of referred patients. Patients with PA have higher cardiovascular morbidity and mortality than age-and sexmatched patients with essential HTN and the same degree of blood pressure elevation. PA is characterized by an autonomous aldosterone production causing sodium retention, plasma renin supression, HTN, cardiovascular damage, and increased potassium excretion, leading to variable degrees of hypokalemia. Aldosterone-producing adenomas (APAs) account for around 40% and idiopathic hyperaldosteronism for around 60% of PA cases. The aldosterone-to-renin ratio is the most sensitive screening test for PA. There are several confirmatory tests and the current literature does not identify a "gold standard" confirmatory test for PA. In our institution, we recommend starting case confirmation with the furosemide test. After case confirmation, all patients with PA should undergo adrenal CT as the initial study in subtype testing to exclude adrenocortical carcinoma. Bilateral adrenal vein sampling (AVS) is the gold standard method to define the PA subtype, but it is not indicated in all cases. An experienced radiologist must perform AVS. Unilateral laparoscopic adrenalectomy is the preferential treatment for patients with APAs, and bilateral hyperplasia should be treated with mineralocorticoid antagonist (spironolactone or eplerenone). Cardiovascular morbidity caused by aldosterone excess can be decreased by either unilateral adrenalectomy or mineralocorticoid antagonist. In this review, we address the most relevant issues regarding PA screening, case confirmation, subtype classification, and treatment. Arch Endocrinol Metab.2017;61(3):305-12.

Context Primary aldosteronism (PA) is the most common cause of endocrine hypertension (HT). HT remission (defined as blood pressure <140/90 mm Hg without antihypertensive drugs) has been reported in approximately 50% of patients with unilateral PA after adrenalectomy. HT duration and severity are predictors of blood pressure response, but the prognostic role of somatic KCNJ5 mutations is unclear. Objective To determine clinical and molecular features associated with HT remission after adrenalectomy in patients with unilateral PA. Methods We retrospectively evaluated 100 patients with PA (60 women; median age at diagnosis 48 years with a median follow-up of 26 months). Anatomopathological analysis revealed 90 aldosterone-producing adenomas, 1 carcinoma, and 9 unilateral adrenal hyperplasias. All patients had biochemical cure after unilateral adrenalectomy. KCNJ5 gene was sequenced in 76 cases. Results KCNJ5 mutations were identified in 33 of 76 (43.4%) tumors: p.Gly151Arg (n = 17), p.Leu168Arg (n = 15), and p.Glu145Gln (n = 1). HT remission was reported in 37 of 100 (37%) patients. Among patients with HT remission, 73% were women (P = 0.04), 48.6% used more than three antihypertensive medications (P = 0.0001), and 64.9% had HT duration <10 years (P = 0.0015) compared with those without HT remission. Somatic KCNJ5 mutations were associated with female sex (P = 0.004), larger nodules (P = 0.001), and HT remission (P = 0.0001). In multivariate analysis, only a somatic KCNJ5 mutation was an independent predictor of HT remission after adrenalectomy (P = 0.004). Conclusion The presence of a KCNJ5 somatic mutation is an independent predictor of HT remission after unilateral adrenalectomy in patients with unilateral PA.

Familial primary aldosteronism (PA) is rare and mostly diagnosed in early-onset hypertension (HT). However, 'sporadic' bilateral adrenal hyperplasia (BAH) is the most frequent cause of PA and remains without genetic etiology in most cases. Our aim was to investigate new genetic defects associated with BAH and PA. We performed whole-exome sequencing (paired blood and adrenal tissue) in 6 patients with PA caused by BAH that underwent unilateral adrenalectomy. Additionally, we conducted functional studies in adrenal hyperplastic tissue and transfected cells to confirm the pathogenicity of the identified genetic variants. Rare germline variants in phosphodiesterase 2A (PDE2A) and 3B (PDE3B) genes were identified in 3 patients. The PDE2A heterozygous variant (p.Ile629Val) was identified in a patient with BAH and early-onset HT at 13 yrs of age. Two PDE3B heterozygous variants (p.Arg217Gln and p.Gly392Val) were identified in patients with BAH and HT diagnosed at 18 and 33 yrs of age, respectively. A strong PDE2A staining was found in all cases of BAH in zona glomerulosa and/or micronodules (that were also positive for CYP11B2). PKA activity in frozen tissue was significantly higher in BAH from patients harboring PDE2A and PDE3B variants. PDE2A and PDE3B variants significantly reduced protein expression in mutant transfected cells compared to WT. Interestingly, PDE2A and PDE3B variants increased SGK1 and SCNN1G/ENaCg at mRNA or protein levels. In conclusion, PDE2A and PDE3B variants were associated with PA caused by BAH. These novel genetic findings expand the spectrum of genetic etiologies of PA.

Context Primary aldosteronism (PA) screening relies on an elevated aldosterone to renin ratio with a minimum aldosterone level, which varies from 10 to 15 ng/dL (277 to 415.5 pmol/L) using immunoassay. Aim To evaluate intraindividual coefficient of variation (CV) of aldosterone and aldosterone to direct renin concentration ratio (A/DRC) and its impact on PA screening. Methods A total of 671 aldosterone and DRC measurements were performed by the same chemiluminescence assays in a large cohort of 216 patients with confirmed PA and at least two screenings. Results The median intraindividual CV of aldosterone and A/DRC was 26.8% and 26.7%. Almost 40% of the patients had at least one aldosterone level &lt;15 ng/dL, 19.9% had at least two aldosterone levels &lt;15 ng/dL and 16.2% had mean aldosterone levels &lt;15 ng/dL. A lower cut-off of 10 ng/dL was associated with false negative rates for PA screening of 14.3% for a single aldosterone measurement, 4.6% for two aldosterone measurements and only 2.3% for mean aldosterone levels. Considering the minimum aldosterone, true positive rate of aldosterone thresholds was 85.7% for 10 ng/dL and 61.6% for 15 ng/dL. An A/DRC &gt;2 ng/dL/µIU/mL had a true positive rate for PA diagnosis of 94.4% and 98.4% when based on one or two assessments, respectively. CV of aldosterone and A/DRC were not affected by sex, use of interfering anti-hypertensive medications, PA lateralization, hypokalemia, age and number of hormone measurements. Conclusion Aldosterone concentrations had a high CV in PA patients, which results in an elevated rate of false negative test in a single screening for PA. Therefore, PA screening should be based in at least two screenings with concomitant aldosterone and renin measurements.

Primary aldosteronism (PA) is the most common cause of endocrine hypertension. The 2016 Endocrine Society’s Guideline for PA management recommend that patients with a positive screening undergo one or more confirmatory tests to definitively confirm or exclude the diagnosis. Confirmatory testing procedures include oral sodium loading, saline infusion test (SIT), fludrocortisone suppression, captopril test (CT) and furosemide upright test (FUT). The FUT, mainly proposed by the Japan Endocrine Society, does not have limitation in patients with severe uncontrolled hypertension and heart failure. A positive FUT is defined as a plasma renin activity (PRA) <2 ng/mL/h after 2h, but it has not been standardized using a direct renin assay. The aim of this prospective study was to evaluate the FUT positive rate in a Brazilian cohort of PA patients and to establish a cut-off level to confirm PA diagnosis using direct renin concentration (DRC). We performed the FUT in 45 consecutive patients (25 males; median age 50 yrs, from 31 to 67 yrs) with PA diagnosis confirmed by biochemical cure after unilateral adrenalectomy or by adrenal venous sampling. Patients received furosemide 40 mg iv and stayed in upright position for 2h, starting at 8-9.30 AM. Blood samples for DRC, aldosterone, and potassium were drawn at time zero and after 2h. Aldosterone and DRC were measured by a chemiluminescent immunoassay (LIAISON®). Median A/DRC ratio was 10.3 (range, 2.54 to 66.4). Hypokalemia was evidenced in 27 out of 45 (60%) patients. Median DRC before and after 2h FUT was 2.8 uUI/mL (1.2 to 8.3) and 3.0 uUI/mL (0.5 to 19), respectively. Using the conversion factor of 12 to calculate PRA, FUT was positive (DRC/12= PRA <2 ng/mL/h) in all patients. Based on the highest renin level after FUT, the most suitable cut-off of direct renin concentration to confirm PA diagnosis was 20 uUL/mL. Additionally, potassium levels did not significantly change after FUT. Among these 45 PA patients, 39 performed an additional confirmatory test (recumbent SIT in 24 and CT in 15 patients). The positive rate for SIT was 83% using an aldosterone cut-off of 10 ng/dL and 100% using a cut-off of 6.8 ng/dL. CT and FUT were positive in all PA patients. In conclusion, FUT was a safe and reliable test for PA confirmation. In addition, we suggest a renin cut-off <20 uUI/mL after FTU to confirm PA diagnosis. Support: CNPq (403256/2016-0) to MQA

Primary aldosteronism (PA) is the most common cause of endocrine hypertension (HT) with an estimated prevalence of 10% in referred populations and 15-20% in patients with resistant hypertension. The most common cause of unilateral PA is aldosterone-producing adenomas (APAs). HT and hypokalemia improve in nearly 100% of patients with unilateral PA after unilateral adrenalectomy. However, complete clinical success (defined as blood pressure ≤130x80 mmHg without anti-hypertensive drugs) has been reported in about 50% (range, 35-80%) of patients with unilateral PA after surgery. HT duration and severity have been associated with clinical outcome after adrenalectomy, but few reports with a limited number of cases evaluated the prognostic role of somatic KCNJ5 mutations. In this study, our aim was to determine clinical and molecular features associated with complete clinical success after unilateral adrenalectomy in unilateral PA patients. We retrospectively evaluated 103 PA patients (42 males; median age 49 yrs, 20-74) with a median follow-up of 25 months. Hypokalemia was present in 78% of the cases. Anatomopathological analysis revealed 94 APAs and 9 unilateral adrenal hyperplasias. All patients had biochemical cure after unilateral adrenalectomy. KCNJ5 mutations were identified in 27 out of 67 (40%) tumors: p.Gly151Arg (n= 13), p.Leu168Arg (n= 13) and p.Glu145Gln (n= 1). Complete clinical success was reported in 32 out of 103 (31%) patients. In univariate analysis, HT duration, body mass index (BMI kg/m2), female sex and somatic KCNJ5mutations were associated with HT resolution after adrenalectomy. Complete clinical success was reported in 50% of patients with HT duration ≤5 yrs (vs. 24% with HT duration &gt;5 yrs; p= 0.011), in 40% of patients with BMI &lt;25 (vs. 22% with BMI ≥25; p= 0.042), in 38% of women (vs. 21% of men; p= 0.079) and in 70% of the patients with tumors harboring KCNJ5 somatic mutations (vs. 30% with WT tumors; p= 0.003). According to a stepwise multivariate logistic regression analysis, only the presence of a somatic KCNJ5 mutation was an independent predictor of complete success after adrenalectomy (relative risk 4.8, 95% confidence interval 1.24 to 19.21; p= 0.023). In conclusion, the presence of a somatic KCNJ5 mutation was an independent predictor of complete clinical success after unilateral adrenalectomy in patients with unilateral PA.

Primary aldosteronism (PA) is the most common cause of endocrine hypertension (HT) with an estimated prevalence of 10% in referred populations and 15–20% in patients with resistant HT. Aldosterone-producing adenomas are the most common cause of unilateral PA. Primary unilateral adrenal hyperplasia (PUH) is a rare cause of PA, but is probably underestimated. PUH can be diffuse or nodular, with poorly capsulated micronodules. To date, there is a paucity of data characterizing this condition. In this study, our aim was to report the clinical and imaging features of patients with PA caused by PUH. We retrospectively evaluated clinical, imaging and histopathological data of 183 PA patients. PUH was diagnosed in 9 out of 183 patients (5%). All patients had biochemical cure of PA after unilateral adrenalectomy and anatomopathological analysis showed micronodular adrenal hyperplasia in all cases. At the diagnosis, median age was 52 yrs, ranging from 33 and 74 yrs (6 men and 3 women). Hypokalemia was reported in 63% of the cases. Aldosterone/plasmatic renin activity ratio was 123.6 (range, 52 to 379). The median duration of HT was 18 yrs (range, 1 to 52). Because of HT duration before diagnosis, only a patient had HT cure after adrenalectomy. The median follow-up was 46 months (7 to 117 months). Computed tomography (CT) accuracy to determine the lateralization was 67%. The adrenal CT findings were: normal adrenals (n= 1), bilateral hyperplasia (n= 1; right incidentaloma 1.9 cm and left PUH 1.4 cm), unilateral hyperplasia (n= 1), bilateral nodules (n= 1) and unilateral nodules (n= 5; median 1.3 cm, from 0.9 to 1.5). Adrenal venous sampling was performed in 5 patients (successful rate 80%). In the remaining cases, surgery was guided by CT. PUH was in the left adrenal in 7 out of 9 cases (78%). Hot spot somatic mutations in aldosterone-driver genes ( KCNJ5 , ATP1A1 , ATP2B3 and CTNNB1) were excluded by Sanger automated sequencing and the presence of chimeric CYP11B1/CYP11B2 gene was ruled out by long-PCR in all cases. In conclusion, PUH prevalence in our cohort was higher than previously reported. PUH was more frequent in men and in the left adrenal. The most common CT finding was a unilateral nodule smaller than 1.5 cm. However, CT accuracy was low and AVS should be the gold standard to define lateralization. Support: CNPq (403256/2016-0) to MQA; FAPESP (2017/13394-8) to MRC.

Primary aldosteronism (PA) is the most common cause of endocrine hypertension. PA subtypes include bilateral hyperplasia and unilateral PA, typically aldosterone-producing adenomas. Adrenal venous (AV) sampling (AVS) is a key step to define PA subtype and guide PA management. According current PA guidelines, most PA patients should undergo AVS, which is a challenging procedure, especially in terms of successfully cannulating the right AV. The aim of this study was to report a single tertiary center experience with AVS in PA patients. We retrospectively evaluated 84 AVS from 1984 to 2019. Sequential AVS was performed by an experienced interventional radiologist. AV and inferior vena cava (IVC) samples were obtained under cosyntropin continuous infusion. Successful catheterization was defined by a selectivity index [SI= AV/IVC cortisol (C) concentrations] ≥5. Unilateral disease was defined by a lateralization index [LI= aldosterone (A)/C ratio in the dominant AV divided by A/C in the non-dominant AV] ≥4. The relative aldosterone secretion index (RASI= A/C ratio in AV divided by A/C in IVC) was calculated in each side. A RASI &lt;1 was defined as contralateral suppression (CS). In patients with unsuccessful AV catheterization (mostly right AV) or undetermined LI (3-4), CS was used to indicate adrenalectomy. The biochemical cure of PA after adrenalectomy was defined as the gold standard parameter to confirm unilateral disease. Successful bilateral AV catheterization was achieved in 75% of the cases. After 2015, the use of intra-procedural rapid cortisol assay improved angiographer experience and increased AVS successful rate from 52 to 80%. LI revealed unilateral and bilateral aldosterone excess in 68 and 32% of the cases, respectively. A LI ≥4 had a sensitivity of 100% and specificity of 98% to define unilateral PA among patients with successful catheterization. In addition, RASI in the non-dominant AV was significantly lower in unilateral PA according the LI when compared to bilateral cases [0.12 (0.03 to 1.18) vs. 1.1 (0.04 to 4.56), p= 0.0001]. RASI in the non-dominant AV was inversely correlated with LI (r= -0.81, p= 0.0001). A CS index ≤0.5 had a high sensitivity (90%) and specificity (94%) to define unilateral aldosterone excess. In conclusion, the LI is the most valuable parameter in AVS for PA subtyping. Additionally, CS (cut-off of 0.5) is very useful to define lateralization and can be used in cases of borderline LI or unsuccessful AV catheterization.CAPES Grant to Freitas TC.