Unilateral adrenalectomy in bilateral adrenal hyperplasia with primary aldosteronism.

PURPOSE: Mineralocorticoid receptor antagonists are the first-line treatment for bilateral adrenal hyperplasia (BAH) with primary aldosteronism (PA), while unilateral adrenalectomy is the standard treatment for aldosterone-producing adenoma (APA). In this study, we investigated the outcomes of patients with BAH after unilateral adrenalectomy and compared them with those of patients with APA. METHODS: From January 2010 to November 2018, 102 patients with a diagnosis of PA confirmed by adrenal vein sampling (AVS) and available NP-59 scans were enrolled. All patients underwent unilateral adrenalectomy based on the lateralization test results. We prospectively collected the clinical parameters over 12 months and compared the outcomes of BAH and APA. RESULTS: A total of 102 patients were enrolled in this study: 20 (19.6%) had BAH and 82 (80.4%) had APA. Significant improvements in serum aldosterone-renin ratio (ARR), potassium level, and reduction of antihypertensive drugs were observed in both groups at 12 months after surgery (all p < 0.05). Patients with APA showed a significant decrease in blood pressure after surgery (p < 0.001) than those with BAH. Additionally, multivariate logistic regression analysis indicated that APA was associated with biochemical success (odds ratio: 4.32, p = 0.024) compared to BAH. CONCLUSION: Patients with BAH had a higher failure rate in clinical outcomes, and APA was associated with biochemical success after unilateral adrenalectomy. However, significant improvements in ARR, hypokalemia, and a decreased use of antihypertensive drugs were noted in patients with BAH after surgery. Unilateral adrenalectomy is feasible and beneficial in selected patients, and could potentially serve as a treatment option.

Adrenal androgens versus cortisol for primary aldosteronism subtype determination in adrenal venous sampling.

OBJECTIVE: We examined if measurement of adrenal androgens adds to subtype diagnostics of primary aldosteronism (PA) under cosyntropin-stimulated adrenal venous sampling (AVS). DESIGN: A prospective pre-specified secondary endpoint analysis of 49 patients with confirmed PA, of whom 29 underwent unilateral adrenalectomy with long-term follow-up. METHODS: Concentrations of androstenedione, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate (DHEAS) were measured during AVS in addition to aldosterone and cortisol. Subjects with lateralisation index (LI) of ≥4 were treated with unilateral adrenalectomy, and the immunohistochemical subtype was determined with CYP11B2 and CYP11B1 stains. The performance of adrenal androgens was evaluated by receiver operating characteristics (ROC) curve analyses in adrenalectomy and medical therapy groups. RESULTS: During AVS, the correlations between cortisol and androstenedione, DHEA and DHEAS for LI and selectivity index (SI) were highly significant. The right and left side SIs for androstenedione and DHEA were higher (p < .001) than for cortisol. In ROC analysis, the optimal LI cut-off values for androstenedione, DHEA and DHEAS were 4.2, 4.5 and 4.6, respectively. The performance of these LIs for adrenal androgens did not differ from that of cortisol. CONCLUSIONS: Under cosyntropin-stimulated AVS, the measurement of androstenedione and DHEA did not improve the cannulation selectivity. The performance of cortisol and adrenal androgens are confirmatory but not superior to cortisol-based results in lateralisation diagnostics of PA.

Utility of Epinephrine Levels in Determining Adrenal Vein Cannulation During Adrenal Venous Sampling for Primary Aldosteronism.

OBJECTIVE: In patients with primary aldosteronism, adrenal venous sampling (AVS) is performed to determine the presence of unilateral or bilateral adrenal disease. During AVS, verification of catheter positioning within the left adrenal vein (AV) and the right AV by comparison of AV and inferior vena cava (IVC) cortisol levels can be variable. The objective of this study was to determine the utility of AV epinephrine levels in assessing successful AV cannulation. METHODS: This was a single institution, retrospective review of patients who underwent AVS with cosyntropin stimulation for primary aldosteronism between 2009 and 2018. Successful cannulation of the AV was defined by an AV/IVC cortisol ratio selectivity index (SI) ≥3:1. Epinephrine thresholds to predict catheter placement in the AV were determined using logistic regression. The calculated epinephrine thresholds were compared with previously published thresholds. RESULTS: AVS was performed on 101 consecutive patients and, based on the SI, successful cannulation of the left AV and right AV occurred in 98 (97%) and 91(90%) patients, respectively. The calculated optimal epinephrine threshold to predict AV cannulation was 364 pg/mL (sensitivity, 92.1%; specificity, 94.6%) and the calculated optimal AV/IVC epinephrine ratio threshold was 27.4, (sensitivity, 92.1%; specificity, 91.3%). Among the 14 patients with failed AV cannulation, 3 patients would have been considered to have successful AVS using AV epinephrine levels >364 pg/mL and AV/IVC epinephrine ratio >27.4 thresholds. CONCLUSION: Obtaining 2 right AV samples routinely as well as AV and IVC epinephrine levels during AVS could prevent unnecessary repeat AVS in patients with failed AV cannulation based on cortisol-based SI <3:1.

[Primary aldosteronism : Genetics and pathology]. / Primärer Hyperaldosteronismus : Genetik und Pathologie.

BACKGROUND: Primary aldosteronism, the excessive production of the steroid hormone aldosterone, is the most common cause of secondary hypertension. Common subforms include bilateral adrenal hyperplasia and aldosterone-producing adenoma. OBJECTIVES: The goal of this review is to summarize important publications on the genetic basis of primary aldosteronism. RESULTS: Somatic mutations in the KCNJ5, CACNA1D, ATP1A1, and ATP2B3 genes have been described as causes of aldosterone-producing adenomas. They eventually all lead to increased cellular calcium influx and aldosterone production. The mechanisms of rare CTNNB1 mutations are less defined. Correlations between mutations and different histologic characteristics as well as gender and ethnicity remain unexplained. Recent publications suggest that bilateral hyperplasia is at least partially due to so-called aldosterone-producing cell clusters, often with mutations in CACNA1D. Rare familial forms show mutations in the CYP11B2, CLCN2, KCNJ5, CACNA1H, or CACNA1D genes. CONCLUSIONS: These results suggest that a significant fraction of primary aldosteronism is due to somatic mutations in single genes.

[Primary hyperaldosteronism: difficulties in diagnosis].

Primary hyperaldosteronism (PA) - is the clinical syndrome, results from autonomous of the major regulators of secretion, aldosterone overproduction by a tumorous or hyperplastic tissue in adrenal cortex. Being the most frequent cause of secondary hypertension, PA may be represented by disorders with unilateral or bilateral aldosterone overproduction and differential diagnosis between them is crucial for choosing a right therapeutic approache: lifelong medical therapy with mineralocorticoid receptor antagonists or unilateral adrenalectomy. Adrenal venous sampling (AVS) is currently the «gold standard¼ test for identifying laterality of excess hormone production, unlike imaging tests, sensitivity and specificity of which is not enough, due to inability to evaluate functional activity with confidence, and also to limitations in detecting tiny abnormalities of adrenals, such as microadenoma or hyperplasia. Excluding certain cases, AVS is recommended to patients with confirmed PA, planning surgical treatment, to determine the lateralization of aldosterone hypersecretion. Described clinical case of patient with confirmed lateralization from adrenal without any detected lesions on CT-imaging and nonfunctioning tumour on contralateral side, highlights the importance of using AVS for decision to refer patients for surgery.

Subtype Diagnosis of Primary Aldosteronism: Is Adrenal Vein Sampling Always Necessary?

Aldosterone producing adenoma and bilateral adrenal hyperplasia are the two most common subtypes of primary aldosteronism (PA) that require targeted and distinct therapeutic approaches: unilateral adrenalectomy or lifelong medical therapy with mineralocorticoid receptor antagonists. According to the 2016 Endocrine Society Guideline, adrenal venous sampling (AVS) is the gold standard test to distinguish between unilateral and bilateral aldosterone overproduction and therefore, to safely refer patients with PA to surgery. Despite significant advances in the optimization of the AVS procedure and the interpretation of hormonal data, a standardized protocol across centers is still lacking. Alternative methods are sought to either localize an aldosterone producing adenoma or to predict the presence of unilateral disease and thereby substantially reduce the number of patients with PA who proceed to AVS. In this review, we summarize the recent advances in subtyping PA for the diagnosis of unilateral and bilateral disease. We focus on the developments in the AVS procedure, the interpretation criteria, and comparisons of the performance of AVS with the alternative methods that are currently available.

Temporal trends in clinical features of patients with primary aldosteronism over 20 years.

Primary aldosteronism (PA) accounts for approximately 5-10% of hypertension cases. Over the past 20 years, the reported incidence of PA has increased due to widespread screening for secondary hypertension and imaging studies. We aimed to evaluate the temporal trends in the clinical characteristics and subtypes of PA. A total of 1064 patients with PA in two tertiary hospitals between 2000 and 2021 were categorized into three groups according to the year of diagnosis: 2000-2009, 2010-2015, and 2016-2021. The clinical characteristics of the patients over the three time periods were compared using a trend analysis. The age at diagnosis and sex of patients with PA did not change over 20 years. The proportion of patients with bilateral hyperaldosteronism (BHA) increased (11%, 25%, and 40%, P for trend <0.001). The proportion of hypokalemia (87%, 61%, and 40%) and plasma aldosterone concentration (36.0, 30.8, and 26.6 ng/dL) decreased (all P for trend <0.001). There was a trend toward an increased proportion of incidentally detected patients compared to clinically symptomatic patients (36%, 55%, and 61%, P for trend <0.001). The concordance rate of imaging and adrenal venous sampling results decreased (91%, 70%, and 57% P for trend <0.001). However, the proportion of patients with resistant hypertension and comorbidities did not differ. In conclusion, among patients with PA, patients with BHA and incidental detection have increased over 20 years, and more patients are likely to present with milder clinical symptoms and biochemical profiles.

Clinical prediction model for primary aldosteronism subtyping and special focus on adrenal volumetric assessment.

PURPOSE: Our aim was to develop a prediction model based on a simple score with clinical, laboratory, and imaging findings for the subtype diagnosis of primary aldosteronism (PA). The contribution of adrenal volumetric assessment to PA subtyping was also investigated. METHODS: Thirty-five patients with adequate cannulation in adrenal venous sampling (AVS) were included. Laboratory data, the saline infusion test (SIT), and the AVS results of patients with PA were retrospectively evaluated. Volumetric assessment was performed using magnetic resonance imaging (MRI) and the ratio of adrenal volumes was calculated after adjusting for gender- and side-specific mean reference values of both adrenal glands. RESULTS: The AVS was consistent with unilateral PA in 49% and bilateral in 51% of the patients. Hypertension as a reason for work-up, the highest aldosterone/lowest potassium value higher than 12, the percentage of plasma aldosterone concentration (PAC) reduction after SIT by equal or less than 43.5%, the use of oral potassium replacement, unilateral disease at pre-AVS imaging, and a ratio of adjusted adrenal volumes equal to or below 1.7 were indicative of unilateral disease in univariate logistic regression analysis concerning the distinction of PA subtyping (p < 0.05). Multivariate logistic regression analysis also revealed that adrenal volumetric assessment has an impact on PA subtyping (p < 0.05). In the prediction model, when each of the six parameters that were significant in the univariate logistic regression analysis was assigned one point, < 4 predicted bilateral PA, whereas ≥ 4 predicted unilateral PA (AUC:0.92, p < 0.001). CONCLUSION: This prediction model before AVS may serve as a convenient and practical approach, while an adjusted adrenal volumetric assessment can make a positive contribution to PA subtyping.

Bilateral Adrenal Hyperplasia: Pathogenesis and Treatment.

Bilateral adrenal hyperplasia is a rare cause of Cushing's syndrome. Micronodular adrenal hyperplasia, including the primary pigmented micronodular adrenal dysplasia (PPNAD) and the isolated micronodular adrenal hyperplasia (iMAD), can be distinguished from the primary bilateral macronodular adrenal hyperplasia (PBMAH) according to the size of the nodules. They both lead to overt or subclinical CS. In the latter case, PPNAD is usually diagnosed after a systematic screening in patients presenting with Carney complex, while for PBMAH, the diagnosis is often incidental on imaging. Identification of causal genes and genetic counseling also help in the diagnoses. This review discusses the last decades' findings on genetic and molecular causes of bilateral adrenal hyperplasia, including the several mechanisms altering the PKA pathway, the recent discovery of ARMC5, and the role of the adrenal paracrine regulation. Finally, the treatment of bilateral adrenal hyperplasia will be discussed, focusing on current data on unilateral adrenalectomy.

Prevalence, diagnosis and outcomes of treatment for primary aldosteronism.

Primary aldosteronism (PA) is the most common potentially curable form of hypertension. The overproduction of aldosterone leads to an increased risk of cardiovascular and cerebrovascular events as well as adverse effects to the heart and kidney and psychological disorders. PA is mainly caused by unilateral aldosterone excess due to an aldosterone-producing adenoma or bilateral excess due to bilateral adrenocortical hyperplasia. The diagnostic work-up of PA comprises three steps: screening, confirmatory testing and differentiation of unilateral surgically-correctable forms from medically treated bilateral PA. These specific treatments can mitigate or reverse the increased risks associated with PA. Herein we summarise the prevalence, outcomes and current and future clinical approaches for the diagnosis of primary aldosteronism.

Classification of microadenomas in patients with primary aldosteronism by steroid profiling.

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.

Circulating miRNA Expression Profiling in Primary Aldosteronism.

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.

Timeline of Advances in Genetics of Primary Aldosteronism.

The overwhelming majority of cases of primary aldosteronism (PA) occur sporadically due to a unilateral aldosterone-producing adenoma (APA) or bilateral idiopathic adrenal hyperplasia. Familial forms of PA are rare with four subtypes defined to date (familial hyperaldosteronism types I-IV). The molecular basis of familial hyperaldosteronism type I (FH type I or glucocorticoid-remediable aldosteronism) was established in 1992; two decades later the genetic variant causing FH type III was identified and germline mutations causing FH type IV and FH type II were determined soon after. Effective diagnostic protocols and methods to detect the overactive gland in unilateral PA by adrenal venous sampling followed by laparoscopic adrenalectomy have made available APAs for scientific studies. In rapid succession, following the widespread use of next-generation sequencing, recurrent somatic driver mutations in APAs were identified in genes encoding ion channels and transporters. The development of highly specific monoclonal antibodies against key enzymes in adrenal steroidogenesis has unveiled the heterogeneous features of the diseased adrenal in PA and helped reveal the high proportion of APAs with driver mutations. We discuss what is known about the genetics of PA that has led to a clearer understanding of the disease pathophysiology.

A unique case of ectopic Cushing's syndrome from a thymic neuroendocrine carcinoma.

Ectopic adrenocorticotropic hormone (ACTH) production leading to ectopic ACTH syndrome accounts for a small proportion of all Cushing's syndrome (CS) cases. Thymic neuroendocrine tumors are rare neoplasms that may secrete ACTH leading to rapid development of hypercortisolism causing electrolyte and metabolic abnormalities, uncontrolled hypertension and an increased risk for opportunistic infections. We present a unique case of a patient who presented with a mediastinal mass, revealed to be an ACTH-secreting thymic neuroendocrine tumor (NET) causing ectopic CS. As the diagnosis of CS from ectopic ACTH syndrome (EAS) remains challenging, we emphasize the necessity for high clinical suspicion in the appropriate setting, concordance between biochemical, imaging and pathology findings, along with continued vigilant monitoring for recurrence after definitive treatment. Learning points: Functional thymic neuroendocrine tumors are exceedingly rare. Ectopic Cushing's syndrome secondary to thymic neuroendocrine tumors secreting ACTH present with features of hypercortisolism including electrolyte and metabolic abnormalities, uncontrolled hypertension and hyperglycemia, and opportunistic infections. The ability to undergo surgery and completeness of resection are the strongest prognostic factors for improved overall survival; however, the recurrence rate remains high. A high degree of initial clinical suspicion followed by vigilant monitoring is required for patients with this challenging disease.

Three-Quarters Adrenalectomy for Infantile-Onset Cushing Syndrome due to Bilateral Adrenal Hyperplasia in McCune-Albright Syndrome.

BACKGROUND: Bilateral adrenalectomy is performed in cases with infantile-onset Cushing syndrome due to bilateral adrenal hyperplasia in McCune-Albright syndrome (MAS) because severe Cushing syndrome with heart failure and liver dysfunction can have a lethal outcome. This procedure can completely ameliorate hypercortisolism, although lifetime steroid replacement therapy and steps to prevent adrenal crisis are necessary. Recently, the efficacy of unilateral adrenalectomy has been reported in adult cases of bilateral macronodular adrenal hyperplasia, but there is no consensus regarding the appropriate surgical treatment for bilateral adrenal hyperplasia in MAS. OBJECTIVE: A 6-month-old girl presented with café-au-lait spots, short stature, central obesity, a moon face, and hypertension. Endocrinological tests and imaging studies led to the diagnosis of ACTH-independent Cushing syndrome due to bilateral adrenal hyperplasia induced by MAS. "Three-quarters adrenalectomy", namely right-sided total adrenalectomy and left-sided half adrenalectomy, was carried out. An activating mutation of the GNAS1 gene (p.Arg201Cys) was identified in the adrenal tissues. Since the operation, our patient has been in a state of clinical remission for more than 2 years. CONCLUSION: Our original surgical intervention, three-quarters adrenalectomy, may be a new treatment option for Cushing syndrome associated with MAS.

Prevalence and Clinical Manifestations of Primary Aldosteronism Encountered in Primary Care Practice.

BACKGROUND: Despite being widely recognized as the most common form of secondary hypertension, among the general hypertensive population the true prevalence of primary aldosteronism (PA) and its main subtypes, aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH), remains a matter of debate. OBJECTIVES: This study sought to determine the prevalence and clinical phenotype of PA in a large cohort of unselected patients with hypertension, consecutively referred to our hypertension unit, by 19 general practitioners from Torino, Italy. METHODS: Following withdrawal from all interfering medications, patients were screened for PA using the ratio of serum aldosterone to plasma renin activity. PA was diagnosed according to Endocrine Society guidelines. The diagnosis was confirmed or excluded by an intravenous saline infusion test or captopril challenge test and subtype differentiation was performed by adrenal computed tomography scanning and adrenal vein sampling, using strict criteria to define successful cannulation and lateralization of aldosterone production. RESULTS: A total of 1,672 primary care patients with hypertension (569 newly diagnosed and 1,103 patients already diagnosed with arterial hypertension) were included in the study. A total of 99 patients (5.9%) were diagnosed with PA and conclusive subtype differentiation by adrenal vein sampling was made in 91 patients (27 patients with an APA and 64 patients with BAH). The overall prevalence of PA increased with the severity of hypertension, from 3.9% in stage 1 hypertension to 11.8% in stage 3 hypertension. Patients with PA more frequently displayed target organ damage and cardiovascular events compared with those without PA, independent of confounding variables. CONCLUSIONS: Our results demonstrated that PA is a frequent cause of secondary hypertension, even in the general population of patients with hypertension, and indicates that most of these patients should be screened for PA.

Clinical Management and Outcomes of Adrenal Hemorrhage Following Adrenal Vein Sampling in Primary Aldosteronism.

Aldosterone-producing adenoma and bilateral adrenal hyperplasia account for >90% of all primary aldosteronism cases. Distinguishing between bilateral and unilateral disease is of fundamental importance because it allows targeted therapy. Adrenal vein sampling (AVS) is the only reliable means to preoperatively differentiate between unilateral and bilateral subtypes. A rare but serious complication of AVS is an adrenal hemorrhage (AH). We retrospectively examined in detail 24 cases of AH during AVS in 6 different referral hypertension centers. AH more often affected the right adrenal (n=18) than the left (n=5, P<0.001); 1 bilateral. Median duration of experience of the radiologist in AVS at the time of AH was 5.0 years (0.6-7.8) and AH occurred with both highly experienced (>10 years) and less experienced radiologists. Of 9 patients who suffered AH in the gland contralateral to an aldosterone-producing adenoma and who underwent complete (n=6) or partial (n=3) unilateral adrenalectomy, only one required long-term corticosteroid replacement for adrenal insufficiency. No reduction in blood pressure or biochemical resolution of primary aldosteronism occurred in any of those patients who experienced AH in the gland ipsilateral to an aldosterone-producing adenoma (n=6) or who had bilateral adrenal hyperplasia (n=9). No patient required invasive treatments to control bleeding or blood transfusion. In conclusion, AH usually has a positive outcome causing either no or minor effects on adrenal function, and AVS should remain the best approach to primary aldosteronism subtype differentiation.

Bilateral symmetrical adrenal hypermetabolism on FDG PET/CT due to Cushing syndrome in well differentiated neuroendocrine carcinoma.

The (18)F-FDG PET/CT scan has been suggested for whole-body imaging to identify ectopic adrenocorticotrophic hormone secreting tumours, but there are some challenges involved. The case of a patient is presented, who was admitted with the pre-diagnosis of ectopic ACTH syndrome. On the CT, a nodular lesion was detected in the medial segment of the right lung. The FDG uptake of the lesion seemed to be increased visually, but was not pathological quantitatively (SUVmax: 1.8) on the PET/CT. There was also diffuse increased uptake (SUVmax: 14.2) in the enlarged adrenal glands. The lesion was reported as a possible malignant lesion with low FDG affinity, such as a low grade neuroendocrine tumour, while the diffuse enlarged adrenal glands with high uptake were interpreted as diffusely hyperplasic, due to Cushing's syndrome. The patient was treated with a surgical wedge resection. The histopathological diagnosis confirmed that the tumour was a grade 1 well-differentiated neuroendocrine carcinoma.

Primary aldosteronism: challenges in diagnosis and management.

Primary aldosteronism (PA) is the main cause of endocrine hypertension, present in approximately 10% of hypertensive patients; about one-third is secondary to aldosterone-producing adenomas. Cardiovascular and renal morbidity are out of proportion to the degree of hypertension. Physicians have compelling rationale to correctly identify and treat PA. Physicians are challenged with patient selection for screening with the aldosterone/renin ratio (ARR), interpretation of ARR, and selecting a confirmatory test. Adrenal vein sampling is performed for subtype differentiation. The treatment depends on the disease subtype and results in control of hypertension and reversal of associated excess morbidity.

An update on novel mechanisms of primary aldosteronism.

Primary aldosteronism (PA) is the most common and curable form of secondary hypertension. It is caused in the majority of cases by either unilateral aldosterone overproduction due to an aldosterone-producing adenoma (APA) or by bilateral adrenal hyperplasia. Recent advances in genome technology have allowed researchers to unravel part of the genetic abnormalities underlying the development of APA and familial hyperaldosteronism. Recurrent somatic mutations in genes coding for ion channels (KCNJ5 and CACNA1D) and ATPases (ATP1A1 and ATP2B3) regulating intracellular ionic homeostasis and cell membrane potential have been identified in APA. Similar germline mutations of KCNJ5 were identified in a severe familial form of PA, familial hyperaldosteronism type 3 (FH3), whereas de novo germline CACNA1D mutations were found in two cases of hyperaldosteronism associated with a complex neurological disorder. These results have allowed a pathophysiological model of APA development to be established. This model involves modifications in intracellular ionic homeostasis and membrane potential, accounting for ∼50% of all tumors, associated with specific gender differences and severity of PA. In this review, we describe the different genetic abnormalities associated with PA and discuss the mechanisms whereby they lead to increased aldosterone production and cell proliferation. We also address some of the foreseeable consequences that genetic knowledge may contribute to improve diagnosis and patient care.