RARE DISEASE
Rare primary hyperaldosteronism
Rare primary hyperaldosteronism
Rare primary hyperaldosteronism
Synonyms: Rare primary aldosteronism
Synonyms: Rare primary aldosteronism
Synonyms: Rare primary aldosteronism
Drug discovery
1
drug
With orphan designation
Overview
Primary hyperaldosteronism (PA), characterized by autonomous aldosterone overproduction, is a leading endocrine cause of hypertension. While historically considered rare, emerging evidence suggests it affects 5%-15% of hypertensives, with higher rates in resistant hypertension populations [1][2][7][15]. Diagnosis requires aldosterone/renin ratio testing, confirmatory suppression tests, and adrenal imaging or venous sampling for subtype classification [1][10][16].
Population
Prevalence: 5%-15% of hypertensive patients, rising to 20%-29% in resistant hypertension [2][7][15]
Common causes: Bilateral adrenal hyperplasia (60%-70%) and aldosterone-producing adenomas (30%-40%) [1][18]
High-risk groups: Those with resistant HTN, hypokalemia, adrenal incidentalomas, or family history [1][10]
Burden
Cardiovascular: 2-4x higher risk of atrial fibrillation, stroke, and CKD vs essential hypertension [4][13][15]
Diagnostic delays: Average 7-10 years from HTN onset, with 42% developing end-organ damage pre-diagnosis [4][7][13]
Quality of life: 74% report significant symptom burden (fatigue, muscle weakness) pre-treatment [4][13]
Therapies
Unilateral disease: Laparoscopic adrenalectomy (cures 80%-96% of cases) [3][6][16]
Bilateral disease: Mineralocorticoid receptor antagonists (spironolactone/eplerenone) with BP control targets [3][6][12]
Emerging options: Selective aldosterone synthase inhibitors and non-steroidal MRAs in clinical trials [3][15]
Categories: rare endocrine diseases
Research Papers
414 drug discovery papers about Rare primary hyperaldosteronism, with 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
414 drug discovery papers about Rare primary hyperaldosteronism, with 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-15 | Subclinical primary aldosteronism: toward a conceptual framework linking primary aldosteronism and low-renin hypertension.
Primary aldosteronism (PA) has traditionally been considered a rare cause of secondary hypertension, but growing evidence supports a broader continuum of renin-independent aldosterone production extending into normotensive and mildly hypertensive populations. Subclinical primary aldosteronism (SPA) has emerged as a conceptual framework describing this milder phenotype. However, a universally accepted definition of SPA remains lacking, and consensus diagnostic criteria have yet to be established. This review synthesizes current evidence regarding SPA, including its epidemiology, pathophysiology, clinical implications, diagnostic challenges, and potential therapeutic strategies. Low-renin phenotypes are observed in a substantial proportion of individuals, although the true prevalence of SPA remains uncertain due to the lack of consensus diagnostic criteria. Observational studies have associated SPA with adverse cardiovascular and renal outcomes, including arterial stiffness, adverse cardiac remodeling, major adverse cardiovascular events, albuminuria, and chronic kidney disease progression, with effects not fully explained by blood pressure elevation alone. Conventional screening strategies based on the aldosterone-to-renin ratio have limitations in detecting this subclinical spectrum. Mineralocorticoid receptor antagonists and aldosterone synthase inhibitors represent hypothesis-generating therapeutic strategies, although prospective interventional evidence in SPA populations is lacking. At present, SPA should be regarded as an emerging risk-associated biochemical phenotype rather than an established disease category, pending prospective validation. Future studies are needed to determine whether consensus diagnostic criteria can be established and to validate clinically applicable screening strategies for this emerging endocrine phenotype.
2026-08-03 | Bilateral adrenal adenomas presenting with ACTH-independent Cushing’s syndrome and primary aldosteronism: diagnostic insights from multi-steroid adrenal venous sampling
Background Primary aldosteronism (PA) is the most prevalent cause of secondary hypertension (HTN), and adrenocorticotropic hormone (ACTH)-independent Cushing’s syndrome (CS) represents a distinct form of adrenal-derived secondary HTN. Their coexistence resulting from aldosterone- and cortisol-producing adenomas (A/CPAs) is an extremely rare clinical entity. This is particularly true for the subtype characterized by bilateral adrenocortical adenomas, in which one adenoma predominantly secretes aldosterone (ALD) and the other predominantly secretes cortisol (COR), for which only limited clinical reports have been published to date. Case description Both female patients were diagnosed with PA and concurrent ACTH-independent CS. Abdominal computed tomography (CT) revealed bilateral adrenal space-occupying lesions. Adrenal venous sampling (AVS) was subsequently performed using 17α-hydroxyprogesterone (17-OHP), androstenedione (ASD), dehydroepiandrosterone (DHEA) as the reference hormone, which demonstrated lateralized dominance of COR and ALD secretion from opposite adrenal glands. Corresponding clinical features confirmed the diagnosis of A/CPAs in both cases. One patient underwent laparoscopic left adrenal CPA resection, while the other underwent laparoscopic right adrenal CPA resection. Following laparoscopic resection of the CPA in both patients, postoperative COR levels declined, consistent with surgical remission. Spironolactone therapy was initiated. Pathological examination confirmed adrenocortical adenoma. Immunohistochemistry (IHC) showed strong positive expression of CYP11B1 (11β-hydroxylase) and weak expression of CYP11B2 (ALD synthase). Their conditions have remained well controlled to date. Conclusions In patients with bilateral adrenal adenomas and concurrent PA and ACTH-independent COR excess, imaging alone may fail to identify the functional source of hormone excess. Multi-steroid adrenal venous sampling demonstrated opposing ALD and COR dominance from contralateral adrenal glands, guiding targeted resection of the COR-dominant lesion and postoperative medical control of residual ALD excess. These cases support multi-steroid AVS for individualized adrenal-sparing management.
2026-05-27 | Familial Hyperaldosteronism Type IV (FH-IV)-Clinical Phenotypes, Genetics and Management of CACNA1H-Related Primary Aldosteronism: A Systematic Review.
Background/Objectives: Familial hyperaldosteronism type IV (FH-IV) is an extremely rare, clinically heterogeneous condition representing the least characterized familial subtype of primary aldosteronism (PA) caused by germline gain-of-function CACNA1H mutations. Despite growing molecular insights, optimal diagnostic and therapeutic strategies remain poorly defined. This systematic review aims to synthesize available evidence regarding the clinical, biochemical, and genetic characteristics of FH-IV, and to evaluate the efficacy of current pharmacological and surgical treatments. Methods: A systematic review was conducted in accordance with PRISMA guidelines and preregistered in PROSPERO (CRD420261324945). A comprehensive search of MEDLINE, Embase, and Web of Science identified studies reporting genetically confirmed FH-IV patients. Data concerning clinical phenotypes, diagnostic evaluations, treatment outcomes, and genetic backgrounds were extracted and analyzed. Results: The primary cohort included 31 fully characterized symptomatic patients, alongside 8 mutation-positive relatives (4 asymptomatic carriers and 4 symptomatic individuals). The genetic landscape was remarkably heterogeneous, encompassing 17 distinct CACNA1H mutations. Clinically, diagnosis was frequently delayed, often complicated by atypical normokalaemic presentations and misleading adrenal imaging. Surgical treatment was generally ineffective, frequently resulting in persistent or recurrent hypertension and biochemical dysregulation. Pharmacologically, patients often required multiple antihypertensive drugs, most frequently a combination of mineralocorticoid receptor antagonists (MRAs) and calcium channel blockers (CCBs). Conclusions: FH-IV is best conceptualized as a systemic adrenal channelopathy. While standard screening parameters are usually elevated, atypical biochemical profiles and misleading structural imaging can complicate the diagnostic process. Optimal management relies on multigene Next-Generation Sequencing (NGS) panels for definitive diagnosis and cascade screening of relatives. Finally, while the combination of MRAs and CCBs is commonly used in PA, it represents a valuable therapy for FH-IV, with dual L-/T-type CCBs emerging as a potential disease-specific option.
2026-05-13 | Resistant hypertension, hyperaldosteronism, and the emerging understanding of hypercortisolism.
This article reviews the evolving landscape and high prevalence of hyperaldosteronism and hypercortisolism, two previously under-recognized disorders for which cardiologists should have a high index of suspicion when managing patients with resistant hypertension. Resistant hypertension is estimated to occur in approximately 10-20% of people with hypertension, or 10 million people in the United States, and is associated with substantially increased cardiovascular morbidity and mortality. Hyperaldosteronism, previously considered a rare disease, has been shown to be a relatively common cause of hypertension and is a multisystem disease associated with a significantly higher risk of multiple comorbid conditions, including resistant hypertension. Likewise, endogenous hypercortisolism, once considered a rare disease, is now known to have a higher prevalence than previously estimated and is associated with a wide spectrum of clinical and biochemical presentations, including resistant hypertension, that result from prolonged exposure to excess cortisol activity. However, despite the prevalence and negative clinical consequences of hyperaldosteronism and hypercortisolism, screening rates remain low. Cardiologists are well positioned to provide timely screening for both hyperaldosteronism and hypercortisolism. To optimize clinical outcomes, patients with these endocrine causes of resistant hypertension require aldosterone-directed and/or cortisol-directed therapy in addition to therapy for hypertension.
2026-05-01 | ADEQUATE MEDICAL MANAGEMENT OF HYPERALDOSTERONISM CARRIES A RISK OF ADVERSE OUTCOMES COMPARABLE TO SURGICAL MANAGEMENT
Objective: Primary hyperaldosteronism (PA), once considered as rare cause of hypertension, is a leading cause of secondary hypertension. When compared to essential hypertension, PA is associated with high rates of cardiovascular diseases and all-cause mortality. Despite the recent advances in PA research, the optimal therapy of choice remains unknown. Some observational studies from single clinics and with short follow-ups have suggested that adrenalectomy may lead to lower all-cause mortality compared to medical management. However, the long-term outcomes of medical versus surgical management in a nationwide patient sample with extended follow-up remain unclear. Design and method: We used data from the FinnGen register-based database that includes nationwide information on diagnoses, procedures, and laboratory values over several decades from 52021 individuals. We identified 1001 participants with a PA diagnosis who were divided into two subgroups: PA without (N=823) and with (N=178) adrenalectomy. We assessed the association between therapy of choice with three adverse outcomes (cardiovascular disease, major adverse cardiovascular events, and arrythmia) using multivariable-adjusted Cox models. We also examined the links between mean post-diagnosis potassium levels and adverse events in a subgroup with potassium data available (N=606). Results: Therapy of choice was not associated with any of the adverse outcomes in the age- and sex-adjusted (P>0.12 for all) or the multivariable-adjusted (P>0.19 for all) analyses (Figure). However, we observed a significant multivariable-adjusted association between potassium levels and incident arrhythmia in the medical therapy group (HR per 1 mmol increase in potassium 0.49; 95% CI 0.24-1.00; P=0.049) and in the whole study sample (HR 0.52; 95% CI 0.28-0.97; P=0.038). Conclusions: Our findings indicate that adequate medical management of PA, with avoidance of hypokalemia, leads to outcomes comparable to those of surgery.
proteins
2026-07-01 | Functional splice site variants in AVPR1A protect against idiopathic hyperaldosteronism
Idiopathic hyperaldosteronism (IHA) is a common form of hypertension and increases the risk of cardiovascular events even after the recommended medical therapy. As the pathogenesis of IHA is largely unclear, elucidation of genetic factors may discover novel therapeutic targets. We performed a whole-genome sequencing on blood samples from 261 IHA and 261 age- and sex-matched healthy controls in the cohort of the Chongqing Primary Aldosteronism Study (CONPASS). We observed a strong association between IHA and a rare, heterozygous single-nucleotide splice variant (c.971-2A>C) in the AVPR1A gene that encodes the arginine vasopressin receptor known to mediate adrenal cell proliferation. In vitro , the splice variant largely blocked AVPR1A downstream pathways. AVPR1A overexpression resulted in a > 25-fold upregulation of CYP11B2 gene expression and markedly increased the secretion of aldosterone and its precursors ( P < 0.001), whereas overexpression of AVPR1A harboring this splice variant rescued these effects. AVPR1A knockdown significantly suppressed aldosterone biosynthesis, with CYP11B2 expression reduced by 80% ( P < 0.001) and aldosterone levels decreased by 50% ( P < 0.001). In vivo , AVPR1A overexpression led to significant elevations in both CYP11B2 expression and circulating aldosterone levels ( P < 0.05). In conclusion, a pathogenic splice site variation in AVPR1A conferred substantial protection from IHA.
2024-10-01 | 9287 CASZ1 gene: From a Promising GWAS Risk Locus To a Possible New Monogenic Etiology For Primary Aldosteronism
Abstract Disclosure: L.S. Santana: None. A.G. Guimaraes: None. F. Freitas-Castro: None. A.W. Maciel: None. G.F. Fagundes: None. M.A. Pereira: None. L.F. Drager: None. L.A. Bortolotto: None. M.C. Fragoso: None. B.B. Mendonca: None. A. Latronico: None. M.Q. Almeida: None. Primary aldosteronism (PA) is the most common cause of endocrine hypertension, with an estimated prevalence of 10-20% in patients referred to tertiary hospitals. The most common causes of PA are bilateral adrenal hyperplasia (BAH) and aldosteronomas. Significant advances in elucidating the pathogenesis of PA have been made over the past decade. Pathogenic/likely pathogenic germline allelic variants in KCNJ5, CACNA1D, CACNA1H, CLCN2, PDE2A, and PDE3B genes have already been documented in individuals diagnosed with PA. However, most of the cases still lack a defined genetic etiology. Genomic investigation of these individuals through whole-exome sequencing (WES) would enable the identification of causal monogenic genotype-phenotype associations in genes not yet linked to bilateral PA. In our study, thirty-one patients were selected, including 29 probands and 2 relatives, with a confirmed diagnosis of bilateral PA by adrenal venous sampling. All probands were previously investigated for KCNJ5 pathogenic/likely pathogenic germline variants. Additionally, all cases also had negative genetic screening for glucocorticoid-remediable PA. WES was performed using BGI Genomics technology, DNA nanoball sequencing, on the DNBSEQ platform. Raw data were processed (bioinformatics) using in-house pipelines. The 31 sequenced samples showed excellent coverage metrics, with coverage ranging from 200-467X and %>10X at 99%. Each patient presented an average of 150,000 variants. After the gene/allelic prioritization workflow, 4 heterozygous SNVs were listed as candidates in 3 out of 29 patients (10.34%). Two of the variants were identified in rare but previously documented germline causes of PA: CACNA1H and CACNA1D (patients 13 and 29, respectively). Patient 4 (hypertension diagnosed at 36 years of age) presented 2 variants in possible new candidate genes, CASZ1 and STRN. The NM_001079843.3(CASZ1):c.1912G>C/p.(Asp638His) variant caught our attention not only for its absence in population genomic databases (gnomAD v.4), but also due to the association between CASZ1 locus and PA. The zinc finger transcription factor CASZ1 has CACNA1D as one of its targets and participates in key biological processes for PA pathogenesis, such as: co-repression of mineralocorticoid receptor transcriptional activity; mediation of tissue response to aldosterone and differential expression in aldosterone-producing cell clusters (APCC) and in zona glomerulosa; its hypoexpression promotes aldosterone-dependent mineralocorticoid receptor transcriptional activity and hyperexpression suppresses aldosterone biosynthesis by adrenal cells. In conclusion, an extremely rare CASZ1 variant was identified in a woman with bilateral PA. The functional characterization of the CASZ1 p.(Asp638His) variant might reinforce its role as a new monogenic cause of PA. Presentation: 6/3/2024
2000-08-01 | Effect of adrenomedullin infusion on basal and stimulated aldosterone secretion in conscious sheep with cervical adrenal autotransplants
In vivo and in vitro studies have shown conflicting effects of adrenomedullin (ADM) on the secretion of steroid hormones from the adrenal gland. While some investigators report no effect of this peptide on the output of various hormones, others have reported both stimulatory and inhibitory roles for ADM. We have shown that basal aldosterone secretion rate (ASR), in conscious sheep with cervical adrenal autotransplants, did not change when ADM was infused directly into the adrenal arterial supply. While not affecting basal ASR, ADM did produce pronounced increases in adrenal blood flow (BF). This elevation of BF in association with ADM infusion was seen in all subsequent experiments. When aldosterone output was acutely stimulated by angiotensin II (AngII), potassium chloride (KCl) and adrenocorticotrophic hormone (ACTH), ADM was seen to drastically reduce the secretion of aldosterone with all agonists studied. After pre-exposure to ADM, all three agonists increased ASR but the magnitude of the responses were somewhat blunted. ADM did not have the same effect on cortisol secretion stimulated by ACTH, suggesting that the ability of this peptide to influence adrenal gland function is limited to the zona glomerulosa. In conditions of chronic elevation of aldosterone levels, such as in Na deficiency, ADM did not display the same inhibitory abilities seen in the acute stimulation experiments. Hence, ADM has been shown to have a direct, inhibitory role on the acute stimulation of aldosterone by AngII, KCl and ACTH while not affecting basal or chronic aldosterone secretion or cortisol secretion stimulated by ACTH.
1998-03-15 | Conferring aldosterone synthesis to human CYP11B1 by replacing key amino acid residues with CYP11B2‐specific ones
Performing residue‐swapping experiments between the highly conserved human steroidogenic proteins CYP11B1 and CYP11B2 we recently demonstrated that replacement of specific residues at position 301, 302 and 320 in the aldosterone‐producing CYP11B2 protein for such residues that were specific for the highly similar cortisol‐producing CYP11B1 protein elevated the 11β‐hydroxylase activity dramatically. Conversely, aldosterone synthesis in the triple mutant was severely impaired. Here we provide evidence that in a reciprocal experiment, CYP11B2‐specific amino acids at position 320 and 335 endowed CYP11B1 with an 18‐oxidase function amounting to 20 % of the CYP11B2 wild‐type activity, thus changing the specificity of steroid hydroxylation by only one point mutation. Combining substitutions at positions 296, 301, 302, 320, 335 and 339 did, however, not result in further enhancement. Paradoxically, 11β‐hydroxylation was not or only marginally affected in CYP11B1 mutants, indicating an alternative structural basis for this activity in CYP11B1 compared with the engineered CYP11B2 variant. Our results suggest that the sequence spanned by amino acids 301 and 335 constitutes part of the substrate‐binding site in CYP11B1 and CYP11B2 as well. By constructing chimeric proteins we further investigated the effect of the C‐terminal portions of both proteins and found that diverging residues at positions 471, 472, 492, 493 and 494 were insignificant for the stereospecificity and regiospecificity of steroid hydroxylation.
gene therapies
2026-09-11 | Therapeutic consequence of adrenal venous sampling complication: remission of primary aldosteronism after adrenal vein thrombosis.
A 43-year-old man with resistant hypertension and hypokalemia was diagnosed with primary aldosteronism (PA), confirmed by biochemical testing and adrenal vein sampling (AVS), which lateralized aldosterone secretion to the right adrenal gland. Shortly after AVS, he developed right flank pain, and imaging showed mild postprocedural changes without overt complications. Three months later, he presented with hyperkalemia and acute kidney injury, but notably, his blood pressure had improved with fewer antihypertensives. Laboratory evaluation revealed suppressed aldosterone, normal renin, and no evidence of catecholamine excess. Imaging and hormonal reassessment suggested spontaneous resolution of PA. Despite plans for adrenalectomy based on initial AVS results, surgery revealed a thrombosed right adrenal vein and infarcted adrenal tissue. Histopathology confirmed hemorrhagic infarction with chronic inflammation. This rare case highlights adrenal vein thrombosis during AVS, inducing an acute, transient biochemical remission of PA via infarction of the aldosterone-producing gland. It underscores the importance of vigilant post AVS monitoring and recognition that procedural complications, while uncommon, may yield unexpected therapeutic benefit in select patients.
2022-08-12 | Clinical Translationality of KCNJ5 Mutation in Aldosterone Producing Adenoma
Hypertension due to primary aldosteronism poses a risk of severe cardiovascular complications compared to essential hypertension. The discovery of the KCNJ5 somatic mutation in aldosteroene producing adenoma (APA) in 2011 and the development of specific CYP11B2 antibodies in 2012 have greatly advanced our understanding of the pathophysiology of primary aldosteronism. In particular, the presence of CYP11B2-positive aldosterone-producing micronodules (APMs) in the adrenal glands of normotensive individuals and the presence of renin-independent aldosterone excess in normotensive subjects demonstrated the continuum of the pathogenesis of PA. Furthermore, among the aldosterone driver mutations which incur excessive aldosterone secretion, KCNJ5 was a major somatic mutation in APA, while CACNA1D is a leading somatic mutation in APMs and idiopathic hyperaldosteronism (IHA), suggesting a distinctive pathogenesis between APA and IHA. Although the functional detail of APMs has not been still uncovered, its impact on the pathogenesis of PA is gradually being revealed. In this review, we summarize the integrated findings regarding APA, APM or diffuse hyperplasia defined by novel CYP11B2, and aldosterone driver mutations. Following this, we discuss the clinical implications of KCNJ5 mutations to support better cardiovascular outcomes of primary aldosteronism.
2021-09-21 | Characteristics of a Novel ATP2B3 K416_F418delinsN Mutation in a Classical Aldosterone-Producing Adenoma
In patients with primary aldosteronism (PA), the prevalence of ATP2B3 mutation is rare. The aim of this study is to report a novel ATP2B3 mutation in a PA patient. Based on our tissue bank of aldosterone-producing adenomas (APA), we identified a novel somatic ATP2B3 K416_F418delinsN mutation. The affected individual was a 53 year-old man with a 4 year history of hypertension. Computed tomography (CT) showed bilateral adrenal masses of 1.6 (left) and 0.5 cm (right) in size. An adrenal venous sampling (AVS) showed a lateralization index (LI) of 2.2 and a contralateral suppression index (CLS) of 0.12; indicating left functional predominance. After a left unilateral adrenalectomy, he achieved partial biochemical and hypertension–remission. This classical adenoma harbored a novel ATP2B3 K416_F418delinsN somatic mutation, which is a deletion from nucleotides 1248 to 1253. The translated amino acid sequence from 416 to 418, reading as lysine-phenylalanine-phenylalanine, was deleted; however, an asparagine was inserted due to merging of residual nucleotide sequences. The CYP11B2 immunohistochemistry staining demonstrated strong immunoreactivity in this classical adenoma. The ATP2B3 K416_F418delinsN mutation is a functional mutation in APA, since HAC15 cells, a human adrenal cell line, transfected with the mutant gene showed increased CYP11B2 expression and aldosterone production.
2004-04-01 | Genetics of primary aldosteronism
Over the last few years, much progress has been made in understanding the genetic basis of primary aldosteronism. This has led to the diagnosis of the familial forms and has aided the understanding of the basis of sporadic forms of the disease. Such information can be exploited to improve the therapeutic approaches used not only for patients with primary aldosteronism, but also with other forms of hypertension. Here, we review the genetic and the phenotypic features of the familial forms, the genetic variants that influence the sporadic forms and the structure and regulation of the CYP11B1 and CYP11B2 genes.
antibodies
2026-09-04 | Immune signatures associated with human adrenocortical hypertension.
The finding of autoantibodies against the angiotensin II type-1 receptor (AT1R) in human primary aldosteronism (PA) suggests a loss of immunological tolerance; however, whether autoreactive AT1R-specific T cells exist and if and how aldosterone or cortisol modulate their activity is unknown. Peripheral blood mononuclear cells from patients with confirmed PA and healthy donors were stimulated with overlapping AT1R peptides to identify autoreactive T cells. The chronic and rapid aldosterone effects on CD4+ and CD8+ T cells and the receptors involved were evaluated using mineralocorticoid receptor (MR) and G-protein estrogen receptor (GPER) antagonists. Cortisol effects and 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) expression were also examined. Functional cytotoxicity of AT1R-specific CD8+ clones toward human endothelial cells was assessed. Compared with healthy donors, PA patients exhibited a marked expansion of AT1R-specific CD8+ T cells recognizing the AFHYESQ epitope of the second extracellular AT1R loop, which was not detected in CD4+ cells. Both T-cell subsets expressed MR and GPER but lacked 11βHSD2 expression. Chronic aldosterone exposure enhanced CD8+ proliferation and IFN-γ production through MR. Rapid aldosterone stimulation activated CD8+ cells via MR and GPER. In CD8+ cells cortisol also increased IFN-γ-production through MR. AT1R-specific CD8+ T-cell clones induced apoptosis of human endothelial cells expressing AT1R. PA patients harbor autoreactive AT1R-specific CD8+ T cells that respond to aldosterone and cortisol through MR and GPER. These findings identify an adaptive autoimmune mechanism in PA and provide insight into how steroid-driven T-cell activation may contribute to hypertension-mediated organ damage in aldosteronism and hypercortisolism.
small molecules
2026-08-15 | Subclinical primary aldosteronism: toward a conceptual framework linking primary aldosteronism and low-renin hypertension.
Primary aldosteronism (PA) has traditionally been considered a rare cause of secondary hypertension, but growing evidence supports a broader continuum of renin-independent aldosterone production extending into normotensive and mildly hypertensive populations. Subclinical primary aldosteronism (SPA) has emerged as a conceptual framework describing this milder phenotype. However, a universally accepted definition of SPA remains lacking, and consensus diagnostic criteria have yet to be established. This review synthesizes current evidence regarding SPA, including its epidemiology, pathophysiology, clinical implications, diagnostic challenges, and potential therapeutic strategies. Low-renin phenotypes are observed in a substantial proportion of individuals, although the true prevalence of SPA remains uncertain due to the lack of consensus diagnostic criteria. Observational studies have associated SPA with adverse cardiovascular and renal outcomes, including arterial stiffness, adverse cardiac remodeling, major adverse cardiovascular events, albuminuria, and chronic kidney disease progression, with effects not fully explained by blood pressure elevation alone. Conventional screening strategies based on the aldosterone-to-renin ratio have limitations in detecting this subclinical spectrum. Mineralocorticoid receptor antagonists and aldosterone synthase inhibitors represent hypothesis-generating therapeutic strategies, although prospective interventional evidence in SPA populations is lacking. At present, SPA should be regarded as an emerging risk-associated biochemical phenotype rather than an established disease category, pending prospective validation. Future studies are needed to determine whether consensus diagnostic criteria can be established and to validate clinically applicable screening strategies for this emerging endocrine phenotype.
2026-08-03 | Bilateral adrenal adenomas presenting with ACTH-independent Cushing’s syndrome and primary aldosteronism: diagnostic insights from multi-steroid adrenal venous sampling
Background Primary aldosteronism (PA) is the most prevalent cause of secondary hypertension (HTN), and adrenocorticotropic hormone (ACTH)-independent Cushing’s syndrome (CS) represents a distinct form of adrenal-derived secondary HTN. Their coexistence resulting from aldosterone- and cortisol-producing adenomas (A/CPAs) is an extremely rare clinical entity. This is particularly true for the subtype characterized by bilateral adrenocortical adenomas, in which one adenoma predominantly secretes aldosterone (ALD) and the other predominantly secretes cortisol (COR), for which only limited clinical reports have been published to date. Case description Both female patients were diagnosed with PA and concurrent ACTH-independent CS. Abdominal computed tomography (CT) revealed bilateral adrenal space-occupying lesions. Adrenal venous sampling (AVS) was subsequently performed using 17α-hydroxyprogesterone (17-OHP), androstenedione (ASD), dehydroepiandrosterone (DHEA) as the reference hormone, which demonstrated lateralized dominance of COR and ALD secretion from opposite adrenal glands. Corresponding clinical features confirmed the diagnosis of A/CPAs in both cases. One patient underwent laparoscopic left adrenal CPA resection, while the other underwent laparoscopic right adrenal CPA resection. Following laparoscopic resection of the CPA in both patients, postoperative COR levels declined, consistent with surgical remission. Spironolactone therapy was initiated. Pathological examination confirmed adrenocortical adenoma. Immunohistochemistry (IHC) showed strong positive expression of CYP11B1 (11β-hydroxylase) and weak expression of CYP11B2 (ALD synthase). Their conditions have remained well controlled to date. Conclusions In patients with bilateral adrenal adenomas and concurrent PA and ACTH-independent COR excess, imaging alone may fail to identify the functional source of hormone excess. Multi-steroid adrenal venous sampling demonstrated opposing ALD and COR dominance from contralateral adrenal glands, guiding targeted resection of the COR-dominant lesion and postoperative medical control of residual ALD excess. These cases support multi-steroid AVS for individualized adrenal-sparing management.
2026-05-27 | Familial Hyperaldosteronism Type IV (FH-IV)-Clinical Phenotypes, Genetics and Management of CACNA1H-Related Primary Aldosteronism: A Systematic Review.
Background/Objectives: Familial hyperaldosteronism type IV (FH-IV) is an extremely rare, clinically heterogeneous condition representing the least characterized familial subtype of primary aldosteronism (PA) caused by germline gain-of-function CACNA1H mutations. Despite growing molecular insights, optimal diagnostic and therapeutic strategies remain poorly defined. This systematic review aims to synthesize available evidence regarding the clinical, biochemical, and genetic characteristics of FH-IV, and to evaluate the efficacy of current pharmacological and surgical treatments. Methods: A systematic review was conducted in accordance with PRISMA guidelines and preregistered in PROSPERO (CRD420261324945). A comprehensive search of MEDLINE, Embase, and Web of Science identified studies reporting genetically confirmed FH-IV patients. Data concerning clinical phenotypes, diagnostic evaluations, treatment outcomes, and genetic backgrounds were extracted and analyzed. Results: The primary cohort included 31 fully characterized symptomatic patients, alongside 8 mutation-positive relatives (4 asymptomatic carriers and 4 symptomatic individuals). The genetic landscape was remarkably heterogeneous, encompassing 17 distinct CACNA1H mutations. Clinically, diagnosis was frequently delayed, often complicated by atypical normokalaemic presentations and misleading adrenal imaging. Surgical treatment was generally ineffective, frequently resulting in persistent or recurrent hypertension and biochemical dysregulation. Pharmacologically, patients often required multiple antihypertensive drugs, most frequently a combination of mineralocorticoid receptor antagonists (MRAs) and calcium channel blockers (CCBs). Conclusions: FH-IV is best conceptualized as a systemic adrenal channelopathy. While standard screening parameters are usually elevated, atypical biochemical profiles and misleading structural imaging can complicate the diagnostic process. Optimal management relies on multigene Next-Generation Sequencing (NGS) panels for definitive diagnosis and cascade screening of relatives. Finally, while the combination of MRAs and CCBs is commonly used in PA, it represents a valuable therapy for FH-IV, with dual L-/T-type CCBs emerging as a potential disease-specific option.
2026-05-13 | Resistant hypertension, hyperaldosteronism, and the emerging understanding of hypercortisolism.
This article reviews the evolving landscape and high prevalence of hyperaldosteronism and hypercortisolism, two previously under-recognized disorders for which cardiologists should have a high index of suspicion when managing patients with resistant hypertension. Resistant hypertension is estimated to occur in approximately 10-20% of people with hypertension, or 10 million people in the United States, and is associated with substantially increased cardiovascular morbidity and mortality. Hyperaldosteronism, previously considered a rare disease, has been shown to be a relatively common cause of hypertension and is a multisystem disease associated with a significantly higher risk of multiple comorbid conditions, including resistant hypertension. Likewise, endogenous hypercortisolism, once considered a rare disease, is now known to have a higher prevalence than previously estimated and is associated with a wide spectrum of clinical and biochemical presentations, including resistant hypertension, that result from prolonged exposure to excess cortisol activity. However, despite the prevalence and negative clinical consequences of hyperaldosteronism and hypercortisolism, screening rates remain low. Cardiologists are well positioned to provide timely screening for both hyperaldosteronism and hypercortisolism. To optimize clinical outcomes, patients with these endocrine causes of resistant hypertension require aldosterone-directed and/or cortisol-directed therapy in addition to therapy for hypertension.
2026-05-01 | ADEQUATE MEDICAL MANAGEMENT OF HYPERALDOSTERONISM CARRIES A RISK OF ADVERSE OUTCOMES COMPARABLE TO SURGICAL MANAGEMENT
Objective: Primary hyperaldosteronism (PA), once considered as rare cause of hypertension, is a leading cause of secondary hypertension. When compared to essential hypertension, PA is associated with high rates of cardiovascular diseases and all-cause mortality. Despite the recent advances in PA research, the optimal therapy of choice remains unknown. Some observational studies from single clinics and with short follow-ups have suggested that adrenalectomy may lead to lower all-cause mortality compared to medical management. However, the long-term outcomes of medical versus surgical management in a nationwide patient sample with extended follow-up remain unclear. Design and method: We used data from the FinnGen register-based database that includes nationwide information on diagnoses, procedures, and laboratory values over several decades from 52021 individuals. We identified 1001 participants with a PA diagnosis who were divided into two subgroups: PA without (N=823) and with (N=178) adrenalectomy. We assessed the association between therapy of choice with three adverse outcomes (cardiovascular disease, major adverse cardiovascular events, and arrythmia) using multivariable-adjusted Cox models. We also examined the links between mean post-diagnosis potassium levels and adverse events in a subgroup with potassium data available (N=606). Results: Therapy of choice was not associated with any of the adverse outcomes in the age- and sex-adjusted (P>0.12 for all) or the multivariable-adjusted (P>0.19 for all) analyses (Figure). However, we observed a significant multivariable-adjusted association between potassium levels and incident arrhythmia in the medical therapy group (HR per 1 mmol increase in potassium 0.49; 95% CI 0.24-1.00; P=0.049) and in the whole study sample (HR 0.52; 95% CI 0.28-0.97; P=0.038). Conclusions: Our findings indicate that adequate medical management of PA, with avoidance of hypokalemia, leads to outcomes comparable to those of surgery.
proteins
2026-07-01 | Functional splice site variants in AVPR1A protect against idiopathic hyperaldosteronism
Idiopathic hyperaldosteronism (IHA) is a common form of hypertension and increases the risk of cardiovascular events even after the recommended medical therapy. As the pathogenesis of IHA is largely unclear, elucidation of genetic factors may discover novel therapeutic targets. We performed a whole-genome sequencing on blood samples from 261 IHA and 261 age- and sex-matched healthy controls in the cohort of the Chongqing Primary Aldosteronism Study (CONPASS). We observed a strong association between IHA and a rare, heterozygous single-nucleotide splice variant (c.971-2A>C) in the AVPR1A gene that encodes the arginine vasopressin receptor known to mediate adrenal cell proliferation. In vitro , the splice variant largely blocked AVPR1A downstream pathways. AVPR1A overexpression resulted in a > 25-fold upregulation of CYP11B2 gene expression and markedly increased the secretion of aldosterone and its precursors ( P < 0.001), whereas overexpression of AVPR1A harboring this splice variant rescued these effects. AVPR1A knockdown significantly suppressed aldosterone biosynthesis, with CYP11B2 expression reduced by 80% ( P < 0.001) and aldosterone levels decreased by 50% ( P < 0.001). In vivo , AVPR1A overexpression led to significant elevations in both CYP11B2 expression and circulating aldosterone levels ( P < 0.05). In conclusion, a pathogenic splice site variation in AVPR1A conferred substantial protection from IHA.
2024-10-01 | 9287 CASZ1 gene: From a Promising GWAS Risk Locus To a Possible New Monogenic Etiology For Primary Aldosteronism
Abstract Disclosure: L.S. Santana: None. A.G. Guimaraes: None. F. Freitas-Castro: None. A.W. Maciel: None. G.F. Fagundes: None. M.A. Pereira: None. L.F. Drager: None. L.A. Bortolotto: None. M.C. Fragoso: None. B.B. Mendonca: None. A. Latronico: None. M.Q. Almeida: None. Primary aldosteronism (PA) is the most common cause of endocrine hypertension, with an estimated prevalence of 10-20% in patients referred to tertiary hospitals. The most common causes of PA are bilateral adrenal hyperplasia (BAH) and aldosteronomas. Significant advances in elucidating the pathogenesis of PA have been made over the past decade. Pathogenic/likely pathogenic germline allelic variants in KCNJ5, CACNA1D, CACNA1H, CLCN2, PDE2A, and PDE3B genes have already been documented in individuals diagnosed with PA. However, most of the cases still lack a defined genetic etiology. Genomic investigation of these individuals through whole-exome sequencing (WES) would enable the identification of causal monogenic genotype-phenotype associations in genes not yet linked to bilateral PA. In our study, thirty-one patients were selected, including 29 probands and 2 relatives, with a confirmed diagnosis of bilateral PA by adrenal venous sampling. All probands were previously investigated for KCNJ5 pathogenic/likely pathogenic germline variants. Additionally, all cases also had negative genetic screening for glucocorticoid-remediable PA. WES was performed using BGI Genomics technology, DNA nanoball sequencing, on the DNBSEQ platform. Raw data were processed (bioinformatics) using in-house pipelines. The 31 sequenced samples showed excellent coverage metrics, with coverage ranging from 200-467X and %>10X at 99%. Each patient presented an average of 150,000 variants. After the gene/allelic prioritization workflow, 4 heterozygous SNVs were listed as candidates in 3 out of 29 patients (10.34%). Two of the variants were identified in rare but previously documented germline causes of PA: CACNA1H and CACNA1D (patients 13 and 29, respectively). Patient 4 (hypertension diagnosed at 36 years of age) presented 2 variants in possible new candidate genes, CASZ1 and STRN. The NM_001079843.3(CASZ1):c.1912G>C/p.(Asp638His) variant caught our attention not only for its absence in population genomic databases (gnomAD v.4), but also due to the association between CASZ1 locus and PA. The zinc finger transcription factor CASZ1 has CACNA1D as one of its targets and participates in key biological processes for PA pathogenesis, such as: co-repression of mineralocorticoid receptor transcriptional activity; mediation of tissue response to aldosterone and differential expression in aldosterone-producing cell clusters (APCC) and in zona glomerulosa; its hypoexpression promotes aldosterone-dependent mineralocorticoid receptor transcriptional activity and hyperexpression suppresses aldosterone biosynthesis by adrenal cells. In conclusion, an extremely rare CASZ1 variant was identified in a woman with bilateral PA. The functional characterization of the CASZ1 p.(Asp638His) variant might reinforce its role as a new monogenic cause of PA. Presentation: 6/3/2024
2000-08-01 | Effect of adrenomedullin infusion on basal and stimulated aldosterone secretion in conscious sheep with cervical adrenal autotransplants
In vivo and in vitro studies have shown conflicting effects of adrenomedullin (ADM) on the secretion of steroid hormones from the adrenal gland. While some investigators report no effect of this peptide on the output of various hormones, others have reported both stimulatory and inhibitory roles for ADM. We have shown that basal aldosterone secretion rate (ASR), in conscious sheep with cervical adrenal autotransplants, did not change when ADM was infused directly into the adrenal arterial supply. While not affecting basal ASR, ADM did produce pronounced increases in adrenal blood flow (BF). This elevation of BF in association with ADM infusion was seen in all subsequent experiments. When aldosterone output was acutely stimulated by angiotensin II (AngII), potassium chloride (KCl) and adrenocorticotrophic hormone (ACTH), ADM was seen to drastically reduce the secretion of aldosterone with all agonists studied. After pre-exposure to ADM, all three agonists increased ASR but the magnitude of the responses were somewhat blunted. ADM did not have the same effect on cortisol secretion stimulated by ACTH, suggesting that the ability of this peptide to influence adrenal gland function is limited to the zona glomerulosa. In conditions of chronic elevation of aldosterone levels, such as in Na deficiency, ADM did not display the same inhibitory abilities seen in the acute stimulation experiments. Hence, ADM has been shown to have a direct, inhibitory role on the acute stimulation of aldosterone by AngII, KCl and ACTH while not affecting basal or chronic aldosterone secretion or cortisol secretion stimulated by ACTH.
1998-03-15 | Conferring aldosterone synthesis to human CYP11B1 by replacing key amino acid residues with CYP11B2‐specific ones
Performing residue‐swapping experiments between the highly conserved human steroidogenic proteins CYP11B1 and CYP11B2 we recently demonstrated that replacement of specific residues at position 301, 302 and 320 in the aldosterone‐producing CYP11B2 protein for such residues that were specific for the highly similar cortisol‐producing CYP11B1 protein elevated the 11β‐hydroxylase activity dramatically. Conversely, aldosterone synthesis in the triple mutant was severely impaired. Here we provide evidence that in a reciprocal experiment, CYP11B2‐specific amino acids at position 320 and 335 endowed CYP11B1 with an 18‐oxidase function amounting to 20 % of the CYP11B2 wild‐type activity, thus changing the specificity of steroid hydroxylation by only one point mutation. Combining substitutions at positions 296, 301, 302, 320, 335 and 339 did, however, not result in further enhancement. Paradoxically, 11β‐hydroxylation was not or only marginally affected in CYP11B1 mutants, indicating an alternative structural basis for this activity in CYP11B1 compared with the engineered CYP11B2 variant. Our results suggest that the sequence spanned by amino acids 301 and 335 constitutes part of the substrate‐binding site in CYP11B1 and CYP11B2 as well. By constructing chimeric proteins we further investigated the effect of the C‐terminal portions of both proteins and found that diverging residues at positions 471, 472, 492, 493 and 494 were insignificant for the stereospecificity and regiospecificity of steroid hydroxylation.
gene therapies
2026-09-11 | Therapeutic consequence of adrenal venous sampling complication: remission of primary aldosteronism after adrenal vein thrombosis.
A 43-year-old man with resistant hypertension and hypokalemia was diagnosed with primary aldosteronism (PA), confirmed by biochemical testing and adrenal vein sampling (AVS), which lateralized aldosterone secretion to the right adrenal gland. Shortly after AVS, he developed right flank pain, and imaging showed mild postprocedural changes without overt complications. Three months later, he presented with hyperkalemia and acute kidney injury, but notably, his blood pressure had improved with fewer antihypertensives. Laboratory evaluation revealed suppressed aldosterone, normal renin, and no evidence of catecholamine excess. Imaging and hormonal reassessment suggested spontaneous resolution of PA. Despite plans for adrenalectomy based on initial AVS results, surgery revealed a thrombosed right adrenal vein and infarcted adrenal tissue. Histopathology confirmed hemorrhagic infarction with chronic inflammation. This rare case highlights adrenal vein thrombosis during AVS, inducing an acute, transient biochemical remission of PA via infarction of the aldosterone-producing gland. It underscores the importance of vigilant post AVS monitoring and recognition that procedural complications, while uncommon, may yield unexpected therapeutic benefit in select patients.
2022-08-12 | Clinical Translationality of KCNJ5 Mutation in Aldosterone Producing Adenoma
Hypertension due to primary aldosteronism poses a risk of severe cardiovascular complications compared to essential hypertension. The discovery of the KCNJ5 somatic mutation in aldosteroene producing adenoma (APA) in 2011 and the development of specific CYP11B2 antibodies in 2012 have greatly advanced our understanding of the pathophysiology of primary aldosteronism. In particular, the presence of CYP11B2-positive aldosterone-producing micronodules (APMs) in the adrenal glands of normotensive individuals and the presence of renin-independent aldosterone excess in normotensive subjects demonstrated the continuum of the pathogenesis of PA. Furthermore, among the aldosterone driver mutations which incur excessive aldosterone secretion, KCNJ5 was a major somatic mutation in APA, while CACNA1D is a leading somatic mutation in APMs and idiopathic hyperaldosteronism (IHA), suggesting a distinctive pathogenesis between APA and IHA. Although the functional detail of APMs has not been still uncovered, its impact on the pathogenesis of PA is gradually being revealed. In this review, we summarize the integrated findings regarding APA, APM or diffuse hyperplasia defined by novel CYP11B2, and aldosterone driver mutations. Following this, we discuss the clinical implications of KCNJ5 mutations to support better cardiovascular outcomes of primary aldosteronism.
2021-09-21 | Characteristics of a Novel ATP2B3 K416_F418delinsN Mutation in a Classical Aldosterone-Producing Adenoma
In patients with primary aldosteronism (PA), the prevalence of ATP2B3 mutation is rare. The aim of this study is to report a novel ATP2B3 mutation in a PA patient. Based on our tissue bank of aldosterone-producing adenomas (APA), we identified a novel somatic ATP2B3 K416_F418delinsN mutation. The affected individual was a 53 year-old man with a 4 year history of hypertension. Computed tomography (CT) showed bilateral adrenal masses of 1.6 (left) and 0.5 cm (right) in size. An adrenal venous sampling (AVS) showed a lateralization index (LI) of 2.2 and a contralateral suppression index (CLS) of 0.12; indicating left functional predominance. After a left unilateral adrenalectomy, he achieved partial biochemical and hypertension–remission. This classical adenoma harbored a novel ATP2B3 K416_F418delinsN somatic mutation, which is a deletion from nucleotides 1248 to 1253. The translated amino acid sequence from 416 to 418, reading as lysine-phenylalanine-phenylalanine, was deleted; however, an asparagine was inserted due to merging of residual nucleotide sequences. The CYP11B2 immunohistochemistry staining demonstrated strong immunoreactivity in this classical adenoma. The ATP2B3 K416_F418delinsN mutation is a functional mutation in APA, since HAC15 cells, a human adrenal cell line, transfected with the mutant gene showed increased CYP11B2 expression and aldosterone production.
2004-04-01 | Genetics of primary aldosteronism
Over the last few years, much progress has been made in understanding the genetic basis of primary aldosteronism. This has led to the diagnosis of the familial forms and has aided the understanding of the basis of sporadic forms of the disease. Such information can be exploited to improve the therapeutic approaches used not only for patients with primary aldosteronism, but also with other forms of hypertension. Here, we review the genetic and the phenotypic features of the familial forms, the genetic variants that influence the sporadic forms and the structure and regulation of the CYP11B1 and CYP11B2 genes.
antibodies
2026-09-04 | Immune signatures associated with human adrenocortical hypertension.
The finding of autoantibodies against the angiotensin II type-1 receptor (AT1R) in human primary aldosteronism (PA) suggests a loss of immunological tolerance; however, whether autoreactive AT1R-specific T cells exist and if and how aldosterone or cortisol modulate their activity is unknown. Peripheral blood mononuclear cells from patients with confirmed PA and healthy donors were stimulated with overlapping AT1R peptides to identify autoreactive T cells. The chronic and rapid aldosterone effects on CD4+ and CD8+ T cells and the receptors involved were evaluated using mineralocorticoid receptor (MR) and G-protein estrogen receptor (GPER) antagonists. Cortisol effects and 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) expression were also examined. Functional cytotoxicity of AT1R-specific CD8+ clones toward human endothelial cells was assessed. Compared with healthy donors, PA patients exhibited a marked expansion of AT1R-specific CD8+ T cells recognizing the AFHYESQ epitope of the second extracellular AT1R loop, which was not detected in CD4+ cells. Both T-cell subsets expressed MR and GPER but lacked 11βHSD2 expression. Chronic aldosterone exposure enhanced CD8+ proliferation and IFN-γ production through MR. Rapid aldosterone stimulation activated CD8+ cells via MR and GPER. In CD8+ cells cortisol also increased IFN-γ-production through MR. AT1R-specific CD8+ T-cell clones induced apoptosis of human endothelial cells expressing AT1R. PA patients harbor autoreactive AT1R-specific CD8+ T cells that respond to aldosterone and cortisol through MR and GPER. These findings identify an adaptive autoimmune mechanism in PA and provide insight into how steroid-driven T-cell activation may contribute to hypertension-mediated organ damage in aldosteronism and hypercortisolism.
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Drug Discovery Landscape
1 orphan drug designation for Rare primary hyperaldosteronism.
1 orphan drug designation for Rare primary hyperaldosteronism.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
spironolactone | small molecules | FDA | — | CMP Pharma, Inc. |
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