GENETICS IN ENDOCRINOLOGY: The expanding genetic horizon of primary aldosteronism

Aldosterone is the main mineralocorticoid hormone in humans and plays a key role in maintaining water and electrolyte homeostasis. Primary aldosteronism (PA), characterized by autonomous aldosterone overproduction by the adrenal glands, affects 6% of the general hypertensive population and can be either sporadic or familial. Aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH) are the two most frequent subtypes of sporadic PA and 4 forms of familial hyperaldosteronism (FH-I to FH-IV) have been identified. Over the last six years, the introduction of next-generation sequencing has significantly improved our understanding of the molecular mechanisms responsible for autonomous aldosterone overproduction in both sporadic and familial PA. Somatic mutations in four genes (KCNJ5, ATP1A1, ATP2B3 and CACNA1D), differently implicated in intracellular ion homeostasis, have been identified in nearly 60% of the sporadic APAs. Germline mutations in KCNJ5 and CACNA1H cause FH-III and FH-IV, respectively, while germline mutations in CACNA1D cause the rare PASNA syndrome, featuring primary aldosteronism seizures and neurological abnormalities. Further studies are warranted to identify the molecular mechanisms underlying BAH and FH-II, the most common forms of sporadic and familial PA whose molecular basis is yet to be uncovered.

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Primary Aldosteronism: The Next Five Years

Hormone and Metabolic Research ◽

10.1055/s-0043-119802 ◽

2017 ◽

Vol 49 (12) ◽

pp. 977-983 ◽

Cited By ~ 11

Author(s):

John Funder

Keyword(s):

Primary Aldosteronism ◽

Germline Mutations ◽

Adrenal Hyperplasia ◽

Bilateral Disease ◽

The Past ◽

Wide Range ◽

Unilateral Disease ◽

Bilateral Adrenal Hyperplasia ◽

Aldosterone Producing Adenoma ◽

Current Guidelines

AbstractThe management of primary aldosteronism is widely varied within various published guidelines, with very little in the way of data supporting the choice of one variation over others. Current estimates of prevalence are probably accurate for aldosterone producing adenoma, but fall very short of that for bilateral adrenal hyperplasia. Discovery at the level of basic science has proven illuminating over the past 6 years in terms of unilateral disease and both somatic and germline mutations, with much less focus on the much more common bilateral disease; Attempts at harmonization have begun – for example, criteria for complete/partial/absent cure after adrenalectomy for unilateral disease; again focus on bilateral disease is muted. A number of possibilities are suggested as agenda for active consideration and change, across a wide range of areas – referral patterns, screening, confirmation and lateralization, what will be needed is discussion and agreement, to fill the lacunae within the current guidelines. Those involved will want to change to make such an agenda possible.

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Unravelling the Genetic Basis of Primary Aldosteronism

Nutrients ◽

10.3390/nu13030875 ◽

2021 ◽

Vol 13 (3) ◽

pp. 875

Author(s):

Niki Mourtzi ◽

Amalia Sertedaki ◽

Athina Markou ◽

George P. Piaditis ◽

Evangelia Charmandari

Keyword(s):

Primary Aldosteronism ◽

Genetic Basis ◽

Molecular Mechanisms ◽

Somatic Mutations ◽

Germline Mutations ◽

Secondary Hypertension ◽

Diagnostic Tools ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing ◽

Made In

Primary aldosteronism (PA), a condition characterized by autonomous aldosterone hypersecretion, constitutes the most common cause of secondary hypertension. Over the last decade, major breakthroughs have been made in the field of genetics underpinning PA. The advent and wide application of Next Generation Sequencing (NGS) technology led to the identification of several somatic and germline mutations associated with sporadic and familial forms of PA. Somatic mutations in ion-channel genes that participate in aldosterone biosynthesis, including KCNJ5, CACNA1D, ATP1A1, and ATP2B3, have been implicated in the development of aldosterone-producing adenomas (APAs). On the other hand, germline variants in CLCN2, KCNJ5, CACNA1H, and CACNA1D genes have been implicated in the pathogenesis of the familial forms of PA, FH-II, FH-III, and F-IV, as well as PA associated with seizures and neurological abnormalities. However, recent studies have shown that the prevalence of PA is higher than previously thought, indicating the need for an improvement of our diagnostic tools. Further research is required to recognize mild forms of PA and to investigate the underlying molecular mechanisms.

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Angiotensin II Type 1 Receptor Autoantibodies in Primary Aldosteronism

Hormone and Metabolic Research ◽

10.1055/a-1120-8647 ◽

2020 ◽

Vol 52 (06) ◽

pp. 379-385

Author(s):

Lucie S. Meyer ◽

Siyuan Gong ◽

Martin Reincke ◽

Tracy Ann Williams

Keyword(s):

Angiotensin Ii ◽

Primary Aldosteronism ◽

Functional Role ◽

Adrenal Hyperplasia ◽

Endocrine Hypertension ◽

Bilateral Adrenal Hyperplasia ◽

Aldosterone Producing Adenoma ◽

Agonistic Autoantibodies

AbstractPrimary aldosteronism (PA) is the most common form of endocrine hypertension. Agonistic autoantibodies against the angiotensin II type 1 receptor (AT1R-Abs) have been described in transplantation medicine and women with pre-eclampsia and more recently in patients with PA. Any functional role of AT1R-Abs in either of the two main subtypes of PA (aldosterone-producing adenoma or bilateral adrenal hyperplasia) requires clarification. In this review, we discuss the studies performed to date on AT1R-Abs in PA.

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Roles of Clinical Criteria, Computed Tomography Scan, and Adrenal Vein Sampling in Differential Diagnosis of Primary Aldosteronism Subtypes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2007-2055 ◽

2008 ◽

Vol 93 (4) ◽

pp. 1366-1371 ◽

Cited By ~ 96

Author(s):

Paolo Mulatero ◽

Chiara Bertello ◽

Denis Rossato ◽

Giulio Mengozzi ◽

Alberto Milan ◽

...

Keyword(s):

Computed Tomography ◽

Sensitivity And Specificity ◽

Primary Aldosteronism ◽

Final Diagnosis ◽

Ct Scans ◽

Lower Sensitivity ◽

Clinical Criteria ◽

Bilateral Adrenal Hyperplasia ◽

Aldosterone Producing Adenoma ◽

Posture Test

Abstract Context: In patients with primary aldosteronism (PA), it is fundamental to distinguish between subtypes that benefit from different therapies. Computed tomography (CT) scans lack sensitivity and specificity and must be followed by adrenal venous sampling (AVS). Because AVS is not widely available, a list of clinical criteria that indicate the presence of an aldosterone-producing adenoma (APA) has been suggested. Objective and Design: The objective of the study was to test the sensitivity and specificity of the last generation CT scans, test prospectively the usefulness of clinical criteria in the diagnosis of APA, and develop a flow chart to be used when AVS is not easily available. Setting: Hypertensive patients referred to our hypertension unit were included in our study. Patients: Seventy-one patients with confirmed PA participated in our study. Intervention: All patients had a CT scan and underwent AVS. Main Outcome Measure: Final diagnosis of APA was the main measure. Results: A total of 44 and 56% of patients were diagnosed as having an APA and a bilateral adrenal hyperplasia (BAH), respectively. Twenty percent of patients with PA displayed hypokalemia. CT scans displayed a sensitivity of 0.87 and a specificity of 0.71. The posture test displayed a lower sensitivity and specificity (0.64 and 0.70, respectively). The distribution grades of hypertension were not significantly different between APA and BAH. Biochemical criteria of high probability of APA displayed a sensitivity of 0.32 and a specificity of 0.95. Conclusions: This study underlines the central role of AVS in the subtype diagnosis of PA. The use of the clinical criteria to distinguish between APA and BAH did not display a satisfactory diagnostic power.

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Mouse Models of Primary Aldosteronism: From Physiology to Pathophysiology

Endocrinology ◽

10.1210/en.2017-00637 ◽

2017 ◽

Vol 158 (12) ◽

pp. 4129-4138 ◽

Cited By ~ 11

Author(s):

Leticia Aragao-Santiago ◽

Celso E Gomez-Sanchez ◽

Paolo Mulatero ◽

Ariadni Spyroglou ◽

Martin Reincke ◽

...

Keyword(s):

Mouse Models ◽

Primary Aldosteronism ◽

Genetic Basis ◽

Plasma Renin ◽

Adrenal Hyperplasia ◽

Endocrine Hypertension ◽

Bilateral Adrenal Hyperplasia ◽

Human Disorder ◽

Aldosterone Producing Adenoma ◽

Functional Mechanisms

Abstract Primary aldosteronism (PA) is a common form of endocrine hypertension that is characterized by the excessive production of aldosterone relative to suppressed plasma renin levels. PA is usually caused by either a unilateral aldosterone-producing adenoma or bilateral adrenal hyperplasia. Somatic mutations have been identified in several genes that encode ion pumps and channels that may explain the aldosterone excess in over half of aldosterone-producing adenomas, whereas the pathophysiology of bilateral adrenal hyperplasia is largely unknown. A number of mouse models of hyperaldosteronism have been described that recreate some features of the human disorder, although none replicate the genetic basis of human PA. Animal models that reproduce the genotype–phenotype associations of human PA are required to establish the functional mechanisms that underlie the endocrine autonomy and deregulated cell growth of the affected adrenal and for preclinical studies of novel therapeutics. Herein, we discuss the differences in adrenal physiology across species and describe the genetically modified mouse models of PA that have been developed to date.

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Masking by hypokalemia—primary aldosteronism with undetectable aldosterone

Clinical Kidney Journal ◽

10.1093/ckj/sfaa150 ◽

2020 ◽

Author(s):

Rebecca A Boyle ◽

Jessica E Baker ◽

Vivek Charu ◽

William E Rainey ◽

Vivek Bhalla

Keyword(s):

Primary Aldosteronism ◽

Molecular Mechanisms ◽

Secondary Hypertension ◽

Extracellular Potassium ◽

Genetic Studies ◽

Dynamic Regulation ◽

Potassium Supplementation ◽

Potassium Regulation ◽

Aldosterone Producing Adenoma

Abstract Primary aldosteronism is the most common cause of secondary hypertension; however, the dynamic regulation of aldosterone by potassium is less well studied and current diagnostic recommendations are imprecise. We describe a young man who presented with resistant hypertension and severe hypokalemia. The workup initially revealed undetectable aldosterone despite acute potassium repletion. Chronic potassium supplementation eventually uncovered hyperaldosteronism. In situ genetic studies revealed a gain-of-function KCNJ5 mutation within an aldosterone-producing adenoma that was clinically responsive to changes in extracellular potassium. We highlight a unique presentation of Conn’s syndrome and discuss the implications for the molecular mechanisms of potassium regulation of aldosterone.

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Subtyping of Patients with Primary Aldosteronism: An Update

Hormone and Metabolic Research ◽

10.1055/s-0043-122602 ◽

2017 ◽

Vol 49 (12) ◽

pp. 922-928 ◽

Cited By ~ 10

Author(s):

Jacques Lenders ◽

Graeme Eisenhofer ◽

Martin Reincke

Keyword(s):

Functional Imaging ◽

Primary Aldosteronism ◽

Non Invasive ◽

Positron Emission ◽

Choice Of Treatment ◽

Bilateral Adrenal Hyperplasia ◽

Potential Alternative ◽

Aldosterone Producing Adenoma ◽

Excessive Secretion ◽

Diagnostic Work

AbstractPrimary aldosteronism (PA) comprises two main subtypes: unilateral aldosteronism, mainly caused by aldosterone-producing adenoma; and bilateral adrenal hyperplasia. Establishing the correct subtype in patients with PA is indispensible for choice of treatment. In addition to established methods, alternative tests are evolving for subtyping. Computed tomography (CT) and adrenal venous sampling (AVS) are currently recommended in the guidelines for the diagnostic work-up of patients with PA. CT cannot be used as a stand-alone test for subtyping because of its limited accuracy but may be used in combination with other tests such as AVS or functional imaging. Nevertheless CT remains mandatory to exclude adrenocortical carcinoma. AVS provides the most accurate test to detect excessive secretion of aldosterone from an adrenal mass but has several practical limitations and disadvantages. Therefore, alternative non-invasive and patient-friendly methods are required to determine the need for adrenalectomy. Functional imaging with specific molecular positron emission tomographic ligands is a potential alternative method that may replace AVS for subclassifying patients with PA. The results of preliminary studies of 11C-metomidate are promising but ligands incorporating radionuclides with longer half-lives that selectively bind to CYP11B2 are needed. Steroid profiling provides another method for subtyping and selecting patients for adrenalectomy, but this technology is in its infancy and prospective outcome-based studies are required to determine if this technique may provide an alternative to AVS.

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Molecular mechanisms in primary aldosteronism

Journal of Endocrinology ◽

10.1530/joe-19-0193 ◽

2019 ◽

Vol 242 (3) ◽

pp. R67-R79 ◽

Cited By ~ 1

Author(s):

Kelly De Sousa ◽

Alaa B Abdellatif ◽

Rami M El Zein ◽

Maria-Christina Zennaro

Keyword(s):

Arterial Hypertension ◽

Adrenal Cortex ◽

Primary Aldosteronism ◽

Molecular Mechanisms ◽

Somatic Mutations ◽

Type I ◽

Adrenal Hyperplasia ◽

New Genes ◽

Aldosterone Production ◽

Bilateral Adrenal Hyperplasia

Primary aldosteronism (PA) is the most common form and an under-diagnosed cause of secondary arterial hypertension, accounting for up to 10% of hypertensive cases and associated to increased cardiovascular risk. PA is caused by autonomous overproduction of aldosterone by the adrenal cortex. It is mainly caused by a unilateral aldosterone-producing adenoma (APA) or bilateral adrenal hyperplasia. Excess aldosterone leads to arterial hypertension with suppressed renin, frequently associated to hypokalemia. Mutations in genes coding for ion channels and ATPases have been identified in APA, explaining the pathophysiology of increased aldosterone production. Different inherited genetic abnormalities led to the distinction of four forms of familial hyperaldosteronism (type I to IV) and other genetic defects very likely remain to be identified. Somatic mutations are identified in APA, but also in aldosterone-producing cell clusters (APCCs) in normal adrenals, in image-negative unilateral hyperplasia, in transitional lesions and in APCC from adrenals with bilateral adrenal hyperplasia (BAH). Whether these structures are precursors of APA or whether somatic mutations occur in a proliferative adrenal cortex, is still a matter of debate. This review will summarize our knowledge on the molecular mechanisms responsible for PA and the recent discovery of new genes related to early-onset and familial forms of the disease. We will also address new issues concerning genomic and proteomic changes in adrenals with APA and discuss adrenal pathophysiology in relation to aldosterone-producing structures in the adrenal cortex.

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The syndromes of low-renin hypertension: "separating the wheat from the chaff"

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/s0004-27302004000500013 ◽

2004 ◽

Vol 48 (5) ◽

pp. 674-681 ◽

Cited By ~ 9

Author(s):

Claudio E. Kater ◽

Edward G. Biglieri

Keyword(s):

Receptor Antagonist ◽

Myocardial Fibrosis ◽

Cardiac Remodeling ◽

Primary Aldosteronism ◽

Renin Activity ◽

Adrenal Hyperplasia ◽

Test Characteristics ◽

Low Renin Hypertension ◽

Bilateral Adrenal Hyperplasia ◽

Aldosterone Producing Adenoma

Primary aldosteronism (PA) is characterized by hypertension and suppressed renin activity with or without hypokalemia and comprises the aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia or idiopatic hyperaldosteronism (IHA). In recent series employing the aldosterone (aldo, ng/dL):renin (ng/mL·h) ratio (ARR) for screening, prevalence of PA among hypertensives soars to 8-20%; current predominance of IHA (>80%) over APA suggests the inclusion of former low-renin essential hypertensives (LREH), in whom plasma aldo can be reduced by suppressive maneuvers. We evaluated the test characteristics of the ARR obtained retrospectively from 127 patients with PA (81 APA; 46 IHA) and 55 with EH (30 LREH; 25 NREH) studied from 1975 to 1990. Using the combined ROC-defined cutoffs of 27 for the ARR and 12ng/dL for aldo, we obtained 89.8% sensitivity (Ss) and 98.2% specificity (Sp) in discriminating PA from EH: all APA and 72% of the IHA patients had values above these limits, but only one (3%) with LREH. Among the 46 IHA patients, 10 (21.7%) had ARR <27, four of whom with aldo <12ng/dL, virtually indistinguishable from LREH. Use of higher cutoff values (ARR >100; aldo >20) may attain 84%Ss and 82.6%Sp in separating APA from IHA. Because IHA and LREH ("the chaff") may be spectrum stages from the same disease, definite discrimination between these entities seems immaterial. However, precise identification of the APA ("the wheat") is critical, since it is the only surgically curable form of PA. Thus, while patients who may harbor an APA must be thoroughly investigated and surgically treated, non-tumoral disease (IHA and LREH) may be best treated with an aldo-receptor antagonist that will also prevent the aldo-mediated inflammatory effects involved in myocardial fibrosis and abnormal cardiac remodeling.

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MicroRNAs and Adrenocortical Tumors: Where do we Stand on Primary Aldosteronism?

Hormone and Metabolic Research ◽

10.1055/a-1116-2366 ◽

2020 ◽

Vol 52 (06) ◽

pp. 394-403

Author(s):

Zsófia Tömböl ◽

Péter István Turai ◽

Ábel Decmann ◽

Peter Igaz

Keyword(s):

Rna Interference ◽

Primary Aldosteronism ◽

Expression Profiles ◽

Microrna Expression ◽

Circulating Microrna ◽

Adrenal Hyperplasia ◽

Aldosterone Secretion ◽

Adrenocortical Tumors ◽

Bilateral Adrenal Hyperplasia ◽

Aldosterone Producing Adenoma

AbstractMicroRNAs, the endogenous mediators of RNA interference, interact with the renin-angiotensin-aldosterone system, regulate aldosterone secretion and aldosterone effects. Some novel data show that the expression of some microRNAs is altered in primary aldosteronism, and some of these appear to have pathogenic relevance, as well. Differences in the circulating microRNA expression profiles between the two major forms of primary aldosteronism, unilateral aldosterone-producing adenoma and bilateral adrenal hyperplasia have also been shown. Here, we present a brief synopsis of these findings focusing on the potential relevance of microRNA in primary aldosteronism.

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