Abstract
Primary aldosteronism is the most common single cause of hypertension and is potentially curable when only one adrenal gland is the culprit. The importance of primary aldosteronism to public health derives from its high prevalence but huge under-diagnosis (estimated to be <1% of all affected individuals), despite the consequences of poor blood pressure control by conventional therapy and enhanced cardiovascular risk. This state of affairs is attributable to the fact that the tools used for diagnosis or treatment are still those that originated in the 1970–1990s. Conversely, molecular discoveries have transformed our understanding of adrenal physiology and pathology. Many molecules and processes associated with constant adrenocortical renewal and interzonal metamorphosis also feature in aldosterone-producing adenomas and aldosterone-producing micronodules. The adrenal gland has one of the most significant rates of non-silent somatic mutations, with frequent selection of those driving autonomous aldosterone production, and distinct clinical presentations and outcomes for most genotypes. The disappearance of aldosterone synthesis and cells from most of the adult human zona glomerulosa is the likely driver of the mutational success that causes aldosterone-producing adenomas, but insights into the pathways that lead to constitutive aldosterone production and cell survival may open up opportunities for novel therapies.
Key points
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Primary aldosteronism (PA) is a common cause of hypertension; it is potentially curable when caused by a unilateral aldosterone-producing adenoma (APA), but it can lead to resistant hypertension and a high cardiovascular risk in cases in which PA is undiagnosed.
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Current clinical guidelines and practice centres on risky tests and procedures, such as saline suppression, adrenal sampling and surgery, and poorly tolerated drugs such as spironolactone; these practices have remained largely unchanged over the past 30 years.
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By contrast, the discovery of somatic mutations over the past decade has identified these as the cause of autonomous aldosterone production in most patients with PA, including 80–90% of APAs; the identified mutations most commonly affect the ion-channel genes KCNJ5 and CACNA1D.
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Several distinct genotype–phenotype patterns and emerging clinical surrogates for genotype suggest the potential for molecular discovery to predict individual patient outcomes, permitting rational stratification of interventions.
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In vivo molecular ligands for aldosterone synthase have been validated for non-invasive PET CT detection of APAs; on the left side, ultrasound-guided endoscopic radiofrequency ablation of PET-imaged APAs seems to be a safe alternative to surgery.
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Genetic deletion models suggest curative potential for the suppression, rather than blockade, of aldosterone synthesis.
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Acknowledgements
E.A.B.A.’s work is supported by the Ministry of Higher Education (MOHE) Malaysia, a Long-term Research Grant Scheme-Jejak Sarjana Ulung (LRGS-JSU), LRGS/1/2021/SKK15/UKM/02/2 (mentored by M.J.B); the Royal Society-Newton Advanced Fellowship, NA170257/FF-2018–033 (co-applicant with M.J.B.); and the UK-MY Joint Partnership on Noncommunicable Diseases 2019 program, NEWTON-MRC/2020/002 (co-applicant with M.J.B.). W.M.D.’s and M.J.B.’s work is supported by the National Institute for Health Research (NIHR, Efficacy and Mechanisms Evaluation project 14/145/09), Barts Charity (Project MGU0360), NIHR Integrated Academic Training Clinical Lectureship, the Medical Research Council (MR/S006869/1) and the British Heart Foundation (PG/16/40/32137). M.J.B. is also supported by the British Heart Foundation (Project MCPG1P3R and PhD studentship FS/14/75/31134) and NIHR Barts Biomedical Research Centre (BRC-1215–20022).
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Azizan, E.A.B., Drake, W.M. & Brown, M.J. Primary aldosteronism: molecular medicine meets public health. Nat Rev Nephrol 19, 788–806 (2023). https://doi.org/10.1038/s41581-023-00753-6
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DOI: https://doi.org/10.1038/s41581-023-00753-6
