An update on novel mechanisms of primary aldosteronism

Abstract

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 w50% 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.

2016 European Society of Hypertension guidelines for the management of high blood pressure in children and adolescents

“…An early-onset primary aldosteronism suggests inherited causes. Three familial aldosteronisms have been described: FH-1 (glucocorticoid-remediable aldosteronism caused by mutations affecting aldosterone synthase), FH-2 (with unknown molecular basis), and FH-3 (two distinct syndromes with or without adrenal hyperplasia resulting from different mutations in genes coding for ion channels) (260). FH-1 is associated with high morbidity and mortality at an early age and should be treated in children with eplerenone to avoid glucocorticoid effects on growth or antiandrogenic effects of spironolactone.…”

ENDOCRINE TUMOURS: The genomics of adrenocortical tumors

“…Since the recent rise of next generation sequencing and in particular exome sequencing, it took only 4 years to identify a new dozen of driver genes in these tumors (Table 1). subsequent Gq/phospholipase C signaling -and the plasma membrane depolarization -with subsequent opening of calcium voltage-dependent channels -respectively (6). In APA, the new mutated genes also demonstrate the central role of intra-cellular calcium for autonomous aldosterone production.…”

“…The strategy is to ascertain the expression of aldosterone synthase (CYP11B2) -the key aldosterone producing enzyme -in the adenoma. This was first achieved by in situhybridization and more recently by immunohistochemistry (see (6) for review). Genomics has brought up the knowledge of somatic mutations in APA (affecting KCNJ5, ATP2B3, ATP1A1 and CACNA1D), and finding such a mutation may also be a way to ascertain the true nature of an APA.…”

“…In primary aldosteronism, familial forms with KNCJ5 mutations have been reported (6). Here again, screening the relatives should help to identify the patients at risk, and diagnose and treat early their hypertension.…”

“…These patients may benefit from calcium channel blockers, beyond the antihypertensive effect of these treatments (see (6) for review).…”