Cellular and Genetic Causes of Idiopathic Hyperaldosteronism

Abstract

<p class="first" id="P1">Primary aldosteronism (PA) affects ~5–10% of hypertensive patients and has unilateral and bilateral forms. Most unilateral PA is caused by computed tomography (CT)-detectable aldosterone-producing adenomas (APA), which express CYP11B2 (aldosterone synthase) and frequently harbor somatic mutations in aldosterone-regulating genes. The etiology of the most common bilateral form of PA, idiopathic hyperaldosteronism (IHA), is believed to be diffuse hyperplasia of aldosterone-producing cells within the adrenal cortex. Herein, a multi-institution cohort of fifteen IHA adrenals were examined with CYP11B2 immunohistochemistry and next generation sequencing (NGS). CYP11B2 immunoreactivity in adrenal glomerulosa harboring non-nodular hyperplasia was only observed in 4/15 IHA adrenals suggesting that hyperplasia of CYP11B2 expressing cells may not be the major cause of IHA. However, the adrenal cortex of all IHA adrenals harbored at least one CYP11B2-positive aldosterone-producing cell cluster (APCC) or a micro-APA. The number of APCCs per case (and individual APCC area) in IHA adrenals was significantly larger than in normotensive controls. NGS of DNA from 99 IHA APCCs demonstrated somatic mutations in genes encoding the L-type calcium voltage-gated channel subunit alpha 1-D ( <i>CACNA1D, n</i>=57; 58%) and potassium voltage-gated channel subfamily J-5 ( <i>KCNJ5, n</i>=1; 1%). These data suggest that IHA may result from not only hyperplasia, but also the accumulation or enlargement of CT-undetectable APCC harboring somatic aldosterone-driver gene mutations. The high prevalence of mutations in the <i>CACNA1D</i> L-type calcium channel provides a potential actionable therapeutic target that could complement mineralocorticoid blockade and inhibit aldosterone overproduction in some IHA patients. </p>