A13439 Cellular and Genetic Causes of Idiopathic Hyperaldosteronism

Abstract

Objectives: Primary aldosteronism (PA) affects ∼10% of hypertensive patients and has unilateral and bilateral forms (30%:70%). 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 (KCNJ5 >> CACNA1D). The etiology of the more common bilateral PA (often termed idiopathic hyperaldosteronism [IHA]) has long been believed to result from diffuse hyperplasia of adrenal cortex cells without incorporation of CYP11B2 expression. Methods: Herein, fifteen IHA adrenals from a multi-institution cohort were examined using CYP11B2 immunohistochemistry and next generation sequencing (NGS). Results: CYP11B2 immunoreactivity in the adrenal cortex was diffusely positive in only 4/15 IHA adrenals, arguing against this as the common cause of IHA. Instead, all adrenals harbored at least one CT-undetectable CYP11B2-expressing cell clusters (termed aldosterone-producing microscopic lesions [APML]), which existed sporadically in adrenal cortex. The median number per case and individual area of APML in IHA was significantly larger than those in normotensive controls. NGS of DNA from 99 adrenal APML demonstrated somatic mutations in CACNA1D (57 / 58%) and KCNJ5 (1 / 1%). Conclusion: These data indicate that the most common cause of PA, IHA, results from the accumulation of image-undetectable aldosterone producing cells harboring somatic aldosterone-driver gene mutations. The high prevalence of mutations in CACNA1D, an L-type calcium channel, indicate a potential actionable therapeutic target to inhibit aldosterone overproduction in IHA patients.