Abstract 057: Cellular and Genetic Causes of Idiopathic Hyperaldosteronism

Background: Primary aldosteronism (PA) affects ~10% of hypertensive patients and has unilateral and bilateral forms (30%:70%). Unilateral PA is caused by aldosterone-producing adenomas (APA), which express CYP11B2 (aldosterone synthase) and frequently harbor somatic mutations in aldosterone regulating genes ( KCNJ5>>CACNA1D ). We recently demonstrated that adrenals from normotensive patients present with pockets of cell expressing aldosterone synthase (CYP11B2). These aldosterone-producing foci (APF) have somatic gene mutations similar to those found in APA ( CACNA1D >> KCNJ5 ). Bilateral PA, which is typically treated by mineralocorticoid receptor (MR) blockade rather than surgery, is termed idiopathic hyperaldosteronism (IHA). Its pathobiology is largely unknown but has been thought to be due to zona glomerulosa (ZG) hyperplasia. Methods: We studied 11 IHA patients (7 males, 4 females) who had unilateral adrenalectomy. Immunohistochemistry for CYP11B2 and next generation sequencing (NGS) targeting genes found in APA were performed on formalin fixed paraffin embedded adrenal tissue. Results were compared to previously described cohorts of 53 age-matched normotensive patients (29 males, 24 females) which were evaluated similarly. Results: CYP11B2 expression was absent from intervening ZG cells in 8/11 (73%) IHA adrenals, but all adrenals harbored at least one APF. The median number and size of APF per case were significantly larger in IHA than normotensive controls (6.1 vs 0 APF/cm 2 of adrenal cortex and 0.25 vs. 0.16 mm 2 , respectively; p<0.0001 and p<0.006). In this IHA cohort, NGS identified CACNA1D and KCNJ5 somatic mutations in 44/71 (62%) and 1/71 (1%) of APF, respectively. Interpretations. Diffuse CYP11B2 expression in adrenal ZG cells was only observed in 3/11 IHA cases, arguing against ZG hyperplasia as the major underlying pathobiology. Rather, we demonstrated increased and enlarged APF in IHA adrenals compared to normotensive controls, supporting potential contribution to the clinical manifestations of hyperaldosteronism. The frequent occurrence of aldosterone-dysregulating CACNA1D somatic mutations in APF support CACNA1D as a potential therapeutic target in IHA to complement current MR blockade approaches.