Pathophysiology of bilateral hyperaldosteronism

Abstract

Purpose of review: Renin-independent aldosterone production from one or both affected adrenal(s), a condition known as primary aldosteronism (PA), is a common cause of secondary hypertension. In this review, we aimed to summarize recent findings regarding pathophysiology of bilateral forms of PA, including sporadic bilateral hyperaldosteronism (BHA) and rare familial hyperaldosteronism.

Recent findings: The presence of subcapsular aldosterone synthase (CYP11B2)-expressing aldosterone-producing micronodules, also called aldosterone-producing cell clusters, appears to be a common histologic feature of adrenals with sporadic BHA. Aldosterone-producing micronodules frequently harbor aldosterone-driver somatic mutations. Other potential factors leading to sporadic BHA include rare disease-predisposing germline variants, circulating angiotensin II type 1 receptor autoantibodies, and paracrine activation of aldosterone production by adrenal mast cells. The application of whole exome sequencing has also identified new genes that cause inherited familial forms of PA.

Summary: Research over the past 10 years has significantly improved our understanding of the molecular pathogenesis of bilateral PA. Based on the improved understanding of BHA, future studies should have the ability to develop more personalized treatment options and advanced diagnostic tools for patients with PA.

Figure 1.. Cellular origins of adrenal aldosterone production.

A and B. CYP11B2 and CYP11B1 immunofluorescent images of normal adrenals from kidney donors. A. Adrenal with continuous CYP11B2-expressing zona glomerulosa, B. Adrenal with aldosterone-producing micronodule (APM) harboring a somatic CACNA1D mutation. CYP11B2 (green); CYP11B1 (red); DAPI (blue); Cap, capsule; ZG, zona glomerulosa; ZF, zona fasciculata; Scale bars 200 μm.

Figure 2.. Schematic presentation of histopathology of an adrenal with BHA and cellular mechanisms leading to renin-independent aldosterone production due to mutations in CACNA1D.

A. An illustration demonstrating possible histopathologic features associated with adrenals from patients with sporadic bilateral hyperaldosteronism (BHA). To describe histologic characteristics of BHA, the nomenclature recommended by Williams et al. [65] was applied in this review. Clinical use of this nomenclature for BHA requires further investigation. CYP11B2-positive MAPM, multiple aldosterone-producing micronodules; APN, aldosterone-producing nodule; APDH, aldosterone-producing diffuse hyperplasia. Refer to reference [65] for detailed histologic classifications and definitions of APM, APN, and APDH. B. Proposed molecular mechanism of inappropriate aldosterone production due to CACNA1D mutations. Mutations in CACNA1D lead to channel activation at less depolarized membrane potentials and increased calcium influx, resulting in enhanced CYP11B2 transcription and aldosterone production.