Cellular and Genetic Causes of Idiopathic Hyperaldosteronism

Hypertension. 2018 Oct;72(4):874-880. doi: 10.1161/HYPERTENSIONAHA.118.11086.

Abstract

Primary aldosteronism affects ≈5% to 10% of hypertensive patients and has unilateral and bilateral forms. Most unilateral primary aldosteronism is caused by computed tomography-detectable aldosterone-producing adenomas, which express CYP11B2 (aldosterone synthase) and frequently harbor somatic mutations in aldosterone-regulating genes. The cause of the most common bilateral form of primary aldosteronism, idiopathic hyperaldosteronism (IHA), is believed to be diffuse hyperplasia of aldosterone-producing cells within the adrenal cortex. Herein, a multi-institution cohort of 15 IHA adrenals was examined with CYP11B2 immunohistochemistry and next-generation sequencing. 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 1 CYP11B2-positive aldosterone-producing cell cluster (APCC) or micro-aldosterone-producing adenomas. The number of APCCs per case (and individual APCC area) in IHA adrenals was significantly larger than in normotensive controls. Next-generation sequencing of DNA from 99 IHA APCCs demonstrated somatic mutations in genes encoding the L-type calcium voltage-gated channel subunit α 1-D ( CACNA1D, n=57; 58%) and potassium voltage-gated channel subfamily J-5 ( KCNJ5, n=1; 1%). These data suggest that IHA may result from not only hyperplasia but also the accumulation or enlargement of computed tomography-undetectable APCC harboring somatic aldosterone-driver gene mutations. The high prevalence of mutations in the CACNA1D L-type calcium channel provides a potential actionable therapeutic target that could complement mineralocorticoid blockade and inhibit aldosterone overproduction in some IHA patients.

Keywords: adrenal cortex; aldosterone; calcium channels; hyperaldosteronism; hypertension.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldosterone* / biosynthesis
  • Aldosterone* / genetics
  • Calcium Channels, L-Type / genetics*
  • Cytochrome P-450 CYP11B2 / metabolism
  • Female
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / genetics*
  • Gene Expression Regulation
  • Humans
  • Hyperaldosteronism* / complications
  • Hyperaldosteronism* / genetics
  • Hyperaldosteronism* / metabolism
  • Hyperplasia
  • Hypertension* / etiology
  • Hypertension* / metabolism
  • Immunohistochemistry
  • Male
  • Mutation
  • Zona Glomerulosa* / metabolism
  • Zona Glomerulosa* / pathology

Substances

  • CACNA1D protein, human
  • Calcium Channels, L-Type
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • KCNJ5 protein, human
  • Aldosterone
  • Cytochrome P-450 CYP11B2