Endocrine Abstracts

Primary aldosteronism is the most common form of secondary arterial hypertension. Its prevalence increases with the severity of hypertension, reaching up to 25% in patients with treatment resistant hypertension. Due to the difficulty of its diagnosis, only a minority of patients are tested for PA and even less are appropriately treated. Somatic and germline mutations have been identified in a majority of aldosterone producing adenoma and in familial forms of primary aldosteronism. In most cases, genetic abnormalities are found in genes coding for ion channels (KCNJ5, CACNA1D, CACNA1H, CLCN2, SLC30A1, MCOLN3) or pumps (ATP1A1, ATP2B3). They occur as somatic mutations in aldosterone producing adenoma and as germline mutations in familial forms of the disease. Mutations in these genes affect intracellular ion homeostasis and/or cell membrane potential, leading to increased intracellular calcium concentrations and activation of calcium signalling, the main regulator of aldosterone biosynthesis. Double mutations in CTNNB1 and GNAQ/GNA11 have been identified in aldosterone producing adenoma presenting in puberty, pregnancy and menopause, while somatic mutations in CADM1 in APA have revealed novel mechanisms of regulation of aldosterone biosynthesis. Beyond categorically overt PA, recent evidence suggests a continuum of dysregulated aldosterone production which affects a substantial proportion of patients with hypertension. Genome-wide association studies suggest that common genetic variation may underlie dysregulated aldosterone production in the general population, leading to PA in extreme cases. Remarkably, PA susceptibility loci have been associated with hypertension related traits and are in part shared between unilateral and bilateral forms of PA. This represents a paradigm shift in our understanding of PA, suggesting a genetically determined continuum between dysregulated aldosterone production and PA in hypertension.