Publication Topic: Adrenal Imaging

Primary aldosteronism (PA) is the most common form of endocrine hypertension and effects one in 50 adults. PA is characterized by inappropriately elevated aldosterone production via renin-independent mechanisms. Driver somatic mutations for aldosterone excess have been found in approximately 90% of aldosterone-producing adenomas (APAs). Using next-generation sequencing, we identified recurrent in-frame deletions in SLC30A1 in five APAs (p.L51_A57del, n=3; p.L49_L55del, n=2). SLC30A1 encodes the ubiquitous zinc efflux transporter ZnT1 (zinc transporter 1). The identified SLC30A1 variants are situated in close proximity of the zincbinding site (H43 and D47) in transmembrane domain II and likely cause abnormal ion transport. PA cases with the unique SLC30A1 mutations showed male dominance and demonstrated increased aldosterone and 18-oxo-cortisol concentrations. Functional studies of the mutant SLC30A1^51_57del variant in a doxycycline-inducible adrenal cell system revealed abnormal Na⁺ conductivity caused by the mutant, which in turn led to the depolarization of the resting membrane potential, and thus to the opening of voltage-gated calcium channels. This resulted in an increase in cytosolic Ca²⁺ activity, which stimulated CYP11B2 mRNA expression and aldosterone production. Collectively, these data implicate the first-in-field zinc transporter mutations as a dominant driver of aldosterone excess in PA.

Recent genome-wide analyses have found 50 loci associated with variation in blood pressure but failed to advance understanding of the molecular basis of hypertension. Whether hypertension is not after all due to multiple common variants or is simply an order of magnitude more complex than previously suspected remains unsettled – in part because only a minority of subjects in the analyses had true hypertension. A better starting point than normotensive subjects for explaining hypertension may be the most common distinct cause of hypertension, primary hyperaldosteronism (PHA). The findings that 40% of patients with an aldosterone-producing adenoma (APA) of the adrenal have somatic gain-of-function mutations in a single gene, KCNJ5, and that this gene is, less frequently, mutated in inherited cases of PHA, potentially transform the understanding and management of hypertension. Firstly, they illustrate how hypertension could be due to a multiplicity of uncommon variants. Mutations that present with abnormal electrolytes and anatomy are the easiest to detect but are likely the tip of the iceberg. Secondly, we found a genotype:phenotype pattern, with KCNJ5 mutations inducing larger APAs in the cortisol-secreting zona fasciculata in young women. Smaller APAs without KCNJ5 mutations usually present in older men with resistant hypertension, having been overlooked earlier because of their size. This reflects their compact zona glomerulosa cells. Routine measurement of plasma renin in hypertension and a new positron emission tomography/computerized tomography allow prompt diagnosis and management of PHA before resistant hypertension ensues. Wider recognition of distinct phenotypes should permit earlier, specific treatment and reduce life-time risk of complications.