Endocrine Abstracts

Classically aldosterone acted uniquely on epithelia, and primary aldosteronism (PA) was considered uncommon and relatively benign, all of which we now know to be not the case. In 2013, we should note that:

i). Mineralocorticoid receptors (MR) evolved millions of years before aldosterone.

ii). Cortisol occupies 90–99% of all MR in the human body.

iii). MR are promiscuous, binding cortisol, aldosterone and progesterone with the same high affinity.

iv). Cortisol is bivalent: normally an antagonist of aldosterone in MR, it acts as an agonist under conditions of tissue damage/reactive oxygen species generation/redox change.

v). Cortisol is thus the cardiac/vascular MR agonist in essential hypertension (EH) and congestive heart failure (CHF).

vi). Spironolactone and eplerenone do not act primarily by denying agonist access to MR, but as inverse agonists in their own right.

vii). Around 40% of PA due to an aldosterone producing adenoma is due to somatic mutation of KCNJ5, with further somatic mutations in press.

viii). Three germline mutations causing PA have been distinguished; Familial Hyperaldosteronism Type l and 3 are rare (<1%), but the prevalence of FH2 is likely to be much higher.

ix). The currently accepted prevalence of PA may be too low, and the upper limit of ‘normal’ aldosterone too high, with evidence accruing that many patients with resistant hypertension and low renin hypertension have autonomous aldosterone secretion, i.e. PA.

x). Even at currently accepted levels for PA fewer than I% of patients are ever screened, diagnosed and specifically treated.

xi). No jurisdiction has the resources – financial or medical – to meaningfully raise this percentage.

xii). Low dose MR antagonists are safe and efficacious in EH, selectively active in resistant hypertension, and game-changing in PA; and so

xiii). Given the much higher cardiovascular risk profile of PA than in age-, sex- and blood pressure-matched EH, and that 99+% of PA remains occult, low dose MR antagonists should be included in first-line therapy for all hypertensives.