Cyclical aldosterone secretion and diagnostic insights of primary hyperaldosteronism informed by a mathematical model

Primary aldosteronism (PA) is the most common cause of secondary hypertension in many populations worldwide. Although hypertension with recurrent hypokalemia from renal potassium wasting and simultaneously elevated plasma aldosterone with suppressed renin is classic and pathognomic of PA, there are numerous instances when patients show unexpected, atypical, and confusing biochemical nuances. A thorough understanding of the appropriate diagnosis based on varied plasma aldosterone-renin-potassium concentrations is therefore necessary. We have derived a mathematical model to teach medical students, residents, experienced clinicians, and educators how to properly diagnose PA. Based on the physiology of aldosterone homeostasis in relation to plasma concentrations of renin, potassium, and adrenocorticotropin (ACTH), a second-order linear ordinary differential equation of the first degree was set up. This yields solutions showing sinusoidal aldosterone secretion in relation to renin and potassium, thereby supporting the plausibility of normal to low plasma aldosterone in certain instances of PA. Evidence from the published literature supports cyclical aldosterone secretion in normal and pathological states. By educating the medical community to appreciate why “normal-appearing” plasma aldosterone, potassium, and renin do not exclude PA, this model achieves its pedagogical goals of advancing clinical awareness to combat diagnostic oversights, preventing the misinterpretation and underdiagnosis of treatable, secondary hypertension.NEW & NOTEWORTHY This mathematical model offers novel insights into the phenomenon of cyclical aldosterone secretion driven by oscillatory feedback homeostatic mechanisms mediated by potassium, renin, and diurnal ACTH. Previously reported but infrequently cited data support the model, which showcases the distinctive subtleties of primary aldosteronism (PA) that often confuse clinicians and also predicts the existence of cyclical PA, an underrecognized entity within the clinical spectrum of PA due to fluctuating aldosterone.