Laboratory investigation of primary aldosteronism

Abstract

Availability and wider application of the plasma aldosterone/renin ratio (ARR) as a screening test for primary aldosteronism (PA) has led to the recognition that PA is the most common potentially curable and specifically treatable form of hypertension, possibly accounting for as many as 5-13% of patients. Aldosterone excess also has adverse cardiovascular consequences that go above and beyond hypertension development. These findings support the concept that PA plays an important role in cardiovascular disease states and should be systematically sought and specifically treated, and have led to the development of a US Endocrine Society clinical guideline for the detection, diagnosis and management of this condition. Reliable detection requires that interfering factors (including medications known to alter the ratio) are controlled before ARR measurement (or their effects taken into account), and reliable methods such as fludrocortisone suppression testing are used to confirm PA. Because computed tomography frequently misses aldosterone-producing adenomas yet demonstrates non-functioning nodules, adrenal venous sampling is the only dependable way to differentiate unilateral (surgically correctable) from bilateral (usually treated with aldosterone antagonist medications) forms of PA. For the glucocorticoid-remediable form of PA (familial hyperaldosteronism type I), genetic testing for the causative 'hybrid' 11beta-hydroxylase/aldosterone synthase gene has greatly facilitated detection. Laboratory assessment (including suppression testing post-operatively, and renin measurement during treatment with aldosterone antagonist medications) can assist in assessing therapeutic responses and in guiding ongoing management. Development of new, highly reliable high-throughput mass spectrometric methods for measuring aldosterone and renin should further enhance detection and reliability of diagnostic workup for PA.

Figure 1

Algorithm describing the case detection, assessment and treatment of primary aldosteronism as performed in the Greenslopes and Princess Alexandra Hospital Hypertension Units. BP = blood pressure. CT = computed tomography; FH-I = familial hyperaldosteronism type I (glucocorticoid-remediable aldosteronism).

Figure 2

Results of (a) fludrocortisone suppression testing (FST); (b) adrenal venous sampling (AVS); and (c) post-operative FST (performed following right unilateral adrenalectomy) in a 39-year-old female patient with right aldosterone-producing adenoma (APA). The patient was referred with hypertension and unprovoked hypokalaemia and was found to have repeatedly elevated upright midmorning aldosterone/renin ratios (ARR) and suppressed renin levels off interfering medications (see day 0 of FST). FST confirmed the diagnosis of primary aldosteronism (PA) (failure of upright plasma aldosterone (aldo) to suppress to <165 pmol/L despite suppression of renin to <8.4 mU/L). The absence of a rise in cortisol between 0700 and 1000 h excluded a stress-induced rise in ACTH which may have prevented aldo suppression. Initial hypokalaemia was successfully corrected and normokalaemia maintained up to day 4 by administration of potassium supplements (Slow K, given 6 hourly). The failure of aldo to rise in response to upright posture (UP) following overnight recumbency (REC) on day 0 (prior to commencement of fludrocortisone) was suggestive of angiotensin II-unresponsive APA or familial hyperaldosteronism type I (FH-I), but not sufficient to exclude bilateral PA. Not shown here are results of genetic testing for the hybrid gene (negative, thereby excluding FH-I), or adrenal CT (13 mm lesion in the right adrenal gland). During AVS, adequate cannulation of both adrenal veins was confirmed by assessment of adrenal/peripheral venous (AV/PV) cortisol gradients which exceeded our criteria (>3.0) for cannulation success. Although both left (LAV) and right (RAV) adrenal venous aldo levels were greater than those in simultaneously collected peripheral blood, only the right aldo/cortisol gradients exceeded peripheral, while left aldo/cortisol gradients were less than peripheral (contralateral suppression), consistent with lateralisation of aldo overproduction to the right adrenal. Following right laparoscopic adrenalectomy, hypertension and hypokalaemia normalised without the need for medications. FST performed two months post-operatively showed normalisation of the day 0 ARR (with renin now ‘unsuppressed’) and normal suppression of aldo by days 3 and 4, consistent with biochemical cure of PA.