A single-step approach to the diagnosis of primary hyperaldosteronism: filling a true void or burdening the bottleneck of adrenal vein sampling?

Abstract

In the present issue of The Journal of Clinical Hypertension, Kline and colleagues propose a fundamental change in the diagnostic workup of patients evaluated for potential primary hyperaldosteronism (PH). Traditionally, the diagnosis of PH is predominantly considered in the presence of hypertension with hypokalemia; severe or resistant hypertension; adrenal incidentaloma, particularly when associated with hypertension; and hypertension of early onset, especially in the context of familial hypertension with early cerebrovascular events. That screening for PH should be initiated by the determination of the Aldosterone-Renin Ratio (ARR) is now widely recommended. A high ARR is followed by one of several confirmatory forms of testing, all of which are based on the principle that contrary to physiological control of aldosterone secretion, autonomous aldosterone secretion cannot be properly turned off in response to salt/volume loading or acute reduction in circulating angiotensin II. Although the need for confirmatory testing is widely accepted, views on the most adequate procedure vary. Reflecting this area of disagreement, the Endocrine Society’s guidelines endorse the use of one of several forms of tests: the oral sodium loading test, saline infusion test, fludrocortisone suppression test, or the captopril challenge test. In principle, only individuals with evidence of autonomous aldosterone secretion in any of these tests are presumed to have “true PH” and are thus referred for further evaluation, including computed tomography (CT) or magnetic resonance imaging scans, followed by adrenal venous sampling (AVS). Individuals with unilateral disease, mostly aldosterone-producing adenoma, are usually referred for surgery and are likely to benefit from adrenalectomy, whereas patients with bilateral adrenal hyperplasia are treated medically. In their present article, Kline and coworkers challenge the need for confirmatory testing and offer an alternative single-step, ARR-based approach to the diagnosis of PH, to be directly followed, when a preset critical ARR is surpassed, by adrenal imaging and AVS. Because of the inconsistent performance of the confirmatory tests, the authors abandoned this phase altogether. Having accumulated considerable experience with this approach, this group now submits evidence from a single referral center that a systematic omission of confirmatory testing has virtually no discernible impact on the clinical outcome of patients evaluated for PH. In the course of 6 years (2005–2011), Kline and associates evaluated 83 hypertensive patients whose initial ARR exceeded 550 pmol/L irrespective of their medication status. Patients with resistant hypertension and normal ARR were re-evaluated after the withdrawal of all medications known to affect aldosterone and/or plasma renin activity (PRA) and maintained on doxazocin and either nifedipine or diltiazem, supplemented, when needed, only by oral potassium-containing tablets. In all, 83 patients whose ARR exceeded 550 pmol/L were considered to have PH. All were referred for adrenal CT and AVS, using a protocol in which adrenal vein aldosterone was measured both before and after the administration of 250 lg of cosyntropin (a synthetic derivative of adrenocorticotropic hormone [ACTH]). Patients whose post-ACTH interadrenal aldosterone/cortisol ratio gradient was higher than 3 were considered to have unilateral disease. In terms of outcome, AVS was technically successful in 80 of 83 (96%) of the patients and an unequivocal AVS-based lateralization was established in 48 patients. Notably, 88% of the lateralized patients had a congruent CT finding, whereas unilateral anomalous CT adrenal was seen in <34% of patients with nonlateralization. Of the 48 lateralized patients, 8 refused surgery. With a median follow-up of 8 months, approximately one third of the operated patients had complete resolution of hypertension; approximately 60% had improvement in blood pressure, whereas only marginal improvement was seen in 2 patients (~5%). The latter patients turned out to have a known contralateral mass identified on CT prior to surgery. Are these data convincing enough to reconsider the traditional “first screen, then confirm/exclude” biphasic approach to the diagnosis of PH and possibly reduce it to a single-step ARR-based strategy? There are 4 fundamental questions that require elucidation before such modification can be contemplated. First, is the cohort treated here representative of the patient population assessed for PH at large? Apparently not, on several accounts: the population base from which the patients were referred for evaluation was not presented in Kline’s report. Referrals to a single center inherently reflect uncharacterized population specifics such as ethnic distribution, salt consumption, referring physicians’ perception of “resistant hypertension,” and access to specialists and/or credible laboratory services. Although not explicitly stated, Kline and colleagues *The first two authors contributed qually to this manuscript.