Primary Aldosteronism: State-of-the-Art Review

Abstract

We are witnessing a revolution in our understanding of primary aldosteronism (PA). In the past 2 decades, we have learned that PA is a highly prevalent syndrome that is largely attributable to pathogenic somatic mutations, that contributes to cardiovascular, metabolic, and kidney disease, and that when recognized, can be adequately treated with widely available mineralocorticoid receptor antagonists and/or surgical adrenalectomy. Unfortunately, PA is rarely diagnosed, or adequately treated, mainly because of a lack of awareness and education. Most clinicians still possess an outdated understanding of PA; from primary care physicians to hypertension specialists, there is an urgent need to redefine and reintroduce PA to clinicians with a modern and practical approach. In this state-of-the-art review, we provide readers with the most updated knowledge on the pathogenesis, prevalence, diagnosis, and treatment of PA. In particular, we underscore the public health importance of promptly recognizing and treating PA and provide pragmatic solutions to modify clinical practices to achieve this.

Keywords: adrenal; aldosterone; blood pressure; hypertension; primary aldosteronism; renin.

Graphical Abstract

Figure 1.

Models for the pathogenesis of primary aldosteronism. (a) Young human adrenals display a continuous pattern of CYP11B2 expression in the zona glomerulosa. With aging, CYP11B2 expression becomes discontinuous, and there are greater numbers of aldosterone-producing micronodules (APMs), often harboring pathogenic aldosterone-driver somatic mutations; in parallel, there is greater renin-independent aldosterone production indicative of mild PA. With progressive aging, a proportion of individuals will have expansion of APMs, despite morphologically normal-appearing adrenal glands, contributing to overt PA. (b) Although the vast majority of PA is likely attributable to progressive acquisition of APMs and pathogenic somatic mutations, less commonly, these entities may co-occur or collide with adrenocortical neoplasia to form an APA. Although APAs manifest with the most severe PA clinical phenotype, they likely represent the minority of PA cases. (c) Other stochastic co-occurrences include the combination of APMs with incidental and nonfunctional adrenocortical neoplasia, and the combination of aldosterone production with cortisol production. Models of aldosterone and cortisol coproduction include (i) an aldosterone and cortisol coproducing adenoma; (ii) a cortisol-producing adenoma with a background of APMs; and (iii) separate cortisol- and aldosterone-producing adenomas. Abbreviations: Aldo, aldosterone; APA, aldosterone-producing adenoma; PA, primary aldosteronism; ZG, zona glomerulosa. (Figures created in BioRender.com.).

Figure 2.

The prevalence of primary aldosteronism. The prevalence of “overt PA” among untreated and/or new patients with hypertension has been reported to be as high as 14%–15% when using liberalized diagnostic interpretations; however, the prevalence of milder forms of PA pathophysiology is much higher. Among the subset of hypertensive individuals with resistant hypertension, the prevalence of “overt PA” is at least 25%, although when employing more liberalized criteria to define overt PA, it could be as high as 50%. Beyond this categorical definition of PA, there exists a broad continuum of “PA pathophysiology” in resistant hypertension, providing 1 reason why MR antagonists are especially effective in this situation. Abbreviations: MR, mineralocorticoid receptor; PA, primary aldosteronism.

Figure 3.

Abysmal screening rates for PA: numerous studies from across the world have consistently shown that at best, even among high-risk populations, screening rates for PA are below 2%. This implies that much fewer than 1% of high-risk patients are ever diagnosed with PA. Abbreviation: PA, primary aldosteronism.

Figure 4.

(a) Pragmatic diagnostic approach for all clinicians. High-risk populations are those with a high pretest probability for having PA. In the context of a suppressed renin, a plasma aldosterone >15 ng/dl essentially confirms the diagnosis of overt PA and clinicians can proceed to localization or empiric MR antagonist therapy. In a high-risk patient with a suppressed renin and a very low aldosterone concentration, <5 ng/dl, PA is unlikely; however, MR antagonist therapy should still be considered as an effective treatment for low-renin hypertension. For all other high-risk patients (suppressed renin and aldosterone 5–15 ng/dl), the diagnostic mindset should be that this is “PA until proven otherwise.” Several options are available, including empiric initiation of MR antagonist therapy and dietary sodium restriction, or an aldosterone suppression test (including a 24-hour urine collection to measure aldosterone and sodium excretion) to exclude the possibility of PA or increase confidence in the diagnosis prior to pursuing localization and possible adrenalectomy. (b) Enhanced diagnostic approach for specialist clinicians. When available, specialists may opt to test high-risk populations with a suppressed renin with a 24-hour urine collection to gain a better integrated assessment of aldosterone production. This can be performed on an ad libitum diet since many patients may already be consuming sufficient dietary sodium, or after dietary sodium loading to ensure a high-sodium balance. Ideally, the desired 24-hour urinary sodium balance should be greater than 150 mEq/24 hours (reflective of a dietary intake of ~3.5 g of sodium per day). A 24-hour urinary aldosterone excretion rate of >10 mcg in this context likely confirms PA, whereas values between 6 and 10 mcg are suggestive of PA pathophysiology that is likely to still respond to targeted therapy. Twenty-four-hour urinary aldosterone excretion rates less than 6 mcg suggest PA is unlikely, but MR antagonist therapy may still be beneficial for low-renin hypertension. Abbreviations: MR, mineralocorticoid receptor; PA, primary aldosteronism.

Figure 5.

Targeting renin levels during mineralocorticoid receptor antagonist therapy. The primary objectives of MR antagonist therapy include normalization of blood pressure and potassium. Once these objectives are achieved, a rise in renin is a biomarker that is associated with lower risk for adverse cardiovascular outcomes. An unsuppressed renin activity, 1.0–2.0 ng/ml/h, is an ideal range to target; however, it is likely that any increase in renin from its baseline suppressed state is indicative of beneficial MR blockade. Excessive uptitration of MR antagonists associated with much higher renin levels may herald increased risk for hyperkalemia and/or relative hypovolemia and renal hypoperfusion. Abbreviation: MR, mineralocorticoid receptor.