The Expanding Spectrum of Primary Aldosteronism: Implications for Diagnosis, Pathogenesis, and Treatment

Abstract

Primary aldosteronism is characterized by aldosterone secretion that is independent of renin and angiotensin II and sodium status. The deleterious effects of primary aldosteronism are mediated by excessive activation of the mineralocorticoid receptor that results in the well-known consequences of volume expansion, hypertension, hypokalemia, and metabolic alkalosis, but it also increases the risk for cardiovascular and kidney disease, as well as death. For decades, the approaches to defining, diagnosing, and treating primary aldosteronism have been relatively constant and generally focused on detecting and treating the more severe presentations of the disease. However, emerging evidence suggests that the prevalence of primary aldosteronism is much greater than previously recognized, and that milder and nonclassical forms of renin-independent aldosterone secretion that impart heightened cardiovascular risk may be common. Public health efforts to prevent aldosterone-mediated end-organ disease will require improved capabilities to diagnose all forms of primary aldosteronism while optimizing the treatment approaches such that the excess risk for cardiovascular and kidney disease is adequately mitigated. In this review, we present a physiologic approach to considering the diagnosis, pathogenesis, and treatment of primary aldosteronism. We review evidence suggesting that primary aldosteronism manifests across a wide spectrum of severity, ranging from mild to overt, that correlates with cardiovascular risk. Furthermore, we review emerging evidence from genetic studies that begin to provide a theoretical explanation for the pathogenesis of primary aldosteronism and a link to its phenotypic severity spectrum and prevalence. Finally, we review human studies that provide insights into the optimal approach toward the treatment of primary aldosteronism.

Figure 1.

(a) Normal and physiologic renin-dependent aldosteronism secondary to intravascular volume depletion. In the setting of hypovolemia and renal hypoperfusion, juxtaglomerular cells secrete renin, which initiates the activation of the renin–angiotensin–aldosterone system. The generation of angiotensin II is crucial because it serves as a vasoconstrictor to maintain blood pressure and plays an important role in counteracting the volume depletion. Angiotensin II increases sodium reabsorption in the proximal convoluted tubule, loop of Henle, and distal convoluted tubule such that the delivery of sodium to the distal nephron is decreased. Angiotensin II stimulates the secretion of aldosterone from zona glomerulosa cells, which then activates the MR in principal cells. MR activation in principal cells results in ENaC-mediated sodium reabsorption and, to maintain electroneutrality in the urinary lumen, the excretion of potassium and hydrogen ions. Potassium excretion is minimized by limiting distal sodium delivery and by the direct antagonist actions of angiotensin II in the principal cell. In this manner, the net effect of this physiological renin-dependent aldosteronism is to maximize sodium reabsorption (and water is reabsorbed isotonically) to expand circulating volume while minimizing potassium excretion. Importantly, note that ACTH is also an independent secretagogue of aldosterone and stimulates the secretion of cortisol, a potent mineralocorticoid that is metabolized to the inactive cortisone by 11βHSD2. (b) Normal physiologic renin-independent aldosteronism secondary to extracellular hyperkalemia (presuming a state of replete intravascular volume status). Extracellular hyperkalemia is an independent secretagogue of aldosterone secretion. High extracellular potassium concentrations result in depolarization of zona glomerulosa cells and consequent secretion of aldosterone, which activates the MR and stimulates ENaC-mediated sodium reabsorption in the principal cell. This process is paired with potassium ion excretion. In the setting of volume expansion, angiotensin II is suppressed and proximal tubular sodium reabsorption is decreased. Thus, the delivery of sodium to the distal nephron increases and permits the excretion of more potassium. The net effect is an increased excretion of urinary potassium while minimizing the reabsorption of sodium. AngII, angiotensin II. [© 2018 Illustration ENDOCRINE SOCIETY]

Figure 2.

Comparison of sodium and potassium balance, as well as renin and aldosterone activity, between populations from industrialized societies with high dietary sodium intake vs the Yanomami tribe with low dietary sodium intake. (a) Twenty-four–hour urinary sodium excretion. (b) Twenty-four–hour urinary potassium excretion. (c) Plasma renin activity. (d) Twenty-four–hour urinary aldosterone excretion. (e) Systolic blood pressure. The yellow bars represent data from the Yanomami in the Amazon of Brazil and Venezuela [data extracted from Oliver et al. (40)]. The purple bars represent participants from studies in the United States and Europe that evaluated population level electrolyte balance and renin–angiotensin–aldosterone system parameters [data extracted from Brown et al. (41), Sun et al. (43), and Jin et al. (44)]. [© 2018 Illustration ENDOCRINE SOCIETY]

Figure 3.

Pathophysiologic renin-independent aldosteronism in primary aldosteronism. The primary problem is that one or both adrenal glands contain foci of autonomous aldosterone secretion. There is increased stimulation of the MR in principal cells, despite the fact that circulating volume is expanded and renin and angiotensin II are suppressed. This results in increased and inappropriate sodium reabsorption as well as a vicious cycle of further volume expansion and greater distal delivery of sodium. Because potassium and hydrogen ion excretion are paired with sodium reabsorption in the principal cell, these processes are also increased. The net effect is volume expansion, increases in blood pressure, hypokalemia, and metabolic alkalosis. AngII, angiotensin II. [© 2018 Illustration ENDOCRINE SOCIETY]

Figure 4.

The severity spectrum of primary aldosteronism. (A) Overt primary aldosteronism. The Endocrine Society clinical practice guidelines recommend screening for primary aldosteronism using the aldosterone-to-renin ratio in severe or resistant hypertension. This practice of screening for a high aldosterone-to-renin ratio (>20 to 30 ng/dL per ng/dL per hour in conventional units or >750 to 830 pmol/L per μg/L per hour in SI units) is highly sensitive for detecting patients with severe hypertensive primary aldosteronism, that is, those with an obvious clinical syndrome of excessive MR activation (hypertension and/or hypokalemia) who are confirmed to have biochemically overt primary aldosteronism and likely to have an APA or bilateral adrenal hyperplasia as the cause of their disease. These cases of overt primary aldosteronism have the highest risk for incident cardiovascular disease. (B) Unrecognized, yet biochemically overt primary aldosteronism. Using confirmatory testing thresholds recommended by the Endocrine Society (see Table 3), human studies have demonstrated that a substantial portion of normotensive and mild-to-moderate hypertensive persons, populations for whom primary aldosteronism screening is not routinely recommended, have unrecognized, yet biochemically overt primary aldosteronism. (C) Subclinical or nonclassical primary aldosteronism. Even below the Endocrine Society recommended thresholds of what is currently considered biochemical confirmation of primary aldosteronism, a continuum of renin-independent aldosterone secretion can be detected among healthy normotensive and moderately hypertensive persons, in whom no obvious clinical syndrome of MR overactivation is apparent. These persons have subtle biochemical evidence of renin-independent aldosteronism (renin suppression with inappropriately “normal” or high aldosterone levels) and higher risk for developing hypertension. This phenotype may best be described as subclinical or nonclassical primary aldosteronism (41). The hypothesized pathologic corollaries remain theoretical and are discussed in “What Causes Primary Aldosteronism?” One theory suggests that the newly described finding of APCCs may represent an aldosterone-secretory abnormality wherein a subset may then acquire neoplastic alterations to transform into APAs or bilateral adrenal hyperplasia. An alternative theory suggests that nonfunctional adrenocortical neoplasia may acquire secretory somatic alterations to become APAs or bilateral adrenal hyperplasia. A combination of both or neither theories may also be possible. BAH, bilateral adrenal hyperplasia; PA, primary aldosteronism. Adapted with permission from Brown JM, Robinson-Cohen C, Luque-Fernandez,MA, et al. The spectrum of subclinical primary aldosteronism and incident hypertension: A cohort study. Ann Intern Med. 2017;167(9):630–641. http://annals.org/aim/article-abstract/2657166/spectrum-subclinical-primary-aldosteronism-incident-hypertension-cohort-study ©American College of Physicians. [© 2018 Illustration Presentation ENDOCRINE SOCIETY]

Figure 5.

Proposed modifications to the diagnostic approach to detect overt and milder forms of primary aldosteronism. Biochemical screening for primary aldosteronism is generally pursued when classical indications are observed, as recommended by the Endocrine Society (97). Consideration of expanded screening indications may increase the probability of detecting more cases of primary aldosteronism. A positive screen for primary aldosteronism should suggest renin-independent aldosterone secretion, whereby aldosterone levels are relatively high in the context of a suppressed renin. In the absence of overt evidence for renin-independent aldosteronism on screening, confirmatory testing can be used to affirm the diagnosis (Table 3) (97). Failure or relative failure to suppress aldosterone on dynamic testing may confirm the diagnosis, whereas marked suppression of aldosterone may instead suggest a diagnosis of low-renin hypertension. The diagnosis of primary aldosteronism need not rely on binary thresholds, rather it may exist across a continuum of severity whereby mild and nonclassical cases may be detected as well. Solid arrows indicate recommended decision pathways; dashed arrows indicate the authors’ proposals to consider in the appropriate clinical context. BP, blood pressure. [© 2018 Illustration ENDOCRINE SOCIETY]

Figure 6.

Incident composite cardiovascular events in medically and surgically treated primary aldosteronism when compared with essential hypertension. When compared with age-matched and blood pressure–similar patients with essential hypertension, patients with primary aldosteronism treated with MR antagonists had a nearly threefold higher risk for incident cardiovascular events (myocardial infarction, stroke, heart failure hospitalization) when renin remained suppressed (82). In contrast, patients with primary aldosteronism treated with MR antagonists such that their renin increased, as well as patients with unilateral primary aldosteronism treated with surgical adrenalectomy, had no significant difference in the risk for incident cardiovascular events when compared with essential hypertension (82). Similar findings were observed with respect to the risk for atrial fibrillation (236) and death (82). Dashed lines represent unadjusted cumulative incidence curves; solid lines represent adjusted cumulative incidence curves. PRA, plasma renin activity. Adapted with permission from Hundemer GL, Curhan GC, Yozamp N, et al. Cardiometabolic outcomes and mortality in medically treated primary aldosteronism: a retrospective cohort study. Lancet Diabetes Endocrinol 2018;6(1):51–59. [© 2018 Illustration Presentation ENDOCRINE SOCIETY]

Figure 7.

Optimal medical treatment with MR antagonists in primary aldosteronism. The action of MR antagonists in the principal cell results in decreased ENaC-mediated urinary sodium reabsorption, and consequently decreased volume expansion and potassium and hydrogen ion excretion. If the effect of this action is sufficient, the contraction of the intravascular volume may result in a relative renal hypoperfusion and increased secretion of renin by juxtaglomerular cells. Thus, the rise in renin, from suppressed to unsuppressed, may serve as a biomarker of optimal MR antagonism in primary aldosteronism. AngII, angiotensin II. [© 2018 Illustration ENDOCRINE SOCIETY]

Figure 8.

Modified proposal toward the treatment of primary aldosteronism. The conventional approach to treating primary aldosteronism dictates that surgical adrenalectomy is preferred when there is unilateral disease, and lifelong MR antagonist therapy is preferred for bilateral disease. The pink boxes represent the conventional approach to treatment. The blue boxes represent the authors’ modified proposal toward treatment. Adrenal venous sampling provides results for lateralization, but it can also quantify the degree of relative autonomous aldosterone secretion from each adrenal vein. For patients with known cardiovascular or renal disease and who have grossly asymmetric bilateral primary aldosteronism, unilateral adrenalectomy to attenuate the severity of disease may be considered. When lifelong MR antagonist therapy is employed, the objective is to normalize blood pressure and potassium, and when possible, titrate the dose of the medication to achieve a rise in renin as a biomarker for sufficient MR blockade. When blood pressure or potassium cannot be effectively normalized with MR antagonist therapy, or chronic kidney disease limits the aggressiveness with which these medications can be used, unilateral adrenalectomy and/or additional antihypertensives could be considered. BP, blood pressure. [© 2018 Illustration ENDOCRINE SOCIETY]