Primary Aldosteronism Prevalence – An Unfolding Story

Abstract

Primary aldosteronism (PA) is characterized by dysregulated, renin-independent aldosterone excess. Long perceived as rare, PA has emerged as one of the most common causes of secondary hypertension. Failure to recognize and treat PA results in cardiovascular and renal complications, through processes mediated by both direct target tissue insults and indirectly, by hypertension. PA spans a continuum of dysregulated aldosterone secretion, which is typically recognized in late stages after treatment-resistant hypertension and cardiovascular and/or renal complications develop. Determining the precise disease burden remains challenging due to heterogeneity in testing, arbitrary thresholds, and populations studied. This review summarizes the reports on PA prevalence among the general population and in specific high-risk subgroups, highlighting the impact of rigid versus permissive criteria on PA prevalence perception.

Key words

primary aldosteronism - hypertension - aldosterone - adrenal

Introduction

Primary aldosteronism (PA) is a disorder of dysregulated aldosterone production that occurs independently from the physiological renin-angiotensin system. PA is a common and modifiable cause of secondary hypertension [1]. Compared with equivalent primary hypertension, PA has been associated with a disproportionately greater risk of cardiovascular, metabolic, and renal complications [2] [3] [4] [5] [6] [7], mediated via inappropriate mineralocorticoid receptor (MR) activation within target tissues. Directed therapies, such as unilateral adrenalectomy or MR antagonists, have been shown to mitigate unfavorable outcomes in patients with PA [3] [8] [9] [10] [11]. While determining the true prevalence of PA hinges on a number of variables, such as the population studied, clinical setting, tests, and criteria used to define PA [12] [13] [14] [15] [16], compelling evidence suggests that PA spans a spectrum of severity, of which only the very late stages are typically recognized. In this review, we discuss the reported frequency of PA across its pathophysiological spectrum and various populations at risk.

The evolving definition of primary aldosteronism

In 1955, Dr. Jerome Conn published his clinical journey to solving the first documented case of PA in a 34-year-old woman with severe hypertension, profound hypokalemia, metabolic alkalosis, and intermittent tetany, which resolved after unilateral adrenalectomy [17]. Although hypokalemia and metabolic alkalosis became hallmarks of PA, Dr. Conn acknowledged that such findings only capture the most severe forms of the disease. Moreover, as his expertise in PA evolved, Dr. Conn correctly anticipated that most patients with PA have normokalemic hypertension [18] and that the pathophysiology of PA might emerge in normotensive stages prior to clinically advanced manifestations [19] [20]. In the years that followed, numerous studies revealed the presence of autonomous aldosterone production among both hypertensive and normotensive individuals, supporting a broad spectrum of PA severity [21] [22] [23] [24]. Following the introduction of the aldosterone-to-renin ratio (ARR) as a screening tool for PA in 1981, however, this initial paradigm of a PA severity continuum shifted towards a more pragmatic, binary disease classification [25]. Although intended to help standardize the diagnostic process, the diagnostic criteria for both ARR and the subsequently implemented confirmatory tests have been arbitrary and heterogeneous. An ARR of≥30 (ng/dL)/(ng/mL/h), along with a plasma aldosterone concentration≥15 ng/dL, constitute the most conservative criteria for a positive PA screening test [12]. Less stringent criteria increase the detection rates of both advanced and mild forms of PA [26] [27] [28] [29]. Two recent systematic reviews of ARR testing found that the clinical performance of ARR varied widely with the patient population, clinical setting, and thresholds used, rendering sensitivities from 10% to 100% [30] [31].

Considering the dynamic fluctuations of renin and aldosterone in response to a large number of determinants [32] [33] [34], the current Endocrine Society guideline proposes confirmatory testing in most patients with positive screening results to solidify the PA diagnosis [12]. Notably, however, PA has been diagnosed in individuals with ARR values lower than the commonly used threshold for PA, indicating the limitations of arbitrary screening criteria in capturing the broad continuum of inappropriate aldosterone production. Using fludrocortisone-dexamethasone suppression tests, Markou et al. diagnosed PA in 13 of 100 normotensive women, regardless of baseline plasma aldosterone or ARR values, and 11 of these women developed hypertension within five years, supporting an incipient PA pathophysiology stage in these participants [35]. In a similar study, elevated 24-h urine aldosterone excretion suggestive of PA was found following oral sodium loading in a substantial number of individuals across the entire blood pressure spectrum, including in individuals with ARR considered normal [36]. Nevertheless, the definition of inappropriate aldosterone production relies, yet again, on arbitrary thresholds for each confirmation test. Variability in diagnostic tests and criteria explains inconsistencies in the reported prevalence of PA, which varied from 3.2% to 12.7% in the primary care setting, and from 1% to 29.8% in referral centers [37].

Beyond the heterogeneity of the diagnostic tests, PA prevalence reports also differ across various populations. Generally, the risk of PA is highest in patients with severe hypertension, and hypertension and hypokalemia. High PA prevalence has also been reported in individuals with hypertension and adrenal nodules, obstructive sleep apnea (OSA), or a family history of PA, and several expert guidelines recommended PA screening in these populations [12] [38] [39] [40].

The reported prevalence of overt primary aldosteronism in treatment-resistant hypertension

Although reports of PA prevalence among patients with hypertension have been heterogeneous due to the vast differences in PA definition between studies, findings consistently suggest that PA prevalence increases in parallel with hypertension severity, ranging from 11–22% in the individual with treatment-resistant hypertension ([Table 1]) [14] [27] [36] [41] [42] [43] [44] [45] [46]. On average, only under 3–4% of individuals with treatment-resistant hypertension are screened for PA [14] [16] [47] [48]. When conducted, PA screening usually targets patients with multiple risk factors and those who have already developed cardiovascular and renal complications [47]. Physicians with secondary hypertension expertise, including endocrinologists and nephrologists, who typically also perform confirmatory testing and oversee the management of PA, are more likely to consider and screen for PA than primary care providers [48]. As very few patients with hypertension are referred to specialists, the true prevalence of PA across hypertension stages in the general population remains uncertain. In a meta-analysis of 39 studies of adults with hypertension, the weighted mean prevalence of overt PA was 5.5% for high-normal blood pressure, 4.2% for stage 1-, 10.2% for stage 2-, and 16.4% for stage 3 hypertension [37].

Table 1 Studies of overt primary aldosteronism prevalence across the blood pressure spectrum.

Reference	Criteria	Study population	Prevalence of overt PA
Calhoun 2002 [41]	PRA<1 ng/mL/h AND Positive oral sodium suppression test	Resistant hypertension	20%
Mosso 2003 [42]	ARR>25 (ng/dL)/(ng/mL/h) AND Positive fludrocortisone suppression test	Hypertension (overall)	6.10%
		Stage 1 hypertension	2%
		Stage 2 hypertension	8%
		Stage 3 hypertension	13.20%
Rossi 2006 [43]	ARR≥40 (ng/dL)/(ng/mL/h) AND Positive captopril challenge test and/or LDF score#≥0.5	Hypertension (overall)	11.20%
		Stage 1 hypertension	6.60%
		Stage 2 hypertension	15.50%
		Stage 3 hypertension	19%
Douma 2008 [44]	ARR>20 (ng/dL)/(ng/mL/h)* with ALD>15 ng/dL* AND Positive saline and fludrocortisone suppression test AND Responsive to spironolactone	Resistant hypertension	11.30%
Ito 2011 [49]	ARR>20 (ng/dL)/(ng/mL/h) AND Positive captopril challenge test	Prehypertension	6.80%
		Stage 1 hypertension	3.30%
Markou 2013 [35]	Positive fludrocortisone-dexamethasone suppression test	Normotension	13%
Galati 2016 [45]	ARR>20 (ng/dL)/(ng/mL/h) with ALD>10 ng/dL with PRA<1 ng/mL/h	Hypertension (overall)	4.70%
		Resistant hypertension	10.50%
Monticone 2017 [27]	ARR>30 (ng/dL)/(ng/mL/h) with ALD>10 ng/dL AND Positive saline infusion or captopril challenge test	Hypertension (overall)	5.90%
		Stage 1 hypertension	3.90%
		Stage 2 hypertension	9.70%
		Stage 3 hypertension	11.80%
Brown 2020 [36]	Positive oral sodium suppression test with post-test urine ALD≥12 µg/day	Normotension	11.30%
		Stage 1 hypertension	15.70%
		Stage 2 hypertension	21.60%
		Stage 3 hypertension	22%
Xu 2021 [46]	ARR≥30 (ng/dL)/(ng/mL/h)* with ALD>10 ng/dL AND Positive saline infusion or captopril challenge test	Hypertension (overall)	3.30%
		Stage 1 hypertension	0.70%
		Stage 2 hypertension	3.40%
		Stage 3 hypertension	12.60%
Zekarias 2022 [14]	ARR≥30 (ng/dL)/(ng/mL/h) with ALD≥10 ng/dL	Resistant hypertension	16.90%

^#Logistic discriminant function (LDF) score was described elsewhere. [97]; ^*ARR or ALD values have been converted to common units of measurement for ease of comparison.; Abbreviation; ARR, aldosterone-renin-ratio; ALD, aldosterone; PA, primary aldosteronism; PRA, plasma renin activity; LDF, logistic discriminant function.

The reported prevalence of overt primary aldosteronism in normotension and mild hypertension

Current guideline-directed PA screening may overlook milder cases of autonomous aldosterone production in the pathophysiological continuum of PA, which results in an underestimation of its prevalence among individuals with mild hypertension. Ito and colleagues performed systematic screening of PA during annual health examinations in adults without hypertension and found that 22.7% of prehypertensive subjects (BP 120–139/80–89 mmHg) had a positive ARR screening, and 6.8% had confirmed PA with captopril suppression test [49]. Other observational studies have provided evidence for PA in a subset of individuals with normal or mildly elevated blood pressure ([Table 1]). Importantly, these unrecognized yet biochemically overt PA forms have been linked to unfavorable outcomes. During a four-year observation period in the Framingham Offspring Study, normotensive participants with higher aldosterone levels were more likely to develop incident and worsening hypertension [50]. Similar studies revealed that normotensive participants with suppressed plasma renin activity had a significantly higher risk of developing incident hypertension when compared with those without suppressed renin [51] [52]. These results indirectly suggest that early detection of autonomous aldosterone secretion and targeted therapeutic measures might mitigate cardiovascular complications mediated by inappropriate MR activation. However, the paucity of data on the cost-effectiveness of early screening and directed therapy make strategic interventions of uncertain value in early hypertension stages.

The reported prevalence of overt primary aldosteronism in patients with hypokalemia

Numerous reports have assessed the prevalence of hypokalemia in patients with overt PA. In a meta-analysis of 39 observational studies, hypokalemia was presented in 0–37.5% of patients with PA seen in primary care and 0–67% of those from referral centers [37], with the highest proportion in patients with aldosterone-producing adenoma [43], In contrast, the prevalence of PA among individuals with hypertension and hypokalemia has been poorly studied. Burrello and colleagues [53] retrospectively reviewed the medical records of 840 hypertensive patients with at least a single episode of hypokalemia (potassium level<3.7 mmol/L) and found that the rates of overt PA increased with the decreasing serum potassium levels. Overt PA was diagnosed in 28.1% of the overall cohort and in 88.5% of patients with severe hypokalemia (potassium level<2.5 mmol/L). Additionally, patients with spontaneous hypokalemia had overt PA more often than those with diuretic-induced hypokalemia (37.4% versus 16.5%, respectively) [53].

Hypokalemia was previously viewed as a hallmark of advanced PA [12]. Several reports, however, present normotensive patients diagnosed with hypokalemia prior to recognized PA [54] [55] [56] [57]. The mechanism underlying this entity is poorly understood. High vascular compliance, and an adaptative increase in renal sodium excretion in response to aldosterone excess, to maintain normal blood pressure, have been proposed as possible mechanisms [57]. Since PA has not been systematically screened in patients with isolated hypokalemia without hypertension, the prevalence of normotensive hypokalemic PA remains unknown.

The reported prevalence of overt primary aldosteronism in patients with adrenal incidentaloma

In observational studies of patients with adrenal incidentaloma, the reported prevalence of overt PA ranges between 1 and 30%, depending on the study design and the applied diagnostic criteria ([Table 2]) [58] [59] [60] [61] [62] [63] [64] [65] [66] [67]. Although overt PA is more frequently found in patients with adrenal incidentaloma and hypertension than in normotensives [12] [68] [69] [70], it should be emphasized that adrenal incidentalomas are not always the source of aldosterone. Several studies have found high discrepancy rates between imaging findings and adrenal vein sampling (AVS) results [71] [72] [73]. Moreover, immunohistochemistry targeting aldosterone synthase (CYP11B2) has demonstrated that macroscopic nodules do not always produce aldosterone [74]. Conversely, microscopic CYP11B2-positive areas are not uncommon in patients with overt PA, including when cross-sectional imaging detects no adrenal abnormalities [75] [76].

Table 2 Studies of overt primary aldosteronism prevalence in patients with adrenal incidentaloma.

Reference	Criteria	Study population	Prevalence of overt PA
Mantero 2000 [58]	ARR elevation and suppressed PRA	Adrenal incidentaloma with exclusion of severe hypertension and hypokalemia	1.6% (all were hypertensive)
Bernini 2002 [59]	ARR>20 (ng/dL)/(ng/mL/h)* AND Positive saline suppression or captopril challenge test	Adrenal incidentaloma with exclusion of hypokalemia	4% (all were hypertensive), 5.5% of hypertensive patients
Kim 2005 [60]	Not specified	Adrenal incidentaloma	10% (all were hypertensive), 25% of hypertensive patients
Comlekci 2010 [61]	ARR>25 (ng/dL)/(ng/mL/h) AND Positive saline Suppression test	Adrenal incidentaloma with hypertension	4.4%
Kim 2013 [62]	ARR>20 (ng/dL)/(ng/mL/h)	Adrenal incidentaloma	4.6%
Patrova 2015 [63]	ARR (not specified threshold)	Adrenal incidentaloma with hypertension	1.4%
Tabuchi 2016 [64]	ARR>20 (ng/dL)/(ng/mL/h) AND Positive one of the confirmation tests	Adrenal incidentaloma	10.7% (93.3% were hypertensive)
Stavropoulos 2018 [65]	Positive saline suppression test with post-test ALD≥6 ng/dL	Adrenal incidentaloma	3.35% (all were hypertensive)
Jing 2022 [66]	ARR (not specified threshold) AND Positive saline suppression or captopril challenge test	Adrenal incidentaloma	11.8% (76% were hypertensive and 12% were hypokalemia), 23.2% of hypertensive patients, 75% of hypokalemia patients
Kmieć 2022 [67]	ARR>20 (ng/dL)/(ng/mL/h)* with ALD>4 ng/dL	Adrenal incidentaloma with exclusion of overt PA	25.4% (56.3% were hypertensive) 24.3% of hypertensive patients

^*ARR or ALD values have been converted to common units of measurement for ease of comparison.; Abbreviation; ARR, aldosterone-renin-ratio; ALD, aldosterone; PRA, plasma renin activity; PA, primary aldosteronism.

An unresolved question regarding the evaluation of adrenal incidentaloma is whether we should screen for autonomous aldosterone production in patients who do not have hypertension. It has been suggested that biochemically overt PA is not rare in patients with adrenal incidentaloma and normal blood pressure [77] [78]. Kmieć and colleagues conducted a prospective study attempting to detect subclinical autonomous aldosterone secretion in patients with adrenal incidentaloma by using permissive criteria of ARR>1.2 (ng/dL)/(mIU/L) (approximately 10 (ng/dL)/(ng/mL/h)) and plasma aldosterone concentration>4 ng/dL. Normotensive patients with urine aldosterone excretion>10 µg/day were considered to have mild autonomous aldosterone secretion, while hypertensive patients with urine aldosterone>12 µg/day were diagnosed with overt PA. Overall, 25.4% of individuals with adrenal incidentaloma were found to have mild autonomous aldosterone secretion (24.3% among hypertensive and 26.9% in normotensive participants) [67].

The reported prevalence of overt primary aldosteronism in patients with obstructive sleep apnea

The pathophysiology of OSA has been associated with alterations in the renin-angiotensin-aldosterone system [79]. Studies in animal models suggest that intermittent hypoxia and acute hypercapnia, as observed in OSA, are linked to elevated plasma aldosterone, independently of plasma renin activity [80]. Nonetheless, whether these changes contributed to a higher prevalence of overt PA in patients with OSA remains debatable ([Table 3]). In an Italian study of individuals newly diagnosed with hypertension, patients with OSA confirmed with polysomnography had a much greater prevalence of overt PA (34%) than those without OSA (9.8%) [81]. Another single-center study in Poland showed a 21.3% PA prevalence in 94 patients with hypertension and moderate to severe OSA [82]. In contrast, a substantially lower prevalence of overt PA (8.9%) was reported in the HYPNOS trial, a multi-ethnic cohort study of 203 patients with OSA [83], suggesting that the prevalence of biochemically overt PA among individuals with OSA is comparable to other difficult-to-control hypertensive populations, questioning the current Endocrine Society recommendation to screen patients with OSA for PA. An important caveat of the HYPNOS trial, however, is the heterogeneity of laboratory assays and confirmatory tests used across the seven participating centers from four countries. In addition, the Apnea-Hypopnea Index employed in the HYPNOS trial was derived from cardiorespiratory polygraphy, which is not the gold standard for OSA diagnosis [84]. In an Australian study, only 2 (5%) of 40 participants with OSA and hypertension were identified to have "likely PA" based on ARR. Additionally, 30% of patients were thought to have "possible PA" based on low renin and normal ARR in the context of interfering medications [85]. Nevertheless, Chomsky et al. estimated that screening for PA in patients with OSA remains cost-effective even if it detects only 3% of new PA cases [86]. Therefore, in light of the currently available evidence, the recommendation to screen for PA in patients with OSA is still reasonable. Further studies with standardized protocols are required to characterize the association between PA and OSA.

Table 3 Studies of overt primary aldosteronism prevalence in patients with obstructive sleep apnea (OSA) and hypertension.

Reference	Criteria	Study population	Prevalence of overt PA
Di Murro 2010 [81]	ARR>40 (ng/dL)/(ng/mL/h) with ALD>15 ng/dL with a suppressed renin	Hypertension with and without OSA	34% in OSA, 9.8% in non-OSA
Buffolo 2019 [83]	According to the Endocrine Society guideline	Hypertension with OSA	8.9%
Dobrowolski 2021 [82]	Positive saline suppression test with post-test ALD>10 ng/dL	Hypertension with and without moderate to severe OSA	21.3% in moderate to severe OSA, 8% in non-moderate to severe OSA
Chee 2021 [85]	ARR>20 (ng/dL)/(ng/mL/h)* or renin is suppressed or low, together with an adrenal adenoma	Hypertension with OSA	Likely PA; 5%, Possible PA; 30%

^*ARR or ALD values have been converted to common units of measurement for ease of comparison.; Abbreviation; ARR, aldosterone-renin-ratio; ALD, aldosterone; OSA, obstructive sleep apnea; PA, primary aldosteronism.

The reported prevalence of overt primary aldosteronism in young adults with hypertension

Secondary hypertension should be considered in individuals with early-onset hypertension [87]. PA testing, however, is not recommended routinely in young adults [12] [88]. As such, data on the prevalence of overt PA in young adults are scarce. A prospective observational study conducted in India among adults under age 40 at hypertension onset revealed that 18.8% of participants had positive ARR screening results, and 17.8% overt PA was confirmed by saline suppression test. The recorded prevalence of overt PA was highest in people with hypertension onset at 30–39 years [89]. A 10-year delay between the initial hypertension diagnosis and PA confirmation was noted, suggesting that PA screening should be conducted in patients with early-onset hypertension.

Other conditions associated with primary aldosteronism

Atrial fibrillation has emerged as one of the cardiovascular complications associated with PA. A meta-analysis found atrial fibrillation to be 3.52 times more likely in patients with overt PA than in those with primary hypertension [2]. Nguyen and colleagues performed PA testing among 300 consecutive patients with hemorrhagic or ischemic stroke and found overt PA in 30% of patients with hypertension and atrial fibrillation, compared to 11.1% in the subgroup with treatment-resistant hypertension and 13.3% in those with hypertension and hypokalemia [90]. Another observational study found that overt PA was highly prevalent (42.5%) in participants with atrial fibrillation and no other identifiable causes of arrhythmia, such as structural heart defect or coronary artery disease, suggesting that overt PA might have led to atrial fibrillation in these patients [91]. Current guidelines do not yet endorse screening for PA in patients with atrial fibrillation [12] [38]. Stroke [92] [93], diabetes mellitus [94] [95], and obesity [96] are other disorders associated with overt PA. Further epidemiologic and mechanistic studies are needed to understand these associations prior to expanding PA screening recommendations.

Conclusions

With our expanding understanding of PA pathophysiology and associated multi-system burden, the definition of PA has evolved, to include earlier stages of dysregulated aldosterone production. In parallel, timely testing for overt PA in at-risk populations is likely to uncover various degrees of renin-independent aldosterone excess at even higher than currently recognized rates. Initiatives to increase awareness of the clinical relevance of PA, to define PA across its continuum, and to develop decision algorithms, among others, would encourage the busy clinician to consider PA as a common cause of hypertension.

Funding Information

Doris Duke Charitable Foundation — http://dx.doi.org/10. 13039/100000862; 2019087 National Heart, Lung, and Blood Institute — http://dx.doi. org/10.13039/100000050; 1R01HL15583401

Sources of Funding

AFT was supported by grants 2019087 from the Doris Duke Charitable Foundation; and 1R01HL15583401 from the National Heart, Lung, and Blood Institute.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Publication History

Received: 30 January 2023
Received: 09 March 2023

Accepted: 27 March 2023

Accepted Manuscript online:
30 March 2023

Article published online:
31 May 2023