Normotensive Primary Aldosteronism – Does it Exist?

Abstract

Heightened aldosterone levels are associated with increased risk of renal sequelae, cardiovascular morbidity and mortality. Historically, primary aldosteronism is linked to hypertension. However, growing evidence reveals its presence even in normotensive individuals. This review consolidates data from diverse sources, delves into clinical studies of this underexplored condition, discusses the potential mechanisms, and provides a comprehensive and an up-to-date overview of the current state of knowledge. It highlights the evidence and understanding of normotensive primary aldosteronism, summarizes findings, and identifies opportunities for future research in this area. By addressing the clinical evidence, risk of hypertension development and possible mechanisms involved, this review aims to advance the understanding of this distinct form of primary aldosteronism and inspire further research in this emerging field.

Keywords

hyperaldosteronism - RAAS - normotension - aldosterone-producing cell cluster - subclinical hyperaldosteronism

Introduction

Primary aldosteronism (PA) is increasingly known as the most common cause of secondary hypertension, accounting for up to 20% among patients with resistant hypertension [1]. Traditionally, it has been associated with hypertension and spontaneous hypokalemia, characterized by elevated aldosterone and suppressed renin. However, most patients with PA present with normokalemia. Elevated aldosterone has been demonstrated to be deleterious as it induces inflammation and increases oxidative stress, resulting in a multitude of cardio-metabolic disorders [2] [3] [4], ultimately leading to increased cardiovascular morbidity and mortality [5]. The Endocrine Society guidelines recommend screening for PA in individuals with high likelihood of this disorder, such as those with sustained blood pressure (BP) above 150/100 mmHg, drug-resistant hypertension, and hypertension accompanied by hypokalemia or adrenal incidentaloma [6]. From these criteria, hypertension appears to be a hallmark of PA, and the absence of hypertension is often thought to negate the need for PA screening.

Nevertheless, since the first description of normotensive PA in 1972 [7], several cases have been reported, challenging the traditional understanding that PA is exclusive to hypertensive individuals. While current guidelines advise screening for PA in patients with sustained BP above 150/100 mmHg, emerging evidence indicates that PA can occur even in patients with stage 1 hypertension and in normotensive individuals.

This condition has predominantly been reported among middle-aged Eurasians and Japanese females [8]. Given that patients with elevated aldosterone levels are at a higher risk of cardiovascular, metabolic, and renal complications compared to those with essential hypertension of similar severity, normotensive PA becomes an interesting entity, suggesting a potential continuous spectrum of autonomous aldosterone secretion and mineralocorticoid activity, spanning from normotensive to overtly hypertensive. Hence, this review aims to explore the evolving landscape of PA, offering insights into the mechanisms underlying this condition and its clinical implications.

Clinical evidence of normotensive PA

In a retrospective review of 10 normotensive patients with PA, all were hypokalemic females, and 7 had adrenal masses [9]. Compared to 168 hypertensive PA patients, the normotensive group had lower potassium levels and body mass index, as well as larger adenomas. There was no difference in serum aldosterone, plasma renin activity (PRA), or aldosterone-renin-ratio (ARR) between the two groups, whether in a supine or upright position. It is important to note that serum sodium levels were within the high normal range, and urine sodium excretion was also within the normal range in the normotensive PA patients. This effectively rules out any false elevation of aldosterone due to sodium depletion in these individuals. Five normotensive patients with adrenal adenomas underwent adrenalectomy and experienced lower BP within 2–10 months post-surgery, along with normalization of serum potassium, aldosterone, and renin levels. Aldosterone synthase (CYP11β2) expression was detected in 4 out of the 5 adrenal tumors, confirming PA. Although the confirmatory testing for PA was not performed per international guidelines, the findings of autonomous aldosterone secretion and normalization of parameters post-adrenalectomy suggest a continuum spectrum of renin-independent aldosterone secretion of PA.

Braudand et al. reported that, among 210 normotensive participants with PRA<1 ng/ml/h on a liberalized sodium diet, 14% (n=29) demonstrated autonomous aldosterone secretion following an oral sodium suppression test [10]. Among these, 21% had ARR≥20, higher 24-hour urinary aldosterone and potassium excretion, lower 24-hour urinary sodium-to-potassium excretion ratio, higher aldosterone secretion in response to angiotensin II (Ang II) infusion, and lower stimulated PRA on sodium restriction. With the controlled intakes of sodium, the study was able to effectively eliminate the potential confounding effects of sodium levels on aldosterone measurements, hence maintaining the accuracy and reliability of the diagnosis of normotensive PA. The study findings suggest that normotensive individuals with dysregulated aldosterone secretion could be at risk for PA.

Similarly, Brown et al. demonstrated that 41.8% (n=289) of their 691 participants with suppressed renin activity were normotensive [11]. The prevalence of biochemically overt PA in this cohort was 11.3%. Besides, the aldosterone production in these participants followed a continuum that paralleled the severity of hypertension. Nevertheless, the measurements of sodium in these patients were performed several years before the analysis of renin and aldosterone. Over such a period, variations in sodium balance or dietary intake could have potentially influenced aldosterone secretion.

In a Japanese population study of 195 participants over the age of 40 and not on anti-hypertensive treatment, 34.9% of them were noted to have ARR level of>20, of which 32.4% were normotensive (BP<130/85 mmHg) and 17.6% were pre-hypertensive (BP 130 to 139/85 to 89 mmHg) [12] ([Table 1]). Although sodium measurements were not performed, the patients were advised to maintain an average dietary salt intake for the Asian population above 11 g per day, which was sufficient for accurate confirmatory suppression tests. PA was confirmed in several cases through captopril challenge test performed among 14 participants with ARR>20, of which all were females. Subsequently, when this condition was screened among 292 patients with pre-hypertension (defined as BP 120–139/80–89 mmHg), stages 1 and 2 hypertension, 22.7% of those with pre-hypertension (n=44) were noted to have elevated ARR level [8]. Among these patients, 3 out of 5 participants were confirmed to have PA via captopril challenge test, all 3 of which had adrenal swelling/nodule. Adrenal vein sampling confirmed 2 with lateralization of aldosterone overproduction to one side of the adrenal gland. Both patients who underwent adrenalectomy exhibited notable improvement in BP 1–2 years following surgery, further substantiating the diagnosis of PA. Based on these observed findings the authors deduced that the minimum prevalence of PA in the general population is 2.6%, with 6.8% prevalence in the pre-hypertensive group [8] [12]. The studies reporting prevalence of PA in normotensive individuals is summarized in [Table 1].

Table 1 Prevalence of PA among normotensive individuals.

Author/Year [Ref]	Country	Cohort (n)+definition	Demography	Study design	Confirmatory test of PA and cut-offs	Prevalence of PA	Other findings
Medeau 2008 [9]	France	10 normotensive SBP<140 mmHg+DBP<90 mmHg and/or mean BP on ABPM<125/80 mmHg or mean BP on diurnal ABPM<135/85 mmHg, with no anti-hypertensive	Mean age 47.1, all females	Retro-spective	Supine PAC>500 pmol/l, or upright PAC>750 pmol/l, or urinary aldosterone>63 nmol/24 h with supine or upright plasma aldosterone:active renin ratio>64 pmol/mUI×2, or plasma aldosterone:plasma renin activity>750 pmol/ng/ml/h	–	Hypokalemia found in all normotensives, 7 found to have adrenal mass. BP lowered after adrenalectomy. Aldosterone synthase expression detected in 4/5 of adrenal tumours of normotensives
Ito 2011 [8]	Japan	44 prehypertensive BP 120–139/80–89 mmHg	Mean age 50.1	Cross-sectional	Captopril suppression test ARR>20 AVS performed	60%	AVS lateralized to one adrenal gland in 2 patients. BP reduced in both patients, post-adrenalectomy
Baudrand 2017 [10]	USA, France, Italy	210 normotensive BP<140/90 mmHg with suppressed PRA on liberalized sodium intake, no first degree relative with hypertension before age 60 years	Mean age 40.4, 47% females	Cross-sectional	Oral sodium suppression test. Urinary aldosterone excretion rate>12 μg/24 h with urinary sodium excretion>200 mmol/24 h	14%	Normotensive PA had higher 24 h urinary AER and Ang II-stimulated aldosterone, lower 24 h urinary sodium-to-potassium excretion and stimulated PRA on sodium restriction compared to non-PA
Brown 2020 [11]	USA	289 normotensive SBP 120–135 mmHg+DBP 75–85 mmHg+first degree relative with HPT before age 60 years	Mean age 41, 50.9% females	Cross-sectional	Oral sodium suppression test. Urinary aldosterone excretion rate>12 μg/24 h	11.3%	Every BP category had continuum of renin-independent aldosterone production, greater severity of production associated with higher BP, kaliuresis and lower serum potassium
Karashima 2017 [12]	Japan	79 normotensive SBP<130 mmHg+DBP<85 mmHg 34 prehypertensive BP 130–139/80–89 mmHg	Mean age 62, 63.2% females	Cross-sectional	Captopril suppression test ARR>20	33.3% of normo-tensives	Females had significant differences in ARR between those with age<50 and those aged 51–60

PA: Primary aldosteronism; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; ABPM: Ambulatory blood pressure monitoring; PAC: Plasma aldosterone concentration; BMI: Body mass index; ARR: Aldosterone renin ratio; AVS: Adrenal vein sampling; PRA: Plasma renin activity; AER: Aldosterone excretion rate; Ang II: Angiotensin II; HPT: Hypertension.

Development of hypertension

The Framingham Offspring Study followed 1688 normotensive participants (58% females, mean age 55 years) over four years [13] ([Table 2]). A total of 14.8% of the cohort developed hypertension at 4-year follow up. Each quartile increase in aldosterone levels was associated with 16% higher risk of BP elevation and a 17% higher risk of hypertension. In comparison to the lowest quartile of serum aldosterone level, the highest quartile was associated with 1.6-fold increased risk of BP elevation and 1.61-fold increased risk of hypertension. There were two other similar studies following the Framingham Offspring Study as described below.

Table 2 Risk of hypertension among normotensive PA/dysregulated RAAS.

Study [Ref]	Cohort	Definition	Diagnosis of PA/dysregulated RAAS	Follow up	Findings
Vasan 2004 [13]	1688 normotensives, 58% females	SBP<140 mmHg+DBP<90 mmHg	NA	4 years	Increase in BP category in 33.6%, HPT developed in 14.8%. 16% increase in risk of BP elevation, 17% increase in risk of HPT per quartile increment in serum aldosterone. Highest serum aldosterone quartile associated with 1.6×risk of elevation in BP and 1.61×risk of developing HPT compared to the lowest quartile
Markou 2013 [14]	100 normotensives (mean age 53, 80% females) with no adrenal mass on CT, suppressed ACTH, cortisol, aldosterone and renin post-FDST	SBP<135 mmHg+DBP<85 mmHg at least 3 consecutive visits	Post-FDST ARR>0.93 ng/dl/μU/ml+post-FDST aldosterone>2.96 ng/dl	5 years	31 developed hypertension (11 had PA), 69 remained normotensive (2 had PA). Positive relation of PA, negative relation of serum potassium with development of HPT
Brown 2017 [16]	850 normotensives	SBP<140 mmHg+DBP<90 mmHg, no anti-hypertensive	PRA≤0.5 μg/l/h as suppressed renin phenotype	10 years	46% had suppressed renin phenotype: older, more women and African Americans, higher SBP, higher incidence of HPT. An 18% higher risk for incident HPT per 100 pmol/l aldosterone when PRA≤0.5 μg/l/h

PA: Primary aldosteronism; RAAS: Renin angiotensin aldosterone system; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; NA: Not available; HPT: Hypertension; CT: Computed tomography; ACTH: Adrenocorticotropic hormone; FDST: Fludrocortisone-dexamethasone suppression test; ARR: Aldosterone renin ratio; PRA: Plasma renin activity.

A total of 100 participants who were normotensive with normal CT adrenal were evaluated before and after fludrocortisone-dexamethasone suppression test (FDST) and were subsequently followed up for 5 years to assess incidence of hypertension [14]. The addition of dexamethasone was to eliminate the stimulatory input of ACTH on aldosterone secretion as ACTH can significantly affect the production of aldosterone [15]. At the 5-year follow up, 31 participants developed hypertension, of which 11 were diagnosed as PA. In comparison, out of the 69 participants who remained normotensive, 2 were diagnosed with PA. This is despite comparable risk factors of developing hypertension between the two groups. It was also noted that the baseline renin level was significantly lower, aldosterone and ARR levels post-FDST were significantly higher among the 11 participants who were subsequently diagnosed with PA compared to those who developed hypertension without PA at 5 years. These findings support the hypothesis that normotensive individuals with dysregulated renin-angiotensin-aldosterone system (RAAS) are at risk of developing hypertension.

In another community-based study (Multi-Ethnic Study of Atherosclerosis), 850 normotensive participants were evaluated with measurements of serum aldosterone and PRA, then followed up for a total of 10 years to establish incidence of hypertension [16]. It was noted that 46% of the participants who demonstrated suppressed renin level were older, comprised of more women and African Americans with higher systolic BP. Although these participants had lower serum aldosterone compared to participants with higher renin activity, the former had highest ARR due to suppressed renin levels. This group of participants also had the highest incidence and risk of hypertension, with 85.4 cases per 1000 person-years of follow up and adjusted hazard ratio of 1.68 respectively. Interestingly, higher serum aldosterone levels were associated with lower serum potassium level within the normal range and higher urinary fractional excretion of potassium only among participants with suppressed renin phenotype. The studies which demonstrated development of hypertension in normotensive individuals with dysregulated aldosterone secretion are summarized in [Table 2].

Possible mechanisms

• Aldosterone-producing cell cluster (APCC)

  Aldosterone-producing cell cluster (APCC) may represent one of the underlying mechanisms contributing to the development of normotensive PA. APCC was first described in 2010 [17] and have been found in over two-thirds of normal adrenal glands, with greater APCC content among older individuals [18]. These clusters express CYP11β2, and are found below the adrenal capsule, protruding into the cortisol-producing zona fasciculata which CYP11β2 expression is not typically seen [17]. In comparison to non-functioning adrenal adenoma, APCC was demonstrated to be highly similar to zona glomerulosa cells and found to harbor somatic mutations known to stimulate expression of CYP11β2, which is responsible for production of aldosterone [19]. However, compared to the conventional zona glomerulosa cells that express CYP11β2 sporadically under the influence of RAAS, APCC expresses CYP11β2 remarkably even in conditions with suppressed RAAS [20]. Unlike aldosterone-producing adenoma (APA) which is characterized by pronounced autonomous aldosterone excess, APCC is more likely to exhibit a phenotype of mild autonomous aldosterone secretion [21]. The newly developed APCC is hypothesized to produce aldosterone under RAAS regulation, but aged APCC could undergo mutation leading to formation of APA with autonomous aldosterone secretion [18]. This progression highlights a plausible mechanism by which APCCs could contribute to aldosterone excess in normotensive individuals, providing a pathway for the development of normotensive PA. Nevertheless, it is essential to point out that to date, APCCs have been identified through postmortem specimens only.

  Despite low renin levels in APA, the APCC, which is adjacent to APA, continued to produce aldosterone, suggesting the role of APCC in autonomous, renin-independent aldosterone production [17]. As the APCC mutation spectrum of aldosterone driver mutations is different from that in APA, the authors suggested the possibility of APCC-to-APA transitional lesions and APCC being a precursor which might subsequently develop into PA [22]. When APCCs are large or exist in a large number, they may be responsible for idiopathic hyperaldosteronism (IHA) [23]. The APCC score was noted to be higher in adrenal glands of women [22] although there is no known gender difference in the prevalence of APA [24] [25] [26]. Whether or not this is related to the higher percentage of women with suppressed renin is yet to be determined.

• Subclinical hyperaldosteronism

  Normotensive PA is also believed to be a state of pre-clinical hyperaldosteronism [8]; hence, hypertension may not have developed, similar to the condition of pre-diabetes to diabetes or subclinical hyper- or hypothyroid to overt thyroid disorders. Although it remains unclear whether mineralocorticoid activity is activated in tissues beyond the kidney and colon, as observed in overt PA, it is hypothesized that mineralocorticoid receptor activity in normotensive PA exists on a spectrum, ranging from mild and subtle activation to significantly dysregulated and autonomous activity. The subtle activation of mineralocorticoid activity in normotensive PA may explain the absence of hypertension and long-term complications in these patients. It is also suggested that the duration of hyperaldosteronism may not have been long enough to lead to hypertension [27]. Another theory is that these patients have mild, subclinical form of PA with mildly elevated BP but remain at normotensive levels [8]. Patients with normotensive PA demonstrated marked reduction in BP post-adrenalectomy, supporting this theory [8] [9]. In addition, low sodium intake could have lowered the BP, leading to normal BP among these patients [28] [29].

• Estrogens

Estrogens are demonstrated to play a part in regulating RAAS with vasodilation effect on peripheral blood vessels [30]. Renin and aldosterone levels are noted to be elevated during luteal phase of menstrual cycle when estrogen and progesterone are high, compared to during follicular phase when estrogen and progesterone are lower [31]. Furthermore, there is a significant positive correlation between levels of RAAS hormones and estrogen [32]. Nevertheless, the BP is not elevated as expected with an increase in renin and aldosterone levels. This is postulated to be due to stimulation of endothelial nitric oxide synthase by high levels of estrogen, which leads to vasodilatory effect and downregulation of Ang II type 1 receptors with mitigation of the actions of Ang II [33] [34]. As shown in literature above, majority of normotensive PA patients were middle-aged female.

Fig 1 Summary of features of normotensive PA.

Management of normotensive PA

A summary of the features of normotensive PA is illustrated in [Fig. 1]. The recommendations for managing normotensive PA are not well-established as those with overt presentation. Nevertheless, the approach to treatment in these patients is generally guided by the principles used for overt PA. Key considerations include:

1. Screening and diagnosis

   Normotensive PA appears to be more prevalent among middle-aged females, with most patients presenting with hypokalemia and/or adrenal nodules. Hence, the diagnosis of normotensive PA should be considered in this group of patients, who should undergo the same screening procedures as those with overt disease, including the ARR. However, the optimal cut-off value for diagnosing normotensive PA has yet to be determined.

   Adrenal imaging and adrenal vein sampling (AVS) are essential for determining laterality and confirming the biochemical diagnosis of normotensive PA. Nonetheless, it remains unclear whether AVS findings in this patient group align with those observed in overt PA. An important consideration when assessing patients for normotensive PA is to ensure their sodium levels are not depleted. Sodium depletion can lead to a falsely elevated aldosterone levels, potentially confounding diagnostic interpretation and increasing the risk of misdiagnosis.

   As overt PA is demonstrated to be associated with complications particularly chronic kidney disease, atrial fibrillation, and stroke, guidelines have recommended screening for PA in these patients [35] [36]. On the other hand, as the long-term complications of normotensive PA remain uncertain, there is no established recommendation to screen patients with the aforementioned complications for normotensive PA.

2. Management strategies

   Although it remains uncertain whether normotensive PA shares the same risk profile as overt PA for developing cardiovascular, renal, and metabolic complications, longitudinal studies indicate that these patients have a higher likelihood of developing hypertension over time. The potential for progression to hypertension and the long-term effects of hyperaldosteronism suggest that normotensive PA may still carry significant risks for cardiovascular damage, kidney dysfunction, and metabolic abnormalities. Moreover, hyperaldosteronism has been linked to cardiovascular complications such as left ventricular hypertrophy, atrial fibrillation, and endothelial dysfunction. Therefore, it is recommended that normotensive PA be actively treated to prevent these adverse outcomes [27]. Treatment options are similar to those with overt PA, including adrenalectomy for unilateral disease, particularly if adrenal lesion laterality is identified, or the use of mineralocorticoid receptor antagonists for bilateral disease. In all cases, treatment decisions should be guided by clinical judgment, taking into account the severity of hyperaldosteronism, the presence of any cardiovascular or renal effects, and carefully weighing the risk and potential benefits of intervention to prevent long-term complications.

3. Follow up and monitoring

Patients with normotensive PA who have undergone treatment should receive periodic follow-up, similar to those treated for overt PA. This follow-up is essential for monitoring the effectiveness of treatment, managing potential side effects, and assessing any residual or evolving complications. Conversely, untreated normotensive PA should be closely monitored for the potential development of hypertension and complications related to chronic aldosterone excess. Regular screening for signs of hypertension, hypokalemia, and other aldosterone-related abnormalities is crucial to ensure early intervention if the condition progresses.

Research gaps and future directions

It has been demonstrated that patients with normotensive PA display a more than 15-fold higher risk of developing hypertension compared to controls without PA [14]. However, whether this cohort of patients share the same risks of developing other complications particularly involving the cardiovascular and renal systems, remains unknown. Early identification of hypertensive PA followed by adrenalectomy in surgically treatable patients not only potentially cures hypertension or improves the BP [37], it also reduces important consequences on target organs caused by uncontrolled hypertension, apart from reducing morbidity and mortality [38] [39]. Whether or not this is also beneficial among patients with normotensive PA needs to be further explored. Furthermore, the best treatment option which can improve prognosis of these patients should also be investigated in future studies.

Although hypokalemia is considered a hallmark of normotensive PA, up to two thirds of patients were normokalemic [9]. Adrenal mass was also not reported in all these patients [8], indicating that normotensive PA may be found in individuals without hypokalemia or adrenal mass. Hence the most appropriate screening method for normotensive PA needs to be further elucidated. Screening for this entity using serum K⁺may be feasible and inexpensive, however, it may lead to underdiagnosis especially in those with normokalemia. On the other hand, the use of ARR could be more effective in detecting normotensive PA but it is limited by the cost of testing. Although guidelines have laid out the appropriate cut off diagnostic values of ARR for hypertensive PA, it remains unclear if these values apply to normotensive PA as well. Besides, since ARR has a high false-positive rate, suppression testing may also need to be considered for confirmation of this entity. Furthermore, the target screening cohort is yet to be delineated.

Findings from literature suggest that renin-independent aldosterone autonomous secretion is now known to be not confined to patients with hypertension, and its incidence in normotensive cohort may be more common than previously thought. Beyond our previous understanding of investigating for PA among those with resistant hypertension or those with more severe hypertension, more and more studies demonstrate the recognition of PA beyond this cohort of patients. If indeed PA occurs even among those with stage 1 hypertension, this raises the question whether PA could be the cause among some patients with essential hypertension, especially those with low levels of renin, and contribute to their increased risk of cardiovascular complications and disease progression. In this regard, perhaps larger epidemiological studies are essential, which not only will help determine the prevalence of normotensive PA in the population but also ascertain the appropriate cut off values of ARR and investigation protocol in detecting this underestimated condition.

Although the possible mechanisms have been discussed above, this entity remains poorly understood. More preclinical studies may be able to further elucidate further insights into other possible mechanisms. Besides, somatic and germline mutations in genes involved may be unraveled via studies with improved sensitivity, which can further improve our understanding of the pathophysiology of normotensive PA.

Hence, pending future studies to enhance our understanding of this under-explored entity, based on available findings from current literature, perhaps normotensive patients with unexplained hypokalemia or adrenal mass, patients with borderline or stage 1 hypertension, especially with lower BP in the past, should be considered for screening of normotensive PA.

Conclusion

Patients with elevated aldosterone levels are at risk of cardiovascular and renal complications despite normal BP levels. These observations underline the importance of early detection of normotensive PA with subsequent treatment to prevent deleterious consequences of dysregulated RAAS. More importantly, well-designed studies are imperative to further understand the prevalence, mechanisms, diagnostic tools, consequences, and treatment of normotensive PA.

Data Availability

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

Contributors’ Statement

HHL conceived and designed the work; NS revised it critically for important intellectual content. Both authors read and approved the final version of the manuscript and agree to be accountable for all aspects of the work.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Publication History

Received: 24 October 2024

Accepted after revision: 23 January 2025

Article published online:
06 March 2025