Primary Aldosteronism Diagnosis and Management: A Clinical Approach

Abstract

Primary aldosteronism used to be considered a rare and niche secondary cause of hypertension. However, we have learned that primary aldosteronism is far more common than previously believed. The implications of this increased prevalence are important to public health since autonomous aldosterone secretion contributes to cardiovascular disease and it can be treated in a targeted manner. This review will focus on clinical approaches to diagnosing primary aldosteronism more frequently and earlier in its course, as well as practical treatment objectives to reduce the risk for incident cardiovascular disease.

Introduction:

Primary aldosteronism used to be considered a rare and niche secondary cause of hypertension. However, a rapid flurry of translational research has dramatically changed the landscape of evidence and the way we view this disorder. It is now clear that primary aldosteronism is common, underdiagnosed, and contributes to substantial cardiovascular morbidity. In this review, we will focus on the practical approach to the clinical diagnosis and treatment of primary aldosteronism.

Pathophysiology of Primary Aldosteronism

The hallmark of primary aldosteronism is autonomous secretion of aldosterone from either one or both adrenal glands, independent of its primary regulators: angiotensin II, hyperkalemia, and corticotropin (ACTH). Aldosterone binds to the mineralocorticoid receptor (MR) of the principal cell in the distal nephron, inducing sodium reabsorption via the epithelial sodium channel (ENaC), and a commensurate excretion of potassium or hydrogen ions. The ENaC-mediated sodium reabsorption induces osmolar changes that drive water reabsorption, resulting in volume expansion, glomerular hyperfiltration, and suppression of renin and angiotensin II. Since angiotensin II is an important mediator of proximal nephron sodium reabsorption, suppression of angiotensin II results in greater sodium delivery to the distal nephron, thereby amplifying the aldosterone-driven sodium reabsorption and volume expansion, as well as potassium and acid excretion. These renal and hemodynamic effects explain why patients with primary aldosteronism classically present with hypertension, hypokalemia, and metabolic alkalosis.

Importantly, while the latter explains the pathophysiology mediated via the renal-MR, autonomous aldosterone secretion also induces pathophysiology via activation of extra-renal MR, particularly in the heart and cardiovascular tissues.^1–10 Specifically, the combination of a volume expanded and/or sodium-replete state with excessive MR activation is speculated to be the mechanism for blood pressure independent cardiovascular disease in primary aldosteronism.^1,4–7,9

Prevalence

Historically considered a niche or rare cause of hypertension, recent studies suggest that primary aldosteronism is a common condition that often goes undiagnosed. The challenges in estimating prevalence are multi-fold. In part, true prevalence should reflect an adequate sampling of the population to provide confidence of generalizability; to date, most studies have been too small to achieve this. Secondly, there is no universal or international consensus on the definition of primary aldosteronism,^11,12 and there is no histopathologic or other gold standard. Thus, the flexible nature of characterizing autonomous aldosterone secretion that is sufficient to be considered “primary aldosteronism” has resulted in differing prevalence estimates from a variety of sample populations worldwide.

Regardless, primary aldosteronism is now recognized as the most common cause of endocrine hypertension. In one of the largest studies to attempt an estimate on the prevalence of primary aldosteronism, Monticone et al. tested 1,672 primary care patients with hypertension for primary aldosteronism.¹³ The authors used strict screening and confirmatory thresholds to define primary aldosteronism and reported that 6 percent of their general hypertensive population had the diagnosis. Primary aldosteronism was more common in severe cases of hypertension with approximately 12 percent of patients with an untreated blood pressure of 160–179/100–109 mmHg confirmed to have primary aldosteronism; however, a prevalence of 4 percent was observed even among patients with milder hypertension (140–159/80–99 mmHg). Among the patients in this study who underwent adrenal venous sampling (AVS), approximately one-third of primary aldosteronism cases had unilateral disease (typically due to an aldosterone-producing adenoma [APA]) while the remaining two-thirds had bilateral disease (typically due to bilateral adrenal hyperplasia [BAH] or idiopathic hyperaldosteronism). The prevalence reported from this study was similar to that found in prior studies conducted in other countries with unique sample populations.^14–16

It is important to note, that had these investigators used slightly different criteria for their screening thresholds, or confirmatory testing cut-offs, they may have observed more modest or alarming prevalence estimates, as has been reported before,¹⁷ thus underscoring the challenges in determining prevalence when using relatively arbitrary categorizations.

Prevalence estimates for primary aldosteronism in more severe hypertension populations, for example resistant hypertension, are even greater at approximately 12–20%.^{13,14,18–20} New observations suggest that even this high prevalence in resistant hypertension may be an underestimate, as it did not include milder forms of autonomous aldosterone secretion that do not meet the current (or classical) diagnostic thresholds of primary aldosteronism.^11,21

Health Outcomes in Primary Aldosteronism Prior to Targeted Therapy

The relevance of the relatively large prevalence of primary aldosteronism is best contextualized by the clinical consequences attributed to the disease, especially when it is not diagnosed early. A multitude of studies have demonstrated that prior to targeted therapy with MR antagonist medications or surgical adrenalectomy, patients with primary aldosteronism are at a higher risk for a number of adverse health outcomes compared with patients with essential hypertension, independent of blood pressure. The majority of these studies have focused on cardiometabolic outcomes including myocardial infarction,^13,22–25 heart failure,^13,24,25 stroke,^13,22–24 atrial fibrillation,^13,22–27 diabetes,^28,29 and metabolic syndrome.^29,30 A recent meta-analysis incorporated a number of these studies to demonstrate that the odds ratios (OR) for nearly all clinically relevant cardiometabolic adverse outcomes was higher in patients with primary aldosteronism prior to targeted therapy compared with patients with essential hypertension (Table 1).³¹ Other studies have shown that patients with primary aldosteronism prior to targeted therapy are also at higher risk for kidney disease,^32–37 including glomerular hyperfiltration and albuminuria, as well as death.³⁸

Table 1: Odds ratois for outcomes in patients with primary aldosteronism when compared to similar patients with essential hypertension as reported by Monticone et al.

Data from Monticone S, D’Ascenzo F, Moretti C, et al. Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2018;6(1):41–50. Epub 2017/11/14. doi: 10.1016/S2213-8587(17)30319-4. PubMed PMID: 29129575

	Odds Ratio	95% confidence interval
Coronary artery disease (myocardial infarction or revascularization)	1.77	1.10–2.83
Stroke	2.58	1.93–3.45
Atrial Fibrillation	3.52	2.06–5.99
Heart Failure	2.05	1.11–3.78
Diabetes	1.33	1.01–1.74
Metabolic Syndrome	1.53	1.22–1.91

Diagnostic Approach:

Given the aforementioned risk for cardiometabolic disease in primary aldosteronism, it is imperative that patients with this condition be recognized early so that targeted therapy can be initiated.

Who to Screen for Primary Aldosteronism

The current Endocrine Society guidelines recommend screening for primary aldosteronism among populations where the prevalence has been reported to be the highest (Table 2).¹¹

Table 2:

Indications to screen for primary aldosteronism.

Blood pressure > 150/100 mmHg on three consecutive measurements on different days

Blood pressure > 140/90 mmHg resistant to three conventional antihypertensive medications including a diuretic

Blood pressure < 140/90 mmHg on four or more antihypertensive medications

Hypertension and hypokalemia (spontaneous or diuretic-induced)

Hypertension and adrenal incidentaloma

Hypertension and sleep apnea

Hypertension and a family history of hypertension or stroke prior to age 40

Hypertension and a first-degree relative with primary aldosteronism

It is alarming that only a small fraction of patients who meet the aforementioned indications are screened for primary aldosteronism,³⁹ highlighting the need for greater education of primary aldosteronism prevalence and the importance of case detection. Alternatively, it may be that screening for primary aldosteronism requires more time and resources than are available to many primary care physicians and other non-hypertension specialists. Further, although these are recommendations made by consensus and expert opinion, it should be noted that these indications are likely to identify individuals with more severe and overt forms of primary aldosteronism where a substantial degree of vascular injury may have already occurred. Recent studies have reported that primary aldosteronism may be prevalent in less severe forms of hypertension^13,14,17 and even among normotensive individuals,^40–43 phenotypes that are excluded from the above recommended screening guidelines.

How to Screen for Primary Aldosteronism

The most often recommended screening test for primary aldosteronism is the aldosterone-to-renin ratio (ARR).¹¹ ARR testing can easily be performed in the ambulatory setting typically without any additional preparation. The most widely-accepted definition of a positive screen is an ARR > 30 ng/dL per ng/mL/h with a serum aldosterone level > 15 ng/dL.^11,44 Certainly, the higher the aldosterone level, and the lower the plasma renin activity (PRA), the more obvious the potential diagnosis. Rather than focusing on the ARR metric itself, we emphasize evaluating the absolute aldosterone and renin measures individually to determine whether there is inappropriate and autonomous aldosterone secretion that appears to be independent of renin. The clinical challenge is determining how low an aldosterone level can be in a patient with autonomous and inappropriate aldosterone secretion. Diagnostic cutoffs for what is considered to be a positive screen using the ARR can vary by practice and practitioner, namely because the ARR has not been calibrated or validated against a known gold standard since there exists no universal histopathologic, or other method, for the diagnosis of primary aldosteronism.

Less conservative criteria accept lower aldosterone levels (e.g. > 6 ng/dL or > 9 ng/dL)^11,17,45 in the context of a suppressed PRA (e.g. < 1.0 ng/mL/h).⁴⁶ The suppression of renin, or at least a low renin, is generally a biochemical requisite to support autonomous aldosterone secretion. In this context, determination of how high an aldosterone level should be to be considered a “positive screen” is often dictated by personal style, cost-effectiveness, and other resources in specific settings. Relying on more conservative criteria (a very high aldosterone level with a low renin) may detect overt cases at the expense of missing milder ones (i.e. false negatives), whereas relying on more relaxed criteria (modest or normal aldosterone levels with a low renin) may detect overt and mild cases at the expense of a greater number of false positive screens.¹²

For decades, the main clinical measure of renin has been PRA and this metric has been predominantly used in research studies as well. However, there is a global trend moving to replace PRA measures with renin concentrations. As this shift occurs, a re-calibration of diagnostics will be needed as will reliable comparisons to crudely convert and compare PRA with renin concentration.¹¹ Similarly, aldosterone assays are increasingly performed using LC-MS/MS rather than radioimmunoassay. Aldosterone measurements with LC-MS/MS have been shown to be substantially lower than other assays,⁴⁷ thus suggesting that going forward a new calibration of clinically relevant aldosterone levels, and arbitrary thresholds, will have to be considered.

A common question that arises is which, if any, antihypertensive medications need to be stopped prior to testing to avoid false negative results. Here again, geographical and personal stylistic practices vary. The most common culprit antihypertensive medications are those that raise renin and thus lower the ARR (i.e. MR antagonists, ENaC inhibitors). If renin remains suppressed despite these medications, the renin, aldosterone, and ARR remain valid and interpretable, and therefore testing while on these medications is reasonable. However, if a patient is on one of these potentially interfering medications, and the renin is not suppressed, a washout period (that can take up to 4–6 weeks, although is usually much shorter) may be necessary prior to repeat testing. During this washout period, antihypertensive agents that will not affect renin measurements (e.g. alpha blockers and/or hydralazine) and potassium supplementation can be utilized to control a patient’s blood pressure and serum potassium.

Washout of angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARB) is often recommended¹¹ because in normal physiology these medications can raise renin. However, in the pathophysiology of primary aldosteronism (reviewed earlier), renin and angiotensin II are suppressed, and therefore it is uncommon for ACE inhibitors or ARBs to impart sufficient influence to result in diagnostic misinterpretation. Beta-blockers can lower renin, and therefore increase the risk for false-positive ARR testing by decreasing the denominator;¹¹ however, lowering renin in normal physiology typically also lowers angiotensin II and aldosterone, and thus false-positive testing due to beta-blocker effect alone is not common. Similarly, although calcium channel blockers and diuretics can all potentially influence the ARR, for most practical purposes their influence is not sufficient to dramatically alter diagnostic testing and measurement of the ARR while on these medications can be performed. For these reasons, many experts recommend screening when primary aldosteronism is suspected regardless of which medications are being used by the patient, and to consider an MR antagonist or ENaC inhibitor washout only if the renin is not suppressed.^48–50 When there is uncertainty in interpretation, a washout of additional medications can be considered; however, this should proceed with caution and careful monitoring since patients with primary aldosteronism can have very difficult to control hypertension and hypokalemia.

Confirmatory Testing

Confirming the screening results is often necessary. For patients with hypertension, hypokalemia, undetectable renin activity or levels, and serum aldosterone levels that are sufficiently elevated (i.e. 15 or 20 ng/dL or higher), there is no need for further dynamic testing and the diagnosis can be confirmed.¹¹ In a recent large prospective study, patients with very high ARR values not only had confirmed primary aldosteronism, but a high probability of having unilateral APAs.⁵¹

When the initial screen results are not overwhelmingly convincing, dynamic confirmatory testing can be conducted. Confirmatory tests are effectively aldosterone suppression tests; however, there is substantial variation and lack of consensus on protocols, interpretation of results, and categorical levels that indicate a “positive” or “negative” study. The four main recommended confirmatory tests are as follows:^11,52,53

• Oral sodium load – Patients are instructed to consume an approximately 4–6000 mg sodium diet for 3–4 days with the addition of sodium chloride tablets if needed. Additional potassium supplementation is also commonly required due to an increase in kaliuresis. On the final day of the diet, a 24-hour urine specimen is collected. A 24-hour urine aldosterone excretion of > 12 mcg in the setting of 24-hour urine sodium excretion of > 200 mEq is diagnostic of primary aldosteronism. However, values of > 10 mcg/24hrs are also strongly suggestive.

• Saline infusion test – Patients receive a 2 L infusion of isotonic saline over four hours. Traditionally, this test has been performed with the patient in the recumbent position; however, recent studies suggest that having the patient in a seated position increases the sensitivity without reducing the specificity in identifying primary aldosteronism.^53,54 Blood samples for renin, aldosterone, cortisol, and potassium are measured immediately pre- and post-infusion. At the end of the infusion, a serum aldosterone level > 10 ng/dL is diagnostic of primary aldosteronism, a serum aldosterone level < 5 ng/dL rules out primary aldosteronism, while a serum aldosterone level of 5–10 ng/dL is considered indeterminate. When the test is performed with the patient in a seated position, a post-infusion serum aldosterone level > 6 ng/dL is diagnostic of primary aldosteronism as long as the post-infusion serum cortisol level is lower than the pre-infusion level to exclude an ACTH effect.

• Fludrocortisone suppression test – Patients receive fludrocortisone 0.1 mg every 6 hours for 4 days together with sodium and potassium supplementation. On day 4, serum cortisol is measured at 7 AM while serum aldosterone, PRA, and cortisol are measured at 10 AM with the patient in a seated position. A serum aldosterone > 6 ng/dL with a PRA < 1.0 ng/mL/h and a 10 AM serum cortisol less than the 7 AM value is diagnostic of primary aldosteronism.

• Captopril challenge test – Individuals are given 25–50 mg of captopril after sitting or standing for at least 1 hour. Serum aldosterone and PRA are measured at time zero and at 1 and 2 hours after captopril administration, with the patient remaining seated during this period. Serum aldosterone will be suppressed in normal individuals; however, in primary aldosteronism, aldosterone will remain elevated and PRA will remain suppressed. Many different diagnostic thresholds have bene proposed. A less than 30% suppression of aldosterone from baseline while PRA remains suppressed confirms primary aldosteronism.¹¹ Alternatively, an aldosterone-to-renin ratio >20 or >30 ng/dL per ng/mL/h can also be strongly suggestive of the diagnosis.¹⁶ Finally, a failure to suppress aldosterone below 11 ng/dL has also been suggested to be diagnostic.⁵⁵

Lateralization of Disease

Once the diagnosis of primary aldosteronism has been confirmed, localization can be pursued. Cross-sectional imaging is recommended even for patients who are not interested, or eligible for surgery, to exclude the rare instance of an aldosterone-producing adrenocortical carcinoma (Figure 1). However, reliance on cross-sectional imaging to determine laterality is not widely recommended and can be misleading;^56–59 non-functional adrenal incidentalomas may exist and primary aldosteronism may be present in one or both adrenal glands without a visible abnormality on cross-sectional imaging (Figure 1). The PASO study showed that patients who underwent AVS had a substantially higher likelihood of attaining biochemical cure or biochemical improvement when compared to patients who had only computed tomography-based localization.⁶⁰ For this reason, most experts and professional societies recommend AVS for localization for most patients with primary aldosteronism who are interested and eligible for a potential adrenalectomy. In young (<35 years) patients with a clear unilateral adenoma on imaging and severe primary aldosteronism with hypokalemia, AVS may not be necessary since the visible unilateral adenoma is almost always the culprit lesion.^11,61,62

Figure 1:

A) A CT scan showing a 3.8 cm right adrenocortical carcinoma in a patient that presented with hypokalemia, hypertension, and confirmed primary aldosteronism.

B) A CT scan showing a 2.1 cm right adrenocortical adenoma and a normal appearing left adrenal gland in a patient with confirmed primary aldosteronism. Adrenal venous sampling confirmed bilateral aldosterone production and the patient was treated with mineralocorticoid receptor antagonists.

C) A CT scan showing a 1.3 cm right adrenocortical adenoma and a normal appearing left adrenal gland in a patient with confirmed primary aldosteronism. Adrenal venous sampling confirmed unilateral aldosterone production from the right side and the patient underwent a curative right adrenalectomy.

In contrast, a randomized controlled trial (the SPARTACUS trial) evaluated whether CT-based or AVS-based localization and therapy was more effective and concluded that both approaches resulted in similar blood pressure control one year later.⁶³ However, several limitations and critiques of the study design have emerged, including the fact that the primary outcome was blood pressure control at only one year of follow up, and that there may have been substantial misclassification.^64–66 Thus, although SPARTACUS was a randomized controlled trial, its results have not yet resulted in a dramatic shift in recommendations or practice.

The AVS procedure is technically challenging and should be performed by an expert with ample experience. The optimal methodology and protocol for AVS has been the source of great debate and discussion^67–72 and is discussed in detail in a dedicated article in this issue (see XXXX).

Proposed Diagnostic Approach

Figure 2 displays our proposed diagnostic approach for primary aldosteronism, recognizing that the condition exists across a spectrum of disease severity.

Figure 2: Proposed Diagnostic Approach for Diagnosis of Primary Aldosteronism.

Biochemical screening for primary aldosteronism is generally pursued when classical indications are observed, as recommended by The Endocrine Society and others.¹¹ 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 employed to affirm the diagnosis. 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 may exist across a continuum of severity whereby mild and non-classical cases may be detected as well.

From Vaidya A, Mulatero P, Baudrand R, Adler GK. The Expanding Spectrum of Primary Aldosteronism: Implications for Diagnosis, Pathogenesis, and Treatment. Endocr Rev. 2018;39(6):1057–88. Epub 2018/08/21. doi: 10.1210/er.2018-00139.

MR=mineralocorticoid receptor.

Genetics:

Genetic testing in the evaluation of primary aldosteronism is not a common part of routine clinical practice. Inheritable forms of primary aldosteronism are exceptionally rare. Recent reviews have discussed the genetics primary aldosteronism in great detail.^12,73–77 Herein, we will provide only a brief summary on the genetic aspects of primary aldosteronism that are most pertinent to clinicians in routine practice.

Glucocorticoid Remediable Aldosteronism (GRA)

GRA, also known as Familial Hyperaldosteronism (FH) type I, is a rare form of primary aldosteronism due to BAH that is inherited in autosomal dominant fashion and accounts for < 1% of all cases of primary aldosteronism.⁷⁸ These patients carry a mutation which results in a fusion of the promoter sequence of the CYP11B1 (11β-hydroxylase) gene and the coding sequence of the CYP11B2 (aldosterone synthase) gene resulting in ACTH-driven aldosterone secretion.⁷⁹ GRA patients typically present at a young age and typically carry a strong family history of primary aldosteronism, early onset hypertension, or hemorrhagic stroke at a young age. GRA patients are less likely to be hypokalemic than other patients with primary aldosteronism which may be related to the circadian nature of ACTH secretion.⁸⁰ When suspected clinically, the diagnosis should be confirmed via genetic testing;⁸¹ however, in settings where genetic testing cannot be performed or afforded, dexamethasone suppression testing can be used as a second-line alternative. With dexamethasone suppression testing, dexamethasone can be prescribed at a dose of 1 mg twice daily for three days. A serum aldosterone on day three of < 4 ng/dL is considered a positive test for GRA. Once GRA is confirmed, low-dose glucocorticoids to suppress ACTH, in addition to MR antagonists, can be initiated.

Familial Hyperaldosteronism (FH) Types II–IV

Traditionally, patients with familial forms of primary aldosteronism, when GRA had been excluded, were categorized as having FH-II. FH-II is still considered to be the most common form of FH, is typically thought to be of autosomal dominant inheritance, and is clinically similar to sporadic forms of primary aldosteronism.^78,82 Until recently, the mutations responsible for FH-II have remained unknown; however, linkage analyses have mapped them to chromosome 7p22.^83,84 Two recent studies demonstrated the discovery of mutations in the CLCN2 chloride channel causing inheritable primary aldosteronism that may account for at least some cases of FH-II, thereby setting the stage for a potential reclassification of some FH-II cases.^85,86 FH-III is exceedingly rare and attributable to mutations in the KCNJ5 potassium channel, and presents with severe childhood hypertension and primary aldosteronism.^87–89 FH-IV is also exceedingly rare and attributable to mutations in the CACNA1H T-type voltage-gated calcium channel.^90–93 The phenotype of FH-IV also includes neurocognitive disorders, epilepsy, and autism.^94–97 De novo mutations in the L-type voltage gated calcium gene for CACNA1D can cause primary aldosteronism, and are also linked to childhood seizures and neurologic abnormalities (known as PASNA).^93,95,96

Genetics and Pathogenesis of Aldosterone Producing Adenomas

Although inheritable forms of primary aldosteronism remain rare, it is now becoming evident that the vast majority of APAs harbor known pathogenic mutations that result in autonomous aldosterone secretion.^98,99 For example, a recent study⁹⁸ found that 66/75 studied APAs (88%) had identifiable somatic mutations. The most commonly identified mutations were KCNJ5 (43%), CACNA1D (21%), and ATP1A1 (17%). KCNJ5 mutations have been shown to be more common in women, present at a young age, associate with a more severe primary aldosteronism phenotype, and demonstrate high rates of clinical cure following adrenalectomy.^100–104 Although the voltage-gated calcium channels in zona glomerulosa cells are either directly or indirectly affected by these somatic mutations,^73–75,77 it remains unclear whether primary aldosteronism driven by these mutations is particularly susceptible to treatment with calcium channel blockers. Ultimately, testing for these mutations is not currently part of standard clinical practice and how this knowledge will practically influence routine clinical practice remains to be determined.

Aldosterone-Producing Cell Clusters

In recent years, non-neoplastic clusters of autonomous aldosterone-secreting cells, termed aldosterone-producing cell clusters (APCCs), have been identified in post-mortem studies on individuals with and without primary aldosteronism.^105,106 APCCs are defined as areas of CYP11B2 expression, are known to commonly harbor pathogenic somatic mutations linked to primary aldosteronism,^107,108 can be found in normotensive and hypertensive adrenal glands, and appear to exist in greater quantities with older age.¹⁰⁹ APCCs have been hypothesized to represent one potential explanation for BAH (or idiopathic hyperaldosteronism),¹¹⁰ age-related autonomous aldosteronism,^109,111 and a precursor lesion that may exist prior to neoplastic primary aldosteronism.¹²

Management of Primary Aldosteronism:

Dietary Sodium Restriction

As with essential hypertension, dietary sodium restriction should be encouraged in patients with primary aldosteronism. Physiologically, effective reduction in dietary sodium intake can result in volume contraction leading to a rise in both renin and angiotensin II. This rise in angiotensin II leads to decreased distal sodium delivery, thereby limiting the pathologic consequences of aldosterone-MR-ENaC-mediated distal sodium reabsorption in primary aldosteronism. However, sodium restriction alone is likely inadequate to effectively mitigate the adverse long-term health outcomes in the vast majority of patients with primary aldosteronism. For instance, one prior study showed that over half of patients with confirmed primary aldosteronism had normalization of their ARR due to substantial increases in renin after intense dietary sodium restriction to < 50 mmol/day,¹⁷ a degree of sodium restriction that would be extremely challenging to sustain for most individuals in North America and Europe where the mean dietary sodium intake is 150–200 mmol/day.^112,113

Mineralocorticoid Receptor Antagonists

Lifelong MR antagonist therapy is recommended for patients with bilateral primary aldosteronism as well as those with unilateral primary aldosteronism who are unable to or unwilling to undergo surgical adrenalectomy.¹¹ The two most common MR antagonists are spironolactone and eplerenone, with spironolactone having approximately double the potency of eplerenone,¹¹⁴ but carrying with it a risk for gynecomastia in men which can limit adherence. MR antagonists decrease ENaC-mediated sodium reabsorption and consequent volume expansion, and decrease potassium and hydrogen ion excretion. In this regard, they are usually able to substantially reduce blood pressure (or decrease the number of anti-hypertensive medications) and improve potassium balance.

Despite the recommendation to use lifelong MR antagonists in primary aldosteronism, it has remained uncertain how effective these medications are in reducing long-term adverse health outcomes, when compared to comparable patients with essential hypertension, and how to dose these medications in order to achieve optimal clinical results. A number of recent cohort studies, attempting to fill this knowledge gap have suggested that despite treatment with MR antagonists, patients with primary aldosteronism continue to have worse long-term health outcomes compared with patients with essential hypertension.^115,116 A recent large cohort study compared cardiometabolic outcomes in patients with primary aldosteronism treated with MR antagonists and age-matched patients with essential hypertension and similar blood pressure control.¹¹⁷ Despite treatment with MR antagonists, patients with primary aldosteronism had a two-fold higher risk for developing myocardial infarction, heart failure hospitalization, and stroke compared with patients with essential hypertension, despite similar blood pressure control. Primary aldosteronism patients treated with MR antagonists also had substantially higher risks for developing atrial fibrillation, diabetes mellitus, chronic kidney disease,³⁷ and death.

Importantly, the excess risk for these adverse cardiovascular outcomes (myocardial infarction, heart failure, stroke, atrial fibrillation) and mortality was effectively limited to those patients whose renin remained suppressed (<1.0 ng/mL/h) despite MR antagonist therapy.^117,118 Those patients with primary aldosteronism who achieved a substantial rise in renin (≥1.0 ng/mL/h), and who had also received slightly higher doses of MR antagonists, had a lower risk for incident cardiovascular events and mortality that was similar to that observed among patients with essential hypertension.^117,118 These studies, along with multiple prior studies,^22,23,31,38 highlight the fact that much of the excess risk for adverse health outcomes in primary aldosteronism occurs independent of blood pressure control; therefore, blood pressure alone may not be a sufficient marker of treatment efficacy in primary aldosteronism. In contrast, these studies suggest that a rise in renin, reflective of effective MR blockade and a subsequent volume contraction, may be a clinically useful biomarker to assess MR antagonist adequacy. To achieve a substantial rise in renin, more aggressive MR antagonist dosing is usually needed; however, this may not be always be possible as the anti-androgenic effects of spironolactone and the risk for hyperkalemia, especially among patients with kidney disease, may be limiting factors.³⁷ Combining MR antagonists with sodium restriction to normalize blood pressure and potassium, and raise renin activity into the detectable range, may be the ideal treatment approach when it can be sustainably achieved.

Surgical Adrenalectomy

Surgical adrenalectomy to cure primary aldosteronism is the treatment of choice for patients with unilateral primary aldosteronism who are healthy enough to undergo the surgery.¹¹ This procedure is now primarily performed laparoscopically, or even retropertioneoscopically, which has resulted in a lower complication rate and shorter hospitalizations.^119–121 Multiple studies have demonstrated high success rates in curing primary aldosteronism as demonstrated via resolution of hypokalemia, resolution or reduced severity of hypertension, and biochemical cure.^60,122–128 Direct comparisons of surgical adrenalectomy and MR antagonist medications in the treatment of primary aldosteronism have been limited due to bias in terms of the varied demographics and clinical presentation of unilateral versus bilateral disease; however, the few studies that have attempted to control for these differences have suggested improved long-term cardiovascular outcomes, renal outcomes, and mortality with surgical adrenalectomy compared with MR antagonist therapy.^37,117,118 Therefore, in patients with unilateral primary aldosteronism who are willing and capable to safely undergo surgery, we strongly recommend this as the preferred treatment approach.

A major unanswered question in the treatment of primary aldosteronism is whether unilateral surgical adrenalectomy should be considered in specific cases of bilateral primary aldosteronism with the goal of disease attenuation, as opposed to disease cure in unilateral primary aldosteronism. As discussed above, cohort studies suggest inferior outcomes in primary aldosteronism treated with MR antagonists as compared with both surgical adrenalectomy for unilateral disease and essential hypertension with similar blood pressure control.^37,117,118 In cases of bilateral primary aldosteronism, where the disease is difficult to control with maximal MR dosing or where MR antagonist dosing is limited by side effects such as gynecomastia or hyperkalemia (e.g. due to higher rates of chronic kidney disease), unilateral surgical adrenalectomy could reduce the amount of autonomous aldosterone secretion that needs to be treated medically.¹²⁹ However, given the paucity of existing data to address this issue, this decision is one that needs to be made based on the judgment of individual clinicians on a case-by-case basis.

Conclusion:

Primary aldosteronism is a relatively common, yet often undiagnosed, cause of hypertension that is associated with substantial morbidity and mortality even independent of its effect on blood pressure. In this article, we have discussed the most updated knowledge of this condition and shared our suggested practical diagnostic and treatment approaches based on the most recent available data. Future prospective and interventional studies are necessary to enhance the recognition of earlier and more subtle forms of autonomous aldosteronism and to identify individualized therapies to improve the care of patients with primary aldosteronism.