Primary Aldosteronism Diagnosis and Management: A Clinical Approach

Corresponding Author: Anand Vaidya, MD MMSc, Center for Adrenal Disorders, Brigham and Women’s Hospital, Division of Endocrinology, Diabetes, and Hypertension, 221 Longwood Ave, Boston, MA 02115, ude.dravrah.hwb@aydiavdnana

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

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.

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.

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 recommended 11 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 (