Primary aldosteronism, first described by Dr. Jerome Conn in 1955, has long been considered a rare secondary cause of hypertension.¹ Newer evidence, however, suggests that primary aldosteronism is common and largely under-recognized. It has been shown to be the underlying cause of hypertension in about 6% of patients in primary care settings² and in more than 20% of patients with stage 2 hypertension.³ Even for patients with an indication for case detection, appropriate testing is performed in only 1.6% to 2.1% of cases.^4,5 This under-recognition of primary aldosteronism can lead to delayed diagnosis and treatment, which can cause irreversible end-organ damage.⁶

Background

Primary aldosteronism is the overproduction and over-secretion of aldosterone, occurring independently of the renin-angiotensin-aldosterone system (RAAS). Aldosterone can cause sodium retention and potassium excretion in the renal tubules.

Aldosterone (mineralocorticoid) receptors are also present in vascular endothelial smooth muscle cells and the myocardium. Chronic activation of these receptors is associated with proinflammatory and profibrotic effects,⁷ likely explaining the increased risk of cerebrovascular, cardiovascular, and renal disease in primary aldosteronism compared with essential hypertension^8–12 (Table 1^10–12).

Case Detection

The first step in diagnosing primary aldosteronism is case detection. Current guidelines recommend performing case detection in patients with resistant hypertension, as well as those who have well-controlled hypertension with certain clinical characteristics (Table 2).¹³ Normokalemia should not dissuade clinicians from considering the diagnosis of primary aldosteronism. Hypokalemia is the exception, not the rule, and is seen in only about 30% of patients with primary aldosteronism.¹⁴

Initial case detection for primary aldosteronism is performed by simultaneously measuring plasma aldosterone concentration and plasma renin activity.¹⁰ Aldosterone elevation with suppressed plasma renin activity identifies patients with potential primary aldosteronism^10,13 (Figure 1^10,13,15). An aldosterone-renin ratio of greater than 30 is considered positive.

Medications that significantly alter the RAAS, such as spironolactone, eplerenone, and amiloride, are ideally held before testing and, if needed, other antihypertensives should be substituted (Table 3).¹³

Confirmatory Testing

Confirmatory testing is often needed to make a formal diagnosis of primary aldosteronism. However, in some patients with a high probability of primary aldosteronism based on clinical presentation and initial biochemical screening (e.g., spontaneous hypokalemia [potassium level of less than 3.5 mEq per L] with suppressed plasma renin activity and elevated plasma aldosterone concentration), confirmatory testing can be omitted.¹⁶ Confirmatory testing had a near 100% specificity for a final diagnosis of primary aldosteronism in cases where plasma aldosterone concentration was greater than 30 ng per dL and plasma renin activity was less than 0.6 ng per mL per hour.¹⁵

For patients who require confirmatory testing, several tests are available, but there is no consensus on which one is preferred.¹⁷ Test results are considered positive when aldosterone levels remain elevated despite an intervention that would suppress physiologic aldosterone production. Salt loading and synthetic mineralocorticoid administration can worsen hypertension and hypokalemia; therefore, monitoring of blood pressure and serum potassium levels is recommended. These tests are time-consuming and require meticulous attention to detail; therefore, physicians may consider referral to an endocrinologist for confirmatory testing. These confirmatory tests are described below.