Secondary Hypertension: Primary Hyperaldosteronism and Mineralocorticoid Excess States

Case-Detection Tests

Spontaneous hypokalemia is uncommon in patients with uncomplicated hypertension; when present, it strongly suggests associated mineralocorticoid excess. However, several studies have shown that most patients with primary aldosteronism have baseline serum levels of potassium in the normal range. Therefore, hypokalemia should not be the major criterion used to trigger case detection testing for primary aldosteronism. Patients with hypertension and hypokalemia (regardless of presumed cause), treatment-resistant hypertension (poor control on three antihypertensive drugs), severe hypertension (≥160 mm Hg systolic or ≥100 mm Hg diastolic), hypertension, and an incidental adrenal mass, or onset of hypertension at a young age should undergo screening for primary aldosteronism ( Fig. 14.1 ).

In patients with suspected primary aldosteronism, screening can be accomplished (see Fig. 14.1 ) by paired measurements of PAC and PRA in a random morning ambulatory blood sample (preferably obtained between 8.00 and 10.00 am ). This test may be performed while the patient is taking antihypertensive medications (with some exceptions, discussed later) and without posture stimulation. Marked hypokalemia reduces the secretion of aldosterone, and it is optimal to restore the serum level of potassium to normal before performing diagnostic studies.

It may be difficult to interpret data obtained from patients treated with a mineralocorticoid receptor antagonist (spironolactone and eplerenone). These drugs prevent aldosterone from activating the receptor, resulting sequentially in sodium loss, a decrease in plasma volume, and an elevation in PRA, which will reduce the utility of the PAC/PRA ratio. For this reason, spironolactone and eplerenone should not be initiated until the evaluation is completed and the final decisions about treatment are made. However, there are rare exceptions to this rule. For example, if the patient is hypokalemic despite treatment with spironolactone or eplerenone, then the mineralocorticoid receptors are not fully blocked and PRA or PRC should be suppressed in such a patient with primary aldosteronism. In this unique circumstance, the evaluation for primary aldosteronism can proceed despite treatment with mineralocorticoid receptor antagonists. However, in most patients already receiving spironolactone, therapy should be discontinued for at least six weeks. Other potassium-sparing diuretics, such as amiloride and triamterene, usually do not interfere with testing unless the patient is on high doses.

Angiotensin-converting-enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have the potential to falsely elevate the PRA. Therefore, the finding of a detectable PRA level or a low PAC/PRA ratio in a patient taking one of these drugs does not exclude the diagnosis of primary aldosteronism. However, an undetectably low PRA level in a patient taking an ACE inhibitor or ARB makes primary aldosteronism likely, and the PRA is suppressed (<1.0 ng/mL per hour) in almost all patients with primary aldosteronism.

The PAC/PRA ratio, first proposed as a case-detection test for primary aldosteronism in 1981, is based on the concept of paired hormone measurements. The PAC is measured in nanograms per deciliter, and the PRA in nanograms per milliliter per hour. In a hypertensive hypokalemic patient, secondary hyperaldosteronism should be considered if both PRA and PAC are increased and the PAC/PRA ratio is less than 10 (e.g., renovascular disease). An alternative source of mineralocorticoid receptor agonism should be considered if both PRA and PAC are suppressed (e.g., hypercortisolism). Primary aldosteronism should be suspected if the PRA is suppressed (<1.0 ng/mL per hour) and the PAC is increased. At least 14 prospective studies have been published on the use of the PAC/PRA ratio in detecting primary aldosteronism. Although there is some uncertainty about test characteristics and lack of standardization (see later discussion), the PAC/PRA ratio is widely accepted as the case-detection test of choice for primary aldosteronism.

It is important to understand that the lower limit of detection varies among different PRA assays and can have a dramatic effect on the PAC/PRA ratio. As an example, if the lower limit of detection for PRA is 0.6 ng/mL per hour and the PAC is 16 ng/dL, then the PAC/PRA ratio with an “undetectable” PRA would be 27; however, if the lower limit of detection for PRA is 0.1 ng/mL per hour, the same PAC level would yield a PAC/PRA ratio of 160. Thus, the cutoff for a “high” PAC/PRA ratio is laboratory dependent and, more specifically, PRA assay dependent. In a retrospective study, the combination of a PAC/PRA ratio greater than 30 and a PAC level greater than 20 ng/dL had a sensitivity of 90% and a specificity of 91% for APA. At Mayo Clinic, the combination of a PAC/PRA ratio of 20 or higher, and a PAC level of at least 15 ng/dL is found in more than 90% of patients with surgically confirmed APA. In patients without primary aldosteronism, most of the variation occurs within the normal range. A high PAC/PRA ratio is a positive screening test result, a finding that warrants further testing.

It is critical for the clinician to recognize that the PAC/PRA ratio is only a case-detection tool, and all positive results should be followed by a confirmatory aldosterone suppression test to verify autonomous aldosterone production before treatment is initiated. In a systematic review of 16 studies with 3136 participants, the PAC/PRA cutoff levels used varied between 7.2 and 100. The sensitivity for APA varied between 64% and 100%, and the specificity between 87% and 100%. However, the description of the reference standard and the attribution of diagnosis at the end of the studies were incomplete, and there was a lack of standardization concerning the origin of the study cohort, ongoing antihypertensive medications, use of high-salt versus low-salt diet, and circumstances during blood sampling. The authors concluded that none of the studies provided any valid estimates of test characteristics (sensitivity, specificity, and likelihood ratio at various cutoff levels). In a study of 118 subjects with essential hypertension, neither antihypertensive medications nor acute variation of dietary sodium affected the accuracy of the PAC/PRA ratio adversely; the sensitivities on and off therapy were 73% and 87%, respectively, and the specificities were 74% and 75%, respectively. In a study of African American and Caucasian subjects with resistant hypertension, the PAC/PRA ratio was elevated (>20) in 45 of 58 subjects with primary aldosteronism and in 35 of 207 patients without primary aldosteronism (sensitivity, 78%; specificity, 83%).

The measurement of PRA is time-consuming, shows high interlaboratory variability, and requires special preanalytic prerequisites. To overcome these disadvantages, a monoclonal antibody against active renin is being used by several reference laboratories to measure the plasma renin concentration (PRC) instead of PRA. However, few studies have compared the different methods of testing for primary aldosteronism, and these studies lack confirmatory testing. It is reasonable to consider a positive PAC/PRC test if the PAC is greater than 15 ng/dL and the PRC is below the lower limit of detection for the assay.

Confirmatory Tests

An increased PAC/PRA ratio is not diagnostic by itself, and primary aldosteronism must be confirmed by demonstration of inappropriate aldosterone secretion. The list of drugs and hormones capable of affecting the RAA axis is extensive, and a “medication-contaminated” evaluation is frequently unavoidable in patients with poorly controlled hypertension despite a three-drug program. Calcium channel blockers and α1-adrenergic receptor blockers do not affect the diagnostic accuracy in most cases. It is impossible to interpret data obtained from patients receiving treatment with mineralocorticoid receptor antagonists (e.g., spironolactone, eplerenone) when the PRA is not suppressed (see earlier). Therefore, treatment with a mineralocorticoid receptor antagonist should not be initiated until the evaluation has been completed and the final decisions about treatment have been made. Aldosterone suppression testing can be performed with orally administered sodium chloride and measurement of urinary aldosterone or with intravenous sodium chloride loading and measurement of PAC.