In the past, clinicians would not consider the diagnosis of PA unless the patient presented with spontaneous hypokalemia, and then the diagnostic evaluation would require discontinuation of antihypertensive medications for at least 2 weeks. This diagnostic approach resulte d in predicted prevalence rates of <0.5% of hypertensive patients [3–9]. However, it is now recognized that most patients with PA are not hypokalemic [10–13] and that case detection testing can be completed while the patient is taking antihypertensive drugs with a simple blood test that yields the ratio of plasma aldosterone concentration (PAC) to PRA [11]. The use of the PAC/PRA ratio as a case detection test, followed by aldosterone suppression for confirmatory testing, has resulted in much higher prevalence estimates for PA—5–10% of all patients with hypertension [11–14].

The diagnosis of PA is usually made in patients who are in the third to sixth decade of life. Few symptoms are specific to the syndrome. Patients with marked hypokalemia may have muscle weakness and cramping, headaches, palpitations, polydipsia, polyuria, nocturia, or a combination of these [10]. Periodic paralysis is a very rare presentation in Caucasians, but it is not an infrequent presentation in patients of Asian descent [15]. Polyuria and nocturia are a result of hypokalemia-induced renal concentrating defect, and the presentation is frequently mistaken for prostatism in men. There are no specific physical findings. Edema is not a common finding because of the phenomenon of mineralocorticoid escape. The degree of hypertension is typically moderate to severe and may be resistant to usual pharmacologic treatments [10, 16]. In the first 262 cases of PA diagnosed at Mayo Clinic (1957–1986), the highest blood pressure was 260/155 mmHg; the mean (±SD) was 184/112 ± 28/16 mmHg [16]. Patients with APA tend to have higher blood pressures than those with IHA. Hypokalemia is frequently absent, so all patients with hypertension are candidates for this disorder. In other patients, the hypokalemia becomes evident only with the addition of a potassium-wasting diuretic. Deep-seated renal cysts are found in up to 60% of patients with PA and chronic hypokalemia [17]. Because of a reset osmostat, the serum sodium concentration tends to be high-normal or slightly above the upper limit of normal. This clinical clue is very useful in the initial assessment for potential PA.

Several studies have shown that patients with PA are at higher risk than other patients with hypertension for target organ damage of the heart and kidney [18, 19]. Chronic kidney disease is common in patients with long-standing PA [20]. When matched for age, blood pressure, and duration of hypertension, patients with PA have greater left ventricular mass measurements than patients with other types of hypertension (e.g., pheochromocytoma, Cushing syndrome, essential hypertension) [21]. In patients with APA, the left ventricular wall thickness and mass were markedly decreased 1 year afte r adrenalectomy [22]. A case-control study of 124 patients with PA and 465 patients with essential hypertension (matched for age, sex, and systolic and diastolic blood pressure) found that patients presenting with either APA or IHA had a significantly higher rate of cardiovascular events (e.g., stroke, atrial fibrillation, myocardial infarction) than the matched patients with essential hypertension [19]. A negative effect of circulating aldosterone on cardiac function was found in young nonhypertensive subjects with GRA who had increased left ventricular wall thickness and reduced diastolic function compared with age- and sex-matched controls [18].

The diagnostic approach to PA can be considered in three phases: case detection tests, confirmatory tests, and subtype evaluation tests.

In patients with suspected PA, screening can be accomplished by paired measurements of PAC and PRA in a random morning ambulatory blood sample (preferably obtained between 8 and 10 a.m.). This test may be performed while the patient is taking antihypertensive medications (with some exceptions, discussed later) and without posture stimulation [10]. Hypokalemia reduces the secretion of aldosterone, and it is optimal to restore the serum level of potassium to near-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 PA. In this unique circumstance, the evaluation for PA can proceed despite treatment with mineralocorticoid receptor antagonists. However, in most patients already receiving spironolactone, therapy should be discontinued for at least 6 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 in a patient with PA. 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 PA. However, an undetectably low PRA level in a patient taking an ACE inhibitor or ARB makes PA likely.

The PAC/PRA ratio, first proposed as a case detection test for PA in 1981 [23], is based on the concept of paired hormone measurements. The PAC is measured in nanograms per deciliter (ng/dL) and the PRA in nanograms per milliliter per hour (ng/mL/h). In a hypertensive hypokalemic patient, secondary hyperaldosteronism should be considered if both PRA and PAC are increased and the PAC/PRA ratio is <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). PA should be suspected if the PRA is suppressed (<1.0 ng/mL/h) and the PAC is increased (e.g., >15 ng/dL). Although there is some uncertainty about test characteristics and lack of standardization, the PAC/PRA ratio is widely accepted as the case detection test of choice for PA [11, 24].

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/h 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/h, 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 >30 and a PAC level >20 ng/dL had a sensitivity of 90% and a specificity of 91% for APA [25]. 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 [16]. In patients without PA, most of the variation occurs within the normal range [26]. A high PAC/PRA ratio is a positive case detection test, a finding that warrants further testing [11].

It is critical for the clinician to recognize that the PAC/PRA ratio is only a case detection tool, and, in the absence of spontaneous hypokalemia, all positive results should be followed by a confirmatory aldosterone suppression test to verify autonomous aldosterone production before treatment is initiated [11]. 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 [27]. 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 PA and in 35 of 207 patients without PA (sensitivity, 78%; specificity, 83%) [28].

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 PA, and these stud ies lack confirmatory testing. It is reasonable to consider a positive PAC/PRC test if the PAC is >15 ng/dL and the PRC is lower below the lower limit of detection for the assay.

It is important to recognize that confirmatory testing is not needed in patients with hypertension and spontaneous hypokalemia when the PAC is >20 ng/dL and PRA is suppressed because there is no other disorder except PA that could be responsible for this presentation (Fig. 11.1) [11].

Small APAs may be labeled incorrectly as IHA on the basis of CT findings of bilateral nodularity or normal-appearing adrenals. Also, apparent adrenal microadenomas may actually represent areas of hyperpla sia, and unilateral adrenalectomy would be inappropriate. In addition, nonfunctioning unilateral adrenal macroadenomas are not uncommon, especially in older patients (>40 years) [40]. Unilateral PAH may be visible on CT, or the PAH adrenal may appear normal on CT. Thus, adrenal CT is not accurate in distinguishing between APA and IHA [37, 39, 41]. In one study of 203 patients with PA who were evaluated with both CT and adrenal venous sampling, CT was accurate in only 53% of patients; based on the CT findings, 42 patients (22%) would have been incorrectly excluded as candidates for adrenalectomy, and 48 (25%) might have had unnecessary or inappropriate surgery [37]. In a systematic review of 38 studies involving 950 patients with PA, adrenal CT/MRI results did not agree with the findings from adrenal venous sampling in 359 patients (38%); based on CT/MRI, 19% of the 950 patients would have undergone noncurative surgery, a nd 19% would have been offered medical therapy instead of curative adrenalectomy [41].