Although thought to be daunting and complex in the past, the diagnostic approach to primary aldosteronism is straightforward and can be considered in three phases: case-finding tests, confirmatory tests and subtype evaluation tests.
Spontaneous hypokalaemia is uncommon in patients with uncomplicated hypertension and, when present, strongly suggests associated mineralocorticoid excess. However, several studies have shown that most patients with primary aldosteronism have baseline blood levels of potassium in the normal range.15,20,38–40 Therefore, hypokalaemia is not and should not be the criterion used to make the diagnosis of primary aldosteronism. Patients with hypertension and hypokalaemia (regardless of presumed cause), treatment-resistant hypertension (three antihypertensive drugs and poor control), severe hypertension (≥ 160 mmHg systolic or ≥ 100 mmHg diastolic), hypertension and an incidental adrenal mass, and onset of hypertension at a young age should undergo screening for primary aldosteronism (Fig. 1). In addition, the diagnosis of primary aldosteronism should be considered whenever performing a secondary hypertension evaluation (e.g. when testing for renovascular disease or pheochromocytoma).
Figure 1. When to consider testing for primary aldosteronism and use of the plasma aldosterone concentration-to-plasma renin activity ratio as a case-finding tool. PAC, plasma aldosterone concentration; PRA, plasma renin activity; PRC, plasma renin concentration.
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In patients with suspected primary aldosteronism, screening can be accomplished by measuring a morning (preferably between 0800 and 1000 h) ambulatory paired random PAC and PRA (Fig. 1). This test may be performed while the patient is taking antihypertensive medications [with some exceptions (see below)] and without posture stimulation.19,20,41–44 Hypokalaemia reduces the secretion of aldosterone, and it is optimal to restore the serum level of potassium to normal before performing diagnostic studies. Mineralocorticoid receptor antagonists (e.g. spironolactone and eplerenone)44 and high-dose amiloride are the only medications that absolutely interfere with interpretation of the ratio and should be discontinued at least 6 weeks before testing. Angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor antagonists (ARB) and diuretics have the potential to ‘falsely elevate’ PRA. Therefore, in a patient treated with an ACE inhibitor, ARB or diuretic the finding of a detectable PRA level or a low PAC:PRA ratio does not exclude the diagnosis of primary aldosteronism. However, a very useful clinical point is that when a PRA level is undetectably low in a patient taking an ACE inhibitor, ARB or a diuretic, primary aldosteronism should be highly suspect. Thus, ACE inhibitors, ARBs and non-potassium-sparing diuretics do not need to be discontinued.44 A second important clinical point is that the PRA is suppressed (< 1·0 ng/ml per hour) in almost all patients with primary aldosteronism. Adrenergic inhibitors (e.g. beta-adrenergic blockers and central alpha-2 agonists) suppress renin secretion,44 but also in turn suppress aldosterone secretion (although to a lesser degree than renin) in normal individuals; thus, although the PAC/PRA may rise in hypertensive patients without primary aldosteronism treated with adrenergic inhibitors, the PAC remains less than 416 pmol/l (15 ng/dl) and the case finding test is not significantly affected.44
The PAC:PRA ratio is based on the concept of paired hormone measurements. For example, in a hypertensive hypokalaemic patient (i) secondary hyperaldosteronism should be considered when both PRA and PAC are increased and the PAC:PRA ratio is less than 277 in SI units [10 in convential units (e.g. renovascular disease)]; (ii) an alternate source of mineralocorticoid receptor agonism should be considered when both PRA and PAC are suppressed (e.g. hypercortisolism); and (iii) primary aldosteronism should be suspected when PRA is suppressed (< 1·0 ng/ml per hour) and PAC is increased. At least 14 prospective studies have been published on the use of the PAC:PRA ratio in screening for primary aldosteronism.45 Although there is some uncertainty about test characteristics and lack of standardization (see below), the PAC:PRA ratio is widely accepted as the screening 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. Thus, the cut-off 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 of more than 832 (30 in conventional units) and PAC of more than 555 pmol/l (20 ng/dl) had a sensitivity of 90% and a specificity of 91% for APA.46 At the Mayo Clinic, a PAC (in pmol/l) : PRA (in ng/ml per hour) ratio of 555 (20 in conventional units) or more and PAC of at least 416 pmol/l (15 ng/dl) are found in more than 90% of patients with surgically confirmed APA. A PAC of > 416 pmol/l (15 ng/dl) is the high normal range (normal range, 28–583 pmol/l; 1–21 ng/dl). In patients without primary aldosteronism, most of the variation in PAC:PRA ratios occurs within the normal range.47 A high PAC:PRA ratio is a positive screening test result, a finding that warrants further testing.
It is important for the clinician to recognize that the PAC:PRA ratio is only a case-finding 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 recent 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, with a sensitivity on and off therapy of 73% and 87%, respectively, and a specificity of 74% and 75%, respectively.20 In a study of African American and Caucasian subjects with resistant hypertension, the PAC:PRA ratio was elevated (> 555; > 20 in conventional units) in 45 of 58 subjects with primary aldosteronism and in 35 of 207 patients without primary aldosteronism (sensitivity of 78% and specificity of 83%).42 Furosemide and upright posture do not improve the post-test probability for APA more than the use of the baseline PAC:PRA ratio.48
The measurement of PRA is time consuming, shows poor interlaboratory variability, and requires special pre-analytical prerequisites. To overcome these disadvantages, a monoclonal antibody against active renin is being used by several reference laboratories to measure plasma renin concentration (PRC) instead of PRA. However, few studies have focused on comparing the different methods in the testing for primary aldosteronism and these studies lack confirmatory testing.49,50 In one study with 76 normotensive volunteers and 28 patients with confirmed primary aldosteronism, the PAC:PRC ratio performed as well as the PAC:PRA ratio in differentiating primary aldosteronism patients from normal volunteers.51 Before a recommendation to replace PRA with PRC in the testing for primary aldosteronism can be made, more studies with larger cohorts are needed. Until such studies are completed it would be reasonable to consider a positive PAC/PRC test when the PAC is more than 416 pmol/l (15 ng/dl) and the PRC is below the lower limit of detection for the assay (Fig. 1).
An increased PAC:PRA ratio is not diagnostic by itself, and primary aldosteronism must be confirmed by demonstrating inappropriate aldosterone secretion. The list of drugs and hormones capable of affecting the renin–angiotensin–aldosterone axis is extensive, and frequently in patients with severe hypertension, a ‘medication-contaminated’ evaluation is unavoidable. Certain calcium channel blockers (e.g. verapamil) 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) or high-dose amiloride when PRA is not suppressed. 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. If primary aldosteronism is suspected in a patient receiving treatment with a mineralocorticoid receptor antagonist or high-dose amiloride, the treatment should be discontinued for at least 6 weeks before further diagnostic testing. 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.
Oral sodium loading test. After hypertension and hypokalaemia are controlled, patients should receive a high sodium diet (supplemented with sodium chloride tablets if needed) for 3 days, with a goal sodium intake of 218 mmol of sodium (equivalent to 12·8 g sodium chloride).27 The risk of increasing dietary sodium in patients with severe hypertension must be assessed in each case.52 Because the high salt diet can increase kaliuresis and hypokalaemia, vigorous replacement of potassium chloride may be needed and the serum level of potassium should be monitored daily. On the third day of the high sodium diet, a 24-h urine specimen is collected for measurement of aldosterone, sodium and creatinine. To document adequate sodium repletion, the 24-h urinary sodium excretion should exceed 200 mmol. Urinary aldosterone excretion more than 33 nmol/d (12 µg/24 h) in this setting is consistent with autonomous aldosterone secretion.53 The sensitivity and specificity of the oral sodium loading test are 96% and 93%, respectively.54
Intravenous saline infusion test. The intravenous saline infusion test has also been used widely for the diagnosis of primary aldosteronism.55–58 Normal subjects show suppression of PAC after volume expansion with isotonic saline; subjects with primary aldosteronism do not show this suppression. The test is done after an overnight fast. Two litres of 0·9% sodium chloride solution are infused intravenously with an infusion pump over 4 h into the recumbent patient. Blood pressure and heart rate are monitored during the infusion. At the completion of the infusion, blood is drawn for measurement of PAC. PAC levels in normal subjects decrease to less than 139 pmol/l (5 ng/dl)58; most patients with primary aldosteronism do not suppress to less than 277 pmol/l (10 ng/dl); postsaline infusion PAC values between 139 and 277 pmol/l (5 and 10 ng/dl) are indeterminate and can be seen in patients with IHA.12,55,56,59
Fludrocortisone suppression test. In the fludrocortisone suppression test, fludrocortisone acetate is administered for 4 days (0·1 mg every 6 h) in combination with sodium chloride tablets (2 g three times daily with food). Blood pressure and serum potassium need to be monitored daily. In the setting of low PRA, failure to suppress the upright 1000 h PAC to less than 166 pmol/l (6 ng/dl) on day 4 is diagnostic of PA.60 It should be noted that increased QT dispersion on the electrocardiogram and deterioration of left ventricular function have been reported during fludrocortisone suppression tests.52 Most centres no longer use the fludrocortisone suppression test.