Primary aldosteronism is the most common cause of refractory hypertension in youths and middle-aged adults. Patients have hypertension that is typically moderate but may be severe. Some patients have only diastolic hypertension, without other symptoms and signs. Edema is rarely seen in primary aldosteronism. Hypokalemia can produce muscle weakness (at times with paralysis simulating periodic paralysis), paresthesias with tetany, headache, polyuria, and polydipsia.
Plasma potassium should be determined in hypertensive individuals. However, hypokalemia, once thought to be the hallmark of hyperaldosteronism, is present in only 37% of affected patients: 50% of those with an aldosterone-producing adenoma and 17% of those with adrenal hyperplasia. An elevated serum bicarbonate (HCO3) concentration indicates metabolic alkalosis and is commonly present.
Testing for primary aldosteronism should be considered for all hypertensive patients with any of the following: (1) sustained hypertension above 150/100 mm Hg on 3 different days; (2) hypertension resistant to three conventional antihypertensive drugs, including a diuretic; (3) controlled blood pressure requiring four or more antihypertensive drugs; (4) hypokalemia, particularly when unrelated to diuretics; (5) personal or family history of early-onset hypertension or cerebrovascular accident at age 40 or younger; (6) first-degree relative with primary aldosteronism; (7) presence of an adrenal mass; and (8) low PRA.
For at least 2 weeks prior to testing, patients should have any hypokalemia corrected and then consume a diet high in NaCl (more than 6 g/day) and ideally withhold certain medications: all diuretics, ACE inhibitors, ARBs (stimulate PRA); beta-blockers, clonidine, NSAIDs (suppress PRA); oral estrogens and oral contraceptives should also ideally be held. Medications that are allowed include extended-release verapamil, hydralazine, terazosin, and doxazosin.
For blood testing, the patient should be out of bed for at least 2 hours and seated for 15–60 minutes before the blood draw, which should preferably be obtained between 8 AM and 10 AM. Proper phlebotomy technique is important to avoid spurious increases in potassium. The blood should be drawn slowly with a syringe and needle (rather than a vacutainer) at least 5 seconds after tourniquet release and without fist clenching. Plasma potassium, rather than the routine serum potassium, should be measured in cases of unexpected hyperkalemia, with the separation of plasma from cells within 30 minutes of collection. Plasma potassium levels must be normal, since hypokalemia suppresses aldosterone. For practical purposes, the same blood draw can be used for simultaneous assays for plasma potassium, serum aldosterone, and PRA or direct renin assay (DRA). Patients with primary aldosteronism have a suppressed PRA that is below or near 1.0 ng/mL/h or DRA less than 0.36 ng/mL. PRA of 1.0 ng/mL/h (12.8 pmol/L/min) is equivalent to a DRA of 5.2 ng/mL (8.2 milli-international units/L). Blood specimens for PRA must be transported to the laboratory at room temperature for prompt separation and freezing of plasma. Serum aldosterone should ideally be measured with tandem mass spectrometry. Suppressed PRA or DRA with a serum aldosterone concentration greater than 15 ng/dL (420 pmol/L) indicates probable primary hyperaldosteronism. Serum aldosterone (ng/dL) to PRA (ng/mL/h) ratios less than 24 exclude primary aldosteronism; ratios between 24 and 30 are indeterminate; ratios between 30 and 64 are suspicious; a ratio above 64 helps confirm the diagnosis of primary aldosteronism. In patients with a suppressed PRA or DRA plus a serum aldosterone of 20 ng/day or higher, the diagnosis of primary hyperaldosteronism is confirmed. To further confirm the diagnosis and for patients with a suppressed PRA or DRA but lower serum aldosterone levels, a 24-hour urine is collected in an acidified container for aldosterone, cortisol, and creatinine; urine aldosterone greater than 12 mcg/24 h (33 nmol/24 h) confirms primary aldosteronism with 93% specificity.
Plasma may be assayed for 18-hydroxycorticosterone; a level greater than 100 ng/dL (2750 pmol/L) is seen with adrenal aldosteronomas, whereas levels less than 100 ng/dL (2750 pmol/L) are nondiagnostic. In addition, a posture stimulation test may be performed, but this requires overnight hospitalization. The test is performed by drawing blood for aldosterone at 8 AM while the patient is supine after overnight recumbency and again after the patient is upright for 4 hours. Patients with a unilateral adrenal adenoma usually have a baseline plasma aldosterone level greater than 20 ng/dL (550 pmol/L) that does not rise. Patients with bilateral adrenal hyperplasia typically have a baseline plasma aldosterone level less than 20 ng/dL (550 pmol/L) that rises after 4 hours of upright posture. Exceptions occur and the accuracy of the posture stimulation test is about 85%.
Genetic testing is recommended for patients with confirmed primary aldosteronism by age 20 years and those with a family history of primary aldosteronism or stroke at young age (under age 40). The testing is for familial corticosteroid remediable aldosteronism.
Some patients with undiagnosed primary aldosteronism are incidentally found to have an adrenal nodule (incidentaloma) during abdominal or chest imaging. All patients with biochemically confirmed primary aldosteronism require a thin-section CT scan of the adrenals to screen for a rare adrenal carcinoma. In the absence of a large adrenal carcinoma, adrenal CT scanning cannot reliably distinguish unilateral from bilateral aldosterone excess, having both a sensitivity and specificity of 78% for unilateral aldosteronism. Therefore, the decision to perform a unilateral adrenalectomy should not be based solely on the adrenal CT scan. Adrenal vein sampling is often required.
Unfortunately, bilateral selective adrenal vein sampling is invasive, expensive, not widely available, and often unsuccessful. The procedure (and surgery) may not be required for patients whose blood pressure is well controlled with spironolactone or eplerenone and for those with familial hyperaldosteronism. It is indicated only if surgery is contemplated in order to direct the surgeon to the correct adrenal gland. In such cases, adrenal vein sampling can be useful to identify the adrenal to be removed when there is no visible adrenal adenoma on CT imaging. Adrenal vein sampling can also help avoid mistaken removal of an incidental nonsecreting adrenal adenoma. Adrenal vein sampling is not required in patients who have a classic adrenal adenoma (Conn syndrome), which is characterized by spontaneous hypokalemia and a unilateral adrenal adenoma 10 mm or larger on CT.
Before this procedure, the patient must be properly prepared (see Laboratory Findings). However, patients with a persistently suppressed PRA may continue mineralocorticoid blockade. Both adrenal veins must be catheterized; catheterization of the right adrenal vein is technically difficult and frequently unsuccessful. To ensure that both adrenal veins have been properly catheterized, blood samples are obtained from each adrenal vein and from a peripheral vein or inferior vena cava (IVC) following cosyntropin administration; each sample is assayed for both aldosterone and cortisol. A sample is confirmed to be adrenal vein blood only if the cortisol concentration in the specimen is at least three times higher than the cortisol concentration from simultaneously drawn peripheral vein blood. Lateralization is present when the aldosterone:cortisol ratio from one adrenal vein is at least four times that from the opposite adrenal vein.
When the right adrenal vein has not been catheterized, the data from the left adrenal vein and peripheral vein/IVC sampling can still be useful. In such cases, a left adrenal vein:peripheral vein/IVC aldosterone ratio of 5.5 or more indicates the left adrenal is the source of hyperaldosteronism. Conversely, a left adrenal vein:peripheral vein/IVC aldosterone ratio of 0.5 or less indicates that the right adrenal is the source of hyperaldosteronism. Aldosterone concentration ratios between 0.5 to 5.5 indicate a likelihood bilateral hyperplasia.
Aldosterone hypersecretion that is lateralized to one adrenal usually indicates that adrenal has a unilateral aldosteronoma or hyperplasia, particularly when aldosterone secretion from the contralateral adrenal is suppressed, in which case unilateral surgery improves hypertension in 96%. Adrenal vein sampling has a sensitivity of 95% and a specificity of 100% but only when performed by an experienced radiologist. This procedure entails a 0.6% risk of major complications.