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Am Fam Physician. 2023;108(3):273-277

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Primary aldosteronism is the underlying cause of hypertension in primary care settings in approximately 6% of cases, and it is even more common in patients with resistant hypertension. However, it is estimated that only about 2% of patients who have risk factors for primary aldosteronism have been formally tested or diagnosed. The first step in the diagnosis of primary aldosteronism is case detection and involves testing patients who are at risk, including individuals with resistant hypertension, as well as those with well-controlled hypertension and a first-degree relative with primary aldosteronism, hypokalemia, an adrenal nodule, atrial fibrillation, obstructive sleep apnea, or a family history of an early stroke (i.e., younger than 40 years). Initial case detection is performed by simultaneously measuring plasma aldosterone concentration and plasma renin activity; an elevated aldosterone-renin ratio (greater than 30) indicates independent aldosterone secretion (i.e., aldosteronism). After a positive case detection, confirmatory testing should be performed. Confirmatory tests include the captopril challenge, oral or intravenous salt loading, or fludrocortisone suppression. Results are positive if aldosterone levels remain high after interventions that suppress or interrupt physiologic production of aldosterone. If the confirmatory test is positive, adrenal computed tomography and adrenal vein sampling should be performed to differentiate unilateral from bilateral adrenal production of aldosterone. Patients with unilateral primary aldosteronism should undergo adrenalectomy, whereas those with bilateral production should be treated with mineralocorticoid receptor antagonists, such as spironolactone or eplerenone.

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

Clinical recommendation Evidence rating Comments
Case detection for primary aldosteronism should be done in patients with resistant hypertension and in patients who have well-controlled hypertension with hypokalemia, atrial fibrillation, obstructive sleep apnea, adrenal incidentaloma, a first-degree relative with primary aldosteronism, or a family history of early stroke (i.e., younger than 40 years).13 C Expert opinion and limited-quality disease-oriented evidence
Initial case detection for primary aldosteronism is performed by simultaneously measuring plasma aldosterone concentration and plasma renin levels. Aldosterone elevation with suppressed renin levels identifies patients with potential primary aldosteronism.10,13 C Expert opinion and disease-oriented evidence
Patients with a high probability of primary aldosteronism based on clinical presentation and initial biochemical screening (e.g., spontaneous hypokalemia with suppressed plasma renin activity and elevated plasma aldosterone concentration) may not require confirmatory testing.16 C Disease-oriented case series
Once primary aldosteronism has been diagnosed, the next step is to determine if aldosterone production is unilateral or bilateral. This subtyping is accomplished with adrenal computed tomography and adrenal vein sampling.13,18,19 C Expert opinion and disease-oriented studies
Adrenalectomy is recommended in cases of unilateral aldosterone production and is superior to medical treatment. Patients treated with adrenalectomy have reduced adverse cardiovascular outcomes and superior quality-of-life measures compared with patients who are managed medically.31,32 B Patient-oriented outcomes

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 hypertension812 (Table 11012).

RiskOdds ratio (95% CI)
Atrial fibrillation3.52 (2.06 to 5.99)
Proteinuria2.68 (1.89 to 3.79)
Stroke2.58 (1.93 to 3.45)
Left ventricular hypertrophy2.29 (1.65 to 3.17)
Congestive heart failure2.05 (1.11 to 3.78)
Coronary artery disease1.77 (1.10 to 2.83)

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

Controlled hypertension (any one of the following)
Adrenal nodule
Atrial fibrillation
Family history of early stroke (i.e., younger than 40 years)
First-degree relative with primary aldosteronism
Hypokalemia
Obstructive sleep apnea
Resistant hypertension*
All patients

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 aldosteronism10,13 (Figure 110,13,15). 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

MedicationsHold priorityDuration of hold (weeks)
Mineralocorticoid receptor antagonistsMandatory4
Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta blockers, diuretics, dihydropyridine calcium channel blockersOptional2 to 4
Alpha blockers, nondihydropyridine calcium channel blockers, vasodilatorsContinue

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.

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