Diagnosis of primary aldosteronism

INTRODUCTION — Nonsuppressible (primary) hypersecretion of aldosterone is an underdiagnosed cause of hypertension. The classic presenting signs of primary aldosteronism are hypertension and hypokalemia, but potassium levels are frequently normal in modern-day series of primary aldosteronism. The most common subtypes of primary aldosteronism are:

●Unilateral aldosterone-producing adenomas (APAs; ≥10 mm) or aldosterone-producing micronodules (<10 mm)

●Bilateral idiopathic hyperaldosteronism (IHA; bilateral adrenal hyperplasia)

Less common forms include:

●Familial hyperaldosteronism (FH) types I to IV and primary aldosteronism with seizures and neurologic abnormalities (PASNA) (see "Familial hyperaldosteronism")

●Unilateral hyperplasia or primary adrenal hyperplasia (caused by micronodular or macronodular hyperplasia of the zona glomerulosa of one adrenal gland)

●Pure aldosterone-producing adrenocortical carcinomas

●Ectopic aldosterone-producing tumors

The diagnosis of primary aldosteronism will be reviewed here. The clinical manifestations and treatment of this disorder are discussed separately. (See "Pathophysiology and clinical features of primary aldosteronism" and "Treatment of primary aldosteronism".)

BACKGROUND

Prevalence of primary aldosteronism — Older studies suggested a prevalence of primary aldosteronism of less than 1 percent of patients with hypertension. However, subsequent studies document a considerably higher prevalence [1-4]. In a retrospective, multicenter review, more widespread measurement of the plasma aldosterone concentration (PAC) and plasma renin activity (PRA) as a case-detection test in patients with hypertension resulted in marked increases (1.3- to 6.3-fold) in the annual detection rate of primary aldosteronism and in the proportion of patients with hypertension in whom primary aldosteronism was detected (1 to 2 percent before screening versus 5 to 10 percent after screening) [1,3,5].

In addition, in a cross-sectional study, a continuum of renin-independent aldosterone production was evident within every blood pressure category; greater renin-independent aldosterone production was associated with higher blood pressure, greater kaliuresis, and lower serum potassium levels [6]. The adjusted prevalence estimates for primary aldosteronism were 11.3 percent in patients with normotension and 15.7, 21.6, and 22 percent in those with stage 1, stage 2, and resistant hypertension, respectively. Thus, primary aldosteronism appears to be highly prevalent and underrecognized [6].

Variable presentation — The presence of primary mineralocorticoid excess should be suspected in any patient with the triad of hypertension, unexplained hypokalemia, and metabolic alkalosis [7-9]. However, most patients with primary mineralocorticoid excess have normokalemia and, rarely, some have hypokalemia but normotension (primarily young adult females).

An estimated 9 to 37 percent of patients with primary aldosteronism have hypokalemia [1,5]. This reduction in prevalence likely reflects earlier diagnosis as more patients with hypertension are being screened for primary aldosteronism. (See "Pathophysiology and clinical features of primary aldosteronism", section on 'Hypokalemia: An inconsistent finding'.)

A few patients with primary aldosteronism have hypokalemia but a normal systemic blood pressure [10]. In such patients, surreptitious vomiting, diuretic therapy, and Bartter syndrome should be excluded; these disorders lead to secondary hyperaldosteronism with increased PRA and plasma renin concentration (PRC) rather than the suppressed PRA and PRC values evident in primary aldosteronism. (See 'Other causes of hypertension and hypokalemia' below.)

Patients with the rare genetic disorder glucocorticoid-remediable aldosteronism (GRA) generally present with normokalemia. Important physiologic differences between GRA and other forms of hyperaldosteronism could account for the lesser likelihood of potassium wasting. (See "Familial hyperaldosteronism".)

DIAGNOSIS — Identifying primary aldosteronism is important because of its high prevalence and association with increased cardiovascular morbidity and mortality relative to primary hypertension with the same degree of blood pressure elevation [11]. In patients diagnosed with primary aldosteronism, treatment of the mineralocorticoid excess results in reversal or improvement of hypertension and remediation of the increased cardiovascular risk. (See "Treatment of primary aldosteronism".)

The diagnosis of primary aldosteronism includes:

●Case-detection testing – Testing should be performed in patient groups with a relatively high prevalence of primary aldosteronism (see 'Patient selection' below). Measurements of the plasma renin activity (PRA; or plasma renin concentration [PRC]) and plasma aldosterone concentration (PAC) are obtained in the morning in a seated ambulatory patient. (See 'Case detection' below.)

The initial evaluation should consist of documenting that the PRA or PRC is suppressed (PRA <1 ng/mL/hour; PRC less than the lower limit of reference range) and that the PAC is inappropriately high for the PRA (typically >10 ng/dL [277 pmol/L]) (algorithm 1). (See 'Initial testing' below.)

●Case confirmation – In most patients, an elevated PAC with a low renin level is not sufficient to establish the diagnosis of primary aldosteronism, which must be confirmed by demonstrating inappropriate aldosterone secretion with one of several tests.

The exception to the requirement for confirmatory testing is the patient with all of the following:

•Spontaneous hypokalemia

•Suppressed PRA (<1 ng/mL/hour) or PRC (below the lower limit of the reference range)

•PAC ≥20 ng/dL (555 pmol/L)

In this clinical setting, no diagnosis other than primary aldosteronism can explain the findings. However, for all other patients, aldosterone suppression testing is needed. (See 'Confirmation of the diagnosis' below.)

●Subtype classification – Once the diagnosis of primary aldosteronism has been established, a unilateral aldosterone-producing adenoma (APA), or rarely, carcinoma, must be distinguished from bilateral hyperplasia (idiopathic hyperaldosteronism [IHA]). This distinction is important since the treatment options are different for the two disorders. To differentiate APA from IHA, we employ the algorithm developed at the Mayo Clinic that uses adrenal computed tomography (CT) and adrenal vein sampling (AVS) (algorithm 2). (See 'Subtype classification' below.)

CASE DETECTION — Case-detection testing with measurement of plasma aldosterone concentration (PAC) and renin (plasma renin activity [PRA] or plasma renin concentration [PRC]) should be performed in patient groups with a relatively high prevalence of primary aldosteronism. As noted, the prevalence of primary aldosteronism in patients with hypertension is considerably higher than previously thought (see 'Prevalence of primary aldosteronism' above). In addition, more widespread testing has demonstrated that normokalemic, rather than hypokalemic, hypertension is the most common presentation of primary aldosteronism [1,5,12,13]. (See 'Variable presentation' above.)

Our approach outlined below is consistent with the Endocrine Society 2016 clinical practice guidelines [5]. Recommendations for the treatment of primary aldosteronism are reviewed separately. (See "Treatment of primary aldosteronism".)

Patient selection — We suggest case-detection testing for primary aldosteronism in the following patients (algorithm 1) [5]:

●Hypertension and spontaneous or diuretic-induced hypokalemia

Patients with any of the following should undergo testing even if they have normokalemia (see "Pathophysiology and clinical features of primary aldosteronism", section on 'Cardiovascular risk'):

●Severe hypertension (>150 mmHg systolic or >100 mmHg diastolic) or drug-resistant hypertension (defined as suboptimally controlled hypertension on a three-drug program that includes an adrenergic inhibitor, vasodilator, and diuretic)

●Hypertension with adrenal incidentaloma

●Hypertension with sleep apnea

●Hypertension and a family history of early-onset hypertension or cerebrovascular accident at a young age (<40 years)

●Hypertension and a first-degree relative with primary aldosteronism

●Hypertension and atrial fibrillation [11,14]

We do not recommend case-detection testing in older (eg, >70 years of age) patients with normokalemia and mild hypertension or in patients in whom the diagnosis would not change management (eg, the older patient with hypertension that is easily controlled with a single drug). (See "Overview of hypertension in adults", section on 'Definitions' and "Evaluation of secondary hypertension".)

Low rates of testing — In spite of clinical guidelines that recommend testing in patient groups with a relatively high prevalence of primary aldosteronism (eg, treatment-resistant hypertension or hypertension with hypokalemia), this disorder remains underdiagnosed and untreated [5,6,15].

Clinical data indicate that testing for primary hyperaldosteronism is performed in only approximately 2 to 4 percent of patients meeting criteria for case-detection testing, including those with resistant hypertension and hypokalemia [16-19]. As an example, in a retrospective, multicenter cohort study of 269,010 United States veterans with apparent treatment-resistant hypertension, only 4277 patients (1.6 percent) underwent the recommended testing for primary aldosteronism [16]. Low testing rates were observed at all centers, and no improvements in testing frequency were seen over the 17 years of the study (2000 to 2017). Among those patients who were tested, higher rates of mineralocorticoid receptor antagonist use and better blood pressure control over time were observed.

This low rate of testing underscores the need for additional provider education about the importance of testing, the increased kidney and cardiovascular morbidity from mineralocorticoid excess, and the possibility of preventing this morbidity with appropriate treatment. (See "Treatment of primary aldosteronism", section on 'Treatment goals'.)

Initial testing — The sequential evaluation of a patient with possible primary aldosteronism begins with paired measurement of the PAC and PRA or PRC [7-9]. Some clinicians calculate a PAC/PRA ratio as part of the case-detection strategy, but we prefer to use the paired random PAC and PRA (or PRC). Renin can be measured in terms of its enzymatic activity (PRA) or its mass (PRC) [20]. Details about PRA and PRC measurements are reviewed separately. (See "Assays of the renin-angiotensin-aldosterone system in adrenal disease", section on 'Renin'.)

Blood samples should be collected in the morning (preferably 8 AM) from a seated, ambulatory patient (algorithm 1). Although some antihypertensive drugs may affect these laboratory measurements, most drugs may be continued during initial case-detection testing. Specific antihypertensive drugs are discussed in detail below. (See 'Interfering drugs' below.)

Test interpretation — In patients with primary aldosteronism:

●The PRA and PRC are typically very low, due in part to the associated mild volume expansion. The PRA is usually <1 ng/mL per hour (0.2778 ng/L per sec) and the PRC below the lower limit of normal (algorithm 1) [21]. Conversely, an increased PRA or PRC in a patient with hypokalemia and hypertension is most often due to diuretic therapy, renovascular or malignant hypertension, or, rarely, a renin-secreting tumor. (See 'Other causes of hypertension and hypokalemia' below.)

●The PAC is usually >10 ng/dL (277 pmol/L).

●The PAC/PRA ratio is usually >20 ng/dL per ng/mL/hour (>555 pmol/L per ng/mL/hour) (table 1). In one study, the combination of a PAC above 20 ng/dL (555 pmol/L) and a PAC/PRA ratio above 30 had a sensitivity and specificity of 90 percent for the diagnosis of APA [21].

If findings on initial testing are negative despite high clinical suspicion for primary aldosteronism, we suggest repeat testing given the high degree of intra-individual variability in these analytes in individuals both with and without primary aldosteronism [22,23]. If case detection indicates underlying primary aldosteronism, most patients require subsequent, confirmatory testing. (See 'Confirmation of the diagnosis' below.)

PAC to PRA ratio — Some clinicians calculate a PAC/PRA ratio as part of the case-detection strategy, but this ratio is influenced by several laboratory- and assay-related variables. Therefore, we use the absolute PAC and PRA values to guide interpretation of this ratio rather than using the PAC/PRA ratio in isolation for case-detection testing (algorithm 1). The mean value for the PAC/PRA ratio in healthy individuals and patients with primary hypertension (formerly called "essential" hypertension) is 4 to 10, compared with >30 to 50 in most patients with primary aldosteronism [21,24]. PRA and PRC are low in a significant number of patients with primary hypertension, but patients with a high PAC (typically >10 ng/dL [277 pmol/L]) that is inappropriate for the corresponding PRA or PRC and a truly abnormal ratio are uncommon in the absence of primary aldosteronism.

In general, a PAC/PRA ratio >20 (depending upon the laboratory reference range) is considered suspicious for primary aldosteronism, although others use a cutoff criterion of 30 (table 1) [24]. Cutoff values depend upon whether hormone concentrations are expressed in conventional or SI units, and they vary with the PRA assay. The lower limit of detection varies among the different PRA assays and can have a dramatic effect on the PAC/PRA ratio [25]. As an example, a very different ratio is obtained if the lower limit of detection for PRA is 0.6 ng/mL per hour compared with 0.1 ng/mL per hour; for a PAC of 16 ng/dL (444 pmol/L), the PAC/PRA ratio would be 27 and 160, respectively. For this reason, we favor a PAC >10 ng/dL rather than the PAC/PRA for case detection (algorithm 1). Note that the conventional units for aldosterone are "ng/dL" and SI units are "pmol/L." To convert ng/dL to SI units, multiply by 27.74 (table 1).

The variability in threshold value for the PAC/PRA ratio is also illustrated by the range of thresholds used in various studies. In one study, in which blood was drawn at 8 AM after two hours of ambulation in 62 patients with primary aldosteronism (48 adrenal adenoma, 14 adrenal hyperplasia), 263 with presumed primary hypertension, and 434 patients with normotension, the combination of a PAC ≥20 ng/dL (555 pmol/L) and a PAC/PRA ratio >30 had a sensitivity and specificity of 90 percent for the diagnosis of aldosterone-producing adenoma (APA) [21]. Other studies have suggested that better diagnostic discrimination might be achieved with a ratio ≥50 or ≥40 rather than >30 [24,26,27], or with measurement of the ratio 60 to 90 minutes after a single dose of captopril [28] or losartan [27]. The latter tests are not widely used.

Interfering drugs — Most antihypertensive medications can be continued during biochemical testing, and posture stimulation is not required [26,29-33]. For example, although beta-adrenergic antagonists lower PRA and PRC concentrations and raise the PAC/PRA ratio [33], the increased PAC/PRA ratio is not clinically important in this setting because of the low PAC (<10 ng/dL) in patients without primary aldosteronism [33]. In addition, the risks of modifying antihypertensive medication programs (eg, hypertensive crisis, severe hypokalemia, atrial fibrillation, heart failure) often argue against discontinuation of therapy [34].

Potentially clinically important issues exist with the following drugs:

●Mineralocorticoid receptor antagonists – Data obtained from patients treated with a mineralocorticoid receptor antagonist (spironolactone and eplerenone) may be difficult to interpret. These drugs prevent aldosterone from activating its receptor, resulting sequentially in sodium loss, a decrease in plasma volume, and an elevation in PRA, which could potentially lead to false-negative testing in a patient with primary aldosteronism. 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 exceptions to this rule. For example, if the patient has hypokalemia despite treatment with spironolactone or eplerenone, then the mineralocorticoid receptors are not fully blocked, and PRA or PRC should remain suppressed in patients with primary aldosteronism. Most patients with primary aldosteronism who are treated with mineralocorticoid receptor antagonists are given subtherapeutic doses. Thus, when there is clinical suspicion for primary aldosteronism in patients treated with spironolactone or eplerenone, PAC and PRA should be measured; if the PRA is suppressed in this setting, these medications are not interfering with the evaluation, and case-detection testing, confirmatory testing, and adrenal vein sampling (AVS) can be performed without discontinuing the mineralocorticoid receptor antagonists. However, if PRA is not suppressed, then the mineralocorticoid receptor antagonist should be discontinued for four to six weeks before retesting. Other potassium-sparing diuretics, such as amiloride and triamterene, usually do not interfere with testing unless the patient is on high doses.

●ACE inhibitors, ARBs, direct renin inhibitors – Angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and direct renin inhibitors could potentially elevate PRC and have variable effects on PRA in patients with primary aldosteronism. Thus, in a patient treated with one of these drugs, a PRA >1 ng/mL/hour does not exclude the diagnosis of primary aldosteronism. On the other hand, a PRA <1 ng/mL/hour or a PRC below the lower limit of normal in a patient taking one of these drugs is a strong predictor for primary aldosteronism.

Other causes of hypertension and hypokalemia

●Secondary hyperaldosteronism – Secondary hyperaldosteronism (eg, renovascular disease) should be considered when both the PRA (or PRC) and PAC are increased and the PAC/PRA ratio is <10. In this setting, hypersecretion of renin leads sequentially to increased angiotensin II and then increased aldosterone secretion.

An increased PRA or PRC in a patient with hypokalemia and hypertension is most often due to diuretic therapy, which may be surreptitious. Less common causes include renovascular or malignant hypertension and rare renin-secreting tumors (algorithm 1). Patients with renin-secreting tumors are typically young (average age 22 years in one report) and have severe hypertension and hypokalemia [35]. Contrast-enhanced CT appears to be the diagnostic procedure of choice since false-negative results occur with arteriography or renal vein renin sampling. Surgical removal of the tumor cures the disease.

●Liddle syndrome – Liddle syndrome is a rare autosomal dominant condition in which there is a primary increase in sodium reabsorption in the collecting tubules and, in most cases, potassium secretion. The underlying defect is a gain-of-function mutation in the collecting tubule sodium channel. The evaluation and management of Liddle syndrome are reviewed separately. (See "Genetic disorders of the collecting tubule sodium channel: Liddle syndrome and pseudohypoaldosteronism type 1", section on 'Liddle syndrome'.)

●Cushing syndrome – Cushing syndrome can cause hypertension and hypokalemia due to the mineralocorticoid activity of cortisol. ACTH-mediated causes of Cushing syndrome further lead to hypersecretion of ACTH-dependent mineralocorticoids such as deoxycorticosterone and corticosterone. With ectopic ACTH syndrome, ACTH and cortisol hypersecretion are much higher than with an ACTH-secreting pituitary adenoma, leading to greater prevalence of hypokalemia (50 versus 9 percent in one series) [36]. (See "Epidemiology and clinical manifestations of Cushing syndrome" and "Establishing the cause of Cushing syndrome" and "Apparent mineralocorticoid excess syndromes (including chronic licorice ingestion)".)

●Non-aldosterone mineralocorticoid excess — The combination of suppressed PRA or PRC and a low plasma or urinary aldosterone value in a patient with hypertension and hypokalemia may indicate the presence of some non-aldosterone mineralocorticoid. In addition to Cushing syndrome, these findings can be evident in the following settings (algorithm 1):

•Some types of congenital adrenal hyperplasia (deficiencies of 11-beta-hydroxylase [CYP11B1, P450c11] or 17-alpha-hydroxylase [CYP17, P450c17]) cause hypertension and hypokalemia because of hypersecretion of the mineralocorticoid deoxycorticosterone. Familial cortisol resistance has a similar presentation. (See "Adrenal steroid biosynthesis".)

•A deoxycorticosterone-producing adrenal tumor, which can usually be detected by CT or magnetic resonance imaging (MRI), also leads to non-aldosterone mineralocorticoid excess [1].

•Other causes of mineralocorticoid excess include chronic licorice root ingestion and the rare genetic syndrome of apparent mineralocorticoid excess. (See "Apparent mineralocorticoid excess syndromes (including chronic licorice ingestion)".)

No role for urine potassium measurement — We do not order a 24-hour urine potassium collection for the evaluation of primary hyperaldosteronism; the utility of this test is largely limited to clinical suspicion of surreptitious vomiting or laxative abuse. The low serum potassium concentration induced by mineralocorticoid excess is a result of increased urinary potassium excretion. Thus, in the past, a 24-hour urine collection was typically obtained to document the presence of inappropriate potassium wasting, defined as more than 30 mEq/day in a patient with hypokalemia. An appropriately low rate of potassium excretion may be evident in the setting of either extrarenal losses (vomiting, diarrhea) or active diuretic treatment with urine collected during a nadir of the diuretic effect.

Interpretation of the rate of potassium excretion requires attention to the patient's volume status and rate of sodium excretion. The patient must not have a low sodium intake or hypovolemia (as evidenced by less than 50 mEq of sodium being excreted per day), since the associated decrease in sodium and water delivery to the distal potassium secretory site can diminish potassium excretion even in patients with hyperaldosteronism. On the other hand, the degree of potassium wasting and, therefore, the diagnostic accuracy, can be increased by a high-sodium diet because the combination of increased distal flow and hypersecretion of aldosterone will maximize potassium losses [37].

CONFIRMATION OF THE DIAGNOSIS — In patients with hypertension, an elevated plasma aldosterone concentration (PAC) ≥10 ng/dL (277 pmol/L) and low renin (plasma renin activity [PRA] <1 ng/mL/hour or plasma renin concentration [PRC] less than the lower limit of normal) may reflect primary aldosteronism (high PAC, low PRA or PRC), secondary hyperaldosteronism (high PAC and nonsuppressed PRA or PRC), or non-aldosterone mineralocorticoid excess (low PAC, low PRA or PRC). The biochemical findings in these entities may overlap, and each can be caused by a variety of disorders. Therefore, subsequent confirmatory testing to demonstrate inappropriate aldosterone secretion is needed to verify primary aldosteronism in most patients (algorithm 1). The only exceptions to the requirement for confirmatory testing are the following:

●Patients with spontaneous hypokalemia, low PRA or PRC, and a PAC ≥20 ng/dL

●Patients with low PRA or PRC and a PAC >30 ng/dL

In a study of 252 patients with hypertension and suppressed renin, all 61 patients with PAC >30 ng/dL were confirmed to have primary aldosteronism [38]. In addition, all 26 patients with spontaneous hypokalemia and PAC between 20 to 30 ng/dL were confirmed to have primary aldosteronism [38].

However, aldosterone suppression testing is usually needed, and it can be performed with orally administered sodium chloride and measurement of urine aldosterone excretion or with intravenous sodium chloride loading and measurement of PAC [31,39].

Oral sodium loading — Many centers and experts, including the author of this topic, use oral sodium loading over three days. After hypertension and hypokalemia are controlled (hypokalemia suppresses aldosterone secretion), the patient should receive a high-sodium diet for three days.

Testing protocol — Patients should be given guidance on the sodium content of the types of food they need to consume to achieve a 5000 mg sodium diet. Alternatively, particularly if patients have a taste aversion to high-sodium foods, they can be given oral sodium chloride tablets (eg, two 1 g sodium chloride tablets taken three times daily with food will provide approximately 90 mEq of sodium). On the third day of the high-sodium diet, serum electrolytes are measured, and a 24-hour urine specimen is collected for measurement of aldosterone, sodium, and creatinine. The 24-hour urine sodium excretion should exceed 200 mEq (4600 mg) to document adequate sodium loading. Urine aldosterone excretion >12 mcg/24 hours (33 nmol/day) in this setting is consistent with hyperaldosteronism. (See "Patient education: Collection of a 24-hour urine specimen (Beyond the Basics)".)

During oral sodium loading, the serum potassium level should be measured daily. Sodium-induced hypokalemia itself is strongly suggestive of nonsuppressible hyperaldosteronism. Healthy individuals do not waste potassium during sodium loading, because the increase in distal flow is offset by reduced secretion of aldosterone.

Risks and safety precautions — The risk of increasing dietary sodium in patients with severe hypertension must be assessed for each individual. In addition, since sodium loading typically increases kaliuresis and hypokalemia, patients are at risk for severe hypokalemia. Vigorous replacement of potassium chloride should be prescribed as indicated.

Saline infusion test — An alternate method to suppress endogenous aldosterone production is by the intravenous administration of 2 L of isotonic saline over four hours (from 8 AM to 12 PM), ideally while the patient is seated [39,40]. The PAC will fall below 5 ng/dL (139 pmol/L) in healthy individuals, whereas values above 10 ng/dL (277 pmol/L) are consistent with primary aldosteronism [39]. False-negative rates may be as high as 30 percent, but they appear to be lower if the test is performed with the patient seated rather than recumbent [40,41].

Other — Other available confirmation tests include the fludrocortisone suppression and captopril challenge tests. As noted above, we prefer oral sodium loading. (See 'Oral sodium loading' above.)

SUBTYPE CLASSIFICATION — Once the diagnosis of primary aldosteronism has been established, a unilateral aldosterone-producing adenoma (APA), or rarely, carcinoma, must be distinguished from bilateral hyperplasia (idiopathic hyperaldosteronism [IHA]). This distinction is important since the treatment options differ for these disorders. We suggest the algorithm developed at the Mayo Clinic that uses adrenal CT and adrenal vein sampling (AVS) to differentiate between these etiologies (algorithm 2) [31]. (See "Treatment of primary aldosteronism".)

●APA – In general, patients with APA have higher aldosterone secretion rates, resulting in more severe hypertension, more profound hypokalemia (<3.2 mEq/L), and higher plasma (>25 ng/dL) and urinary (>30 mcg/24 hour) levels of aldosterone; these patients are also typically younger (age <50 years) than those with IHA [31]. In one study, a plasma aldosterone concentration (PAC)/plasma renin activity (PRA) ratio of >32 had a sensitivity of 100 percent and specificity of 61 percent for an APA [26].

The genetic basis of APA can be established in a substantial number of patients. Somatic mutations in KCNJ5, ATP1A1, ATP2B3, CTNNB1, and CACNA1D are found in more than 80 percent of resected APAs [42-45]. In a study of 474 unselected patients with APAs, somatic heterozygous KCNJ5 mutations were present in 38 percent of patients, CACNA1D mutations in 9.3 percent, ATP1A1 mutations in 5.3 percent, and ATP2B3 mutations in 1.7 percent. Patients with KCNJ5 mutations were more frequently female and diagnosed at a younger age compared with CACNA1D mutation carriers or noncarriers [43]. Nonetheless, the presence of one of these somatic mutations does not affect diagnosis or treatment. (See "Pathophysiology and clinical features of primary aldosteronism", section on 'Mutations in aldosterone-producing adenomas' and 'Familial hyperaldosteronism' below.)

●IHA – Bilateral adrenal hyperplasia, which accounts for approximately 60 percent of cases, is generally a milder disease with less hypersecretion of aldosterone and less frequent hypokalemia; it should be treated with a mineralocorticoid receptor antagonist. The genetic basis of primary aldosteronism due to bilateral adrenal hyperplasia has not yet been determined. (See "Treatment of primary aldosteronism".)

●Co-existing APA and IHA – The clear distinction between unilateral aldosteronoma and bilateral adrenal hyperplasia has been challenged by the demonstration of the frequent presence of zona glomerulosa hyperplasia and aldosterone-producing micronodules adjacent to the dominant aldosteronoma. In addition, while ion channel mutations are frequently found in the dominant aldosteronoma, they are not present in the adjacent hyperplasia, suggesting that somatic development of a dominant adenoma may occur in a background of bilateral mild hyperplasia [46,47].

Adrenal CT — Adrenal computed tomography (CT) should be the initial study to determine subtype (adenoma versus hyperplasia) and exclude adrenal carcinoma [48]. For adrenal gland imaging, CT has superior spatial resolution compared with MRI. The CT scan may be done without intravenous contrast; however, if an adrenal mass is detected, contrast administration provides additional imaging information. (See "Evaluation and management of the adrenal incidentaloma", section on 'Typical imaging features'.)

●An adrenal carcinoma should be suspected when a unilateral, large (>4 cm) adrenal mass is found on CT in a patient with primary aldosteronism (image 1) [49-53].

●Bilateral adrenal gland thickening or micronodular changes suggests adrenal hyperplasia; however, patients with hyperplasia may also have normal-appearing adrenal glands on CT [50].

●When a solitary, hypodense, unilateral macroadenoma (>1 cm) and normal contralateral adrenal morphology (image 2) are found in a young patient (<35 years of age) with unequivocal primary aldosteronism (defined as spontaneous hypokalemia and PAC >30 ng/dL), unilateral adrenalectomy is a reasonable therapeutic option [54]. However, because of the age-dependent risk that a solitary unilateral adrenal macroadenoma may be a nonfunctioning cortical adenoma, AVS should be considered in patients over 35 years of age who want to pursue a surgical cure of hyperaldosteronism (algorithm 2).

●For macroadenomas ≥1.5 cm that likely represent an APA, assessment for cortisol cosecretion is warranted, as this informs subsequent management decisions. (See 'Cortisol cosecretion' below.)

Limitations — Some investigators suggest that the findings of hypokalemia, nonsuppressible hyperaldosteronism, a PAC/PRA ratio exceeding 50, and a unilateral mass on CT can be followed directly by surgery to remove a presumed adenoma [24]. However, CT findings are frequently misleading, as many patients with biochemical evidence of nonsuppressible hyperaldosteronism and a unilateral adrenal mass turn out to have bilateral hyperplasia [51,53,55-57].

Another problem is that the absence of a mass does not exclude an adenoma since APAs can be very small (eg, <3 mm in diameter), and lesions <1 cm in diameter may be missed on CT. Further, bilateral lesions are not diagnostic of hyperplasia because some patients with an aldosteronoma in one adrenal gland have a nonfunctioning adrenal nodule in the other [52,53].

The limitations of adrenal CT were illustrated in a study of 203 patients with primary aldosteronism who were evaluated with both CT and AVS; CT was accurate in only 53 percent of patients [56]. Based upon CT, 42 patients (22 percent) would have been incorrectly excluded as candidates for adrenalectomy, and 48 (25 percent) might have had unnecessary or inappropriate surgery. In another study, CT findings coincided with the lateralization determined by AVS in only 80 of 158 (51 percent) patients [58].

In a subsequent systematic review of 38 studies in a total of 950 patients with primary aldosteronism (including the 203 patients described above), adrenal CT/MRI results did not agree with AVS in 359 of 950 patients (37.8 percent) [57]. If CT/MRI alone had been used to determine subtype, the following inappropriate treatment would have been recommended:

●139 patients (14.6 percent) would have inappropriately undergone unilateral adrenalectomy (unilateral mass on CT/MRI but bilateral findings on AVS), which would not have been curative.

●181 patients (19.1 percent) would have been offered medical therapy instead of curative adrenalectomy (bilateral findings on CT/MRI but unilateral secretion on AVS).

●37 patients (3.9 percent) would have undergone adrenalectomy on the wrong side (AVS showing unilateral secretion on the opposite side of CT/MRI abnormalities).

These observations highlight the importance of performing AVS in most patients to distinguish between unilateral and bilateral adrenal aldosterone hypersecretion. (See 'Adrenal vein sampling' below.)

The role of CT and MRI in the evaluation of incidental adrenal masses is reviewed in detail elsewhere. (See "Evaluation and management of the adrenal incidentaloma", section on 'MRI'.)

Adrenal vein sampling — Measurement of aldosterone in samples of adrenal venous blood, obtained by an experienced interventional radiologist, is the criterion standard test to distinguish between unilateral adenoma and bilateral hyperplasia [59]. Unilateral disease is associated with a marked (usually fourfold greater than contralateral adrenal) increase in PAC on the side of the tumor, whereas there is little difference between the two sides in patients with bilateral hyperplasia (figure 1 and figure 2) [56,60,61].

Performance of AVS by experienced personnel is critical to optimize test success and minimize complications. One limitation of AVS is an inability to obtain good samples as the right adrenal vein is small and sometimes difficult to locate; due to this and other technical challenges, success rates vary in part with local expertise. In two series, catheterization was successful in 43 of 49 patients (88 percent) and 194 of 203 patients (96 percent), respectively (figure 2) [55,56]. The complication rate in published studies of AVS is 2.5 percent or less [56,62-65]. The most common complication is groin hematoma; adrenal hemorrhage and adrenal vein dissection are rare [66].

Indications — For patients who would like to pursue surgical management (unilateral adrenalectomy) of their primary aldosteronism, we suggest AVS to confirm unilateral disease if the CT scan is normal, shows bilateral abnormalities, or shows a unilateral abnormality in a patient over age 35 years [54].

We suggest that AVS may not be needed in patients under age 35 years who have severe primary aldosteronism (spontaneous hypokalemia and PAC >30 ng/dL) and who have a unilateral adrenal macroadenoma (>1 cm and <2 cm), because they are unlikely to have a nonfunctioning adrenal adenoma that could be confused with an APA (algorithm 2). The development of adrenocortical nodularity is, in part, a function of age.

Other factors to consider before recommending AVS include the presence of comorbid conditions that could increase surgical risk and the probability of finding an APA [67]. APA is more likely in patients who have spontaneous hypokalemia and marked elevations in aldosterone in blood (eg, >30 ng/dL) or 24-hour urine collection (eg, >30 mcg).

Procedure — Some centers perform AVS without cosyntropin stimulation, but we prefer continuous cosyntropin infusion (50 mcg per hour started 30 minutes before sequential sampling of the adrenal veins and continued throughout the procedure) for the following reasons:

●To minimize stress-induced fluctuations in aldosterone secretion during nonsimultaneous AVS, which could potentially confound the interpretation of lateralization data.

●To maximize the gradient in cortisol from adrenal vein to inferior vena cava (IVC) and thus confirm successful sampling of the adrenal vein.

●To maximize the secretion of aldosterone from an APA [56,60].

Some investigators have suggested that when given as a bolus injection and when the adrenal veins are sampled simultaneously, cosyntropin administration does not improve the diagnostic accuracy of AVS and may misclassify some patients [61,62,68,69]. However, as noted above, we suggest continuous cosyntropin infusion for optimal results [56,60]. Confidence in successful cannulation of both adrenal veins is critical to patient care. If the clinician cannot be confident that both adrenal veins were successfully sampled, the AVS data are not clinically useful.

Aldosterone and cortisol concentrations are measured in the blood from all three sites (right adrenal vein, left adrenal vein, and IVC). All of the blood samples should be assayed at 1:1, 1:10, and 1:50 dilutions; absolute values and accurate laboratory assays for cortisol and aldosterone are essential for successful interpretation of the AVS data. An AVS-specific report should be developed by the laboratory to prevent any confusion on data interpretation (figure 2) [31,56,63].

Confirming successful catheterization — The cortisol concentrations from the adrenal veins and IVC are used to confirm successful cannulation of both adrenal veins. With cosyntropin infusion, the adrenal vein to IVC cortisol ratio is typically more than 10:1 [56]; a ratio of at least 5:1 is required to be confident that the adrenal veins were successfully catheterized (figure 2).

However, when cosyntropin infusion is not used, an adrenal vein to IVC cortisol gradient of more than 3:1 is recommended as the threshold to verify successful catheterization [64]. Some centers require only a 10 percent gradient between an adrenal vein and the IVC [61,62], a change that can be seen in minute-to-minute adrenal cortisol secretion and that is within the coefficient of variation of some cortisol assays. Thus, as noted, we suggest cosyntropin infusion during AVS.

Cortisol-corrected ratios — Dividing the right and left adrenal vein PAC by their respective cortisol concentrations corrects for the dilutional effect of the inferior phrenic vein flow into the left adrenal vein; these are termed "cortisol-corrected ratios."

●At Mayo Clinic, where AVS is performed with cosyntropin infusion, the mean cortisol-corrected aldosterone ratio (APA-side PAC/cortisol to normal adrenal PAC/cortisol) in patients with confirmed APA is 18:1 [56]. We use a cutoff for the cortisol-corrected aldosterone ratio from high-side to low-side of more than 4:1 to indicate unilateral aldosterone excess [56].

●In patients with presumed IHA, the mean cortisol-corrected aldosterone ratio is 1.8:1 (high-side to low-side); a ratio less than 3:1 is suggestive of bilateral aldosterone hypersecretion [56].

Thus, most patients with a unilateral source of aldosterone will have cortisol-corrected aldosterone lateralization ratios greater than 4; ratios greater than 3, but less than 4, represent a zone of overlap. A ratio less than 3 is consistent with bilateral aldosterone hypersecretion [56].

In addition, the contralateral aldosterone to cortisol ratio is less than the IVC aldosterone to cortisol ratio in 93 percent of patients with surgically confirmed APA [56], indicative of suppression of aldosterone secretion by the noninvolved adrenal gland.

Centers that perform AVS without cosyntropin infusion use lower lateralization cutoff values [61,62]. However, using the diagnostic cutoffs described above for cosyntropin-stimulated AVS, the sensitivity and specificity for detecting unilateral aldosterone hypersecretion are 95 and 98.6 percent, respectively [54]. These test characteristics deteriorate when lower cutoffs are used to determine successful catheterization and lateralization.

Special circumstances — AVS may be most useful when no adrenal abnormality is found on CT or when both adrenal glands are abnormal but asymmetric. In one report, for example, 24 of 58 patients (41 percent) with normal adrenal CT and 16 of 33 (49 percent) with bilateral micronodules on CT had a unilateral source of aldosterone by AVS [56].

There are isolated cases of primary aldosteronism due to an ectopic adrenal adenoma (as in the kidney) [70]. These patients have low serum aldosterone concentrations in AVS, and CT or MRI may identify the site of the tumor.

Tests not recommended — Other tests that predate the current approach with adrenal CT and AVS were used to distinguish unilateral APAs from bilateral disease but have limited clinical utility. These tests include:

●Posture stimulation test – The posture stimulation test was based upon the observation that patients with bilateral idiopathic hyperplasia have a characteristic rise in PAC when going from the supine to standing position; this phenomenon has been ascribed to an enhanced sensitivity of the adrenal zona glomerulosa to the small changes in angiotensin II that occur with standing [71]. In contrast, no such changes would be expected in patients with an APA because their aldosterone hypersecretion is autonomous and diurnal.

However, this test does not discriminate well between unilateral adenoma and bilateral hyperplasia [7,49,72,73]. As an example, in a study of 20 patients with primary aldosteronism (15 with a unilateral APA) undergoing a postural stimulation test, PAC increased after four hours of standing in all patients with hyperplasia and in 8 of 15 patients with adenomas (based upon a 30 percent rise) [49].

●18-hydroxycorticosterone – Patients with an APA typically have elevated supine plasma 18-hydroxycorticosterone levels at 8 AM (>100 ng/dL), whereas patients with bilateral IHA do not [48]. However, the accuracy of the test is low, and it does not help with localization [48,73].

●Iodocholesterol scintigraphy – Radionuclide scintigraphy with 131-I-iodocholesterol or an analog (NP-59) is no longer used in most centers. While it has the potential advantage of correlating function with anatomic findings, it is not useful for evaluating small adrenal nodules, as tracer uptake is poor in APAs <1.5 cm in diameter [74]. This imaging modality is no longer available in the United States.

Familial hyperaldosteronism — There are four rare forms of familial hyperaldosteronism (FH) associated with adrenal hyperplasia (see "Familial hyperaldosteronism"):

●FH type I or glucocorticoid-remediable aldosteronism (GRA) due to a CYP11B1/CYP11B2 chimeric gene

●FH type II, caused by germline pathogenic variants in the chloride channel CLCN2 [75]

●FH type III, caused by germline pathogenic variants in the potassium channel subunit KCNJ5

●FH type IV, caused by germline pathogenic variants in the CACNA1H gene, which encodes the alpha subunit of an L-type voltage-gated calcium channel (Cav3.2)

CORTISOL COSECRETION — Clinically important aldosterone-producing adenoma (APA) cosecretion of cortisol may occur in patients with larger APAs (eg, ≥1.5 cm in diameter) [76]. It is reasonable to screen for this possibility in patients with apparent APAs ≥1.5 cm in diameter by measuring a baseline serum dehydroepiandrosterone sulfate (DHEAS) and performing a 1 mg overnight dexamethasone suppression test.

If autonomous cortisol cosecretion is present in a patient with primary aldosteronism and a unilateral adrenal macroadenoma, then adrenal vein sampling (AVS) is not needed. In this setting, the macroadenoma is usually cosecreting aldosterone and cortisol. However, even if the patient has primary aldosteronism caused by bilateral idiopathic hyperplasia or a contralateral adrenal micronodule, adrenalectomy remains warranted for management of hypercortisolism because good, long-term medical treatment options are not available for hypercortisolism. In contrast, if primary aldosteronism persists following unilateral adrenalectomy, mineralocorticoid receptor antagonists are an excellent treatment. When autonomous cortisol cosecretion is documented, patients must be treated perioperatively with stress doses of glucocorticoids followed by a planned postoperative taper. (See "Overview of the treatment of Cushing syndrome", section on 'Adrenal adenomas'.)

PREGNANCY — Primary aldosteronism is uncommon in pregnancy, with fewer than 60 patients reported in the medical literature; most of these patients have had aldosterone-producing adenomas (APAs) [77-81]. Primary aldosteronism can lead to intrauterine growth retardation, preterm delivery, intrauterine fetal demise, and placental abruption [81,82].

Case-detection testing for primary aldosteronism during pregnancy is the same as for nonpregnant patients: morning blood sample for the measurement of plasma aldosterone concentration (PAC) and plasma renin activity (PRA) or renin concentration (PRC) (see 'Patient selection' above). Suppressed renin and an aldosterone level >10 ng/dL is a positive case-detection test for primary aldosteronism. If spontaneous hypokalemia is present with high aldosterone (≥20 ng/dL) and suppressed renin, confirmatory testing is not needed. In patients with normokalemia and a positive case-detection test, confirmatory testing should be pursued. However, the captopril stimulation test is contraindicated in pregnancy, and the saline infusion test may not be well tolerated. One option is measurement of sodium and aldosterone in a 24-hour urine collection on an ambient sodium diet. (See 'Confirmation of the diagnosis' above.)

Subtype testing with abdominal MRI without gadolinium is the test of choice. Adrenal imaging with CT, iodocholesterol scintigraphy, and adrenal vein sampling (AVS) should be avoided in pregnancy. As highlighted in the revised Endocrine Society guidelines on primary aldosteronism [5], AVS may not be needed in patients with severe primary aldosteronism (ie, spontaneous hypokalemia and PAC >30 ng/dL) who are less than 35 years old and have a clear-cut, unilateral adrenal adenoma on cross-sectional imaging [54]. (See 'Subtype classification' above and "Treatment of primary aldosteronism", section on 'Pregnancy'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary aldosteronism".)

SUMMARY AND RECOMMENDATIONS

●Causes of primary aldosteronism – The most common causes of primary aldosteronism are aldosterone-producing adenomas (APAs) and bilateral idiopathic hyperaldosteronism (IHA). Other, rarer causes include familial hyperaldosteronism (FH) type I (glucocorticoid-remediable aldosteronism [GRA]), type II, type III, or type IV. (See 'Introduction' above and "Familial hyperaldosteronism".)

●Prevalence and presentation – The prevalence of nonsuppressible (primary) hypersecretion of aldosterone is considerably higher than previously thought. The classic presenting signs of primary aldosteronism are hypertension and hypokalemia. However, normokalemia is more common than hypokalemia in patients diagnosed with primary aldosteronism. (See 'Prevalence of primary aldosteronism' above and 'Variable presentation' above.)

●Diagnosis – Identifying primary aldosteronism is important because of its high prevalence and association with increased cardiovascular morbidity and mortality relative to primary hypertension with the same degree of blood pressure elevation. (See 'Diagnosis' above.)

•Case detection – Consistent with the Endocrine Society guidelines, we recommend case-detection testing for primary aldosteronism in patients with any of the following (algorithm 1) (see 'Patient selection' above and 'Case detection' above):

-Hypertension and spontaneous or diuretic-induced hypokalemia

-Severe hypertension (>150 mmHg systolic or >100 mmHg diastolic) or drug-resistant hypertension (defined as suboptimally controlled hypertension on a three-drug program that includes an adrenergic inhibitor, vasodilator, and diuretic)

-Hypertension with an adrenal incidentaloma

-Hypertension with sleep apnea

-Hypertension and a family history of early-onset hypertension or cerebrovascular accident at a young age (<40 years)

-Hypertension and a first-degree relative with primary aldosteronism

-Hypertension and atrial fibrillation

•Initial testing – The initial evaluation should consist of documenting that the plasma renin activity (PRA) or plasma renin concentration (PRC) is reduced (PRA <1 ng/mL/hour, PRC less than the lower limit of the reference range) and that the plasma aldosterone concentration (PAC) is inappropriately high for the PRA (typically >10 ng/dL [>277 pmol/L]); the net effect is a PAC/PRA ratio greater than 20 (depending upon the laboratory normals). As noted above, we prefer to use the paired random PAC and PRA (or PRC) for case detection rather than the PAC/PRA ratio (table 1 and algorithm 1). (See 'Diagnosis' above and 'Case detection' above.)

•Confirmation of the diagnosis – We recommend confirming the diagnosis by demonstrating inappropriate aldosterone secretion. For aldosterone suppression testing, we use oral sodium loading and measurement of urine aldosterone excretion. Some experts prefer intravenous sodium chloride loading and measurement of the PAC.

The exceptions to the requirement for confirmatory testing are the patients with spontaneous hypokalemia, low PRA or PRC, and a PAC ≥20 ng/dL, or those patients without spontaneous hypokalemia but with low PRA or PRC and a PAC >30 ng/dL; in these clinical settings, only primary aldosteronism can explain the findings. (See 'Confirmation of the diagnosis' above.)

●Subtype classification – We suggest adrenal CT as the initial test to distinguish between APA and bilateral hyperplasia. Adrenal CT will also exclude adrenocortical carcinoma (algorithm 2). (See 'Adrenal CT' above.)

In patients over the age of 35 years, when the CT scan is normal, shows bilateral abnormalities, or shows a unilateral abnormality, we recommend adrenal vein sampling (AVS) to confirm unilateral disease if the patient would like to pursue surgical management of their primary aldosteronism (figure 2 and algorithm 2). AVS may not be needed in patients under age 35 years who have severe primary aldosteronism (spontaneous hypokalemia and PAC >30 ng/dL) and who have a unilateral adrenal macroadenoma (>1 cm and <2 cm). (See 'Adrenal vein sampling' above.)

AVS should only be performed by an experienced radiologist. (See 'Adrenal vein sampling' above.)

ACKNOWLEDGMENTS — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.

The UpToDate editorial staff acknowledges Norman M Kaplan, MD, who contributed to earlier versions of this topic review.