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:
●Aldosterone-producing adenomas (APAs)
●Bilateral idiopathic hyperaldosteronism (IHA; bilateral adrenal hyperplasia)
Less common forms include:
●Familial hyperaldosteronism (FH) types I to IV (see "Familial hyperaldosteronism")
●Unilateral adrenal hyperplasia
●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 hypertensive patients. However, studies published over the past 15 years document that the prevalence is considerably higher [1-4]. In a retrospective, multicenter review, more widespread use of the plasma aldosterone to renin ratio (plasma aldosterone concentration/plasma renin activity [PAC/PRA] ratio) as a case-detection test in hypertensive patients resulted in marked increases (1.3- to 6.3-fold) in the annual detection rate of primary aldosteronism and in the proportion of hypertensive patients in whom primary aldosteronism was detected (1 to 2 percent before screening versus 5 to 10 percent after screening) [1,3,5].
Variable presentation — The presence of primary mineralocorticoid excess should be suspected in any patient with the triad of hypertension, unexplained hypokalemia, and metabolic alkalosis [6-8]. However, most patients with primary mineralocorticoid excess are normokalemic and, rarely, some are hypokalemic but normotensive (primarily in young adult females).
It is now estimated that only 9 to 37 percent of patients with primary aldosteronism are hypokalemic [1,5]. This is likely related to earlier diagnosis as more patients with hypertension are being screened with the PAC/PRA ratio as a case-detection test 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 [9]. Surreptitious vomiting, diuretic therapy, and Bartter syndrome should be excluded; each of these disorders is associated with secondary hyperaldosteronism as the PRA and plasma renin concentration (PRC) are increased rather than suppressed, as in primary aldosteronism. (See 'Secondary hyperaldosteronism' below.)
Normokalemia is the rule in patients with the rare genetic disorder glucocorticoid-remediable aldosteronism (GRA). There are, however, important physiologic differences between GRA and other forms of hyperaldosteronism that could account for the lesser likelihood of potassium wasting. (See "Familial hyperaldosteronism".)
IMPORTANCE OF TESTING — Identifying primary aldosteronism is important because of its prevalence and association with a higher rate of cardiovascular morbidity and mortality when compared with age- and sex-matched patients with primary hypertension and the same degree of blood pressure elevation [10]. In patients diagnosed with primary aldosteronism, treatment of the mineralocorticoid excess results in reversal or improvement of the hypertension and resolution 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 'Who should be tested?' 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 >15 ng/dL [416 pmol/L], but as low as 10 ng/dL [277 pmol/L]) (algorithm 1). (See 'Protocol' below.)
●Case confirmation – In most patients, an elevated PAC and a low renin does not 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:
•Spontaneous hypokalemia
•Undetectable PRA or PRC
•PAC ≥20 ng/dL (555 pmol/L)
In this clinical setting, there is no other diagnosis except primary aldosteronism to explain these findings. However, for all others, aldosterone suppression testing is 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. (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 is important since the treatment options are different for the two disorders. We suggest 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 [1,5,11,12]. (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".)
Who should be tested? — We suggest case-detection testing for primary aldosteronism in the following patients [5]:
●Hypertension and spontaneous or low-dose, diuretic-induced hypokalemia
The following patients should undergo testing even if they are normokalemic (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)
●All hypertensive first-degree relatives of patients with primary aldosteronism
●Hypertension and atrial fibrillation [10,13]
We do not recommend screening with PAC and renin (PRA or PRC) in older normokalemic patients with mild hypertension or in patients in whom the diagnosis would not change management (eg, the older patient where blood pressure is easily controlled with a single antihypertensive agent). (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 and hypertension with hypokalemia), this disorder remains underdiagnosed and untreated [5,14,15].
One example of low testing rates comes from 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] (see 'Initial testing' below). Low rates were observed at all centers, and no improvements in testing were seen over the 17 years of the study (2000 to 2017). Among those who were tested, higher rates of mineralocorticoid receptor antagonist use and better blood pressure control over time was observed. These observations underscore the need for additional provider education about the importance of testing, the increased renal and cardiovascular morbidity seen with mineralocorticoid excess, and its reversal 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 measurement of the PRA (or PRC) and aldosterone concentration in a blood sample obtained in the morning in a seated ambulatory patient (algorithm 1) [6-8]. Renin can be measured in terms of its enzymatic activity (PRA) or its mass (active renin concentration) [17]. Details about PRA and PRC measurements are reviewed separately. (See "Assays of the renin-angiotensin-aldosterone system in adrenal disease", section on 'Renin'.)
Protocol — The test is performed by measuring a morning (preferably 8 AM), ambulatory, paired, random PAC and PRA or PRC (algorithm 1).
●The PRA and PRC are typically very low (due in part to the associated mild volume expansion) in patients with primary aldosteronism, usually less than 1 ng/mL per hour (0.2778 ng/L per sec) for PRA and usually undetectable or below the lower limit of normal for PRC [18]. On the other hand, increased PRA or PRC in a hypokalemic hypertensive patient is most often due to diuretic therapy, renovascular or malignant hypertension, or, rarely, a renin-secreting tumor (algorithm 1). (See 'Primary aldosteronism' below and 'Secondary hyperaldosteronism' below.)
●The PAC is usually >15 ng/dL (416 pmol/L), but may be as low as 10 ng/dL (277 pmol/L).
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). The mean value for the PAC/PRA ratio in normal subjects and patients with primary hypertension (formerly called "essential" hypertension) is 4 to 10, compared with more than 30 to 50 in most patients with primary aldosteronism [18,19]. PRA and PRC are low in a significant number of patients with primary hypertension, but a high PAC (typically >15 ng/dL [416 pmol/L]) and a truly abnormal ratio are uncommon.
In general, a PAC/PRA ratio greater than 20 (depending upon the laboratory normals) is considered suspicious for primary aldosteronism, although others use a cutoff criterion of 30 (table 1) [19]. 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 [20]. 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. It is for this reason that a PAC >10 ng/dL is part of the case-finding strategy and why we do not favor 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), in 263 with presumed primary hypertension (formerly called "essential" hypertension), and in 434 normotensive patients, the combination of a PAC equal to or 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 aldosterone-producing adenoma (APA) [18]. Other studies have suggested that a ratio 50 or higher or 40 or higher, rather than 30 [19,21,22], or a measurement of the ratio 60 to 90 minutes after a single dose of 25 to 50 mg of captopril [23] or 50 mg of losartan [22], might give better diagnostic discrimination. The latter tests are not widely used.
As noted above, we do not favor the PAC/PRA for case detection. We prefer to use the paired random PAC and PRA (or PRC) (algorithm 1).
Interfering drugs — Most antihypertensive medications can be continued, and posture stimulation is not required [21,24-28]. For example, although beta-adrenergic antagonists do lower PRA and PRC measurements and raise the PAC/PRA ratio [28], 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 [28]. In addition, one should consider the risks of modifying antihypertensive medication programs (eg, hypertensive crisis, severe hypokalemia, atrial fibrillation, heart failure) [29].
There are potentially clinically important issues with the following drugs:
●Mineralocorticoid receptor antagonists – 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 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 primary aldosteronism. In addition, most patients with primary aldosteronism who are treated with mineralocorticoid receptor antagonists are given subtherapeutic doses. Thus, PAC and PRA should be measured in patients treated with spironolactone or eplerenone, and if PRA is suppressed, these medications are not interfering. Thus, if PRA is suppressed, 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 strong predictor for primary aldosteronism is a PRA <1 ng/mL/hour or low PRC in a patient taking one of these drugs.
Interpretation of results
Primary aldosteronism — Primary aldosteronism should be suspected when PRA is suppressed to <1 ng/mL/hour (or PRC is below the lower limit of normal) and PAC is ≥10 ng/dL (277 pmol/L) (algorithm 1). The PAC/PRA ratio is usually >20 ng/dL per ng/mL/hour (>555 pmol/L per ng/mL/hour) (table 1). Most patients require confirmatory testing. (See 'Confirmation of the diagnosis' below.)
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 [18].
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 hypokalemic hypertensive patient 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). (See "Assays of the renin-angiotensin-aldosterone system in adrenal disease".)
Cushing's syndrome may lead to hypokalemia, due in part to the overproduction of corticotropin (ACTH)-dependent compounds such as deoxycorticosterone, corticosterone, and cortisol. However, the diagnosis in this disorder is usually suspected from the classic Cushingoid appearance, including rounded plethoric face, supraclavicular fat pads, central obesity, thick purple-red abdominal striae, proximal muscle weakness, and hirsutism. (See "Epidemiology and clinical manifestations of Cushing's syndrome".)
The degree of ACTH and cortisol hypersecretion (and therefore the frequency of hypokalemia) is much higher in the ectopic ACTH syndrome than with a pituitary adenoma (50 versus 9 percent in one series) [30]. (See "Establishing the cause of Cushing's syndrome".)
Patients with renin-secreting tumors are typically young (average age 22 years in one report) and have severe hypertension and hypokalemia [31]. Contrast-enhanced computed tomography (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's 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. (See "Genetic disorders of the collecting tubule sodium channel: Liddle's syndrome and pseudohypoaldosteronism type 1", section on 'Liddle's syndrome'.)
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. This can occur 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".)
●Chronic licorice root ingestion, the rare genetic syndrome of apparent mineralocorticoid excess, and severe cases of Cushing's syndrome, in which cortisol acts as the primary mineralocorticoid. In the last setting, there may also be hypersecretion of other mineralocorticoids such as deoxycorticosterone and corticosterone. (See "Apparent mineralocorticoid excess syndromes (including chronic licorice ingestion)".)
●A deoxycorticosterone-producing adrenal tumor, which can usually be detected by CT or magnetic resonance imaging (MRI) [1].
●Similar findings in the absence of mineralocorticoid excess are seen in Liddle's syndrome, which is caused by gain-of-function pathogenic variants in the beta or gamma subunits of the amiloride-sensitive collecting tubule sodium channel, resulting in increased sodium reabsorption, potassium wasting, hypertension, and hypokalemia. Clinical genetic testing is available. Blocking the sodium channel with amiloride or triamterene can treat both the hypertension and hypokalemia. (See "Genetic disorders of the collecting tubule sodium channel: Liddle's syndrome and pseudohypoaldosteronism type 1".)
24-hour urine collection — We do not order a 24-hour urine potassium collection unless PRA is not suppressed, PAC is not elevated, or there is a 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.
When a 24-hour collection is obtained, inappropriate potassium wasting is defined as more than 30 mEq/day in a patient with hypokalemia. An appropriately low rate of potassium excretion suggests either extrarenal losses (vomiting, diarrhea) or diuretic treatment with the urine being collected after the diuretic effect has worn off.
Aldosterone excretion can also be measured with high values (>12 mcg/day [33 nmol/day]) on a high-sodium diet (urine sodium excretion >200 mEq/day) being consistent with primary aldosteronism if the PRA is low. (See "Patient education: Collection of a 24-hour urine specimen (Beyond the Basics)".)
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 [32].
A high-sodium diet can also be given as a provocative test in patients with an initial serum potassium concentration in the normal or low-normal range. Sodium-induced hypokalemia is strongly suggestive of nonsuppressible hyperaldosteronism. Normal subjects do not waste potassium during sodium loading, because the increase in distal flow is offset by reduced secretion of aldosterone.
CONFIRMATION OF THE DIAGNOSIS — Among patients with hypertension and 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), the results may suggest either 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). Each can be caused by a variety of disorders (algorithm 1).
In most patients, the diagnosis of primary aldosteronism must be confirmed by demonstrating inappropriate aldosterone secretion with one of several tests. 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 without spontaneous hypokalemia but with low PRA or PRC and a PAC >30 ng/dL; in this clinical setting, there is no other diagnosis except primary aldosteronism to explain these findings [33].
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 [33]. In addition, all 26 patients with spontaneous hypokalemia and PAC between 20 to 30 ng/dL were confirmed to have primary aldosteronism [33].
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 [26,34].
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 patients should receive a high-sodium diet for three days.
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. In circumstances of high-sodium dietary intolerance, patients 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). The risk of increasing dietary sodium in patients with severe hypertension must be assessed in each case. In addition, since sodium loading typically increases kaliuresis and hypokalemia, serum potassium should be measured daily and vigorous replacement of potassium chloride should be prescribed as indicated.
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.
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 [34,35]. The PAC will fall below 5 ng/dL (139 pmol/L) in normal subjects, whereas values above 10 ng/dL (277 pmol/L) are consistent with primary aldosteronism [34]. 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 [35,36].
Other — Other available confirmation tests include the fludrocortisone suppression and captopril challenge tests. As noted above, we suggest 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 is important since the treatment options are different for the two disorders. We recommend using the algorithm developed at the Mayo Clinic that uses adrenal computed tomography (CT) and adrenal vein sampling (AVS) (algorithm 2) [26]. (See "Treatment of primary aldosteronism".)
●In general, APA patients 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 younger (<50 years) than those with IHA [26]. In one study, a plasma aldosterone concentration/plasma renin activity (PAC/PRA) ratio of >32 had a sensitivity of 100 percent and specificity of 61 percent for an APA [21].
Somatic mutations in KCNJ5, ATP1A1, ATP2B3, CTNNB1, and CACNA1D are found in more than 80 percent of resected APAs [37-40]. In a study of 474 unselected patients with APAs, somatic heterozygous KCNJ5 mutations were present in 38 percent, 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 younger, compared with CACNA1D mutation carriers or noncarriers [38]. However, 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.)
●Bilateral adrenal hyperplasia, which accounts for approximately 60 percent of cases, is generally a milder disease with less hypersecretion of aldosterone and less hypokalemia; it should be treated with a mineralocorticoid receptor antagonist. The cause of primary aldosteronism due to bilateral adrenal hyperplasia has not yet been determined. (See "Treatment of primary aldosteronism".)
●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 cell clusters 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 [41,42].
Adrenal CT — Adrenal computed tomography (CT) should be the initial study to determine subtype (adenoma versus hyperplasia) and exclude adrenal carcinoma [43]. When imaging adrenal glands, CT has superior spatial resolution compared with magnetic resonance imaging (MRI). The CT scan may be done without intravenous contrast; however, if an adrenal mass is detected, contrast administration provides additional imaging information.
●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) [44-48].
●Bilateral adrenal gland thickening or micronodular changes suggests adrenal hyperplasia; however, patients with hyperplasia may also have normal-appearing adrenal glands on CT [45].
●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 vigorous primary aldosteronism, unilateral adrenalectomy is a reasonable therapeutic option [49]. 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).
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 [19]. 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 [46,48,50-52].
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 less than 1 cm in diameter may be missed on CT), and 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) [47,48].
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 [51]. 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 80 of 158 (51 percent) patients [53].
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) [52]. 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 [54]. 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) [51,55,56].
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 but the patient is over age 35 years [49].
We suggest that AVS may not be needed in patients under age 35 years 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 [57]. 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 suggest 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 [51,55].
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 [56,58,59]. However, as noted above, we suggest continuous cosyntropin infusion for optimal results [51,55]. 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) [26,51,60].
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 [51]; 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 [61]. Some centers require only a 10 percent gradient between an adrenal vein and the IVC [56,58], 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 [51]. 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 [51].
●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 [51].
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 [51].
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 [51], indicative of suppression of aldosterone secretion by the noninvolved adrenal gland.
Centers that perform AVS without cosyntropin infusion use lower lateralization cutoff values [56,58]. 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 [49]. These test characteristics deteriorate when lower cutoffs are used to determine successful catheterization and lateralization.
Results — AVS may be most useful when there is no adrenal abnormality 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 [51].
There are isolated cases of primary aldosteronism due to an ectopic adrenal adenoma (as in the kidney) [62]. These patients have low serum aldosterone concentrations in AVS, and CT or MRI may identify the site of the tumor.
One limitation to AVS is an inability to obtain good samples as the right adrenal vein is small and sometimes difficult to locate. 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) [50,51].
The complication rate in published studies is 2.5 percent or less [51,58,60,61,63]. The most common complication is groin hematoma; adrenal hemorrhage and adrenal vein dissection are rare [64].
Tests not recommended — Other tests that have been used in the past to distinguish unilateral APAs from bilateral disease before the development of the adrenal CT and AVS approach 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 (thought to be due to an enhanced sensitivity of the adrenal zona glomerulosa to the small changes in angiotensin II that occur with standing) [65]. In contrast, no such changes would be expected in patients with an APA, because their hypersecretion of aldosterone is autonomous and diurnal.
However, this test does not discriminate well between unilateral adenoma and bilateral hyperplasia [6,44,66,67]. 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) [44].
●18-hydroxycorticosterone – Patients with an APA typically have elevated supine plasma 18-hydroxycorticosterone levels at 8 AM (>100 ng/dL), while patients with bilateral IHA do not [43]. However, the accuracy of the test is low, and it does not help with localization [43,67].
●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 [68]. In addition, 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 [69]
●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) cortisol cosecretion may occur in patients with larger APAs (eg, ≥1.5 cm in diameter) [70]. 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. When autonomous cortisol cosecretion is documented, it is important to cover the patient perioperatively with stress doses of glucocorticoids and a planned postoperative taper.
PREGNANCY — Primary aldosteronism is uncommon in pregnancy, with fewer than 60 patients reported in the medical literature; most patients have had aldosterone-producing adenomas (APAs) [71-75]. Primary aldosteronism can lead to intrauterine growth retardation, preterm delivery, intrauterine fetal demise, and placental abruption [75,76].
Case-detection testing for primary aldosteronism in the pregnant woman is the same as for nonpregnant patients: morning blood sample for the measurement of aldosterone and plasma renin activity or renin concentration (see 'Who should be tested?' above). Suppressed renin and an aldosterone level >10 ng/dL is a positive case-detection test for primary aldosteronism. If spontaneous hypokalemia is present in the woman with high aldosterone (≥20 ng/dL) and suppressed renin, confirmatory testing is not needed. In the normokalemic woman with 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 magnetic resonance imaging (MRI) without gadolinium is the test of choice. Adrenal imaging with computed tomography (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 vigorous primary aldosteronism who are less than 35 years old and have a clear-cut, unilateral adrenal adenoma on cross-sectional imaging [49]. (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
●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 may be more common than hypokalemia in patients diagnosed with primary aldosteronism. (See 'Prevalence of primary aldosteronism' above and 'Variable presentation' above.)
●Importance of testing – Excessive secretion of aldosterone is associated with an increased risk of cardiovascular disease and morbidity, including left ventricular hypertrophy, atrial fibrillation, myocardial infarction, and stroke. (See 'Importance of testing' above.)
●Causes of primary aldosteronism – The most common causes of primary aldosteronism are aldosterone-producing adenomas (APAs) and bilateral adrenal hyperplasia, and in rare cases, familial hyperaldosteronism (FH) type I (glucocorticoid-remediable aldosteronism [GRA]), type II, type III, or type IV. (See 'Subtype classification' above and "Familial hyperaldosteronism".)
●Case detection – Consistent with the Endocrine Society guidelines, we recommend case-detection testing for primary aldosteronism in patients with (see 'Who should be tested?' above):
•Hypertension and spontaneous or low-dose, 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)
•All hypertensive first-degree relatives of patients with primary aldosteronism (see 'Case detection' above)
•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 (typically undetectable) 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 'Case detection' above and 'Initial testing' 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, there is no other diagnosis except primary aldosteronism to explain the findings. (See 'Confirmation of the diagnosis' above.)
●Subtype classification – We suggest adrenal computed tomography (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.)
When the CT scan is normal, shows bilateral abnormalities, or shows a unilateral abnormality, but the patient is over age 35 years, 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). (See 'Adrenal vein sampling' above.)
AVS should only be performed by an experienced radiologist. (See 'Adrenal vein sampling' above.)
DISCLOSURE — 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.
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Norman M Kaplan, MD, who contributed to earlier versions of this topic review.
