Hyperaldosteronism

Alejandro Dominguez; Vijayadershan Muppidi; Stephen Leslie; Sonu Gupta

Hyperaldosteronism

Author: Alejandro Dominguez Author: Vijayadershan Muppidi Author: Stephen W. Leslie Editor: Sonu Gupta Updated: 7/25/2024 2:01:42 PM

Introduction

Aldosterone is a mineralocorticoid hormone that promotes sodium (salt) and water (fluid) retention, ultimately raising blood pressure. Aldosterone also increases urinary potassium excretion, resulting in hypokalemia. Please see StatPearls' companion resource, "Physiology, Aldosterone," for more information. Aldosterone is secreted by the zona glomerulosa—the outermost layer of the adrenal cortex.[1] Excess production of aldosterone is referred to as hyperaldosteronism.[1] This condition typically presents initially as hypertension, which can range from mild to severe and resistant to treatment. Often, the underlying hyperaldosteronism responsible for the hypertension goes undiagnosed.

Hyperaldosteronism can be of primary or secondary origin. Although both forms present similarly, they are differentiated through laboratory testing and diagnostic studies. Primary hyperaldosteronism is characterized by low plasma renin concentrations, usually less than 1 ng/mL/h, and elevated serum aldosterone levels, typically more than 20 ng/dL, due to inappropriate autonomous hypersecretion of adrenal aldosterone. Secondary hyperaldosteronism results from excessive renin production and activity due to various conditions, including renal artery stenosis, left heart failure, liver failure with ascites, cor pulmonale, pregnancy, renin-secreting tumors, excessive licorice ingestion, renal tubular acidosis, nutcracker syndrome, kidney failure, and genetic conditions such as Bartter and Gitelman syndromes.

The initial definitive laboratory measurements to diagnose hyperaldosteronism include plasma renin concentration and activity, serum aldosterone levels, and the aldosterone-to-renin ratio. Please see StatPearls' companion resource, "Primary Hyperaldosteronism," for more information. Patients with hyperaldosteronism, especially women, often experience significant diagnostic delays, with more than one-third of patients waiting over 5 years to receive a correct diagnosis.[2]

Routine screening for hyperaldosteronism (serum aldosterone >20 ng/dL or an aldosterone-to-renin ratio >20:1) is recommended for all patients newly diagnosed with hypertension, particularly those unresponsive to standard antihypertensive medications.[2][3][4][5] Understanding the diagnosis and differentiation of hyperaldosteronism is essential to determine the appropriate treatment, whether surgical for unilateral primary hyperaldosteronism or medical for bilateral adrenal disease and secondary hyperaldosteronism.

Etiology

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Etiology

The underlying cause of the excess aldosterone production differentiates primary from secondary hyperaldosteronism.[6] High serum aldosterone with low renin levels suggests primary hyperaldosteronism, while high plasma renin indicates secondary disease.

Primary Hyperaldosteronism

Primary hyperaldosteronism, also known as Conn syndrome, was first described in 1956 and is caused by excessive autonomous aldosterone production by the adrenal gland, specifically the zona glomerulosa. Please see StatPearls' companion resource, "Physiology, Adrenal Gland," for more information.[7] In 90% of patients, primary hyperaldosteronism most often presents as a unilateral hypersecreting glandular adrenal tumor, but it may also present as bilateral adrenal hyperplasia. Please see StatPearls' companion resource, "Conn Syndrome," for more information.[8] "Primary hyperaldosteronism" is the preferred terminology, whether due to a unilateral primary adenoma, which is treated surgically, or bilateral idiopathic adrenal hyperplasia, managed medically.

Infrequent forms of primary hyperaldosteronism include unilateral adrenal hyperplasia, ectopic aldosterone-secreting tumors (usually in the kidneys or ovaries), aldosterone-producing adrenocortical carcinomas, and familial hyperaldosteronism, with type I being the most common.[1] Newer data suggest that the incidence of bilateral adrenal hyperplasia may account for up to 75% of all cases of primary hyperaldosteronism.

Genetic causes of primary hyperaldosteronism are rare. However, 3 types of familial hyperaldosteronism are usually described in the literature, as mentioned below.

Type I familial primary hyperaldosteronism: This is caused by a 2-part chimeric gene (CYP11B1/CYP11B2) with a regulatory segment from 11B-hydroxylase and a synthesis portion from aldosterone synthase.[9] When adrenocorticotropic hormone (ACTH) stimulates the gene, it activates the aldosterone synthase portion and increases aldosterone production. Type I familial primary hyperaldosteronism is a rare autosomal dominant heritable disorder associated with increased production of 18-oxocortisol and 18-hydroxycortisol.[9] The condition is glucocorticoid-remediable. Please see StatPearls' companion resource, "Conn Syndrome," for more information.[9][10][9][11][12]

Type II familial primary hyperaldosteronism: This is associated with band 11q13 of gene 7p22, resulting in the histological equivalent of adrenal hyperplasia.[9] This type of familial primary hyperaldosteronism is not glucocorticoid-remediable. Please see StatPearls' companion resource, "Conn Syndrome," for more information.[9][10][11][12]

Type III familial primary hyperaldosteronism: This occurs due to a T158A mutation in a potassium channel gene, KCNJF, which increases cellular calcium levels, leading to increased aldosterone production by the glomerulosa cells.[9][11][13] Type III familial primary hyperaldosteronism is not glucocorticoid-remediable. Please see StatPearls' companion resource, "Conn Syndrome," for more information.[9][10][11][12]

Secondary Hyperaldosteronism

Secondary hyperaldosteronism occurs due to excessive and inappropriate activation of the renin-angiotensin-aldosterone system (RAAS). Please see StatPearls' companion resource, "Physiology, Renin Angiotensin System," for more information. Any reduction in renal blood flow can stimulate the RAAS, resulting in increased aldosterone production and secretion. Please see StatPearls' companion resource, "Bartter Syndrome," for more information. This overproduction can result from a renin-producing tumor, hyperkalemia from chronic renal failure, or renal artery stenosis, as well as generalized edematous disorders like left ventricular heart failure, pregnancy, cor pulmonale, Bartter or Gitelman syndrome, nutcracker syndrome, hepatic cirrhosis with ascites, obstructive sleep apnea, or nephrotic syndrome. Please see StatPearls' companion resource, "Bartter Syndrome," for more information.

In some cases, such as cardiac failure, aldosterone production may be within the normal range; however, its metabolism by the liver may be reduced due to decreased hepatic blood flow, resulting in elevated serum levels of aldosterone. Patients with secondary hyperaldosteronism tend to have higher blood pressures and greater levels of serum aldosterone than those with primary disease.

Epidemiology

Primary hyperaldosteronism can be seen in at least 10% of all patients with hypertension.[4][14][15][16] The incidence of primary hyperaldosteronism increases with the severity of the associated hypertension.[17] The prevalence is over 20% in patients with resistant hypertension, especially in those younger than 40 or those who exhibit hypokalemia.[17][18][19][20][21][22] Earlier studies grossly underestimated the incidence of hyperaldosteronism due to differences in patient selection, diagnostic methods, definitions of hypertension, and a general failure to test patients who met the currently recommended criteria for screening.[20][21][23][24][25][26][27]

Secondary hyperaldosteronism is diagnosed less often than primary hyperaldosteronism. Both primary and secondary hyperaldosteronism are more prevalent in women. Africans and Black Americans tend to have a higher prevalence of hyperaldosteronism than the general population, particularly idiopathic bilateral adrenal hyperplasia.[28][29]

Pathophysiology

Aldosterone is the primary mineralocorticoid in the body, acting on the epithelial sodium channels in the collecting tubules and causing sodium reabsorption. This creates a negative potential in the tubular lumen, leading to the movement of cations, primarily potassium and hydrogen ions, into the tubular lumen to maintain electrical neutrality. This process results in hypokalemia, aciduria, and metabolic alkalosis. Please see StatPearls' companion resource, "Physiology, Aldosterone," for more information. The increased reabsorption of sodium and water leads to intravascular volume expansion and hypertension.[23]

Aldosterone production is usually confined to the zona glomerulosa of the adrenal glands, where aldosterone synthase enzymatically converts 11-deoxycorticosterone to aldosterone, a process mediated by serum potassium and angiotensin II levels.[1] ACTH also stimulates aldosterone production, contributing to the observed diurnal pattern of hormone secretion.[1]

Primary Hyperaldosteronism

Primary hyperaldosteronism occurs due to excess autonomous aldosterone production by the adrenal gland.[1] The most common causes of primary hyperaldosteronism are idiopathic bilateral adrenal hyperplasia and a hypersecreting adenomatous tumor in the zona glomerulosa, both of which can directly cause an inappropriate increase in serum aldosterone. Please see StatPearls' companion resource, "Conn Syndrome," for more information. These patients are often asymptomatic but typically present with hypertension that is difficult to control; hypokalemia may also be present.[24] Both primary and secondary hyperaldosteronism can present with a broad clinical range.[23] Approximately one-fifth of all patients with primary hyperaldosteronism will also demonstrate reduced glucose tolerance from their hypokalemia, even though the overall incidence of diabetes is the same as in the general population.[30][31][32][33] Metabolic alkalosis may also be present.

The renal response to decreased vascular perfusion or increased serum renin levels causes secondary hyperaldosteronism. The juxtaglomerular cells detect this reduction in renal blood flow and release renin, which activates the renin-angiotensin system and synthesizes angiotensin II. Angiotensin II increases systemic blood pressure by enhancing proximal tubular sodium reabsorption, causing generalized vasoconstriction, and stimulating aldosterone secretion. The net effect is sodium retention, increased intravascular volume, high renin levels, elevated blood pressure, and secondary hyperaldosteronism.

The following 3 pathophysiological features of primary hyperaldosteronism, as originally described by Conn et al in 1964, remain the mainstay of the diagnostic approach:

Autonomous aldosterone production lowers plasma renin, producing a high aldosterone-to-renin ratio and a low serum renin level.
Reduced renin response to stimulation (eg, administering an angiotensin-converting enzyme [ACE] inhibitor).
Lack of suppression of aldosterone production by volume expansion or salt loading, usually tested by an intravenous saline infusion or significant dietary salt ingestion.[17][34]

Secondary Hyperaldosteronism

Secondary hyperaldosteronism occurs due to the excess stimulation of the RAAS. While it can result from the physiological state of transient RAAS activation (eg, hypovolemia), it is also seen in pathological states of sustained activation of the system, including the following conditions:

Renal artery stenosis (eg, atherosclerosis or fibromuscular dysplasia) decreases kidney blood flow, stimulates a false sense of hypovolemia, and increases aldosterone secretion.

Left-sided congestive heart failure and cor pulmonale cause a decrease in cardiac output, leading to stimulation of aldosterone production.

In patients with cirrhosis, nephrotic syndrome, and ascites, the reduction in circulating fluid volume leads to decreased perfusion through the kidneys and results in increased aldosterone secretion.

Poor hepatic blood flow causes secondary hyperaldosteronism due to decreased liver metabolism of aldosterone, resulting in higher serum levels even though adrenal production of the hormone is in the normal range.

RAAS can also be activated by a renin-producing tumor in the juxtaglomerular cells, although this is a very uncommon finding. Please see StatPearls' companion resource, "Bartter Syndrome," for more information.

Histopathology

Histopathology is not typically used as a standard tool for diagnosing hyperaldosteronism, although immunohistochemical staining can be helpful. Up to one-third of aldosterone-producing adrenal adenomas may show hyperplasia of the zona glomerulosa. This hyperplasia can be localized to a broad area or present as generalized thickening throughout the cortex. Extensions of the cortical glomerulosa may also appear to penetrate centrally.

Idiopathic bilateral hyperaldosteronism exhibits a variable histological appearance, ranging from nearly normal-appearing hyperplasia to micronodular and macronodular patterns. Immunohistochemical staining of cytochrome P450 (CYP)-11B2 in aldosterone-producing adenomas has proven highly valuable. This staining helps differentiate among the various types and subtypes of adenomas, micronodules, and aldosterone-producing cell clusters, with CYP-11B1 stains being positive for cortisol-producing cells.[35]

History and Physical

Clinical Features of Hyperaldosteronism

The clinical features of hyperaldosteronism can vary depending on the severity and may sometimes be asymptomatic. Resistant hypertension is the most common presenting symptom for these patients, especially when associated with hypokalemia. A characteristic presentation of hyperaldosteronism is a young woman who remains inadequately controlled on 3 or more antihypertensive medications.[24] Other common symptoms include fatigue, headache, weakness, abdominal distension, ileus, polyuria, polydipsia, and nephrogenic diabetes insipidus secondary to hypokalemia.

Blood pressure in hyperaldosteronism can range from normotensive to severe hypertension and is often refractory to standard antihypertensive treatments. Hypertension in aldosteronism is primarily caused by sodium reabsorption, volume expansion, and increased peripheral vascular resistance.[23] Symptoms are typically a result of moderate to severe hypertension or secondary to hypokalemia. High blood pressure may lead to headaches, dizziness, vision problems, chest pain, and dyspnea. Additionally, antidiuretic hormone resistance in the renal tubules due to hypokalemia can contribute to diabetes insipidus in aldosteronism.[23]

Hypokalemia may lead to muscle weakness, fatigue, cardiac palpitations, cramps, polydipsia, and polyuria due to nephrogenic diabetes insipidus. A thorough medical history should also be obtained, as there may be a family history of hypertension or early cardiovascular events, such as stroke.[23]

Patients with secondary hyperaldosteronism may present with varying blood pressure levels, but most will have some degree of hypertension. Conditions such as renal artery stenosis and coarctation of the aorta also contribute to elevated blood pressure. Please see StatPearls' companion resource, "Renal Artery Stenosis," for more information. Hypovolemia can occur in patients using diuretics or with heart failure, cirrhosis, or nephrotic syndrome. Gitelman and Bartter syndromes often present with mild hypotension. Please see StatPearls' companion resources, "Bartter Syndrome" and "Gitelman Syndrome" for more information.[23] Although no specific physical signs are diagnostic of hyperaldosteronism, long-term hypertension can lead to left ventricular hypertrophy, which may manifest as an S4 heart sound due to the passage of blood into a stiff and noncompliant left ventricle. Other signs of chronic hypertension may also be observed.

Risk Factors for Hyperaldosteronism

Factors associated with an increased risk for hyperaldosteronism include:

Family history of hypertension or cardiovascular events at young ages.
Hypertension, diagnosed before age 40.
Hypokalemia, whether spontaneous or induced by thiazide diuretics.
Incidental discovery of an adrenal adenoma in a patient with hypertension, particularly if the blood pressure is difficult to control.
Resistant or intractable hypertension, which remains poorly controlled despite the use of 3 or more standard antihypertensive medications, including a diuretic.[17]

Evaluation

Hyperaldosteronism Screening

Screening for hyperaldosteronism is recommended for all patients newly diagnosed with hypertension, especially those with early-onset significant hypertension, hypokalemia, resistant or intractable high blood pressure, obstructive sleep apnea, or an adrenal mass. The high prevalence of hyperaldosteronism among hypertensive individuals, with many cases going undiagnosed, underscores the importance of such screening.[4][5][20][24][36][37][38][39][40][41]

Hyperaldosteronism screening is grossly underutilized, with only about 3% of patients with resistant hypertension receiving appropriate testing.[27][42][43] Frequent misdiagnosis of hyperaldosteronism is due to several factors, including a general lack of awareness about its prevalence, high levels of subclinical hyperaldosteronism in the population, complexity of confirmatory testing, absence of standardized screening protocols, high prevalence of atypical presentations, and difficulties in interpreting test results.[20][44][45][46]

Screening for hyperaldosteronism typically involves a simple plasma renin and aldosterone blood test. A low renin level combined with an aldosterone-to-renin ratio of more than 20 or a plasma aldosterone concentration (PAC) of more than 20 ng/dL commonly indicates hyperaldosteronism. Please see StatPearls' companion resource, "Primary Hyperaldosteronism," for more information.[1][41][47] Confirmatory testing, computed tomography (CT) imaging, and selective bilateral adrenal venous sampling may then be performed.[48]

Laboratory Findings Suggestive of Hyperaldosteronism

The aldosterone-to-renin ratio has long been considered a reliable screening test for hyperaldosteronism, but results may be somewhat variable in certain situations.[17][49][50] The levels should be drawn in the morning, and any interfering drugs should be eliminated, but this is not always safe or practical.[17][24][51] The aldosterone-to-renin ratio can be affected by posture, diurnal variations, electrolytes (eg, potassium levels), and several medications other than anti-hypertensives, including various antidepressants, antihistamines, dopaminergic meds, estrogens, licorice, and nonsteroidal anti-inflammatory drugs (NSAIDs).[17][24][51][52][53][54] Other laboratory findings may demonstrate hypokalemia, mild hypernatremia, and mild hypomagnesemia, but these are not diagnostic.[55][56][57]

Hypokalemia has historically been considered a hallmark finding closely associated with hyperaldosteronism but is now recognized as a relatively rare occurrence.[17][58][59][60] Therefore, the lack of hypokalemia should not be used to exclude a diagnosis of hyperaldosteronism.[17] Current estimates indicate that less than 37% of those with confirmed primary hyperaldosteronism will demonstrate low serum potassium levels.[29] Metabolic alkalosis is frequently observed in hyperaldosteronism due to the net loss of hydrogen ions in the urine from aldosterone-induced renal sodium retention, in which hydrogen ions are excreted in exchange for sodium.[61] The historically well-documented association of hyperaldosteronism with hypokalemia has been observed in fewer than 40% of patients in published studies.

The role of the 24-hour urine collection in hyperaldosteronism is controversial, although it can detect inappropriate potassium wasting, defined as >30 mEq/d.[62][63][64] This test can be useful in evaluating the role of extrarenal losses and diuretic abuse in hypokalemia, especially when the increase in aldosterone is barely detectable to mild. A urinary aldosterone-to-creatinine ratio has been suggested to facilitate the initial diagnosis of primary hyperaldosteronism by using an aldosterone-to-creatinine ratio of 3 ng aldosterone per 1 mg creatinine as the threshold.[65] The validity of this test has not yet been established or fully verified.[65]

Primary Hyperaldosteronism Diagnostic Evaluation

In primary hyperaldosteronism, plasma renin activity (PRA) is less than 1 ng/mL/h, and the plasma renin concentration is either very low or undetectable. Excess aldosterone originates from the zona glomerulosa itself and not an extrinsic pathway. Therefore, a morning serum aldosterone-to-renin ratio of more than 20:1 indicates a renin-independent etiology consistent with primary hyperaldosteronism.[1]

The PAC/PRA ratio is a confirmatory test for primary hyperaldosteronism. Most studies support an elevated PAC/PRA ratio of more than 30:1 and a PAC of more than 20 ng/dL with a sensitivity and specificity of more than 90% as being diagnostic for primary hyperaldosteronism. Please see StatPearls' companion resource, "Primary Hyperaldosteronism," for more information. However, a PAC/PRA ratio greater than 20:1 and a PAC of more than 15 ng/dL are reportedly sufficient to support the diagnosis. Please see StatPearls' companion resource, "Primary Hyperaldosteronism," for more information.[24][66][67]

Secondary Hyperaldosteronism Diagnostic Evaluation

In secondary hyperaldosteronism, both the plasma renin concentration and PRA levels are increased, as renin is the primary stimulator for the excess production of aldosterone, and the serum aldosterone-to-renin ratio will, therefore, be much lower than in primary hyperaldosteronism. These levels are usually measured in the morning after patients have been out of bed. The results are more accurate when the labs are drawn at least 2 hours after the patient is out of bed and spends at least 5 minutes sitting. The serum aldosterone-to-renin ratio will be less than 20:1. PRA, plasma renin concentration, and renin levels increase in secondary hyperaldosteronism, but the PAC/PRA ratio is less than in primary hyperaldosteronism.[24][66][67][68]

Primary Versus Secondary Hyperaldosteronism

Serum renin levels are the most effective way to differentiate between primary and secondary hyperaldosteronism.[34] Primary hyperaldosteronism always significantly suppresses renal renin production, whereas secondary hyperaldosteronism is associated with elevated serum renin concentrations.[32] Secondary hyperaldosteronism tends to have higher aldosterone levels and blood pressure.

Hyperaldosteronism Confirmation

Confirmation of primary hyperaldosteronism may not be necessary in selected cases that demonstrate the combination of a markedly elevated plasma aldosterone, suppressed serum renin, hypokalemia, and resistant hypertension, although localization studies would still be needed.[41][69][70]

Confirmatory testing for hyperaldosteronism typically includes measuring an elevated serum aldosterone level, conducting a 24-hour urinary aldosterone excretion test, or performing an aldosterone suppression test using salt-loading, captopril, or fludrocortisone, which would typically be expected to cause aldosterone suppression. All of these tests, except the captopril suppression test, may increase hypertension, induce fluid overload, and produce hypokalemia.[41] No specific confirmatory test is officially preferred; however, a comparative meta-analysis suggested that the captopril challenge test may be the most feasible as it is easy to perform and considered relatively safe.[41][71]

Before performing confirmatory testing, any existing hypokalemia should be corrected.[41] Negative or equivocal results from confirmatory testing in patients with positive blood screening of an aldosterone-to-renin ratio of more than 20 with low serum renin likely have mild hyperaldosteronism. They are typically treated medically with mineralocorticoid receptor antagonists (eg, spironolactone).[41] Each of these confirmatory tests is conducted using the methods mentioned below.

Oral salt-loading test: This test usually involves significant dietary sodium loading and subsequent measurement of aldosterone levels. The oral salt-loading test consists of oral sodium loading over 3 days, usually 5000 to 6000 mg of dietary sodium daily or 90 mEq sodium tablets. Potassium supplements are provided to those who develop hypokalemia. After the sodium loading, a 24-hour urine aldosterone measurement is taken, with a value of more than 12 mcg/d commonly used to confirm primary hyperaldosteronism. Adequate oral salt intake is indicated by a 24-hour urine sodium test of more than or equal to 200 mEq. Some considerations with this test include the fact that renal failure can complicate result interpretation by producing false negatives. Additionally, the test should not be administered to patients with a history of congestive heart failure, uncontrolled significant hypertension, or cardiac arrhythmias.[41]

Intravenous salt-loading test: This test is performed by administering 2 L of isotonic saline intravenously over 4 hours. Plasma aldosterone levels greater than 10 ng/dL following the infusion are consistent with primary hyperaldosteronism; however, the saline infusion has a false-negative rate of 30%.[24] A modified version of the saline infusion test, which includes 0.5 mg of oral dexamethasone every 6 hours for 2 days, has demonstrated greater sensitivity.[72] Drawbacks of this test include the need for hospitalization and potential risks such as fluid overload, worsening heart failure, hypokalemia, and increased blood pressure.

Captopril suppression test: The results of this test confirm primary hyperaldosteronism by evaluating the response to captopril—an angiotensin II blocker. In patients with primary hyperaldosteronism, aldosterone production remains elevated, while it should decrease in all other conditions. Patients are administered 25 to 50 mg of captopril, and serum aldosterone, renin, and cortisol levels are measured before and 1 to 2 hours after captopril administration.

In primary hyperaldosteronism, aldosterone is expected to decrease by at least 30%, resulting in an aldosterone-to-renin ratio of less than 30:1. However, serum aldosterone levels will typically remain elevated (≥8.5 ng/dL) with an aldosterone-to-renin ratio greater than 30:1 and low renin levels. The captopril suppression test is relatively safe, quick to perform as an outpatient, and inexpensive. Despite this, it has a relatively high rate of equivocal and false-negative results. Additionally, it is not recommended for suspected renovascular hypertension and may cause angioedema.[41]

Fludrocortisone suppression test: This test aims to lower aldosterone levels by administering oral fludrocortisone along with potassium supplementation and salt loading. If aldosterone levels are not adequately suppressed after 4 days of treatment, it is considered confirmatory for primary hyperaldosteronism.[73][74] Patients receive 0.1 mg of oral fludrocortisone every 6 hours, with potassium and sodium chloride tablets taken 3 times daily with meals and a high sodium diet. Aldosterone and renin levels are measured after 4 days.

A serum aldosterone level of more than 6 ng/dL is considered a positive test and indicative of primary hyperaldosteronism.[73][74] However, this test is labor-intensive and relatively costly. Adding a 2 mg dose of dexamethasone at midnight can enhance the reliability, sensitivity, and specificity of the fludrocortisone suppression test, improving its ability to detect milder forms of primary hyperaldosteronism.[75][76][77][78][79][80]

Negative or equivocal results from confirmatory testing in patients with positive blood screenings showing an aldosterone-to-renin ratio >20 with low serum renin suggest probable mild hyperaldosteronism. Such cases are generally treated medically with mineralocorticoid receptor antagonists, such as spironolactone.[41]

Differentiating Unilateral From Bilateral Disease

Determining laterality is essential as it directly affects treatment and outcomes. Differentiating between adenoma and adrenal hyperplasia also aids in establishing laterality. The following findings may be helpful:

Serum 18-hydroxycorticosterone levels are elevated in adenomas but normal in bilateral adrenal hyperplasia. Please see StatPearls' companion resource, "Conn Syndrome," for more information.

An adrenal adenoma shows a paradoxical decrease in serum aldosterone levels after 2 hours of upright positioning, whereas adrenal hyperplasia usually shows a normal or expected increase. Please see StatPearls' companion resource, "Conn Syndrome," for more information.

Adrenal adenomas that autonomously overproduce aldosterone tend to be glucocorticoid-responsive, while bilateral idiopathic adrenal hyperplasia is generally not, although it may still respond somewhat to serum renin levels.[81]

None of these findings are considered definitive to demonstrate laterality, which would require imaging studies or the more challenging but definitive adrenal vein sampling procedure.

Diagnostic studies: Radiological imaging, such as a CT scan, can distinguish adenomas from bilateral adrenal hyperplasia. However, studies have found that CT imaging alone cannot always reliably distinguish between them.[82] The overall sensitivity and specificity of CT imaging for aldosterone-producing adenomas are about 78% and 75%, respectively.

All patients with primary aldosteronism should undergo imaging to rule out large adrenal masses or carcinomas.[24] Aldosterone-producing adrenal tumors tend to be homogenous and lipid-rich with low Hounsfield density numbers, but imaging alone cannot reliably distinguish between functioning and nonfunctioning adrenal adenomas.[83][84][85] However, nonfunctional adrenal adenomas are extremely rare in children and young adults.[24]

Adrenal vein sampling is used to differentiate unilateral from bilateral pathology if radiological imaging is not helpful and the patient is potentially a candidate for adrenal surgery.[41] Cortisol and aldosterone are measured in the right and left adrenal veins (LAVs); cortisol is used to verify catheter placement. Bilateral hyperplasia will demonstrate similar values on either side. However, a significant variance in the aldosterone concentration, at least double, or an aldosterone-to-cortisol ratio of at least 5-fold between the 2 sides suggests unilateral disease.[1][24][86][87] A 4-fold difference in adrenal vein aldosterone levels is used as the cutoff threshold when optional cosyntropin stimulation is administered.[24][86][87]

Adrenal vein sampling is not recommended in patients aged 35 and younger with spontaneous hypokalemia, marked levels of aldosterone, and highly suspicious adrenal adenomas on CT imaging. Nonfunctioning adrenal adenomas are rare in such younger populations. However, adrenal vein sampling is not required even in patients aged 40 or older with marked hyperaldosteronism with a clear solitary, unilateral adrenal adenoma on CT, those who are not surgical candidates, those suspected of adrenal cancer, and those with known familial hyperaldosteronism.[88]

Adrenal vein sampling is still considered the gold standard for differentiating unilateral from bilateral adrenal hyperaldosteronism.[41] However, the test is complex and technically demanding, as the vessels are relatively small; therefore, the interpretation can be challenging.[86] The right adrenal vein, in particular, can be exceedingly challenging to cannulate. Even unilateral adrenal vein sampling can be helpful.

In 2016, Pasternak et al suggested the following method for cases where only unilateral adrenal vein sampling was accomplished:

The below formula is used to calculate the LAV/IVC ratio cutoff value:[89]
- (Adrenal vein aldosterone ÷ cortisol) / (inferior vena cava [IVC] aldosterone ÷ IVC cortisol).

Values greater than 5.5 indicate unilateral hyperaldosteronism on the side tested, while results less than 0.5 predict the same but on the contralateral side.[89]

Values between 5.5 and 0.5 are not interpretable and may indicate either bilateral or unilateral disease.[89]

This method has an estimated specificity of 100% but only 50% sensitivity; other studies have confirmed these findings.[89][90][91]

Adrenal venous sampling carries risks, including adrenal venous rupture, infarction, thrombus formation, bleeding, and hematoma formation. Therefore, the procedure should ideally be performed in centers of excellence with experience and expertise in this procedure. For these reasons, various noninvasive alternative diagnostic modalities to adrenal venous sampling are being explored. These tend to be cumbersome to perform with somewhat limited accuracy but may be helpful where there is experience and availability.

Alternative diagnostic modalities: Alternative diagnostic modalities for determining laterality in hyperaldosteronism include:

Scintigraphy with NP-59 (131 I-6-β-iodomethyl-19-norcholesterol) with dexamethasone suppression can be used in selected cases to help differentiate between unilateral functioning adenomas and bilateral hyperplasia, especially if adrenal vein sampling is unsuccessful or cannot be performed and the patient would otherwise be a candidate for surgical intervention.[92][93][94] This modality can also identify laterality in primary hyperaldosteronism and may be beneficial in patients with chronic kidney disease where standard biochemical testing is more problematic.[93][94] The positive predictive value and sensitivity in this modality have been reported as about 92%.[93] However, it is a difficult test and may not be available in many centers.

The ¹¹C-metomidate positron emission tomography (PET)-CT scanning modality with and without dexamethasone suppression is a sensitive and specific test for primary hyperaldosteronism and adrenocortical tumors.[95][96][97][98][99][100] In addition, this scan may reliably predict the response to medical therapy for hyperaldosteronism.[98]

Gallium-68 pentixafor PET-CT scanning has demonstrated a correlation in differentiating between unilateral and bilateral hyperaldosteronism.[101] In a study, the gallium-68 PET-CT scan showed a 90% correlation with adrenal vein sampling compared to only 54% with CT scans.[101]

Genetic Testing

Genetic testing is recommended for patients with primary aldosteronism who are aged 20 or younger or have a family history of the disorder. Familial hyperaldosteronism accounts for approximately 6% to 7% of all adult cases of primary hyperaldosteronism. Notably, 4 types of familial hyperaldosteronism have been described, with type I (glucocorticoid-responsive hyperaldosteronism) and type III (glucocorticoid-unresponsive hyperaldosteronism) being the most common.[24] In severe cases, bilateral adrenalectomies may be necessary to manage blood pressure and severe hypokalemia, which requires lifelong glucocorticoid and mineralocorticoid replacement therapy.

Hyperaldosteronism Evaluation Summary

The initial step in evaluating hyperaldosteronism is to differentiate between primary and secondary hyperaldosteronism. This is relatively straightforward, as primary hyperaldosteronism is characterized by a high aldosterone-to-renin ratio (>20:1) and low serum renin levels. A confirmatory test is typically recommended but may be omitted in selected cases.[17][23][69][70]

If primary hyperaldosteronism is diagnosed, the next step is to differentiate between unilateral disease, which is treated surgically, and bilateral disease, which is managed with medical therapy.[102][103][104][105] Unilateral disease is traditionally confirmed with bilateral selective adrenal venous sampling, although CT scans and other imaging modalities may also be utilized.[24][86] Secondary hyperaldosteronism, characterized by elevated serum renin levels, is best treated by eliminating the underlying etiology and using appropriate medical therapy.

Treatment / Management

Unilateral Primary Hyperaldosteronism Management

Primary hyperaldosteronism caused by unilateral disease is best treated surgically. Robotic or laparoscopic adrenalectomy is preferred as these procedures are associated with fewer complications and a shorter hospital stay compared to open surgery.[83] Complete adrenalectomy is preferred to partial gland removal due to greater efficacy and resolution of symptoms. Primary hyperaldosteronism is the most frequently encountered surgically curable etiology of hypertension.[106]

Preoperative spironolactone to control blood pressure for 4 to 6 weeks is recommended. Patients who fail to normalize their blood pressure on spironolactone preoperatively are likely to continue to be hypertensive even after surgery. Following surgery, about two-thirds of patients will eventually develop stable, normal blood pressure, although this may take a year. Please see StatPearls' companion resource, "Conn Syndrome," for more information.

Patients with hyperaldosteronism due to unilateral disease fare better long-term with surgery than with medical therapy regarding blood pressure control, maintaining serum potassium levels, and improved vascular remodeling.[107] Failure of surgery to control hypertension despite the normalization of aldosterone levels suggests the following:

An erroneous or inadequate initial diagnosis of unilateral hyperaldosteronism
Underlying essential hypertension
Vascular abnormalities or damage from chronic hyperaldosteronism
Other unrelated causes of hypertension (eg, pheochromocytoma or renovascular disease)

Good outcomes from surgery without adequate localization occur in less than 20% of patients.[108] The medical therapy of choice for nonsurgical candidates is mineralocorticoid receptor antagonists, such as spironolactone and eplerenone. Please see StatPearls' companion resources, "Spironolactone" and "Eplerenone," for more information.[109][110][111] Amiloride, a potassium-sparing diuretic, may also be used.[41](B2)

Transcatheter and percutaneous adrenal ablation appear to be acceptable, less invasive surgical therapies for primary unilateral hyperaldosteronism, with a clinical success rate reported at about 75%.[112][113][114][115][116][117] These procedures are currently recommended for suitable patients unwilling to have surgery or take long-term medications.[112][113][114][115][116][117] Partial adrenalectomy may be possible in some patients as it provides similar outcomes with fewer postoperative complications, but it carries a potential risk of leaving part of the abnormal aldosterone-secreting tissue behind.[118](A1)

Treatment of Primary Hyperaldosteronism Secondary to Bilateral Hyperplasia

Mineralocorticoid receptor antagonists are the treatments of choice for primary hyperaldosteronism caused by bilateral hyperplasia and for patients who are not surgical candidates. Spironolactone or eplerenone is most commonly used. see StatPearls' companion resources, "Spironolactone" and "Eplerenone," for additional information. Selection among these agents depends on the adverse effect profile, physician experience, and individual patient characteristics.

Spironolactone

Spironolactone is usually the preferred medical therapy, starting at 12.5 to 25 mg daily and titrated upward every 2 weeks according to the 2016 Endocrine Society Guidelines.[111] Maintenance is often reached at a daily dosage of about 100 mg of spironolactone. Please see StatPearls' companion resource, "Spironolactone," for more information. Gynecomastia is a significant known adverse effect of spironolactone use in men, which may occur in up to 50% of male patients who take more than 150 mg daily. Please see StatPearls' companion resource, "Spironolactone," for more information.

Eplerenone

Eplerenone is a more specific medication that, unlike spironolactone, does not block androgen receptors. This makes it more acceptable and preferred for long-term treatment in men as it avoids possible gynecomastia and erectile dysfunction, especially if low-dose spironolactone is not effective. Eplerenone has a relatively short half-life of about 4 hours, which is longer than spironolactone's half-life of only 1.4 hours. However, spironolactone is more effective in controlling blood pressure.[119] Eplerenone is usually started at 50 mg daily and titrated upward, up to a maximum of about 200 mg twice a day. Please see StatPearls' companion resources, "Spironolactone" and "Eplerenone," for additional information.(A1)

Other Potassium-Sparing Diuretics

The clinical course ultimately dictates the drug selection, dosage, and frequency. Reports of spontaneous remission of primary hyperaldosteronism after long-term therapy with mineralocorticoid receptor antagonist medications are rare.[120] Triamterene and amiloride are potassium-sparing diuretics that may have an adjunctive role in managing aldosterone-related hypertension. However, amiloride is preferred as triamterene may form urinary calculi. Please see StatPearls' companion resource, "Triamterene," for more information.[121][122][123][124]

Canrenone is an active metabolite of spironolactone with similar activity but a much longer half-life (16.5 hours versus 1.4 hours) and fewer sexual adverse effects.[125] Canrenone appears to have a direct beneficial myocardial effect beyond its antihypertensive actions. Although currently available in Europe, canrenone is not yet available in the United States. Medications specifically targeting aldosterone-producing adrenal CYP-11B2 cells are being developed and investigated, though this is complex due to the close similarity between CYP-11B2 and CYP-11B1 cells.[126][127][128](B3)

Combination therapy

Combination therapy, including medications, sodium restriction (usually <100 mEq/d), avoidance of alcohol, smoking cessation, aerobic exercise, and maintaining ideal body weight, generally yields the best results.[111][129][130] Additional treatments, such as glucocorticoids, amiloride, and calcium channel blockers, may be used to manage hypertension and other symptoms not adequately controlled by mineralocorticoid receptor antagonists alone.[41] In rare cases, surgery involving bilateral adrenalectomies may be considered for patients with hyperaldosteronism secondary to bilateral adrenal hyperplasia who are refractory to maximum medical treatment.[131](B3)

Secondary Hyperaldosteronism Management

Secondary hyperaldosteronism is best managed by addressing the underlying disease, which typically resolves the symptoms. ACE inhibitors (ACE I) and angiotensin receptor blockers are preferred for blood pressure control in these patients due to their renal protective benefits. Please see StatPearls' companion resource, "Spironolactone," for more information. In addition, salt restriction is recommended for better control of blood pressure.[132](A1)

Potassium supplements and potassium-sparing diuretics may also be used to manage secondary hyperaldosteronism. The treatment approach is similar to that for primary hyperaldosteronism caused by idiopathic adrenal hyperplasia. In cases of renal artery stenosis, surgical intervention or revascularization may be necessary to achieve optimal blood pressure control. Please see StatPearls' companion resource, "Renal Artery Stenosis," for additional information.

Differential Diagnosis

Presentations similar to hyperaldosteronism can be observed in various conditions, including essential hypertension, Liddle syndrome, syndrome of apparent mineralocorticoid excess, congenital adrenal hyperplasia, primary glucocorticoid resistance, Cushing syndrome (hypercortisolism), aldosterone-producing renin-responsive adenomas, adrenocortical carcinomas, metabolic alkalosis, diabetes insipidus, preeclampsia, Gitelman syndrome, renal artery stenosis, Bartter syndrome, pheochromocytoma, Chrétien syndrome, excessive licorice intake, and ectopic ACTH syndrome. Please see StatPearls' companion resources, "Bartter Syndrome" and "Gitelman Syndrome" for more information.[1][41][133]

The following presentations are some of the shared clinical features:

17-Alpha-hydroxylase deficiency: This condition can closely mimic hyperaldosteronism.[134] Patients typically present with hypogonadism and immature genitalia.[134] Genetic testing may be required for a definitive diagnosis.[134] Please see StatPearls' companion resource, "17-Hydroxylase Deficiency," for additional information.

Chrétien syndrome: This syndrome is a rare disorder caused by excess secretion of proopiomelanocortin, a precursor of ACTH, from a pituitary adenoma. This results in adrenocortical hypertension.[135]

Congenital adrenal hyperplasia: This condition is typically associated with a family history of 11-beta-hydroxylase or 17-alpha-hydroxylase deficiency and is characterized by low aldosterone levels. Please see StatPearls' companion resources, "Congenital Adrenal Hyperplasia" and "17-Hydroxylase Deficiency," for additional information.

Ectopic ACTH syndrome: This condition is characterized by elevated ACTH levels that cannot be suppressed with high-dose dexamethasone. These patients often have an underlying tumor.[136][137][138][139]

Essential hypertension: This condition typically presents with a normal PAC/PRA ratio. Please see StatPearls' companion resource, "Essential Hypertension," for additional information.

Excessive licorice intake: This condition inhibits the renal conversion of cortisol to cortisone, producing a cortisol excess, which acts as a mineralocorticoid agonist simulating hyperaldosteronism.[140][141][140]

Liddle syndrome: This syndrome is a rare genetic disorder that presents with low aldosterone levels and typically manifests in childhood. Symptoms include hypertension, hypokalemia, and metabolic alkalosis, which are similar to mineralocorticoid excess disorders. Liddle syndrome is often referred to as pseudohyperaldosteronism, which is characterized by high urinary potassium secretion and sodium reabsorption in the renal collecting tubules despite low aldosterone levels. Please see StatPearls' companion resource, "Liddle Syndrome (Pseudohyperaldosteronism)," for additional information.

Primary glucocorticoid resistance: This condition features low aldosterone levels, elevated ACTH and cortisol, and often has a family history of the syndrome.[142][143][144]

Syndrome of apparent mineralocorticoid excess: This syndrome presents with hypertension, low aldosterone levels, high urinary free cortisol levels, hypokalemia, ACTH suppression, hereditary implications, and a history of excessive licorice consumption.[145] Genetically, it is an autosomal recessive disorder.[145]

Hyperaldosteronism and Hypercortisolism

Hyperaldosteronism and hypercortisolism (ie, Cushing syndrome and disease) share several clinical and laboratory features due to their involvement with abnormal adrenal function. Both conditions are 3 times more common in women than in men, are most frequently diagnosed in patients aged 25 to 50, and typically present with hypertension, hypokalemia, and hypernatremia.

In hyperaldosteronism, patients typically present with intractable hypertension resistant to standard drug therapies.[24] Hyperaldosteronism is a relatively common disorder, affecting approximately 10% of all hypertensive individuals, with over 20% experiencing resistant hypertension.[21][146] Therefore, hyperaldosteronism should be considered in any patient with hypertension that is difficult to control. Diagnosis often begins with a blood test showing a high aldosterone-to-renin ratio and low plasma renin levels, as previously described. Please see StatPearls' companion resource, "Primary Hyperaldosteronism," for more information.[1][23][35]

Conversely, patients with hypercortisolism often exhibit less severe hypertension. Hypercortisolism is rare, occurring at an estimated rate of 60 cases per million individuals.[147] Hypercortisolism is initially suspected based on clinical features such as weight gain, muscle weakness, thin extremities, a rounded face, a fat pad at the base of the neck, easy bruising, thin skin, acne, hirsutism, and purplish stretch marks. Please see StatPearls' companion resource, "Cushing Syndrome," for more information. A 24-hour urine test for free cortisol is typically used for the initial diagnosis, while a dexamethasone suppression test serves as a confirmatory measure. Please see StatPearls' companion resources, "Dexamethasone Suppression Test" and "Hypercortisolism," for additional information.[146][163]

Prognosis

Few studies have examined mortality rates for either form of hyperaldosteronism, but results suggest that the reported 10-year survival rates for treated patients range from 90% to 95%. The most common morbidity associated with hyperaldosteronism is cardiovascular-related, although overall mortality rates do not significantly differ from those of the general population.

If hypokalemia persists, it can lead to symptoms such as weakness, paralysis, constipation, and polyuria. Additionally, primary hyperaldosteronism and hypokalemia can impair insulin secretion, increasing the risk of developing diabetes mellitus.[30][31][32] About two-thirds of patients become normotensive after adrenal surgery, although this improvement may take up to a year. By 5 years post-surgery, about half of these patients remain normotensive without medication. Untreated hyperaldosteronism is associated with significant morbidity and mortality, largely due to uncontrolled hypertension and cardiac arrhythmias.

Complications

The most common complication and comorbidity associated with hyperaldosteronism is the increased risk of cardiovascular mortality due to excessive aldosterone secretion. Clinical manifestations can include atrial fibrillation, left ventricular hypertrophy, hypertension, myocardial infarction, and stroke.[148][149][150][151][152] In addition, myocardial fibrosis has been reported in patients with long-standing hyperaldosteronism.[153][154]

Postoperative and Rehabilitation Care

Sodium restriction to less than 100 mEq/d, alcohol cessation, smoking cessation, maintaining an ideal body weight, and engaging in regular aerobic exercise are beneficial for postoperative care and overall health maintenance.

Consultations

Endocrinologists and nutritionists are generally well-equipped to manage this condition on a long-term basis. Surgical consultation is indicated for a subset of patients with unilateral primary hyperaldosteronism.

Deterrence and Patient Education

Patients should be thoroughly informed and educated about their condition, emphasizing the importance of adhering to long-term treatment recommendations, including dietary modifications (eg, salt restriction) and full compliance with prescribed medications.

Pearls and Other Issues

Key facts to bear in mind when managing hyperaldosteronism include:

Hyperaldosteronism testing should be routinely considered in all newly diagnosed patients with hypertension that is difficult to control with standard antihypertensives, especially if they are younger than 40, have hypokalemia, or have obstructive sleep apnea.[3][24][40][155]

A morning aldosterone-to-renin ratio is a reasonable initial screening test for hyperaldosteronism.

A PAC/PRA ratio greater than 20:1, with a PAC of more than 20 ng/dL, is highly suggestive of primary hyperaldosteronism, especially when associated with low renin and/or hypokalemia.

Serum renin levels are the most straightforward method for differentiating between primary and secondary hyperaldosteronism. In primary hyperaldosteronism, renin activity is typically suppressed, whereas it is elevated in secondary hyperaldosteronism. Additionally, blood pressure and aldosterone levels are generally higher in secondary hyperaldosteronism compared to primary hyperaldosteronism.

A 17-alpha-hydroxylase deficiency can closely mimic primary or secondary hyperaldosteronism. Patients with this deficiency will often present with juvenile, undeveloped genitalia and hypogonadism.[134]

Normal serum potassium in a patient with hypertension does not rule out hyperaldosteronism. Up to one-third or more of patients with primary hyperaldosteronism may have normal serum potassium levels at baseline.

A significant overlap in aldosterone-to-renin ratios exists between primary hyperaldosteronism and essential resistant hypertension. However, if the patient has hypokalemia, an aldosterone-to-renin ratio is often sufficient to diagnose hyperaldosteronism. Please see StatPearls' companion resource, "Primary Hyperaldosteronism," for more information.

Hypokalemia has traditionally been a key indicator of hyperaldosteronism but is present in fewer than 20% of cases.[156]

Hypokalemia may be masked in patients on a salt-restricted diet.

Patients with primary hyperaldosteronism due to functional adrenal adenomas are more likely to demonstrate hypokalemia.[157]

Hyperaldosteronism is found in about 10% of all patients with high blood pressure but is present in over 20% of patients with medication-resistant hypertension.[17][18][19][20][21][22]

A patient's clinical history and presentation, family history, and response to prior treatment will guide which disorders should be tested for.[68]

Genetic testing for familial hyperaldosteronism should be considered in patients with proven primary hyperaldosteronism who also have a suggestive family history.

Various computerized models utilizing machine learning, which integrate CT findings with clinical and biochemical data, are being developed to enhance the classification, subtyping, and lateralization of primary hyperaldosteronism.[158][159][160][161][162][163]

Enhancing Healthcare Team Outcomes

Diagnosing and managing hyperaldosteronism can be complex and is best handled by an interprofessional healthcare team, which includes a radiologist, pathologist, internist, endocrinologist, nurse practitioner, pharmacist, nurse, and surgeon. For primary hyperaldosteronism caused by unilateral disease, surgery is the preferred treatment. Robotic adrenalectomy is preferred due to its association with fewer complications and a shorter hospital stay compared to laparoscopy or open adrenal surgery. Complete adrenalectomy is preferred over partial adrenalectomy due to its greater efficacy and more complete resolution of symptoms.

For nonsurgical candidates, mineralocorticoid receptor antagonists are the preferred medical therapy. In cases of bilateral hyperaldosteronism, medical treatment is recommended, and the initial drug of choice is spironolactone. However, eplerenone may be preferred for long-term management in men due to its lower risk of gynecomastia and sexual dysfunction. Pharmacists should support the clinical team by educating patients on the importance of long-term compliance with medical therapy. In addition, patients should also be informed about the risk of gynecomastia and sexual dysfunction with spironolactone, particularly at higher doses (>150 mg/d). Please see StatPearls' companion resource, "Spironolactone," for more information.

Primary care clinicians, nurses, and dietitians should educate patients and their families on the importance of salt restriction, alcohol cessation, smoking cessation, maintaining an ideal body weight, and regular aerobic exercise. Follow-up is essential due to the high risk of adverse cardiac events in these patients.[130] Only through an interprofessional team approach with close communication among members is crucial to reducing the morbidity associated with hyperaldosteronism.[111]

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