Hyperaldosteronism

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Hyperaldosteronism occurs due to the excess production of aldosterone from the adrenal gland. Though it can go undiagnosed, hyperaldosteronism can initially present as essential and refractory hypertension. This disorder can be of primary or secondary origin; both present similarly but are differentiated by laboratory testing and diagnostic studies. Primary hyperaldosteronism from a unilateral abnormally functioning adrenal gland is best treated with surgical therapy consisting of a complete unilateral laparoscopic or robotic adrenalectomy. Patients with bilateral disease and those who are not surgical candidates are best treated medically with mineralocorticoid receptor antagonists such as spironolactone and eplerenone. 

This activity for healthcare professionals aims to enhance learners' competence in selecting appropriate diagnostic tests, managing hyperaldosteronism, and fostering effective interprofessional teamwork to improve outcomes. This activity reviews the cause of hyperaldosteronism and highlights the role of the interprofessional team in its management.

Objectives:

  • Identify the causes of primary and secondary hyperaldosteronism.

  • Interpret the laboratory features of primary and secondary hyperaldosteronism.

  • Apply evidence-based tailored treatment strategies for patients with hyperaldosteronism.

  • Strategize ways to improve care coordination among interprofessional team members in order to improve outcomes for patients affected by hyperaldosteronism.

Introduction

Aldosterone is a mineralocorticoid hormone that increases sodium (ie, salt) and water (ie, fluid) retention, ultimately increasing blood pressure.[1] Aldosterone also increases potassium urinary excretion, resulting in hypokalemia.[1] The zona glomerulosa secretes aldosterone, the outermost layer of the adrenal cortex.[2] Excess production of aldosterone is referred to as hyperaldosteronism.[2]

Hyperaldosteronism initially presents most often as mild or severe refractory hypertension, which frequently goes undiagnosed. The condition can be of primary or secondary origin; each presents similarly but can be differentiated by laboratory and diagnostic studies. Low plasma renin concentrations and usually less than 1 ng/mL/h activity identify primary hyperaldosteronism due to the inappropriate autonomous hypersecretion of aldosterone from a dysfunctional zona glomerulosa in the adrenal gland. Secondary hyperaldosteronism is due to excessive renin production and activity from a variety of diseases, 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 (eg, Bartter and Gitelman syndromes). The initial definitive laboratory measurements to diagnose hyperaldosteronism include plasma renin concentration (PRC), plasma renin activity (PRA), and the aldosterone/renin ratio.[3] 

Patients with hyperaldosteronism, especially women, experience considerable diagnostic delay, with more than one-third of patients waiting over 5 years to be correctly diagnosed.[4] Routine screening for hyperaldosteronism is suggested for all newly diagnosed patients with hypertension and should be performed in patients unresponsive to standard antihypertensive medications.[4][5] This review highlights the diagnosis and differentiation of hyperaldosteronism to determine if the indication for treatment is surgical (eg, unilateral primary hyperaldosteronism) or medical (eg, bilateral disease and secondary hyperaldosteronism).

Etiology

The underlying cause of the excess production of aldosterone differentiates primary from secondary hyperaldosteronism.[6]

Primary Hyperaldosteronism

Primary hyperaldosteronism, also known as Conn syndrome, is due to excessive autonomous aldosterone production by the adrenal gland, specifically the zona glomerulosa.[7] In 90% of patients, primary hyperaldosteronism most often presents as a unilateral hypersecreting glandular tumor. It may also present as bilateral adrenal hyperplasia.[8][9]

Less common forms of primary hyperaldosteronism are unilateral adrenal hyperplasia, ectopic aldosterone-secreting tumors usually in the kidneys or ovaries, aldosterone-producing adrenocortical carcinomas, and familial hyperaldosteronism of which Type I is the most common.[2] Newer data suggests 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. Three types are described in the literature, usually classified as type I, type II, and type III familial hyperaldosteronism.[8][10][11][12][13]

  • Type I familial primary hyperaldosteronism is caused by a 2-part chimeric gene (CYP11B1/CYP11B2) with a regulatory segment from 11B-hydroxylase and a synthesis portion from aldosterone synthase.[11] When 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.[11] However, the condition is a glucocorticoid-remediable disorder.
  • Type II familial primary hyperaldosteronism is associated with band 11q13 of gene 7p22, resulting in the histological equivalent of adrenal hyperplasia.[11] This type of familial primary hyperaldosteronism is not glucocorticoid-remediable.
  • Type III familial primary hyperaldosteronism is due to a T158A mutation in a potassium channel gene, KCNJF, which increases cellular calcium levels that cause the glomerulosa cells to increase their aldosterone production.[11][12][14] Type III familial primary hyperaldosteronism is not glucocorticoid-remediable.

Secondary Hyperaldosteronism

Secondary hyperaldosteronism occurs due to excessive and inappropriate activation of the renin-angiotensin-aldosterone system (RAAS).[15] Any reduction in renal blood flow can stimulate the RAAS system, resulting in increased aldosterone production and secretion.[16] This overproduction can be due to 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, or hepatic cirrhosis with ascites, obstructive sleep apnea, or nephrotic syndrome.[16] In some cases (eg, cardiac failure), aldosterone production may be in the normal range, but its hepatic metabolism may be reduced due to decreased hepatic blood flow, resulting in elevated serum levels of aldosterone.

Epidemiology

Primary hyperaldosteronism can be seen in approximately 10% of all hypertensive patients. In various studies, the reported incidence ranges from 4.6% to 16.6%, depending on patient selection, diagnostic methods, and severity of hypertension.[17][18][19] However, many studies have shown that this may be significantly underestimated as most patients who meet the recommended criteria are not tested.[18][20][21][22] The incidence of primary hyperaldosteronism rises as the severity of the associated hypertension increases.[23] Its prevalence is 10% to 20% in patients with resistant hypertension, especially in those aged younger than 40 years or who exhibit hypokalemia.[23][24][25]

However, several reviews of large populations indicate that only 1.6% to 2.1% of all patients with resistant hypertension who meet the recommended criteria for hyperaldosteronism per published guidelines receive appropriate testing for the disease.[22][26] Secondary hyperaldosteronism is diagnosed less often than primary hyperaldosteronism. Both primary and secondary hyperaldosteronism are more prevalent in women. Africans and African Americans tend to have a higher prevalence of hyperaldosteronism than the general population, particularly idiopathic bilateral adrenal hyperplasia.[27][28]

Pathophysiology

Aldosterone is the primary mineralocorticoid in the body, acting on the epithelial sodium channels in the collecting tubules and causing sodium reabsorption.[1] This creates a negative potential in the tubular lumen and, in turn, causes the movement of cations, primarily potassium and hydrogen ions, into the tubular lumen to maintain electrical neutrality, resulting in hypokalemia, aciduria, and metabolic alkalosis.[1] The increased reabsorption of sodium and water leads to intravascular volume expansion and hypertension.[17] Aldosterone production is usually limited to the zona glomerulosa of the adrenal glands, where aldosterone synthase enzymatically catalyzes 11-deoxycorticosterone to aldosterone, mediated by serum potassium and angiotensin II levels.[2] ACTH also plays a role in stimulating aldosterone production, which explains the observed diurnal pattern of hormone secretion.[2] 

Primary hyperaldosteronism occurs due to excess autonomous aldosterone production by the adrenal gland.[2] The most common causes of primary hyperaldosteronism are idiopathic bilateral adrenal hyperplasia and a hypersecreting adenomatous tumor in the zona glomerulosa, which can directly cause an inappropriate increase in serum aldosterone.[8] These patients are usually asymptomatic but can typically present with hypertension and hypokalemia.[18] Both primary and secondary hyperaldosteronism can present with a broad clinical range.[17] About 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.[29][30][31]

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

Secondary hyperaldosteronism occurs due to the excess stimulation of the renin-angiotensin-aldosterone system (RAAS). Secondary hyperaldosteronism can result due to the physiologic state of transient RAAS activation (eg, hypovolemia) but can also be seen in pathological states of sustained activation of the system, including the following:[16]

  • Renal artery stenosis (eg, atherosclerosis or fibromuscular dysplasia) causes decreased kidney blood flow, simulates a false sense of hypovolemia, and increases aldosterone secretion.
  • In left-sided congestive heart failure and cor pulmonale, a decrease in cardiac output leads 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.
  • Patients with poor hepatic blood flow may also demonstrate secondary hyperaldosteronism from decreased aldosterone metabolism by the liver, resulting in higher serum levels even though adrenal production of the hormone is in the normal range.
  • A renin-producing tumor in the juxtaglomerular cells, though a very uncommon finding [16]

Histopathology

Histopathology is not a standard tool used for the diagnosis of hyperaldosteronism, although immunohistochemical staining can be of some help. Up to a third of aldosterone-producing adrenal adenomas may demonstrate hyperplasia of the zona glomerulosa hyperplasia. Hyperplasia may be found in a broad but localized area or as a generalized thickening throughout the cortex. Extensions of the cortical glomerulosa may appear to penetrate centrally.

Idiopathic bilateral hyperaldosteronism has a variable histological appearance that ranges from almost normal-appearing hyperplasia to micronodular and macronodular. Immunohistochemical staining of CYP-11B2 in aldosterone-producing adenomas has been immensely valuable. This can be useful to differentiate the variable types and subtype classifications of adenomas, micronodules, and aldosterone-producing cell clusters, which are CYP-11B1 stains positive for cortisol-producing cells.[32]

History and Physical

Clinical Features of Hyperaldosteronism

The clinical features of hyperaldosteronism may vary depending on the severity. Patients often can present asymptomatically also. Resistant hypertension is the most common presenting symptom for these patients, especially if associated with hypokalemia. The characteristic presentation of a patient with hyperaldosteronism is a young female on 3 different antihypertensive medications with hypertension that remains inadequately controlled.[18] Other common symptoms include fatigue, headache, weakness, abdominal distension, ileus, polyuria, and polydipsia. Blood pressure can range from normotensive to severe hypertension and often be refractory to standard antihypertensive treatment. Sodium reabsorption, volume expansion, and increased peripheral vascular resistance are the causative factors for hypertension in aldosteronism.[17] Symptoms are usually the result of moderate to severe high blood pressure or secondary to hypokalemia. High blood pressure can cause headaches, dizziness, vision problems, chest pain, and dyspnea. Also, antidiuretic hormone resistance in the renal tubules due to hypokalemia has been implicated in causing diabetes insipidus in aldosteronism.[17] Hypokalemia may cause 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 strokes.[17]

Patients with secondary hyperaldosteronism can present with different blood pressure measurements, but most will have some degree of hypertension. Renal artery stenosis and coarctation of the aorta will also cause higher blood pressure.[33] Hypovolemia can be seen in patients with diuretic use, heart failure, cirrhosis, and nephrotic syndrome. Patients with Gitelman’s and Bartter’s syndromes tend to have mild hypotension.[16][17][34]

While there are no specific physical signs of hyperaldosteronism, long-term hypertension can lead to left ventricular hypertrophy, which may cause an S4 heart sound due to the passage of blood into a relatively stiff and noncompliant left ventricle. Other signs of long-standing hypertension may also be present.

Risk Factors for Hyperaldosteronism

Factors that are associated with an increased risk for hyperaldosteronism include:

  • Hypertension identified before the age of 40 years
  • Hypokalemia, either spontaneous or thiazide-induced
  • Resistant or intractable hypertension, not well controlled even using ≥3 standard antihypertensive drugs, including a diuretic
  • Incidental finding of an adrenal adenoma in a patient with hypertension
  • Family history of cardiovascular events at young ages or hypertension [23]

Evaluation

The initial definitive laboratory measurements to diagnose hyperaldosteronism include plasma renin concentration (PRC), plasma renin activity (PRA), and the aldosterone/renin ratio.[3] The following 3 pathophysiological features of primary hyperaldosteronism, as originally described by Conn and colleagues in 1964, remain the mainstay of the diagnostic approach:

  1. Autonomous aldosterone production that lowers plasma renin levels, resulting in a high aldosterone/renin ratio, low plasma renin levels
  2. Reduced response of renin to stimulation (eg, the administration of an angiotensin-converting enzyme inhibitor)
  3. Lack of suppression of aldosterone production by volume expansion or salt loading, usually tested by an IV saline infusion or a significant dietary salt ingestion.[23][35]

Primary Hyperaldosteronism

In primary hyperaldosteronism, the plasma renin activity is less than 1 ng/mL/hour, 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/renin ratio of more than 20:1 indicates a renin-independent etiology consistent with primary hyperaldosteronism.[2]

The plasma aldosterone concentration/renin activity (PAC/PRA) ratio is a confirmatory test for primary hyperaldosteronism. Most studies support an elevated PAC/PRA ratio >30:1 and a PAC >20 ng/dL with a sensitivity and specificity of over 90% as being diagnostic for primary hyperaldosteronism.[3] However, a PAC/PRA ratio greater than 20:1 and PAC greater than 15 ng/dL are reportedly sufficient to support the diagnosis.[18][3][36][37]

Secondary Hyperaldosteronism

In secondary hyperaldosteronism, both the plasma renin concentration and activity levels are increased, as renin is the primary stimulator for the excess production of aldosterone, and the serum aldosterone/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/renin ratio will be less than 20:1. PRA, PRC, and renin levels increase in secondary hyperaldosteronism, but the PAC/PRA is less than in primary hyperaldosteronism.[18][36][37][38] 

Initial Laboratory Studies for Hyperaldosteronism

The aldosterone/renin ratio has long been considered a reliable screening test for hyperaldosteronism, but results may be somewhat variable in certain situations.[23][39][40] The levels should be drawn in the morning, and any interfering drugs should be eliminated, but this is not always safe or practical.[18][23][41] The aldosterone/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-inflammatories drugs (NSAIDs).[18][23][41][42][43][44] Other laboratory findings may demonstrate hypokalemia, mild hypernatremia, and mild hypomagnesemia, but these are not diagnostic.[45][46][47]

Hypokalemia has historically been considered a hallmark finding closely associated with hyperaldosteronism but is now recognized as a relatively rare occurrence.[23][48][49][50] Therefore, the lack of hypokalemia should not be used to exclude a diagnosis of hyperaldosteronism.[23] Current estimates indicate that less than 37% of those with confirmed primary hyperaldosteronism will demonstrate low serum potassium levels.[28] Metabolic alkalosis is frequently observed in hyperaldosteronism. This is 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.[51] The historically well-documented association of hyperaldosteronism with hypokalemia has been observed to be less than 40% in published studies.

The role of the 24-hour urine collection in hyperaldosteronism is controversial, although it can detect inappropriate potassium wasting, defined as over 30 mEq per day.[52][53][54] 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 simple test of the urinary aldosterone/creatinine ratio has been suggested to facilitate the initial diagnosis of primary hyperaldosteronism by using an aldosterone/creatinine ratio of 3 ng aldosterone/mg creatinine as the threshold.[55] The validity of this test has not yet been established or fully verified.[55]

Primary Versus Secondary Hyperaldosteronism

Differentiating primary and secondary hyperaldosteronism is most easily accomplished using serum renin levels.[35] Primary hyperaldosteronism will always significantly suppress renal renin production, while secondary hyperaldosteronism is associated with elevated serum renin concentrations.[35] Aldosterone levels and blood pressure will tend to be higher in secondary compared to primary hyperaldosteronism. 

Hyperaldosteronism Confirmation

Confirmation of a hyperaldosteronism diagnosis typically includes an elevated serum aldosterone level, a 24-hour urinary aldosterone excretion test, or an aldosterone suppression test using salt-loading, captopril, or fludrocortisone that would typically be expected to cause aldosterone suppression. No specific confirmatory test is officially preferred. Still, a comparative meta-analysis suggested that the captopril challenge test was perhaps the most feasible as it is easy to perform and considered safe.[56]

  • 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 5,000 to 6,0000 mg sodium in the diet daily or 90 mEq sodium tablets. Potassium supplements are also given to those who develop hypokalemia. Following the sodium loading, 24-hour urine aldosterone is measured with a value of >12 mcg/day, which is generally used to confirm the diagnosis of primary hyperaldosteronism. A 24-hour urine sodium ≥200 mEq or more indicates adequate oral salt intake. Some considerations with this test are that the presence of renal failure can make interpretation of the results difficult by producing false negatives and that patients with a history of congestive heart failure, uncontrolled significant hypertension, or cardiac arrhythmias should not be given this test.
  • Intravenous salt-loading test: This test is performed by administering 2 L of isotonic intravenous (IV) saline infusion over 4 hours. After the saline infusion, findings of plasma aldosterone levels >10 ng/dL are consistent with primary hyperaldosteronism; however, the saline infusion has a false negative rate of 30%.[18] A modified saline infusion test, which adds 0.5 mg of oral dexamethasone every 6 hours for 2 days, has demonstrated greater sensitivity.[57] Drawbacks of this test include the requirement of hospitalization and the risks of fluid overload, worsening heart failure, hypokalemia, and increasing blood pressure.
  • Captopril suppression test: The results of this test help to confirm primary hyperaldosteronism because lower aldosterone production should be observed in all patients except those with primary hyperaldosteronism. Patients are given 25 to 50 mg of captopril, an angiotensin II blocker. Serum aldosterone, renin, and cortisol levels are measured before captopril administration and 1 to 2 hours afterward. Aldosterone would generally be expected to decrease by at least 30% with an aldosterone/renin ratio <30:1 in patients with primary hyperaldosteronism; the serum aldosterone levels will remain elevated, usually ≥8.5 ng/dL, with an aldosterone/renin ratio >30:1, and low renin levels. A consideration with the captopril suppression test is that though the test is relatively safe, can be done quickly as an outpatient, and is comparatively inexpensive; there are relatively high rates of equivocal and false negative results reported. Additionally, this test is not recommended in suspected cases of renovascular hypertension and may cause angioedema.
  • Fludrocortisone suppression test: This test is designed to lower aldosterone levels by administering an oral corticosteroid with potassium supplementation and salt loading. Failure to adequately suppress aldosterone levels after 4 days of such treatment is considered confirmatory for primary hyperaldosteronism.[58][59] Oral fludrocortisone is given at 0.1 mg every 6 hours, along with oral potassium supplements, sodium chloride tablets 3 times daily with meals, and a high sodium diet. Aldosterone and renin levels are measured after 4 days. A serum aldosterone >6 ng/dL is considered a positive test and indicative of primary hyperaldosteronism.[58][59] However, the testing is labor-intensive and relatively costly. Adding a 2 mg dose of dexamethasone at midnight has been used to make the fludrocortisone suppression test more reliable, sensitive, and specific, allowing it to detect milder forms of primary hyperaldosteronism.[60][61][62][63][64][65]

Differentiating Unilateral From Bilateral Disease

Determining laterality is essential as it directly affects treatment. However, differentiating the underlying etiology as an adenoma or adrenal hyperplasia contributes to determining laterality. The following findings may be suggestive of this:

  • Serum 18-hydroxycorticosterone levels are elevated in adenomas but normal in bilateral adrenal hyperplasia.[8]
  • An adrenal adenoma would tend to show a paradoxical decrease in serum aldosterone levels after a 2-hour upright positioning compared to the normally expected increase found in adrenal hyperplasia.[8] 
  • Adrenal adenomas that autonomously overproduce aldosterone tend to be glucocorticoid responsive, while bilateral idiopathic adrenal hyperplasia is not, although it may remain somewhat responsive to serum renin levels.[66]

None of these findings is considered definitive, and they would not demonstrate laterality, which would require imaging studies or the more challenging but definitive adrenal vein sampling procedure.

Radiological imaging, such as computed tomography (CT), can distinguish adenomas from bilateral adrenal hyperplasia. However, studies have found that CT imaging alone cannot always distinguish between both reliably.[67] The overall sensitivity and specificity of CT imaging for aldosterone-producing adenomas is about 78% and 75%, respectively. All patients with primary aldosteronism should undergo imaging to rule out large adrenal masses or carcinomas.[18] Aldosterone-producing adrenal tumors tend to be homogenous and lipid-rich with low Hounsfield density numbers, but imaging alone cannot reliably distinguish between functioninonfunctioningtioning adrenal adenomas.[68][69][70]  However, nonfunctional adrenal adenomas are extremely rare in children and young adults.[18]

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. An incongruence in levels, usually a 2-fold increase on the side of the adenoma, indicates unilateral origin, whereas equivalent levels suggest bilateral sources.[18][71] A 4-fold increase is used as the cutoff threshold when optional cosyntropin stimulation is administered.)[18][71] Adrenal vein sampling is not recommended in patients younger than 35 years with spontaneous hypokalemia, marked levels of aldosterone, and highly suspicious adrenal adenomas on CT imaginNonfunctioningtioning adrenal adenomas are rare in such younger populations. However, adrenal vein sampling is not required even in patients aged 40 years or older with marked hyperaldosteronism with a clear solitary, unilateral adrenal adenoma on CT, who are not surgical candidates, those suspected to have adrenal cancer, or those with known familial hyperaldosteronism.[72] 

Adrenal vein sampling is still considered the gold standard for differentiating unilateral from bilateral adrenal hyperaldosteronism. However, the test is difficult and technically demanding as the vessels are relatively small, and interpretation is sometimes difficult.[71] The right adrenal vein, in particular, can be exceedingly challenging to cannulated. Even unilateral adrenal vein sampling can be helpful. In 2016, Pasternak and colleagues suggested using the following formula in cases where only unilateral adrenal vein sampling was accomplished.[73] 

  • The formula is adrenal vein aldosterone ÷ cortisol/inferior vena cava (IVC) aldosterone ÷ IVC cortisol.[73] 
  • Values over 5.5 indicate unilateral hyperaldosteronism on the side tested, while results <0.5 predicted the same but on the contralateral side.[73]
  • Values between 5.5 and 0.5 were not interpretable and could indicate either bilateral or unilateral disease.[73] 
  • The specificity of this formula and technique has been estimated at 100% but with only about 50% sensitivity.[73] 
  • Other studies have confirmed these findings.[74][75]

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 for determining laterality in hyperaldosteronism include the following:

  • 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.[76][77][78] It can also identify laterality in primary hyperaldosteronism.[78] It may be beneficial in patients with chronic kidney disease where standard biochemical testing is more problematic.[77] Its positive predictive value and sensitivity have been reported as about 92%.[77] However, it is a difficult test and may not be available in many centers.
  • 11C-metomidate PET-CT scanning with and without dexamethasone suppression also appears to be a sensitive, specific test for primary hyperaldosteronism as well as adrenocortical tumors.[79][80][81][82][83][84] In addition, it may also be able to reliably predict the response to medical therapy of hyperaldosteronism.[82]
  • Gallium-68 pentixafor PET-CT scanning has demonstrated a 90% correlation in the differentiation between unilateral and bilateral hyperaldosteronism.[85] In one study, the Gallium-68 PET-CT scan showed a 90% correlation with adrenal vein sampling compared to only 54% with CT scans alone.[85]

Genetic testing is advised in primary aldosteronism seen in patients younger than 20 years and in those with a family history of the disorder.

  • Familial hyperaldosteronism comprises about 6% to 7% of all adult primary patients with primary hyperaldosteronism.
  • Four types of familial hyperaldosteronism have been described, but the most common are type I (ie, glucocorticoid responsive hyperaldosteronism)  or type III (ie, glucocorticoid unresponsive.[18] 
  • In severe cases, bilateral adrenalectomies may be required to control blood pressure and severe hypokalemia, which necessitate lifelong glucocorticoid and mineralocorticoid replacement therapy.

Summary of Hyperaldosteronism Evaluation

The initial step in evaluating hyperaldosteronism is the differentiation of primary from secondary hyperaldosteronism. This is relatively simple, as primary hyperaldosteronism will have a high aldosterone/renin ratio (>20:1) and low serum renin levels. A confirmatory test is usually recommended.[17][23]

If primary hyperaldosteronism is diagnosed, the next issue is to differentiate unilateral disease, treated by surgery, from bilateral disease, where medical therapy is utilized.[86][87][88][89] Unilateral disease has traditionally been confirmed with bilateral adrenal venous sampling, but CT scans and other imaging modalities may also be helpful. 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

Primary hyperaldosteronism caused by unilateral disease is best treated surgically. Robotic or laparoscopic adrenalectomy is preferred as this procedure is associated with fewer complications and a shorter hospital stay compared to open surgery.[68] Complete adrenalectomy is preferred to partial gland removal due to greater efficacy and resolution of symptoms. Primary hyperaldosteronism is the most frequently encountered etiology of hypertension that is surgically curable.[90] Preoperative spironolactone to control blood pressure for 4 to 6 weeks is recommended.[8] Patients who fail to normalize their blood pressure on spironolactone preoperatively are likely to continue to be hypertensive even after surgery.[8] Following surgery, about two-thirds of patients will eventually develop stable, normal blood pressure, although this may take a year.[8]

Patients with hyperaldosteronism due to unilateral disease do better long-term with surgery than with medical therapy regarding blood pressure control, maintaining serum potassium levels, and improved vascular remodeling.[91] Failure of surgery to control hypertension despite the normalization of aldosterone levels is suggestive of the following:

  • An erroneous 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)

For nonsurgical candidates, the medical therapy of choice is mineralocorticoid receptor antagonists (MRAs) (eg, spironolactone and eplerenone).[92][93][94][95][96]

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%.[97][98][99][100][101][102] Transcatheter and percutaneous adrenal ablation are currently recommended for suitable patients unwilling to have surgery or take long-term medications.[97][98][99][100][101][102]

Primary Hyperaldosteronism Secondary to Bilateral Hyperplasia

For primary hyperaldosteronism caused by bilateral hyperplasia and for patients who are not surgical candidates, mineralocorticoid receptor antagonists are the treatments of choice. Spironolactone or eplerenone is most commonly used.[95][96] Selection among these agents depends on the adverse side effect profile. 

According to the 2016 Endocrine Society Guidelines, the starting dose of spironolactone is 12.5 to 25 mg daily and titrated upward every 2 weeks.[94] Maintenance is often reached at a daily dosage of about 100 mg of spironolactone.[95] Gynecomastia is a significant known side effect of spironolactone use in men, which may occur in up to 50% of male patients who take more than 150 mg daily. Eplerenone is usually started at 50 mg daily and titrated upward, up to a maximum of about 200 mg twice a day.[96] Eplerenone is a more specific medication that, unlike spironolactone, does not block androgen receptors.[96] 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.[96] Eplerenone has a relatively short half-life of about 4 hours, which is still longer than spironolactone, which only has a half-life of only 1.4 hours.[96] However, spironolactone is more effective in controlling blood pressure.[103] See StatPearls' companion references on "Spironolactone" and "Eplerenone."[95][96]

The clinical course ultimately dictates the drug selection, dosage, and frequency. There are a few rare case reports of spontaneous remission of primary hyperaldosteronism after long-term therapy with mineralocorticoid receptor antagonist medications.[104] Triamterene and amiloride are potassium-sparing diuretics that may have an adjunctive role in managing patients with aldosterone-related hypertension. However, amiloride is preferred as triamterene may form urinary calculi.[105][106][107][108][109] Combination therapy, consisting of medications, sodium restriction, usually less than 100 mEq per day, avoidance of alcohol, smoking cessation, aerobic exercise, and maintaining ideal body weight, has produced the best results.[94][110][111] Glucocorticoids, amiloride, and calcium channel blockers may also help manage hypertension and other symptoms not adequately controlled with mineralocorticoid receptor antagonists alone.

Canrenone, a metabole, has a similar action to spironolactone but has a much longer half-life (16.5 hours vs 1.4 hours). Canrenone appears to have a direct beneficial myocardial effect beyond its antihypertensive actions. Canrenone may also have fewer sexual side effects. The medication is currently available in Europe but not in the US. Medications specifically targeting the aldosterone-producing adrenal CYP-11B2 cells are being developed and investigated.[112][113][114] This is complex due to the great similarity between the CYP-11B2 and CYP-11B1 type cells.

Secondary Hyperaldosteronism

Secondary hyperaldosteronism is best treated by eliminating or treating the underlying disease, which will lead to the resolution of the symptoms. Angiotensin-converting enzyme inhibitors (ACE I) and angiotensin receptor blockers (ARB) are the agents of choice for controlling blood pressure in these patients due to their renal protective benefits.[95] Salt restriction is also recommended for better efficacy in blood pressure control.[115] Potassium supplements and potassium-sparing diuretics may also be used. The treatment is essentially the same as for primary hyperaldosteronism caused by idiopathic adrenal hyperplasia. Renal artery stenosis might need surgical intervention/revascularization to control the blood pressure optimally.[33] See StatPearls' companion reference on "Renal Artery Stenosis."[33]

Differential Diagnosis

Similar presentations have been observed in essential hypertension, Liddle syndrome, syndrome of apparent mineralocorticoid excess, congenital adrenal hyperplasia, primary glucocorticoid resistance, and ectopic adrenocorticotropic hormone (ACTH) syndrome. The following presentations are some of the shared clinical features:

  • Essential hypertension presents with a normal PAC/PRA ratio.[116]
  • Liddle syndrome is a rare genetic mutation that will have low aldosterone levels and will typically present in childhood.[117] Symptoms include hypertension, hypokalemia, and metabolic alkalosis, which are similar to mineralocorticoid excess disorders. Sometimes called pseudohyperaldosteronism, Liddle syndrome is characterized by high levels of urinary potassium secretion combined with sodium reabsorption from the renal collecting tubules but has low aldosterone levels.[117] 
  • Syndrome of apparent mineralocorticoid excess will present with hypertension, low aldosterone levels, high urinary free cortisol levels, hypokalemia, ACTH suppression, hereditary implications, and a history of excessive licorice consumption.[118] Genetically, it is an autosomal recessive disorder.[118]
  • Congenital adrenal hyperplasia will have a family history of 11-beta-hydroxylase or 17-alpha-hydroxylase deficiency and low aldosterone levels.[119][120]
  • 17-alpha-hydroxylase deficiency can closely mimic hyperaldosteronism.[121] Patients will be hypogonadal with immature genitalia.[121] Genetic testing may be needed for a definitive diagnosis.[121]
  • Primary glucocorticoid resistance will have low aldosterone levels, elevated ACTH and cortisol, and a family history of this syndrome.[122][123]
  • Patients with ectopic adrenocorticotropic hormone syndrome patients have elevated ACTH levels that cannot be suppressed with high-dose dexamethasone. These patients typically have an underlying tumor.[124][125][126][127]

Prognosis

Few studies have been performed on the mortality rates of either form of hyperaldosteronism, but 10-year survival rates have been reported between 90% and 95% in patients treated. The most common morbidity associated with this disorder is cardiovascular. Cardiovascular mortality is increased in these patients, but all-cause mortality is not significantly different from the general population. If hypokalemia persists, it may lead to weakness, paralysis, constipation, and polyuria. Primary hyperaldosteronism and hypokalemia also impair the secretion of insulin and promote the development of diabetes mellitus.[29][30][31]

Complications

The most common complication and comorbidity associated with these patients is the increased risk of cardiovascular mortality. This is related to excessive aldosterone secretion and can present as atrial fibrillation, left ventricular hypertrophy, hypertension, myocardial infarction, and stroke.[128][129][130][131][132] Myocardial fibrosis has been reported in patients with long-standing hyperaldosteronism.[133][134]

Postoperative and Rehabilitation Care

Sodium restriction of less than 100 mEq per day, alcohol cessation, smoking cessation, ideal body weight maintenance, and regular aerobic exercise are beneficial in postoperative care and health maintenance.

Consultations

Endocrinologists and nutritionists can generally better manage these patients on a long-term basis. Surgery is indicated for a subset of this disorder with unilateral primary hyperaldosteronism.

Deterrence and Patient Education

Patients need to be fully informed and educated about their disease. This should include the importance of following long-term treatment recommendations regarding diet (eg, salt restriction) and full compliance with medications if prescribed.

Pearls and Other Issues

Key facts to bear in mind include:

  • Testing for hyperaldosteronism should be routinely considered for all newly diagnosed patients with hypertension that is hard to control with standard antihypertensives, especially if they are younger than 40 years old or have hypokalemia.[5][18] 
  • A morning aldosterone/renin ratio is a reasonable initial screening test for hyperaldosteronism.
  • Plasma aldosterone concentration/plasma renin activity >30:1 with a plasma aldosterone concentration >20 ng/dL highly suggests primary hyperaldosteronism.
  • Serum renin levels are the easiest way to differentiate primary and secondary hyperaldosteronism. Renin activity is always suppressed in primary hyperaldosteronism but elevated in secondary. Blood pressure and aldosterone levels are generally higher in secondary hyperaldosteronism compared to primary disease.
  • 17-alpha-hydroxylase deficiency can closely mimic primary or secondary hyperaldosteronism. These patients will demonstrate juvenile, undeveloped genitalia and hypogonadism.[121]
  • Normal serum potassium in a hypertensive patient does not rule out hyperaldosteronism. There is a significant overlap in angiotensin/renin ratios between primary hyperaldosteronism and essential resistant hypertension. However, if the patient has hypokalemia, an angiotensin/renin ratio is often sufficient to make the diagnosis of hyperaldosteronism.[3]
  • Hypokalemia has traditionally been an essential clue to the presence of hyperaldosteronism but is found in fewer than 20% of cases.[135] Patients with primary hyperaldosteronism due to functional adrenal adenomas are more likely to demonstrate hypokalemia.[136]
  • Secondary hypertension will be found in only about 5% to 10% of all patients with high blood pressure. Determining which disorders should be tested will include the patient's clinical history and presentation, family history, and response to prior treatment.[38]
  • Genetic testing for familial hyperaldosteronism should be considered in patients with proven primary hyperaldosteronism who also have a suggestive family history.
  • Various computerized models using machine learning with CT findings combined with clinical and biochemical data are being developed to facilitate the classification, subtypes, and lateralization in patients with primary hyperaldosteronism.[137][138][139][140][141][142]

Enhancing Healthcare Team Outcomes

Diagnosing and managing hyperaldosteronism can be complex and best done by an interprofessional team that includes a radiologist, pathologist, internist, endocrinologist, nurse practitioner, pharmacist, and surgeon. Surgery is the preferred treatment in primary hyperaldosteronism caused by unilateral disease. Robotic adrenalectomy is preferred as it is associated with fewer complications and a shorter hospital stay as compared to laparoscopy or open adrenal surgery. Complete adrenalectomy is preferred to partial due to greater efficacy and resolution of symptoms.

For nonsurgical candidates, mineralocorticoid receptor antagonists are the preferred medical therapy. If the patient has bilateral hyperaldosteronism, then medical treatment is recommended, and the initial drug of choice is spironolactone. However, eplerenone may be preferred for long-term treatment in men due to its decreased risk of gynecomastia and sexual dysfunction. The pharmacist should assist the clinical team and educate the patient on the importance of long-term compliance with medical therapy. In addition, the patient needs to be told that there is a risk of developing gynecomastia and sexual dysfunction with spironolactone, especially at higher doses (ie, >150 mg/d).[95]

Primary care clinicians, nurses, and dietitians should educate the patient and family on the importance of salt restriction, alcohol cessation, smoking cessation, maintenance of ideal body weight, and aerobic exercise. Follow-up is necessary as the risk of adverse cardiac events is high in these patients.[111] Only through a team approach with close communication among the members can the morbidity of hyperaldosteronism be lowered.[94] 

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Alejandro Dominguez

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Vijayadershan Muppidi

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Stephen W. Leslie

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