Primary Aldosteronism 

Updated: Mar 02, 2018
Author: Gabriel I Uwaifo, MD; Chief Editor: Romesh Khardori, MD, PhD, FACP 

Overview

Practice Essentials

Although initially considered a rarity, primary aldosteronism now is considered one of the more common causes of secondary hypertension (HTN). Litynski reported the first cases, but Conn was the first to well characterize the disorder, in 1956. Conn syndrome, as originally described, refers specifically to primary aldosteronism due to the presence of an adrenal aldosteronoma (aldosterone-secreting benign adrenal neoplasm). (See Etiology.)

Based on older data, it was originally estimated that primary aldosteronism accounted for less than 1% of all patients with HTN. Subsequent data, however, indicated that it may actually occur in as many as 5-15% of patients with HTN. Primary aldosteronism may occur in an even greater percentage of patients with treatment-resistant HTN and may be considerably underdiagnosed; this is especially true if patients with treatment-refractory HTN are not specifically referred for evaluation to an endocrinologist. (See Epidemiology.)

Although primary aldosteronism is still a considerable diagnostic challenge, recognizing the condition is critical because primary aldosteronism–associated HTN can often be cured (or at least optimally controlled) with the proper surgical or medical intervention. The diagnosis is generally 3-tiered, involving an initial screening, a confirmation of the diagnosis, and a determination of the specific subtype of primary aldosteronism. (See Presentation, Workup, Treatment, and Medication.)

Although prior studies suggested that aldosteronomas were the most common cause of primary aldosteronism (70-80% of cases), later epidemiologic work indicated that the prevalence of aldosteronism due to bilateral idiopathic adrenal hyperplasia (IAH; sometimes also abbreviated as BAH) is higher than had previously been believed. These reports suggested that IAH may be responsible for as many as 75% of primary aldosteronism cases. Moreover, reports have described a rare syndrome of primary aldosteronism characterized by histologic features intermediate between adrenal adenoma and adrenal hyperplasia, which often is unilaterally localized (also referred to earlier literature as “intermediate aldosteronism”) (see Etiology). (See the images below.)

Magnetic resonance imaging (MRI) scan in a patient Magnetic resonance imaging (MRI) scan in a patient with Conn syndrome showing a left adrenal adenoma.
Scintigram obtained by using iodine-131-beta-iodom Scintigram obtained by using iodine-131-beta-iodomethyl-norcholesterol (NP-59) in a 59-year-old man with hypertension shows fairly intense radionuclide uptake in the right adrenal tumor. At surgery, a Conn tumor was confirmed.

Clinically, the distinction between the 2 major causes of primary aldosteronism is vital because the treatment of choice for each is markedly different. While the treatment of choice for aldosteronomas is surgical extirpation, the treatment of choice for IAH is medical therapy with aldosterone antagonists. (See Treatment and Medication.)

Entities known to cause aldosteronism include the following (see the image below):

  • Aldosterone-producing adenomas (APAs)[1]

  • Aldosterone-producing renin-responsive adenomas (AP-RAs; also abbreviated as RRAs)

  • Bilateral idiopathic adrenal (glomerulosa) hyperplasia or IAH (also known as primary adrenal hyperplasia or PAH)

  • Familial forms of primary aldosteronism

  • Ectopic secretion of aldosterone (The ovaries and kidneys are the 2 organs described in the literature that, in the setting of neoplastic disease, can be ectopic sources of aldosterone, but this is a rare occurrence.)

  • Pure aldosterone-producing adrenocortical carcinomas (very rare; physiologically behave as APAs)

    Scintigram obtained by using iodine-131-beta-iodom Scintigram obtained by using iodine-131-beta-iodomethyl-norcholesterol (NP-59) in a 59-year-old man with hypertension shows fairly intense radionuclide uptake in the right adrenal tumor. At surgery, a Conn tumor was confirmed.

Aldosterone, by inducing renal reabsorption of sodium at the distal convoluted tubule (DCT), enhances secretion of potassium and hydrogen ions, causing hypernatremia, hypokalemia, and alkalosis. (See Prognosis, Workup, and Treatment.)

Genetic-familial primary aldosteronism

Three distinct genetic-familial varieties of primary aldosteronism exist. Sutherland and colleagues first described the type 1 variety of familial primary aldosteronism, glucocorticoid-remediable aldosteronism (GRA), in 1966. In GRA, HTN responds clinically to small doses of glucocorticoids in addition to other antihypertensive agents.[2] The type 1 form of familial primary aldosteronism is due to an aberrantly formed chimeric gene product that combines the glucocorticoid-responsive (inhibitable) promoter of the 11beta-hydroxylase gene (CYP11B1) with the coding region of the aldosterone synthetase gene (CYP11B2). Under ambient glucocorticoid levels, the promoter is not fully transcriptionally silenced, and this leads to overexpression of aldosterone synthetase, with subsequent increased synthesis and secretion of aldosterone. (See Etiology and Workup.)

The type 2 variant of familial primary aldosteronism (which is not glucocorticoid sensitive) was first described in 1991. Although the exact genetic abnormality for type 2 primary aldosteronism has not been identified, data suggest that the locus for this disease is on band 7p22.[3]

The type 3 variant of familial primary aldosteronism is due to KCNJ5 (potassium inwardly rectifying channel, subfamily J, member 5) potassium channel mutations. This type was described by Lifton’s group in 2011.[4]

Workup

Screening (first-tier) tests for primary aldosteronism include the following:

  • Serum potassium and bicarbonate levels
  • Sodium and magnesium levels
  • Plasma aldosterone/plasma renin activity ratio

Confirmatory (second-tier) tests include the following:

  • Serum aldosterone level
  • 24-hour urinary aldosterone excretion test
  • Salt-loading test

Tests for determining the primary aldosteronism subtype (third-tier tests) include the following:

  • Postural stimulation test
  • Furosemide (Lasix) stimulation test
  • Diurnal rhythm of aldosterone

The initial radiologic investigation in the workup of primary aldosteronism is high-resolution, thin-sliced (2-2.5 mm) adrenal computed tomography (CT) scanning with contrast.

Other tests include the following:

  • NP-59 iodo-methyl-norcholesterol scintigraphy: Although fairly difficult to set up and not routinely available, this test can be useful in select cases for distinguishing between adenomas and hyperplasia
  • Adrenal venous sampling: Adrenal venous sampling probably has its greatest utility when adrenal imaging findings are completely normal despite biochemical evidence for primary aldosteronism and in settings in which bilateral adrenal pathology is present on imaging and the biochemistry suggests the presence of a functional aldosteronoma
  • Dexamethasone suppression test: This test is relevant only in the setting of possible familial aldosteronism
  • Metoclopramide (Reglan) test: This is a noninvasive test for distinguishing between aldosteronomas and idiopathic adrenal hyperplasia (IAH)

Management

Pharmacologic therapy includes use of the following:

  • Calcium channel blockers
  • Mineralocorticoid antagonists
  • Glucocorticoids

Surgery is the treatment of choice for the lateralizable variants of primary aldosteronism, including typical aldosteronomas, renin-responsive adenomas (RRAs), and primary adrenal hyperplasia (PAH). An adrenalectomy can be performed via a formal laparotomy or by using a laparoscopic technique (with performance of the latter becoming increasingly common).

Pathophysiology

The most important factors that predict the pathophysiologic association of hypokalemia with primary aldosteronism are (1) aldosterone hypersecretion, which acts on the cortical collecting duct to stimulate potassium secretion into the tubular fluid, thus enhancing renal/urinary potassium wasting[5] ; (2) adequate intravascular volume, which enables adequate water delivery (tubular flow rate) to the renal distal convoluted tubules (DCTs) and collecting ducts to enable renal potassium loss; and (3) adequate dietary sodium intake, which, in turn, increases total body potassium, renal/ tubular sodium delivery, and, thus, enhances renal potassium loss via the countercurrent transport system.

The absence of 1 or more of the physiologic circumstances described above may explain the absence of frank hypokalemia in many patients with proven primary aldosteronism.

The associated metabolic alkalosis in primary aldosteronism is due to increased renal hydrogen ion loss mediated by hypokalemia and aldosterone.

Almost 20% of patients with primary aldosteronism have impaired glucose tolerance resulting from the inhibitory effect of hypokalemia on insulin action and secretion; however, diabetes mellitus is no more common than in the general population.

Etiology

The cardinal anomaly causing primary aldosteronism syndrome is autonomous (nonsuppressible) aldosterone production. In addition to nonsuppressible aldosterone production, suppressed and poorly stimulative levels of plasma renin are coexisting with only mildly expanded intravascular and extravascular fluid volume. Normal regulation of aldosterone secretion is mediated to varying degrees by renin, serum potassium and sodium levels, intravascular volume status, and corticotropin.

Regulation of aldosterone production by these factors may be altered in various ways, depending on the subtype of primary aldosteronism. Generally, aldosterone-producing adenomas (APAs) and GRA remain corticotropin responsive, while idiopathic adrenal hyperplasia (IAH) and aldosterone-producing renin-responsive adenomas (RRAs) maintain responsiveness to the renin-angiotensin system (RAS).

In glucocorticoid-remediable aldosteronism (GRA), the RAS is suppressed, and aldosterone is regulated by corticotropin because of the chimeric gene fusion of a corticotropin-sensitive promoter with the coding regions of the aldosterone synthetase gene (which normally does not have such a promoter). Thus, ambient corticotropin levels pathologically overstimulate aldosterone synthesis inappropriately.[6]

In patients with GRA, the administration of dexamethasone (or any other glucocorticoid) at doses sufficient to suppress excessive corticotropin production results in a reduction in aldosterone synthesis and natriuresis and the eventual correction of the biochemical anomalies of primary aldosteronism.[7] Histologic studies in this disease have shown specific hyperplasia of the zona fasciculata, with concomitant atrophy of the zona glomerulosa.

Causes

The exact cause of sporadic primary aldosteronism due to an adenoma or hyperplasia is unclear. The existence of trophic factors (eg, endothelins, cytokines) has been postulated in cases of hyperplasia. Somatic mutations of genes leading to growth advantage in the adrenal adenomatous tissue are a possible, but unproven, cause.

In familial forms of primary aldosteronism, the molecular basis of GRA is known. GRA is due to a mutation that results from a hybrid gene product.[3] The 11beta-hydroxylase and aldosterone synthetase genes that are normally located close to each other on chromosome 8 cross over to create a novel hybrid gene product. This hybrid gene consists of the regulatory corticotropin-responsive sequence of the 11beta-hydroxylase gene (CYP11B1) fused to the structural component of the aldosterone synthetase gene (CYP11B2).[2]

Most sporadic aldosteronomas arise from the zona fasciculata, and they often have surrounding glandular hyperplasia close to the adenoma. This suggests that a proliferative response of cells to some presently unidentified paracrine/autocrine factor occurs. Within this zone of hyperplasia, a clonal change in a single cell is believed to take place, thus providing the nidus for the developing adenoma.

The genetic basis of type 2 familial aldosteronism is unclear; however, the locus for this disease has been mapped on 7p22 (band 11q13).[3] This syndrome can histologically manifest as hyperplasia or adenomas.

The genetic basis for type 3 familial aldosteronism has recently been deciphered. Mutations in the KCNJ5 potassium channel-coding gene results in loss of ion selectivity, cell membrane depolarization, increased Ca2+ entry in adrenal glomerulosa cells, and increased aldosterone synthesis.[4]

Tertiary aldosteronism

The existence of tertiary aldosteronism as a separate entity remains controversial. The entity is presumed to result from chronic elevations in plasma renin levels and secondary aldosteronism, which eventually establishes a state of autonomous, unregulated aldosteronism with a histologic picture of mixed hyperplasia and adenomas in the affected adrenocortical tissue. This clinicopathologic picture is considered to be the irreversible end-result of prolonged neurohumoral effects on vascular resistance and “terminal” hypertrophy of the aldosterone-producing adrenocortical tissue.

Few well-described cases exist, but in most, the adrenal glands are hyperplastic, often with nodular hyperplasia (which can cause diagnostic confusion). Virtually all of the cases described are in the setting of renal artery stenosis, which complicates further the attribution of the hypertensive state to chronic “inappropriate” aldosterone excess.

Initially, renin levels are elevated, which is typical of secondary aldosteronism. When the tertiary (autonomous) phase develops, the biochemical profile changes to a low-renin/high-aldosterone state. The paradigm is analogous to the pathogenesis of tertiary hyperparathyroidism.

Epidemiology

Occurrence in the United States

The exact prevalence of primary aldosteronism is unclear, but estimates suggest that 5-15% of essential hypertension (HTN) cases may be due to primary aldosteronism. The prevalence of primary aldosteronism is probably higher in patients who have a low serum potassium level, in patients who are elderly, and in patients who have HTN that is resistant to single medication use.

International occurrence

No evidence demonstrates that primary aldosteronism, in its more common forms, occurs in relative excess in any part of the world.[8, 9]

Race-, sex-, and age-related demographics

Primary aldosteronism occurs worldwide. Several reports suggest a higher prevalence in African Americans, persons of African origin, and, potentially, other blacks. This appears to be particularly true of the idiopathic adrenal hyperplasia (IAH) variant of the disease.

Aldosterone-producing adenomas (APAs) are more common in women than in men, with a female-to-male ratio of 2:1. The typical patient with an APA is a woman aged 30-50 years.

Accumulating data for IAH suggest different demographics for this condition, with the idiopathic disease being 4 times more prevalent in men than in women and peaking in the sixth decade of life.

Prognosis

The morbidity and mortality associated with primary aldosteronism, especially Conn syndrome, are primarily related to hypokalemia and hypertension (HTN).[10, 11] Hypokalemia, especially if severe, causes cardiac arrhythmias, which can be fatal.

Complications from chronic HTN include myocardial infarction, cerebrovascular disease, and congestive heart failure. Treatment can also lead to complications, such as drug reactions and complications from surgery.

Evidence exists to show that chronic aldosteronism in and of itself, in the absence of elevated blood pressure (eg, as occurs in secondary aldosteronism), is also associated with increased risk for cardiac injury, including ischemic, hypertrophic, and fibrotic injury. Furthermore, studies have shown that patients with primary aldosteronism are more likely to have or develop left ventricular hypertrophy, stroke, and acute coronary syndromes than are patients with similar degrees of HTN from other causes.[12, 13]

This was supported by a study by Ohno et al, which indicated that the risk of developing cardiovascular disease is higher in individuals with primary aldosteronism than in those with essential HTN. Cardiovascular disease (including stroke, ischemic heart disease, and heart failure) had a prevalence of 9.4% in patients with primary aldosteronism, greater than that in patients with essential HTN. The difference in stroke prevalence between the two groups was particularly large. Risk factors for cardiovascular disease in primary aldosteronism were found to include hypokalemia, unilateral primary aldosteronism, and plasma aldosterone levels at or above 125 pg/mL.[14]

Of course, patients with HTN due to primary aldosteronism are also at risk of developing the entire spectrum of complications of chronic HTN, including hypertensive nephropathy and retinopathy.

 

Presentation

History

The clinical presentation of primary aldosteronism is not distinctive, and the correct diagnosis requires a high index of suspicion on the part of the physician. The common clinical scenarios in which the possibility of primary aldosteronism should be considered include the following:

  • Patients with spontaneous or unprovoked hypokalemia, especially if the patient is also hypertensive[15]

  • Patients who develop severe and/or persistent hypokalemia in the setting of low to moderate doses of potassium-wasting diuretics

  • Patients with treatment-refractory/-resistant hypertension (HTN)

Patients with severe hypokalemia report fatigue, muscle weakness, cramping, headaches, and palpitations. They can also have polydipsia and polyuria from hypokalemia-induced nephrogenic diabetes insipidus. Long-standing HTN may lead to cardiac, retinal, renal, and neurologic problems, with all the associated symptoms and signs.

In a study comparing the cardiac effects of primary versus secondary aldosteronism, Cesari et al determined that while both types of aldosteronism were frequently characterized by left ventricular hypertrophy and diastolic dysfunction, only primary aldosteronism was associated with evident subclinical systolic dysfunction. Moreover, patients with primary aldosteronism had lower heart rates and higher blood pressure and vascular resistance values than did those with the secondary condition, while plasma renin activity was lower in primary than in secondary aldosteronism (0.56 vs 15.00 ng/mL/h, respectively).[16]

Familial primary aldosteronism

The 2 major familial varieties of primary aldosteronism are glucocorticoid-remediable aldosteronism (GRA; type 1 familial primary aldosteronism) and a non–glucocorticoid-remediable type (type 2 familial primary aldosteronism).

The recognition of GRA is particularly important because of its implications for patients who are hypertensive and whose family members are apparently unaffected. HTN, strokes, and other significant cardiovascular events are described in young persons with this syndrome.

Although the syndrome is uncommon, heightened levels of suspicion are essential for the diagnosis. Fewer than 200 well-validated cases exist in the literature. All patients with GRA should be treated medically with glucocorticoids and without surgery.

Although uncommon, GRA may be more prevalent than was previously presumed. A significant subgroup of patients with the milder normokalemic variety of this syndrome is probably incorrectly presumed to have essential HTN.[10]

A family history of HTN (particularly with a young age of onset), HTN in children, low-renin HTN, and presumed IAH are the typical situations in which this diagnosis should be considered.

The third type of familial PA, due to mutations in the KCNJ5 potassium channel-coding gene, is considered to be exceedingly rare, but can also lead to HTN and hypokalemia at a very early age.

Physical Examination

Patients with primary aldosteronism do not present with distinctive clinical findings, and a high index of suspicion based on the patient's history is vital in making the diagnosis. The findings could include the following:

  • Hypertension (HTN) - This condition almost invariably occurs, although a few rare cases of primary aldosteronism unassociated with HTN have been described in the literature.

  • Weakness

  • Abdominal distention

  • Ileus from hypokalemia

  • Findings related to complications of HTN - These include cardiac failure, hemiparesis due to stroke, carotid bruits, abdominal bruits, proteinuria, renal insufficiency, hypertensive encephalopathy (confusion, headache, seizures, changes in the level of consciousness), and hypertensive retinal changes

It is important to note that primary aldosteronism in and of itself is typically not associated with edema, despite the volume-expanded state associated with it. The lack of edema results from spontaneous natriuresis and diuresis (called the "aldosterone escape") that occurs in patients with primary aldosteronism and that appears to be mediated by atrial natriuretic peptide (ANP).[17, 18] Of note, this effect is probably based on the activation of the apical ATP/UTP/P2Y2 receptor system (at the connecting tubule/collecting duct level), leading to increased presentation of sodium, which, in turn, induces closure of the epithelial sodium channel (ENaC), with resultant decrease in sodium reabsorption (ie, enhanced natriuresis).[19] Hence, the finding of significant edema in patients who are presumed to have aldosteronism suggests either that a wrong diagnosis has been made or that associated complications, such as renal or cardiac failure, are present.

 

DDx

Diagnostic Considerations

Consider the diagnosis of primary aldosteronism in all persons with hypertension (HTN) and hypokalemia. Making the correct diagnosis may be the only way to achieve adequate blood pressure control and thus, to prevent the sequelae of poorly controlled HTN.

Conditions to consider in the differential diagnosis of primary aldosteronism include the following:

  • HTN

  • Malignant HTN

  • Hypertensive encephalopathy

  • Hypokalemia

  • Metabolic alkalosis

  • Renal artery stenosis

  • Renovascular HTN

  • Low-renin essential HTN - Constitutes about 40% of essential HTN

  • Tobacco chewing

  • Carbenoxolone intoxication

  • Apparent mineralocorticoid excess (AME) syndrome

  • Various causes of secondary aldosteronism - Unlike primary aldosteronism, these causes are associated with elevated renin (plasma renin activity) levels

  • Chrétien syndrome - This rare syndrome is characterized by mineralocorticoid excess and adrenocortical HTN secondary to a pituitary adenoma producing pro-opiomelanocortin (POMC)[20]

  • Deoxycorticosterone (DOC)–secreting adrenal tumors

  • Renovascular ischemia

  • Preeclampsia (toxemia of pregnancy)

  • Renin-secreting tumor - These are rare tumors arising from the juxtaglomerular apparatus

  • Excessive licorice intake - In this situation, the glycyrrhizinic acid component inhibits 11beta-hydroxysteroid dehydrogenase, impairing conversion of cortisol to cortisone in the kidneys; hence, cortisol binds to mineralocorticoid receptors and acts as a mineralocorticoid

Additional select genetic/familial disorders and syndromes to consider include the following:

  • Gitelman syndrome - This is due to a defective sodium/chloride cotransporter (NCCT); it is basically a salt-losing tubulopathy with secondary aldosteronism

  • Barrter syndrome - This is a phenocopy of at least 3 distinct genetic defects (ie, hyperactivition of the sodium-potassium-dichloride cotransporter [NKCC2], the renal outer medullary potassium channel [ROMK1], or the renal epithelial chloride channel [ClCKb],the latter encoded by the barttin gene; this is also a salt-losing tubulopathy with secondary aldosteronism and is pathophysiologically similar to Gitelman syndrome

  • Gordon syndrome - This is due to inactivating mutations of the serine-threonine kinases WNK1 and WNK4 (“with no lysine [K]” kinases), leading to hypertension, hyperkalemia, mild hyperchloremia, acidosis, and suppressed plasma renin activity

  • Pseudoaldosteronism (Liddle syndrome) - This is a rare autosomal dominant disorder due to hyperactivating mutations of the renal epithelial sodium channel (ENaC), with excessive sodium reabsorption in the renal distal tubule; levels of renin and aldosterone are low

  • 11beta-hydroxysteroid dehydrogenase deficiency

  • Glucocorticoid resistance - This is due to inactivating mutations of the glucocorticoid receptor

Differential Diagnoses

 

Workup

Approach Considerations

Individuals with primary aldosteronism may present with hypokalemic metabolic alkalosis; however, as many as 38% of patients with primary aldosteronism may be normokalemic at presentation.[15, 21]

Routine laboratory studies can show hypernatremia, hypokalemia, and metabolic alkalosis resulting from the action of aldosterone on the renal distal convoluted tubule (DCT) (ie, enhancing sodium reabsorption and potassium and hydrogen ion excretion).[22]

Historical tests

Adrenal phlebography

This procedure had been attempted in the 1980s and aimed to invasively visualize the venous patterns encircling adrenocortical adenomas. The procedure has fallen into disrepute because of the risk of adrenal infarction and is no longer used.

Therapeutic trial of spironolactone (Aldactone)

This procedure is also no longer used as a diagnostic test for primary aldosteronism, because easier and more rapid alternatives exist; hence, it is currently of historic value.

For reasons of completeness, the spironolactone therapeutic trial involved the administration of spironolactone orally at a dose of 100 mg 4 times daily for 5 weeks. A positive test would be characterized by a decrease in diastolic blood pressure of at least 20 mm Hg.

Screening (First-Tier) Tests

Serum potassium and bicarbonate levels

Hypokalemia and metabolic alkalosis have low sensitivities and specificities for primary aldosteronism when these levels are tested by themselves. Hypokalemia (serum potassium level < 3.6 mEq/L) has a sensitivity of 75-80% while the patient is on a normal sodium diet.[5] Typically, it is associated with mild metabolic alkalosis (serum bicarbonate level >31 mEq/L) and inappropriate kaliuresis (urinary potassium excretion >30 mmol/day).

Sodium and magnesium levels

Mild serum hypernatremia in the 143-147 mEq/L range and mild hypomagnesemia from renal magnesium wasting are other associated biochemical findings in established primary aldosteronism.[23] (See Medscape Reference Laboratory Medicine articles Serum Sodium and Magnesium.)

Plasma aldosterone/plasma renin activity ratio

Because the random plasma aldosterone/plasma renin activity (PRA) ratio is fairly constant over many physiologic conditions, it can be used for screening. Normal values are less than 270 when aldosterone concentration is expressed in pmol/L, or are less than 10 when aldosterone concentration is expressed in ng/dL. (See the chart below.)[24]

Algorithm for screening for potential primary aldo Algorithm for screening for potential primary aldosteronism.

When aldosterone is measured in ng/dL and PRA is measured in ng/mL/h, a plasma aldosterone/PRA ratio of greater than 20-25 has 95% sensitivity and 75% specificity for primary aldosteronism. When aldosterone is measured in pmol/L, a ratio greater than 900 is consistent with primary aldosteronism.[25, 26]

Limitations

Limitations in the usefulness of the plasma aldosterone/PRA ration include the following:

  • A major limitation of these tests is the inherent variability of aldosterone secretion due to an intrinsic circadian rhythm

  • Most recommendations suggest performing the test while all antihypertensives that can affect the renin-angiotensin system (RAS) are withheld; this can be difficult to accomplish when severe disease dictates the continuation of some medications to control hypertension (HTN) and hypokalemia during testing.

  • Obtaining the plasma aldosterone/PRA ratio in the setting of chronic angiotensin-converting enzyme (ACE) inhibitor use (ie, >4 wk of use) increases the specificity of the ratio test but reduces the sensitivity

  • Although the usefulness of plasma aldosterone/PRA ratio testing has been well validated in whites and Asians, it has not been validated in other major racial groups.

Medication interference

The plasma aldosterone/PRA ratio should not be calculated when the patient is taking medications that can interfere with this measurement. Spironolactone, an aldosterone receptor antagonist, should be stopped for 6 weeks prior to testing. Eplerenone, another aldosterone receptor antagonist, can also interfere with testing and should be stopped for at least 2 weeks before testing.

Alpha-blockers, such as doxazosin, do not interfere with the PA/PRA ratio. Beta-blockers and calcium channel blockers do not affect the diagnostic accuracy of the ratio in most cases.

PRA after salt and water depletion and/or upright posture

In primary aldosteronism, PRA is less than 1 ng/mL/h and fails to rise above 2 ng/mL/h following salt and water depletion, furosemide administration, or 4 hours of erect posture. This test, along with the captopril suppression tests, has been used either as a screening test or as a confirmatory (second-tier) test for primary aldosteronism, depending on personal preferences of various groups involved in primary aldosteronism research.

Confirmatory tests are based on the concept that aldosterone is secreted in an unregulated fashion in primary aldosteronism and therefore cannot be suppressed by usual physiologic regulatory inputs. In a similar fashion, the PRA is chronically and tonically suppressed and cannot be stimulated

Captopril and losartan suppression tests

This involves the oral administration of a single dose of captopril (25-50 mg), an ACE inhibitor. In healthy individuals, aldosterone levels will be suppressed to less than 15 ng/dL. The test has a sensitivity of 90-100% but a specificity of only 50-80%.

In a study of 135 patients who underwent captopril and losartan (an angiotensin-II receptor blocker [ARB]) tests, Wu et al concluded that the values for the PRA ratio and aldosterone concentration derived using the losartan test were more accurate than those obtained through the captopril test for the diagnosis of primary aldosteronism.[27]

The authors found that when a PRA ratio (ng/dL per ng/mL/h) of greater than 35 and an aldosterone concentration of more than 10 ng/dL were used, the diagnostic specificity values for captopril and losartan were 89.1% and 93.8%, respectively, and the respective diagnostic sensitivity values were 66.2% and 84.5%. The authors recommend the preferential performance of the losartan suppression test.

Confirmatory (Second-Tier) Tests

Serum aldosterone level

After 3 days of an unrestricted sodium diet and 1 hour of full recumbency, healthy individuals have aldosterone levels of less than 15 ng/dL. When serum aldosterone is elevated above 22 ng/dL and renin is suppressed, the serum aldosterone (S-Aldo) test virtually confirms the diagnosis of primary aldosteronism. However, because aldosterone secretion is variable, the negative and positive predictive value of a single random aldosterone level is limited.

As many as 40% of patients with primary aldosteronism have serum aldosterone levels that remain within the reference range on repeated testing, as is typically the case in essential hypertension (HTN). (See the chart below.)

Algorithm for confirmation of primary aldosteronis Algorithm for confirmation of primary aldosteronism.

24-Hour urinary aldosterone excretion test

The 24-hour urinary aldosterone (U-Aldo) excretion test is one of the most useful confirmatory diagnostic tools because it is an index for total daily aldosterone secretion (in a fashion similar to the 24-h urinary free cortisol [UFC], which is typically elevated in patients with Cushing syndrome).

In most patients with primary aldosteronism, the 24-hour U-Aldo is greater than 14 mcg/day (after 3 days of salt loading). Only about 7% of patients with primary aldosteronism have values of less than 14 mcg/day.

Salt-loading test

The salt-loading test can be done by using either an intravenous salt-loading protocol or an oral salt-loading protocol. The oral protocol calls for daily ingestion of at least 10-12 g of sodium chloride for at least 5 days before the test is performed. When the oral protocol has been met, 24-hour U-Aldo, sodium, potassium, and creatinine excretions are measured, and serum aldosterone and PRA should be determined. In normal individuals, the major U-Aldo metabolite, urinary aldosterone-18-glucuronide, should fall below a level of 17 mcg/day. Nonsuppressibility of U-Aldo-18G is highly suggestive of primary aldosteronism. Nonetheless, this test is cumbersome and rarely performed.

The 24-hour urinary creatinine measurement validates the adequacy of the urine sample collection, while a 24-hour urinary sodium value of at least 250 mEq/day confirms an adequate salt load during the days prior to the test and therefore validates the other measurements.

The alternate version of the salt loading test involves the intravenous the infusion of 500 mL/h of isotonic sodium chloride solution over 4 hours (total of 2 L of fluid volume). The serum aldosterone level and PRA are measured at baseline, 2 hours, and 4 hours. In healthy individuals, aldosterone levels are suppressed to less than 8.5 ng/dL, while the PRA is suppressed to less than 0.6 ng/mL/h. Again, S-Aldo is highly suggestive of primary aldosteronism. Rapid infusion of isotonic saline should be avoided in patients with frank volume overload due to renal or cardiac failure or other medical reasons.

Determination of Primary Aldosteronism Subtype (Third-Tier) Tests

Once the diagnosis of primary aldosteronism has been confirmed by a first- or second-tier test, the next step is to determine the subtype of primary aldosteronism and to identify surgically curable disease. For practical purposes, this means distinguishing between an adrenal adenoma and idiopathic adrenal hyperplasia (IAH). (See the chart below.)[22, 28]

Algorithm for distinguishing subtypes of primary a Algorithm for distinguishing subtypes of primary aldosteronism.

In general, patients with adenomas are younger than patients with hyperplasia and have more severe hypertension (HTN) and hypokalemia, as well as higher urinary aldosterone (U-Aldo) levels, than do patients with IAH. However, these clinical parameters are not reliable enough to accurately distinguish adenoma from IAH.

Postural stimulation test

Aldosteronomas are associated with an anomalous decrease in the aldosterone level with upright posture, in contrast to patients with idiopathic adrenal hyperplasia (IAH), in whom a renin-angiotensin system (RAS)–mediated increase in aldosterone level occurs with upright posture.

Similarly, a serum aldosterone level surge occurs in patients with renin-responsive adenomas (RRAs), low-renin essential HTN, and very rare cases of unilateral adrenal hyperplasia (the latter presenting with features intermediate between idiopathic adrenal hyperplasia [IAH] and aldosterone-producing adrenal adenoma; occasionally designated as “intermediate aldosteronism”).[29]

When abdominal computed tomography (CT) and magnetic resonance imaging (MRI) scans are combined with postural stimulation, the positive predictive value (PPV) of an abnormal postural test in predicting surgically correctable primary aldosteronism due to a single adenoma is 98%.

The standard postural test protocol involves obtaining baseline values for serum aldosterone (S-Aldo) and plasma renin activity (PRA) levels, as well as these levels 2 hours after the patient has assumed an erect posture. S-Aldo levels typically rise in this setting at least 50% above baseline in healthy persons, in persons with essential HTN, and in the subgroup of patients with primary aldosteronism who have either idiopathic adrenal hyperplasia (IAH) or RRAs.

Among patients with aldosteronomas (aldosterone-producing adenomas; APAs), S-Aldo levels typically do not rise or paradoxically fall to this level. The sensitivity and specificity of this test in the differential diagnosis of the main causes of primary aldosteronism have been reported to be as high as 80-85%.

Furosemide (Lasix) stimulation test

This test is often combined with the upright posture test. The typical test involves the oral administration of 40 mg of furosemide the night before as well as the morning of the test. On the morning of the test, after the furosemide dose has been administered, the patient remains upright 2-3 hours; then, S-Aldo and PRA levels are assayed. The interpretation of the test results is similar to that described above for the postural stimulation test.

Diurnal rhythm of aldosterone

The circadian rhythm of aldosterone secretion in healthy individuals parallels that of cortisol and is corticotropin-dependent. The lowest values are observed around 11:30 pm to midnight, and the highest values occur early in the morning around 7:30-8:00 am (assuming a normal sleep-wake cycle). While this is preserved in patients with aldosteronomas, it is typically lost in patients with IAH.

Elevated levels of 18OH corticosterone and/or 18OH cortisol in plasma and urine may be found in some patients with aldosteronomas but are uncommon in IAH.[30, 31]

CT Scanning and MRI

CT scanning

The initial radiologic investigation in the workup of primary aldosteronism is high-resolution, thin-sliced (2-2.5 mm) adrenal CT scanning with contrast.

Aldosteronomas tend to be small, in contrast to cortisol-producing adrenocortical adenomas; only aldosteronomas that are at least 1 cm in diameter can be detected reliably and consistently.

The overall sensitivity of high-resolution, thin-slice adrenal CT scanning is greater than 90%, but the picture is complicated by the many false-positive findings associated with incidentalomas, which are reported in some series to be found in up to 10-15% of the general population (their prevalence increases with age).[32]

Moreover, high-resolution CT studies can actually be detrimental, because these scans often detect the hyperplasia accompanying adenomas and may result in a tendency to overdiagnose idiopathic adrenal hyperplasia (IAH). Similarly, because long-term adrenal hyperplasia is associated with pseudonodule and nodule formation, this radiographic picture may often be confused with the diagnosis of autonomous adenomas.

Surgical indications

Some investigators suggest that when a solitary, unilateral macroadenoma (>1 cm) is detected on a CT scan in a young patient in the setting of unequivocal aldosteronism, unilateral adrenalectomy is indicated. However, because of the age-dependent risk that a solitary, unilateral adrenal macroadenoma may be a nonfunctioning adenoma, some experts believe that adrenal vein sampling[22] should be performed in patients older than 40 years.

MRI

It is generally accepted that MRI is not superior to contrast-enhanced CT scanning for adrenal visualization. High-resolution CT scans may actually have better adrenal definition. (See the image below.)

Magnetic resonance imaging (MRI) scan in a patient Magnetic resonance imaging (MRI) scan in a patient with Conn syndrome showing a left adrenal adenoma.

If the screening (CT scanning and/or MRI) of a patient with primary aldosteronism is completely normal, a 6- to 12-month treatment trial with aldosterone antagonists is generally recommended, after which the imaging studies should be repeated. Treatment with glucocorticoids may also be considered for glucocorticoid-remediable aldosteronism (GRA), if this condition is suspected.

NP-59 Iodo-methyl-norcholesterol Scintigraphy

Although fairly difficult to set up and not routinely available, this test can be useful in select cases for distinguishing between adenomas and hyperplasia. In large nuclear medicine referral centers, the discriminant value of the test approaches that of adrenal venous sampling (ie, close to 90%), especially with larger tumors of 1.5 cm in diameter or larger. (See the image below.) The typical administered activity is 37 MBq (1 milliCurie; mCi).

Scintigram obtained by using iodine-131-beta-iodom Scintigram obtained by using iodine-131-beta-iodomethyl-norcholesterol (NP-59) in a 59-year-old man with hypertension shows fairly intense radionuclide uptake in the right adrenal tumor. At surgery, a Conn tumor was confirmed.

The test results are improved if there has been previous dexamethasone suppression of the adrenals using 0.5-1 mg of oral dexamethasone every 6 hours. In this setting, adenoma images remain visible, while hyperplastic gland images fade after 2-3 days of dexamethasone therapy.

Standard scanning may produce a false-negative result for small aldosteronomas; however, the diagnostic yield can be increased by coadministration of spironolactone. This is the major diagnostic alternative to adrenal venous sampling (AVS).

A retrospective study by Di Martino et al indicated that in select cases, primary aldosteronism can be preoperatively localized using the NP-59 test in place of adrenal venous sampling. Basing the test’s performance on pathologic results, the sensitivity and positive predictive value were 90.9% and 83.3%, respectively; basing the performance on postoperative blood pressure control resulted in a sensitivity and positive predictive value of 91.6% (for both).[33]

Adrenal Venous Sampling

Because this procedure is highly dependent on the availability of technically proficient interventional radiologists, it cannot (and should not) be performed universally, despite the fact that it is the criterion standard for the confirmation of lateralizable aldosterone excess.[34, 35, 36] Indeed, adrenal venous sampling may be performed selectively only when preoperative imaging cannot definitively lateralize a presumed unilateral aldosteronoma. A report by Dekkers et al supports this line of argument and challenges the notion of performing adrenal venous sampling in all patients with primary aldosteronism. The study found that at 1-year follow-up, intensity of hypertensive medication and clinical benefits did not significantly differ between patients assessed by adrenal venous sampling and those evaluated by adrenal CT scan.[37]

Adrenal venous sampling probably has its greatest utility when adrenal imaging findings are completely normal despite biochemical evidence for primary aldosteronism and in settings in which bilateral adrenal pathology is present on imaging and the biochemistry suggests the presence of a functional aldosteronoma.

The test also has utility in resolving the exact etiology in cases of primary aldosteronism in which discordance exists between the biochemical findings and the radiologic findings with regard to whether the primary aldosteronism is due to idiopathic adrenal hyperplasia (IAH) or an aldosteronoma.

One series reported that 41% of patients with a normal adrenal CT scan who had biochemical evidence of primary aldosteronism actually had lateralizable disease, while 49% of patients with bilateral micronodules on CT scan also had lateralizable disease.[38] Even in cases in which only a single adrenal nodule was found on imaging, when adrenal venous sampling was performed, it confirmed lateralizable disease in just 51-66% of cases.

A retrospective study by Kline et al indicated that using the strictest adrenal venous sampling criteria in the lateralization of primary aldosteronism may cause a large number of patients to be incorrectly diagnosed as having a bilateral, rather than unilateral, condition and, consequently, to be excluded from surgical intervention. Looking at 80 primary aldosterone cases that were addressed with surgery, the investigators found that the use of lateralization indexes of 3:1 to 5:1 would have resulted in a missed surgical opportunity in 10-23%.[39]

Technique

The adrenal veins are catheterized via a percutaneous femoral venous approach. Right and left venous catheters should be placed in the ipsilateral adrenal veins to prevent errors in handling the samples. (Cannulation of the right adrenal vein is technically difficult because of the short length of this vessel. The left adrenal vein is longer, allowing for more stable catheter placement.)

At baseline and following corticotropin stimulation (preferably by continuous infusion at 50 mcg/h for the duration of the sampling study), blood samples are obtained simultaneously from both adrenal veins, as well as from the inferior vena cava, and the samples are assayed for aldosterone and cortisol.

In order to document the placement of the catheters within the adrenal veins, an adrenal-to–vena cava cortisol ratio (post corticotropin) is calculated; it should be greater than 5-10.

Diagnosis

The accuracy of the test exceeds 95% when the procedure is technically successful. If autonomous, unilateral secretion of aldosterone is present on either side, the ratio of aldosterone concentrations between the right and left adrenal veins generally exceeds 10:1. False-positive results can occur when renal artery stenosis is present; hence, renal artery stenosis needs to be thoroughly excluded, especially before a highly invasive test is performed.

Most patients with a unilateral source of aldosterone have adrenal-to-adrenal aldosterone-to-cortisol ratios of greater than 4. Ratios of less than 3 suggest hyperplasia, and values of 3-4 are considered indeterminate results.

Risks

Adrenal venous sampling is not without risks. Adrenal and iliac venous thrombosis, adrenal hemorrhage, adrenal insufficiency, or even major venous hemorrhage due to transmural tears and catheter dislocations are among the potential complications.

Hydroxycorticosterone and Oxocortisol-Hydroxycortisol Assays

Because of the different adrenocortical zones involved in idiopathic hyperplasia, in comparison with adenomas, assays of plasma 18-hydroxycorticosterone (18-OHB) or plasma and/or urine 18-oxocortisol (18-oxo-F)/18-hydroxycortisol may be of diagnostic use. (See the image below.)[30, 31]

Transitional zone adrenocortical steroids. Transitional zone adrenocortical steroids.

Aldosteronomas are typically associated with 18-OHB levels of greater than 100 ng/dL. Similarly, glucocorticoid-remediable aldosteronism (GRA; type 1 familial hyperaldosteronism), though a hyperplastic disease by definition, is also associated with an increased production of these 18-oxo/hydroxy derivatives. This distinct biochemistry is not present in renin-responsive adenomas (RRAs). At this point, few centers send out for these specialized biochemistry tests, and their current value is mainly historical.

Fludrocortisone Suppression Test

This test works on the same principle that the sodium chloride intravenous infusion or the oral salt-loading tests are based on for confirming a diagnosis of primary aldosteronism. The fludrocortisone suppression test has lost much of its popularity, however, because it requires hospitalization of the patient and 4-5 days to complete, and it currently is mainly of historical interest.

For reasons of completeness, the description of this test is as follows: fludrocortisone is administered orally at a dose of 0.1-0.2 mg every 6 hours, along with supplemental sodium chloride and potassium. In the healthy individual, following this stimulation, the serum aldosterone (S-Aldo) level is typically suppressed to less than 8 ng/dL, with a corresponding urinary aldosterone (U-Aldo) excretion of less than 12 mcg/day.

In patients with primary aldosteronism, neither the urinary aldosterone level nor the plasma aldosterone level suppresses to the above-noted thresholds.

Dexamethasone Suppression Test

This test is relevant only in the setting of possible familial aldosteronism. Customarily, in patients with primary aldosteronism, dexamethasone is associated with a transient slight-to-moderate reduction of plasma and urinary aldosterone levels, although not into the normal reference range.[7]

In the subset of primary aldosteronism patients with glucocorticoid-remediable aldosteronism (GRA), small doses of dexamethasone (1-2 mg/day) induce full normalization in plasma and urinary aldosterone levels. This is invariably associated with improvement in hypertension (HTN) in these patients. Other reports suggest a cut-off level for plasma aldosterone of less than 4 ng/dL and/or a relative plasma aldosterone suppression of greater than 80% of the baseline for the diagnosis of GRA following the dexamethasone challenge.

Three variants of familial primary aldosteronism exist. Type 1 familial primary aldosteronism (also called GRA) is associated with improvement in HTN using low-dose dexamethasone. Types 2 and 3 familial primary aldosteronism are not dexamethasone suppressible.

Metoclopramide (Reglan) Test

This is a noninvasive test for distinguishing between aldosteronomas and idiopathic adrenal hyperplasia (IAH). It takes advantage of the differential expression of the dopamine receptors on the cell membrane of adrenocortical cells.

Under normal conditions, dopamine causes tonic inhibition of aldosterone, whereas serotonin (5-HT) causes increased aldosterone secretion in vivo. Metoclopramide is a D2 dopamine receptor antagonist, as well as a serotonin receptor-4 (5-HT4) partial agonist, and, hence, its administration leads in increased aldosterone levels. This normal pattern of response is retained in patients with aldosteronomas and low-renin hypertension (HTN), but not in patients with IAH.[40]

Following a 10-mg intravenous injection of metoclopramide, serum aldosterone levels increase significantly in patients with aldosteronomas, but they remain either unchanged or paradoxically reduced in patients with IAH. This test saw some increased usage in the mid 1990s, especially in Europe, but is rather rarely used in the United States today.

Additional Laboratory Studies

Corticotropin stimulation test

The corticotropin stimulation test uses the standard 250-mcg intravenous injection. In aldosteronomas, a robust aldosterone response is typically observed. In idiopathic adrenal hyperplasia (IAH), the aldosterone surge is considerably more feeble. The test is no longer used, because the discriminant value of the test is rather poor.[6]

Angiotensin-II infusion test

This test involves evaluating the response of plasma renin activity (PRA) and serum aldosterone (S-Aldo) to a continuous angiotensin-II infusion. The response characteristics are similar to those observed in the posture tests, with an appropriate increase in aldosterone level observed in IAH but not in aldosteronomas.

The angiotensin-II infusion test is much less popular than other aldosteronism tests because it requires continuous infusion and close hemodynamic monitoring, and it is rarely used today.

Histological Findings

Histologic findings vary according to the type of primary aldosteronism that a patient has. Typical aldosteronomas are characterized by adenomatous tissue, usually with zona fasciculata–type morphology. Most of these tumors are small (< 3 cm in diameter), and most of the cells are lipid-laden cells arranged in acini or cords. Associated focal and/or diffuse hyperplasia often occurs.

Renin-responsive adenomas (RRAs) are characterized by zona glomerulosa–type morphology. The only other distinctive features are predictable, unique biochemical features.

Idiopathic adrenal hyperplasia (IAH) is characterized by diffuse hyperplasia that may be micronodular, macronodular, or a mixture of both. The morphology of the cells is commonly akin to the zona glomerulosa.

In primary adrenal hyperplasia (PAH), diffuse hyperplasia, which is unilateral and has zona fasciculata morphology, is typically observed.

Primary aldosteronism syndrome rarely occurs in the setting of adrenal carcinoma, whereby the cause of the hypersecretion of aldosterone is a malignancy (rather than a benign adenoma). In such cases, histopathology reveals the typical features of adrenocortical carcinoma (ACC), including mitotic figures, local invasion, and locoregional lymph node metastases.

 

Treatment

Approach Considerations

Among the major goals of therapy for primary aldosteronism are (1) normalization of blood pressure, (2) normalization of levels of serum potassium and other electrolytes, and (3) normalization of serum aldosterone levels.[22, 41]

The appropriate treatment for primary aldosteronism depends on its cause. Although hypertension (HTN) is frequently cured after unilateral adrenalectomy in patients with primary aldosteronism secondary to an adrenal aldosteronoma, the mean HTN cure rate is only 19% after unilateral or even bilateral adrenalectomy in patients with idiopathic adrenal hyperplasia (IAH). Therefore, medical management is the treatment of choice for the IAH variant of primary aldosteronism. (See the chart below.)

Effects of main antihypertensives on the renin-ang Effects of main antihypertensives on the renin-angiotensin system.

In patients with an aldosteronoma, medical therapy is used preoperatively to control blood pressure and correct hypokalemia, thus decreasing surgical risk. Medical therapy is also administered to patients with persistent HTN postoperatively, poor surgical candidates, and patients who refuse surgery.

In patients with heart failure who have secondary aldosteronism, aldosterone antagonism by spironolactone and eplerenone has been demonstrated to confer survival benefit.[42]

Pharmacologic Therapy

Calcium channel blockers

By inhibiting the intracellular calcium flux in the adrenocortical cells, the dihydropyridine calcium channel blockers reduce the production of aldosterone in response to a variety of stimulants, including potassium, corticotropin, and angiotensin-II.

Nifedipine is the most extensively studied of these medications; however, although nifedipine causes a significant improvement in patients with hypertension (HTN), it does not address the pathophysiology of the condition. The plasma renin activity (PRA), aldosterone levels, plasma volume, and serum potassium concentrations remain essentially unchanged while using nifedipine.

Mineralocorticoid antagonists

Mineralocorticoid antagonists, such as spironolactone, are inhibitory ligands to the mineralocorticoid receptor (MR). They achieve remarkable blood pressure control and normalization of plasma volume and serum potassium concentrations, particularly in patients with aldosteronomas.[43]

The salutary effects of spironolactone appear to be due mainly to its impact on salt and water balance rather than to its antagonism of aldosterone in the kidney. The combination of spironolactone and thiazides often provides even better blood pressure control than does spironolactone alone.

Because of the estrogenlike adverse effects of spironolactone, including impotence and gynecomastia, the incentive to develop a similarly effective antialdosterone agent without these adverse effects is considerable. Eplerenone is a selective antialdosterone agent that may fulfill this promise, because it is a specific aldosterone receptor antagonist that does not have the additional antiandrogen effects associated with spironolactone.

Glucocorticoids

In the subgroup of patients with glucocorticoid-remediable aldosteronism (GRA), the treatment of choice is the administration of the lowest possible dose of glucocorticoid that can be used to achieve adequate blood pressure control. Because of the potential adverse effects that can result from even subtle glucocorticoid excess, using short-acting glucocorticoids, such as prednisone and hydrocortisone (rather than dexamethasone), is generally best.

Other

ACE inhibitors and angiotensin receptor blockers (ARBs) are also potential treatment options. Less ideal medical treatment options include potassium-sparing diuretics, such as triamterene and amiloride, that are not mineralocorticoid antagonists. Amiloride acts at the level of the distal convoluted tubule but does not bind to mineralocorticoid receptors.

A few reports of the use of percutaneous injection of ethanol or acetic acid into aldosteronomas as a treatment modality exist; in these cases, the treatment was usually administered to patients for whom surgery was contraindicated.[44] This technique is neither popular nor well validated. Furthermore, it requires the technical expertise of a highly skilled interventional radiologist.

Considerations

Nonsurgical therapy is also a viable treatment option in patients who have lateralizable disease but who are poor surgical candidates because of other coexisting comorbidities. It is also a viable treatment option in the rare setting of bilateral functional adrenal adenomas that would otherwise require bilateral adrenalectomy.

Adrenal Surgery

Surgery is the treatment of choice for the lateralizable variants of primary aldosteronism, including typical aldosteronomas, renin-responsive adenomas (RRAs), and primary adrenal hyperplasia (PAH).

Preoperatively, once the biochemical and anatomic diagnoses are made and confirmed, the patient should be started on a 3- to 5-week course of spironolactone. This serves as an additional diagnostic tool (in confirming the diagnosis of primary aldosteronism) and as a means of predicting the blood pressure response that can be expected postsurgery.

An adrenalectomy can be performed via a formal laparotomy or by using a laparoscopic technique (with performance of the latter becoming increasingly common). The laparoscopic option now makes it possible to offer surgical therapy to relatively frail patients who would be unable to withstand a formal laparotomy. Ongoing studies are systematically evaluating the place of adrenal-conserving operations versus total unilateral adrenalectomy in these patients.[45]

Among the options being studied are (1) partial adrenalectomy, in which a wedge resection of the gland with the adenoma is performed along with aldosteronoma enucleation, and (2) medulla-sparing adrenalectomy, in which an attempt is made to retain the adrenal medullary tissue while removing the cortex.

Outcomes

About 60-70% of patients are rendered normotensive following curative surgery for aldosteronomas when evaluated 1 year postoperatively. Hypertension (HTN) typically does not resolve immediately postoperatively but, rather, over 3-6 months. (Although following surgery, virtually all patients with an aldosteronoma have significant reductions in aldosterone secretion and blood pressure and also demonstrate a correction of hypokalemia.[46, 47, 48, 49, 50] )

A retrospective study of 168 patients with primary aldosteronism who underwent an adrenalectomy found that HTN was cured or controlled in 77% of patients with a unilateral adenoma and in 68% of patients with aldosteronism who had no adenoma, but whose aldosterone-to-cortisol ratio was at least 5 times higher on the dominant side than on the nondominant side.[48]

The percentage of patients who remain normotensive 5 years postoperatively is about 53%. The resolution of HTN following adrenalectomy invariably occurs in the setting of a family history in which HTN is absent and/or when there has been preoperative use of 2 or fewer antihypertensives by the patient.

Adrenalectomy has very little utility in the setting of idiopathic adrenal hyperplasia (IAH). In reported cases in which surgery has unintentionally been performed on patients with IAH, the effects on blood pressure, hypokalemia, and aldosterone hypersecretion have been minimal, further underpinning the necessity of making a correct diagnosis before making a case for adrenalectomy.

Persistence of HTN following apparent surgical treatment of lateralizable disease is most common in patients older than 45 years, in those who had HTN for more than 5 years prior to surgery, and in persons who did not respond preoperatively to spironolactone.[48, 49]

Persistent HTN may be related to resetting of baroreceptors, established hemodynamic changes, structural changes in the blood vessels, or coincidental essential HTN.

Another possibility to consider in persistent HTN is an incomplete resection of the adenoma, with remaining remnant hyperplastic tissue. The coexistence of hypertensive nephrosclerosis in some patients with persistent HTN is also a distinct possibility. The coexistence of other secondary causes of HTN needs to be considered as well; renal artery stenosis is an important consideration.

Preoperative and postoperative care

Prior to surgery, patients should receive at least 8-10 weeks of medical therapy in order to decrease blood pressure and to correct the metabolic syndromes that are often associated with primary aldosteronism.

Postoperatively, metabolic profiles should be closely monitored. Most patients do not develop permanent hypomineralocorticoidism and therefore do not require fludrocortisone replacement.

For patients who develop hypoaldosteronism, the symptoms may persist for a long time and may be akin to the delay observed in adrenal glucocorticoid recovery following chronic corticotropin suppression by exogenous steroids. However, if significant hyperkalemia develops, potassium supplements should be discontinued, and the patient can be started on furosemide at doses of 80-160 mg daily.

Diet

A low-salt diet, although helpful in achieving blood pressure control in primary aldosteronism, may be associated with false-negative results on biochemical testing.

A high-salt diet makes the achievement of blood pressure control more difficult and may cause false-positive results on biochemical testing.

 

Guidelines

Guidelines Summary

A series of recommendations on the management of primary aldosteronism were developed by the French Endocrinology Society (SFE), the French Hypertension Society (SFHTA), and the Francophone Endocrine Surgery Association (AFCE).[51, 52, 53, 54, 55, 56, 57, 58] They include a recommendation to screen for primary aldosteronism in patients with any of the following:

  • Severe hypertension (systolic blood pressure of 180 mm Hg or greater or diastolic blood pressure of 110 mm Hg or greater)
  • Resistant hypertension (systolic blood pressure of 140 mm Hg or greater or diastolic blood pressure of 90 mm Hg or above, even after the use of at least three antihypertensive agents, including a thiazide diuretic)
  • Hypokalemia-associated hypertension (either spontaneous or diuretic associated)
  • Hypertension or hypokalemia related to an adrenal incidentaloma

Regarding surgery, the recommendations state that laparoscopic adrenalectomy should be used for patients with lateralized primary aldosteronism who are candidates for surgery. In terms of medical treatment, the use of amiloride is recommended for patients with spironolactone intolerance, while eplerenone is suggested as another alternative in cases of spironolactone intolerance or if amiloride does not sufficiently control hypertension.

In a 2016 update to its 2008 clinical practice guidelines for the diagnosis and treatment of primary aldosteronism, the Endocrine Society included the following recommendations[59, 60] :

  • Screening for the condition in subjects with sustained blood pressure above 150/100 mm Hg, as found on each of three measurements obtained on different days, as well as in patients with hypertension (blood pressure >140/90 mm Hg) resistant to three conventional antihypertensive drugs (including a diuretic) or with controlled blood pressure (< 140/90 mm Hg) on four or more antihypertensive drugs, with hypertension and spontaneous or diuretic-induced hypokalemia, with hypertension and adrenal incidentaloma, with hypertension and sleep apnea, or with hypertension and a family history of early onset hypertension or cerebrovascular accident at a young age (< 40 years); screening should also be performed in all hypertensive first-degree relatives of patients with primary aldosteronism
  • The use of the plasma aldosterone/renin ratio for detection of possible primary aldosteronism in the above patient groups
  • The use of one or more confirmatory tests in patients with a positive plasma aldosterone/renin ratio to definitively confirm or exclude the diagnosis
  • The use of adrenal CT scanning in all patients with primary aldosteronism to exclude large masses that may represent adrenocortical carcinoma and to assist the interventional radiologist and surgeon where anatomically appropriate
  • When surgical treatment is feasible and desired by the patient, the use of adrenal venous sampling to make the distinction between unilateral and bilateral adrenal disease
  • The use of genetic testing for familial hyperaldosteronism type 1 in patients in whom the onset of primary aldosteronism is confirmed before age 20 years and in those with a family history of primary aldosteronism or stroke at a young age (< 40 y)
  • The use of unilateral laparoscopic adrenalectomy in patients with documented unilateral primary aldosteronism (ie, aldosterone-producing adenoma or unilateral adrenal hyperplasia), or, in patients who are unable or unwilling to undergo surgery, the administration of medical treatment including a mineralocorticoid receptor antagonist
  • The administration of medical treatment with a mineralocorticoid receptor antagonist in patients with primary aldosteronism due to bilateral adrenal disease
  • In patients with glucocorticoid-remediable aldosteronism, administration of the lowest dose of glucocorticoid to lower adrenocorticotropic hormone and thus normalize blood pressure and potassium levels as the first-line treatment; if blood pressure fails to normalize with glucocorticoid alone, a mineralocorticoid receptor antagonist may be added
 

Medication

Medication Summary

In nonsurgical primary aldosteronism, medical therapy is the treatment of choice. The drug that is the treatment of first choice for most variants of nonsurgical primary aldosteronism is spironolactone, which is used to achieve normoaldosteronism and to assist with blood pressure control. Potassium supplementation should not be routinely administered with spironolactone because of the potential for the development of hyperkalemia.

In patients who are unable to tolerate spironolactone, other potassium-sparing diuretics, such as amiloride and triamterene, can be used, although these are considered less ideal options.[42]

Glucocorticoid-remediable aldosteronism (GRA) is treated with small doses of glucocorticosteroids (ie, hydrocortisone, prednisone). At optimal doses, glucocorticosteroids normalize aldosterone and blood pressure.

Various antihypertensives may be added to achieve adequate blood pressure control. The dihydropyridine calcium channel blockers (eg, nifedipine) directly inhibit aldosterone production; however, while producing significant improvement in patients with hypertension (HTN), they do not address pathophysiology. Plasma renin activity (PRA), aldosterone levels, plasma volume, and serum potassium concentrations remain essentially unchanged with nifedipine use.

Other second-step agents for blood pressure control include thiazide diuretics, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers.[27]

A sodium-restricted diet (< 80 mEq or < 2 g of sodium daily), maintenance of ideal body weight, and regular aerobic exercise contribute substantially to the success of pharmacologic treatment.

Aldosterone Antagonists, Selective

Class Summary

These agents compete with aldosterone receptor sites, reducing edema and ascites.

Spironolactone (Aldactone)

Spironolactone competitively binds receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule. It provides diuretic and antihypertensive effects, causing increased excretion of sodium and water, while retaining potassium. Spironolactone is administered alone or with a diuretic agent that acts on the proximal renal tubule. Spironolactone may block the effects of aldosterone on arteriolar smooth muscles.

Eplerenone (Inspra)

Eplerenone selectively blocks aldosterone at the mineralocorticoid receptors in epithelial (eg, kidney) and nonepithelial (eg, heart, blood vessels, brain) tissues, thus decreasing blood pressure and sodium reabsorption.

Potassium-Sparing Diuretics

Class Summary

These agents are used as second-line medication for the treatment of primary aldosteronism due to nonlateralizing disease and/or lateralizing disease for which surgery is otherwise contraindicated or refused. They often must be used with other antihypertensives to achieve the best blood pressure control, because they are not potent antihypertensives.

Triamterene (Dyrenium)

Triamterene is a potassium-sparing diuretic with relatively weak natriuretic properties. It exerts a diuretic effect on the distal renal tubule to inhibit reabsorption of sodium in exchange for potassium and hydrogen. Triamterene increases sodium excretion and reduces the excessive loss of potassium and hydrogen associated with hydrochlorothiazide. It is not a competitive antagonist of mineralocorticoids; its potassium-conserving effect is observed in patients with Addison disease (ie, without aldosterone).

The onset and duration of activity with triamterene are similar to those of hydrochlorothiazide. No predictable antihypertensive effect is demonstrated. It is rapidly absorbed following oral administration, and peak plasma levels are achieved within 1 hour of dosing. Triamterene is primarily metabolized to a sulfate conjugate of hydroxytriamterene. Plasma and urine levels of this metabolite greatly exceed triamterene levels.

Amiloride

Amiloride is a pyrazine-carbonyl-guanidine unrelated chemically to other known antikaliuretic or diuretic agents. It is a potassium-conserving (antikaliuretic) drug that, compared with thiazide diuretics, possesses weak natriuretic, diuretic, and antihypertensive activity. Amiloride's effects have been partially additive to the effects of thiazide diuretics in some clinical studies. When it is administered with a thiazide or loop diuretic, it has been shown to decrease the enhanced urinary excretion of magnesium that occurs when a thiazide or loop diuretic is used alone.

Amiloride has potassium-conserving activity in patients receiving kaliuretic-diuretic agents. Amiloride is not an aldosterone antagonist, and its effects are observed in the absence of aldosterone. It exerts its potassium-sparing effect through the inhibition of sodium reabsorption at the distal convoluted tubule, cortical collecting tubule, and collecting duct. This decreases the net negative potential of the tubular lumen and reduces potassium and hydrogen secretion and their subsequent excretions.

Amiloride usually begins to act within 2 hours after an oral dose. Its effect on electrolyte excretion reaches a peak between 6-10 hours and lasts about 24 hours. Peak plasma levels are obtained in 3-4 hours, and the drug's plasma half-life varies between 6 and 9 hours.

Amiloride is not metabolized by the liver; it is instead excreted unchanged by the kidneys. Within 72 hours, about 50% of a dose of amiloride is excreted in urine and 40% in stool. The drug has little effect on the glomerular filtration rate or on renal blood flow. Because the liver does not metabolize amiloride hydrochloride, drug accumulation is not anticipated in patients with hepatic dysfunction; however, accumulation can occur if hepatorenal syndrome develops.

Amiloride should rarely be used alone. Used as single agents, potassium-sparing diuretics, including amiloride, result in an increased risk of hyperkalemia (approximately 10% with amiloride). Amiloride should be used alone only when persistent hypokalemia has been documented and only with careful titration of the dose and close monitoring of serum electrolyte levels.

Thiazide Diuretics

Class Summary

Thiazide diuretics inhibit the reabsorption of sodium in the distal tubules, increasing the excretion of sodium, water, and potassium and hydrogen ions. They have been effective in treating hypertension of various etiologies. Besides diminishing sodium reabsorption, they also appear to diminish the sensitivity of blood vessels to circulating vasopressor substances. In all patients treated with diuretics, electrolyte levels should be monitored. Examples of thiazide diuretics are hydrochlorothiazide and chlorthalidone.

Hydrochlorothiazide (Microzide)

Hydrochlorothiazide inhibits reabsorption of sodium in distal tubules, causing increased excretion of sodium and water, as well as of potassium and hydrogen ions.

Chlorthalidone (Thalitone)

Chlorthalidone inhibits the reabsorption of sodium in distal tubules, causing increased excretion of sodium and water, as well as of potassium and hydrogen ions.

Calcium channel Blockers

Class Summary

Calcium channel blockers affect blood pressure by decreasing vascular peripheral resistance. With short-acting calcium channel blockers, the cardiac response to this action is variable and tachycardia can occur. Long-acting preparations may cause a decrease in heart rate.

Calcium channel blockers are classified by their structure and have different degrees of selectivity in their effects on vascular smooth muscle. The dihydropyridines do not exert electrophysiologic effects and are commonly used to manage hypertension. Facial flushing may occur. Examples of calcium channel blockers include amlodipine and isradipine.

Amlodipine (Norvasc)

Amlodipine is generally regarded as a dihydropyridine, although experimental evidence suggests that it also may bind to nondihydropyridine binding sites. It is appropriate for the prophylaxis of variant angina and has antianginal and antihypertensive effects. Amlodipine blocks the postexcitation release of calcium ions into cardiac and vascular smooth muscle, thereby inhibiting the action of adenosine triphosphatase (ATPase) on myofibril contraction.

The overall effect of amlodipine is reduced intracellular calcium levels in cardiac and smooth-muscle cells of the coronary and peripheral vasculature, resulting in dilatation of coronary and peripheral arteries. Amlodipine also increases myocardial oxygen delivery in patients with vasospastic angina, and it may potentiate angiotensin-converting enzyme (ACE) inhibitor effects.

During depolarization, amlodipine inhibits the entrance of calcium ions into slow channels and voltage-sensitive areas of vascular smooth muscle and myocardium. It benefits nonpregnant patients with systolic dysfunction, hypertension, or arrhythmias. It has a substantially longer half-life than nifedipine and diltiazem and is administered once daily.

Felodipine

Felodipine relaxes coronary smooth muscle and produces coronary vasodilation, which, in turn, improves myocardial oxygen delivery. It benefits nonpregnant patients with systolic dysfunction, hypertension, or arrhythmias. It can be used during pregnancy if clinically indicated.

Calcium channel blockers potentiate ACE inhibitor effects. Renal protection is not proven, but these agents reduce morbidity and mortality rates in congestive heart failure. Calcium channel blockers are indicated in patients with diastolic dysfunction. They are effective as monotherapy in black patients and elderly patients.

Isradipine (DynaCirc CR)

Isradipine is a dihydropyridine calcium channel blocker. It inhibits the entrance of calcium into select voltage-sensitive areas of vascular smooth muscle and myocardium during depolarization. This causes relaxation of coronary vascular smooth muscle, which results in coronary vasodilation. Vasodilation reduces systemic resistance and blood pressure, with a small increase in resting heart rate. Isradipine also has negative inotropic effects.

Nifedipine, extended-release (Adalat CC, Nifedical XL, Procardia XL)

Extended-release nifedipine relaxes coronary smooth muscle and produces coronary vasodilation, which, in turn, improves myocardial oxygen delivery.

ACE Inhibitors

Class Summary

Angiotensin-converting enzyme (ACE) inhibitors prevent the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, and lower aldosterone secretion. They are effective and well-tolerated drugs with no adverse effects on plasma lipid levels or glucose tolerance. They prevent the progression of diabetic nephropathy and other forms of glomerulopathies but appear to be less effective in black patients than in white patients. ACE inhibitors are contraindicated in pregnancy.

Patients with high plasma renin activity (PRA) may have an excessive hypotensive response to ACE inhibitors. Patients with bilateral renal vascular disease or with a single kidney, whose renal perfusion is maintained by high levels of angiotensin II, may develop irreversible acute renal failure when treated with ACE inhibitors, and caution should be exercised with their use in these patients. Interestingly, although primary aldosteronism is a condition associated with low plasma renin, aldosterone secretion seems to be exquisitely sensitive to even subnormal concentrations of angiotensin II. This phenomenon seems to be the basis for the efficacy of ACE inhibitors in primary aldosteronism (specifically idiopathic adrenal hyperplasia [IAH]).

Cough and angioedema are less common with newer members of this class than with captopril. Serum potassium and serum creatinine concentrations should be monitored for the development of hyperkalemia and azotemia. Agents in this class include captopril, lisinopril, and enalapril.

Captopril

Captopril prevents the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion. It is rapidly absorbed, but bioavailability is significantly reduced with food intake. Captopril achieves a peak concentration in 1 hour and has a short half-life. The drug is cleared by the kidney; impaired renal function requires reduction of the dosage. Captopril is absorbed well orally.

Give captopril at least 1 hour before meals. If it is added to water, use it within 15 minutes. The dose can be low initially, then titrated upward as needed and as tolerated by the patient.

Enalapril (Vasotec)

Enalapril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion. The drug helps to control blood pressure and proteinuria. Enalapril decreases the pulmonary-to-systemic flow ratio in the catheterization laboratory and increases systemic blood flow in patients with relatively low pulmonary vascular resistance.

Enalapril has a favorable clinical effect when administered over a long period. Because it helps to prevent potassium loss in the distal tubules, enalapril reduces the amount of oral potassium supplementation needed by the patient.

Lisinopril (Prinivil, Zestril)

Lisinopril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion.

Benazepril (Lotensin)

Benazepril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion.

When pediatric patients are unable to swallow tablets or the calculated dose does not correspond with tablet strength, an extemporaneous suspension can be compounded. Combine 300 mg (15 tabs of 20 mg strength) in 75 mL of Ora-Plus suspending vehicle and shake well for at least 2 minutes. Let the tablets sit and dissolve for at least 1 hour, then shake again for 1 minute. Add 75 mL of Ora-Sweet. The final concentration is 2 mg/mL, with a total volume of 150 mL. The expiration time is 30 days with refrigeration.

Fosinopril

Fosinopril is a competitive ACE inhibitor. It prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion. It decreases intraglomerular pressure and glomerular protein filtration by decreasing efferent arteriolar constriction.

Quinapril (Accupril)

Quinapril is a competitive ACE inhibitor. It reduces angiotensin II levels, decreasing aldosterone secretion.

Ramipril (Altace)

Ramipril inhibits partially inhibits both tissue and circulating ACE activity, therefore reducing the formation of angiotensin II in the tissue and plasma. Ramipril has an antihypertensive effect even in patients with low-renin hypertension.

Angiotensin II Receptor Blockers

Class Summary

Angiotensin II receptor blockers lower blood pressure by blocking the final receptor (ie, angiotensin II) in the renin-angiotensin axis. Like angiotensin-converting enzyme (ACE) inhibitors, they are contraindicated in pregnancy. Serum electrolyte and creatinine levels should be monitored. Irbesartan and losartan are examples of angiotensin II receptor blockers (ARBs). Interestingly, although primary aldosteronism is a condition associated with low plasma renin, aldosterone secretion seems to be exquisitely sensitive to even subnormal concentrations of angiotensin II. This phenomenon seems to be the basis for the efficacy of ARBs in primary aldosteronism (specifically idiopathic adrenal hyperplasia [IAH]).

Irbesartan (Avapro)

Irbesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II at the tissue receptor site. It may induce a more complete inhibition of the renin-angiotensin system than do ACE inhibitors. In addition, irbesartan does not affect the response to bradykinin, and it is less likely to be associated with cough and angioedema.

Losartan (Cozaar)

Losartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II. It may induce a more complete inhibition of the renin-angiotensin system than ACE inhibitors do. In addition, losartan does not affect the response to bradykinin, and it is less likely to be associated with cough and angioedema. It is suitable for patients who are unable to tolerate ACE inhibitors.

Olmesartan (Benicar)

Olmesartan blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to angiotensin II type 1 receptors in vascular smooth muscle. Its action is independent of the pathways for angiotensin II synthesis.

Valsartan (Diovan)

Valsartan is a prodrug that displaces angiotensin II from angiotensin II type 1 receptors, blocking the vasoconstrictor effects of angiotensin II. Valsartan may also lower blood pressure through its effects on aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses.

Valsartan may induce a more complete inhibition of the renin-angiotensin system than ACE inhibitors do. In addition, it does not affect the response to bradykinin and is less likely to be associated with cough and angioedema. Valsartan is suitable for patients who are unable to tolerate ACE inhibitors.

Telmisartan (Micardis)

Telmisartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland and therefore reduces blood pressure. There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis and telmisartan has much greater affinity for the AT1 receptor than for the AT2 receptor

Corticosteroids

Class Summary

This class of agents are therapeutically appropriate only for the GRA subtype of primary aldosteronism. The treatment of choice in GRA is the administration of the lowest possible dose of glucocorticoid that can be used to achieve adequate blood pressure control. Because of the potential adverse effects that can result from even subtle glucocorticoid excess, using short-acting glucocorticoids, such as prednisone and hydrocortisone (rather than dexamethasone), is generally best.

Prednisone

Prednisone is a short-acting prodrug that exerts its effects after it undergoes metabolism and is converted to prednisolone. Prednisone mimics naturally occurring cortisol and is used in GRA to rapidly suppress aldosterone levels and resolve the volume expansion and hypertension in this disorder, being generally efficacious within 2 weeks of treatment initiation.

Hydrocortisone (Solu-Cortef, Cortef)

Hydrocortisone possesses a molecular similarity to aldosterone and therefore not only binds to the glucocorticoid receptor (thus resulting in resulting in lower aldosterone levels in GRA), but also the mineralocorticoid receptor (MR), thus also providing competitive inhibition of ambient aldosterone levels at the MR level (resulting in decreased physiologic effects of existing ambient aldosterone levels in GRA).

 

Questions & Answers

Overview

What is the relationship between primary aldosteronism and secondary hypertension (HTN)?

How common is secondary hypertension (HTN) due to primary aldosteronism?

What is the importance of a diagnosis of primary aldosteronism?

What is the relationship between primary aldosteronism i and idiopathic adrenal hyperplasia (IAH)?

Why is it important to determine the cause of primary aldosteronism?

What causes primary aldosteronism?

What is the role of aldosterone in primary aldosteronism?

What are the genetic-familial varieties of primary aldosteronism?

What are the screening tests for primary aldosteronism?

Which tests confirm primary aldosteronism?

Which tests are used to determine primary aldosteronism subtype?

What is the initial radiologic study in the workup of primary aldosteronism?

What other tests are used in the workup of primary aldosteronism?

Which medications are used in the treatment of primary aldosteronism?

What is the treatment of choice for lateralized primary aldosteronism?

What is the pathophysiologic association between hypokalemia and primary aldosteronism?

What causes metabolic alkalosis in primary aldosteronism?

How does primary aldosteronism affect glucose tolerance?

What is the main cause of primary aldosteronism syndrome?

What causes glucocorticoid-remediable aldosteronism (GRA)?

How is glucocorticoid-remediable aldosteronism (GRA) in primary aldosteronism treated?

What causes sporadic primary aldosteronism?

What is the role of glucocorticoid-remediable aldosteronism (GRA) in familial primary aldosteronism?

What causes sporadic aldosteronoma in primary aldosteronism?

What is the genetic basis of type 2 familial aldosteronism?

What is the genetic basis of type 3 familial aldosteronism?

What is tertiary aldosteronism?

How is tertiary aldosteronism characterized?

How common is primary aldosteronism in the US?

What is the global prevalence of primary aldosteronism?

Does primary aldosteronism have a racial predilection?

Is primary aldosteronism more common in men or women?

What are the age-related demographics of primary aldosteronism?

What are the morbidity and mortality of primary aldosteronism?

What are the complications of primary aldosteronism?

What is the prognosis of primary aldosteronism?

Presentation

What are the clinical scenarios in which primary aldosteronism should be considered?

What are the symptoms of severe hypokalemia associated with primary aldosteronism?

How are the cardiac effects of primary aldosteronism distinguished from the cardiac effects of secondary aldosteronism?

What are the subtypes of familial primary aldosteronism?

Why is the distinction between type 1 (GRA) and type 2 primary aldosteronism important?

What family history should raise suspicion of primary aldosteronism?

What are the considerations of type 3 familial primary aldosteronism?

What are the initial clinical findings of primary aldosteronism?

What is the role of edema in primary aldosteronism?

DDX

When is a diagnosis of primary aldosteronism indicated?

Which conditions should be considered in the differential diagnosis of primary aldosteronism?

What are the differential diagnoses for Primary Aldosteronism?

Workup

What are the approach considerations in the workup of primary aldosteronism?

What is the role of adrenal phlebography in the workup of primary aldosteronism?

What is the role of a therapeutic trial of spironolactone in the workup of primary aldosteronism?

What is the role of serum potassium and bicarbonate testing in the workup of primary aldosteronism?

What is the role of sodium and magnesium testing in the workup of primary aldosteronism?

What is the role of plasma aldosterone/plasma renin activity ratio testing in the workup of primary aldosteronism?

What are the limitations of the plasma aldosterone/plasma renin activity ratio in the workup of primary aldosteronism?

Which medications interfere with the plasma aldosterone/plasma renin activity ratio in the workup of primary aldosteronism?

What is the role of the plasma aldosterone/plasma renin activity ratio after salt and water depletion and/or upright posture in the workup of primary aldosteronism?

How are the captopril and losartan suppression tests used in the workup of primary aldosteronism?

What is the role of serum aldosterone testing to confirm primary aldosteronism?

What is the role of 24-hour urinary aldosterone (U-Aldo) excretion testing to confirm primary aldosteronism?

How is the salt-loading test used to confirm primary aldosteronism?

How is the subtype of primary aldosteronism determined once a diagnosis has been confirmed?

How is the postural stimulation test used to determine primary aldosteronism subtype?

How are imaging studies used with postural stimulation to identify surgically correctable primary aldosteronism?

What is the postural test protocol for primary aldosteronism?

How is the furosemide (Lasix) stimulation test used in the workup of primary aldosteronism?

What are the indications of the diurnal rhythm of aldosterone in the workup of primary aldosteronism?

What is the initial imaging study in the workup of primary aldosteronism?

How are aldosteronomas characterized on CT scans?

How accurate is CT scanning in the workup of primary aldosteronism?

What are the disadvantages of high-resolution CT studies in the workup of primary aldosteronism?

What is the role of CT scanning in identifying surgical candidates for the treatment of primary aldosteronism?

What is the role of MRI in the workup of primary aldosteronism?

How is the NP-59 test used in the workup of primary aldosteronism?

How accurate is NP-59 testing in the workup of primary aldosteronism?

When is adrenal venous sampling indicated in the workup of primary aldosteronism?

What is the role of adrenal venous sampling in the workup of primary aldosteronism?

How is adrenal venous sampling performed in the workup of primary aldosteronism?

How accurate is adrenal venous sampling in the workup of primary aldosteronism?

What is the diagnostic value of the aldosterone-to-cortisol ratios in the workup of primary aldosteronism?

What are the risks of adrenal venous sampling in the workup of primary aldosteronism?

What is the role of hydroxycorticosterone and oxocortisol-hydroxycortisol assays in the workup of primary aldosteronism?

What is the role of the fludrocortisone suppression test in the workup of primary aldosteronism?

How is the fludrocortisone suppression test performed in the workup of primary aldosteronism?

When is the dexamethasone suppression test indicated in the workup of primary aldosteronism?

How is the dexamethasone suppression test used to diagnose primary aldosteronism?

What is the role of the metoclopramide (Reglan) test in the workup of primary aldosteronism?

How is the metoclopramide (Reglan) test performed in the workup of primary aldosteronism?

What is the role of the corticotropin stimulation test in the workup of primary aldosteronism?

What is the role of the angiotensin-II infusion test in the workup of primary aldosteronism?

How are the histologic findings of primary aldosteronism characterized?

What are the histologic findings of renin-responsive adenomas (RRAs) in primary aldosteronism?

What are the histologic findings of idiopathic adrenal hyperplasia (IAH) in primary aldosteronism?

What are the histologic findings of primary adrenal hyperplasia (PAH) in primary aldosteronism?

What are histologic findings of adrenal carcinoma in the workup of primary aldosteronism?

Treatment

What are the goals of therapy for primary aldosteronism?

How is the appropriate treatment for primary aldosteronism determined?

What is the role of medical therapy in the treatment of aldosteronoma in primary aldosteronism?

Which medications are indicated in the treatment of aldosteronism and heart failure?

How are calcium channel blockers used to treat primary aldosteronism?

How are mineralocorticoid antagonists used in the treatment of primary aldosteronism?

How are glucocorticoids used to treat primary aldosteronism?

What novel therapies are used to treat primary aldosteronism?

Which nonsurgical treatments are available for adenomas in primary aldosteronism?

What is the treatment of choice for lateralizable primary aldosteronism?

What is the preoperative protocol for adrenal surgery in the treatment of primary aldosteronism?

Which surgical techniques are used to perform adrenalectomy in the treatment of primary aldosteronism?

How effective is adrenalectomy in the treatment of hypertension associated with primary aldosteronism?

Is adrenalectomy an effective treatment for idiopathic adrenal hyperplasia (IAH) associated with primary aldosteronism?

What are the indications of persistent hypertension (HTN) after adrenal surgery in the treatment of primary aldosteronism?

What is the preoperative care for patients undergoing adrenal surgery to treat primary aldosteronism?

What is the postoperative care for patients undergoing adrenal surgery to treat primary aldosteronism?

What is the treatment for hypoaldosteronism after adrenal surgery to treat primary aldosteronism?

How does dietary salt affect biochemical testing results in primary aldosteronism?

Guidelines

What are the French recommendations on the management of primary aldosteronism?

What are the Endocrine Society practice guidelines for the diagnosis and treatment of primary aldosteronism?

Medications

What is the treatment of choice in nonsurgical primary aldosteronism?

How is glucocorticoid-remediable aldosteronism (GRA) treated in primary aldosteronism?

Which antihypertensives are used to treat primary aldosteronism?

What other factors contribute to the success of pharmacologic treatment of primary aldosteronism?

Which medications in the drug class Corticosteroids are used in the treatment of Primary Aldosteronism?

Which medications in the drug class Angiotensin II Receptor Blockers are used in the treatment of Primary Aldosteronism?

Which medications in the drug class ACE Inhibitors are used in the treatment of Primary Aldosteronism?

Which medications in the drug class Calcium channel Blockers are used in the treatment of Primary Aldosteronism?

Which medications in the drug class Thiazide Diuretics are used in the treatment of Primary Aldosteronism?

Which medications in the drug class Potassium-Sparing Diuretics are used in the treatment of Primary Aldosteronism?

Which medications in the drug class Aldosterone Antagonists, Selective are used in the treatment of Primary Aldosteronism?