AUTHOR AND EDITOR INFORMATION

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• Medication
• Follow-up
• Miscellaneous
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INTRODUCTION

Section 2 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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Background

Although initially considered a rarity, primary hyperaldosteronism (PH) 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 PH secondary to an adrenal aldosteronoma.

While older data suggest that PH is rare, with an estimated prevalence of less than 1% of all patients with HTN, more recent data suggest that it may actually occur in as many as 5-15% of patients with HTN. It may occur in an even greater percentage of patients with treatment-resistant HTN. Although still a considerable diagnostic challenge, recognizing this condition is critical because PH-associated HTN can often be cured with the proper surgical intervention. The diagnosis is generally 3-tiered, involving an initial screening, a confirmation of the diagnosis, and a determination of the specific subtype of PH.

Although prior studies suggest that aldosteronomas are the most common causes of PH (70-80% of cases), more recent epidemiologic work suggests a higher prevalence of PH due to bilateral idiopathic adrenal hyperplasia (IAH) than previously believed. These reports suggest that IAH may be responsible for as many as 75% of PH cases. Moreover, reports describe a rare syndrome of PH characterized by histologic features intermediate between adrenal adenoma and adrenal hyperplasia. Clinically, the distinction between the 2 major causes of PH is vital because the treatment of choice for each is different. While the treatment of choice for aldosteronomas is surgical extirpation, the treatment of choice for IAH is medical therapy with aldosterone antagonists.

The complete list of entities known to cause PH includes aldosterone-producing adenomas (APAs), aldosterone-producing renin-responsive adenomas (AP-RAs), bilateral adrenal (glomerulosa) hyperplasia or IAH, primary adrenal hyperplasia (PAH), and familial forms of PH.

Two distinct genetic-familial varieties of PH exist. Sutherland and colleagues first described the type 1 variety of familial PH, glucocorticoid-remediable aldosteronism (GRA), in 1966. In GRA, HTN responds clinically to small doses of glucocorticoids in addition to other antihypertensive agents (see Image 2). The type 1 form of familial PH is due to a chimeric gene product that combines the promoter of the 11beta-hydroxylase gene with the coding region of the aldosterone synthetase gene. The type 2 variant of familial PH (which is not glucocorticoid sensitive) was first described in 1991. Although the exact genetic abnormality for type 2 PH has not been identified, recent data suggest that this type may be associated or closely linked with the MEN1 gene locus on band 11q13.

Pathophysiology

The cardinal pathophysiologic anomaly causing PH syndrome is autonomous aldosterone production. In addition to nonsuppressible aldosterone production, suppressed and poorly stimulative levels of plasma renin are in the presence of only mildly expanded intravascular and extravascular fluid volume. Normal regulation of aldosterone secretion is mediated by renin, serum potassium and sodium levels, intravascular volume status, and adrenocorticotropic hormone (ACTH) to varying degrees. Depending on the subtype of PH, regulation of aldosterone production by these factors may alter in a variable fashion. Generally, APAs and PAH (see Image 1) remain ACTH-responsive, while IAH and AP-RAs maintain responsiveness to the renin-angiotensin system (RAS).

In GRA, the RAS is suppressed, and aldosterone is regulated by ACTH because of the chimeric genetic combination of an ACTH-sensitive promoter with the coding regions of the aldosterone synthetase gene, which normally does not have such a promoter. Thus, ambient ACTH levels pathologically overstimulate aldosterone synthesis inappropriately. In patients with GRA, the administration of dexamethasone (or any other glucocorticoid) at doses sufficient to suppress ACTH production results in a reduction in aldosterone synthesis and natriuresis and in the correction of the biochemical anomalies of PH. Histologic studies in this disease have shown specific hyperplasia of the zona fasciculata with concomitant atrophy of the zona glomerulosa.

Frequency

United States

The exact prevalence of PH is unclear. PH appears to contribute more significantly to the prevalence of (what would otherwise be believed to be) essential HTN than previously believed. Current estimates suggest that 5-15% of essential HTN cases may be due to PH. The prevalence of PH 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

No evidence demonstrates that PH, in its more common forms, occurs in relative excess in any part of the world.

Race

PH occurs worldwide. Several reports suggest a higher prevalence in African Americans, persons of African origin, and, potentially, other blacks. This appears particularly true of the IAH variant of the disease.

Sex

APAs are more common in women than in men, with a female-to-male ratio of 2:1. IAH is more common in men than in women, with a male-to-female ratio of 4:1.

Age

The typical patient with APA is a woman aged 30-50 years. Accumulating data for IAH suggest different demographics. IAH is more prevalent in men than in women and peaks in the sixth decade of life.

CLINICAL

Section 3 of 11  

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History

The clinical presentation of PH 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 PH should be considered include the following:
• • Patients with spontaneous or unprovoked hypokalemia, especially if the patient is also hypertensive

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

  • Patients with refractory HTN

• The 2 major familial varieties of PH are GRA (type 1 familial PH) and a non–glucocorticoid-remediable type (type 2 familial hyperaldosteronism).
• • 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 150 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 earlier presumed. A significant subgroup of patients with the milder normokalemic variety of this syndrome are probably incorrectly presumed to have essential HTN.

  • 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.

Physical

Patients with PH 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 is almost invariable though there have been a few rare cases of primary aldosteronism described in the literature unassociated with hypertension.

  • Weakness

  • Abdominal distension

  • Ileus from hypokalemia

  • Findings related to complications of HTN (eg, cardiac failure, hemiparesis due to stroke, carotid bruits, abdominal bruits, proteinuria, renal insufficiency, hypertensive encephalopathy, hypertensive retinal changes)

  • Of importance to note is the fact that primary aldosteronism in and of itself is typically not associated with edema despite the volume expanded state associated with it. This is due to spontaneous natruesis and diuresis that occurs in these patients (called the aldosterone escape) that appears to be mediated by atrial naturetic peptide (ANP). Thus the finding of significant edema in subject presumed to have primary aldosteronism suggests either as wrong diagnosis or associated complications such as renal or cardiac failure.

Causes

The exact cause of sporadic PH due to an adenoma or a hyperplasia is unclear. The existence of trophic factors has been postulated in hyperplasia. Somatic mutations of genes leading to growth advantage in the adrenal adenomatous tissue are possible but unproven causes.

• In familial forms of PH, the molecular basis of GRA is known. GRA is due to a mutation that results from a hybrid gene product. The 11beta-hydroxylase and aldosterone synthetase genes that are normally located closely to each other on chromosome 8 cross over to create a novel hybrid gene product. This hybrid gene consists of the regulatory ACTH responsive sequence of the 11beta-hydroxylase gene fused to the structural component of the aldosterone synthetase gene.
• 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 occur, thus providing the nidus for the developing adenoma.
• The genetic basis of type 2 familial hyperaldosteronism is unclear; however, several reports of patients with this type have shown loss of heterozygosity close to the MEN1 gene locus (band 11q13). Whether menin mutations exist in the adrenal tissue of these patients is currently unknown. This syndrome can histologically manifest as hyperplasia or adenomas.
• The existence of tertiary hyperaldosteronism as a separate entity remains controversial. The entity is presumed to result from chronic elevations in plasma renin levels and secondary hyperaldosteronism, which eventually establishes a state of autonomous unregulated hyperaldosteronism with a histologic picture of mixed hyperplasia and adenomas in the affected 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.

  • Initially, renin levels are elevated, which is typical of secondary hyperaldosteronism. 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.

DIFFERENTIALS

Section 4 of 11  

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Other Problems to be Considered

All causes of mineralocorticoid excess and HTN
Low-renin essential HTN (constitutes about 40% of essential HTN)
11beta-hydroxylase deficiency variant of congenital adrenal hyperplasia (CAH)
17beta-hydroxylase deficiency variant of CAH
11beta-hydroxysteroid dehydrogenase deficiency
Licorice ingestion
Tobacco chewing
Carbenoxolone intoxication
Apparent mineralocorticoid excess (AME) syndrome
Glucocorticoid resistance
Various causes of secondary hyperaldosteronism (Unlike PH, these causes are associated with elevated renin levels.)
Bartters syndrome
Gitelman syndrome
Pseudohyperaldosteronism (Liddle syndrome)
History of exogenous mineralocorticoid ingestion or exposure
Chretien syndrome (This rare syndrome is characterized by mineralocorticoid excess and adrenocortical HTN secondary to a pituitary adenoma producing proopiomelanocortin [POMC].)
Deoxycorticosterone (DOC)–secreting adrenal tumors
Gordon syndrome
Renovascular ischemia

WORKUP

Section 5 of 11  

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• Follow-up
• Miscellaneous
• Multimedia
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Lab Studies

• Individuals with primary hyperaldosteronism (PH) may present with hypokalemic metabolic alkalosis; however, as many as 38% of patients with PH may be normokalemic at presentation.
  
  
  • The most important factors that predict the association of hypokalemia with PH are (1) aldosterone hypersecretion, which acts on the cortical collecting duct to stimulate potassium secretion into the tubular fluid thus enhancing renal potassium wasting; (2) adequate intravascular volume, which enables adequate water delivery to the distal convoluted tubules and collecting ducts to enable renal potassium loss; and (3) adequate dietary sodium intake, which, in turn, increases total body potassium, renal sodium delivery, and by the countercurrent transport system thus enhancing renal potassium loss.
  
  
  
  • The absence of one or more of the physiologic circumstances described above in the individual may explain the absence of hypokalemia in many patients with proven PH.
  
  
  
  • The associated metabolic alkalosis in PH is due to increased renal hydrogen ion loss mediated by hypokalemia and aldosterone.

• Screening (first-tier) tests (see Image 4)

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



• Mild serum hypernatremia in the 143-147 mEq/L range and mild hypomagnesemia from renal magnesium wasting are other associated biochemical findings in established PH.

• Random plasma aldosterone/plasma renin activity (PRA) ratio: Because this ratio is fairly constant over many physiologic conditions, it can be used as a screening test. Normal values are less than 270 when aldosterone concentration is expressed in pmol/L or less than 10 when aldosterone concentration is expressed in ng/dL.

• Plasma aldosterone - PRA ratio
  
  
  • When aldosterone is measured in ng/dL and PRA is measured in ng/mL/h, a ratio greater than 20-25 has a 95% sensitivity and a 75% specificity for PH. When aldosterone is measured in pmol/L, a ratio greater than 900 is consistent with PH.
  
  
  
  • 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 RAS are withheld (see Image 3). This can be difficult to accomplish when severe disease dictates the continuation of some medications to control HTN and hypokalemia during testing.
  
  
  
  • Obtaining the 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.
  
  
  
  • This test has been well validated in whites and Asians but not in other major racial groups.

• PRA after salt and water depletion and/or upright posture: In PH, 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 a confirmatory (second-tier) test (see Image 5) for PH, depending on personal preferences of various groups involved in PH research. Confirmatory tests are based on the concept that aldosterone is secreted in an unregulated fashion in PH and, hence, cannot be suppressed by usual physiologic regulatory inputs. In a similar fashion, PRA is chronically and tonically suppressed and cannot be stimulated.

• Captopril suppression test: This involves the oral administration of a single dose of captopril (25-50 mg). In healthy individuals, aldosterone levels suppress to less than 15 ng/dL. The test has a sensitivity of 90-100% but a specificity of only 50-80%.

• Confirmatory (second-tier) tests (see Image 5)

• Serum aldosterone level
  
  
  • After 3 days of an unrestricted sodium diet and 1 hour of full recumbency, healthy individuals have aldosterone levels 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 PH. 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 PH have serum aldosterone levels that remain within the reference range on repeated testing, as is typically the case in essential HTN.

• 24-hour urinary aldosterone excretion
  
  
  • 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 PH, the 24-hour U-Aldo is greater than 14 mcg/d (after 3 d of salt loading). Only about 7% of patients with PH have values less than 14 mcg/d.

• 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, along with a determination of serum aldosterone and PRA. Urinary aldosterone-18-glucuronide should normally fall below 17-20 mcg/d. This test is rarely performed. The 24-hour urinary creatinine measurement validates the adequacy of the collection, while a 24-hour urinary sodium value of at least 250 mEq/d confirms an adequate salt load during the days prior to the test, and, therefore, validates the other measurements.
  
  
  
  • The intravenous protocol calls for an infusion of 500 mL/h of isotonic sodium chloride solution for 4 hours (total of 2 L). Serum aldosterone level and PRA are measured at baseline, 2 hours, and 4 hours. In healthy patients, aldosterone levels are suppressed to less than 8.5 ng/dL, while PRA is suppressed to less than 0.6 ng/mL/h.

• Determination of PH subtype (third-tier) tests (see Image 6)

• Postural stimulation test
  
  
  • Aldosteronomas are associated with an anomalous decrease in aldosterone level with upright posture, in contradistinction to patients with IAH, when an increase in aldosterone level occurs with upright posture (which is RAS mediated). Moreover, a serum aldosterone level surge is expected to happen (and indeed occurs) in patients with renin responsive adenomas (RRAs), low-renin essential HTN, and intermediate hyperaldosteronism. When abdominal CT scans or MRIs are combined with postural stimulation, the positive predictive value (PPV) of an abnormal postural test in predicting surgically correctable PH due to a single adenoma is 98%.
  
  
  
  • The standard postural test protocol involves obtaining baseline values of serum aldosterone and PRA levels, as well as the same parameters 2 hours after assuming an erect posture. Serum aldosterone 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 PH who have either IAH or RRAs. Among patients with aldosteronomas, the aldosterone 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 PH 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 administration of 40 mg of furosemide orally the night before and the morning of the test. On the morning of the test, the patient remains standing upright 2-3 hours, then PRA and serum aldosterone levels are assayed. The interpretation of the test results is similar to those 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 ACTH dependent. The lowest values are observed around 11:30 pm to midnight, and highest values occur early in the morning around 7:30-8 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, 18OH cortisol, or both in plasma and urine may be found in some patients with aldosteronomas but is uncommon in IAH.

Imaging Studies

• Initial radiologic investigation in the workup of PH is high-resolution, thin-slice (2-2.5 mm) adrenal CT scanning with contrast.

• Because aldosteronomas tend to be small in contrast to cortisol-producing adrenocortical adenomas, only those at least 1.5 cm in diameter can be detected reliably and consistently.

• The overall sensitivity of the test is greater than 90%, but the picture is further complicated by the many false-positive findings associated with incidentalomas, which are reported in some series to be found in up to 10% of the general population (the prevalence increases with age).

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

• Adrenal venous sampling

• Because this procedure is highly dependent on the availability of technically proficient interventional radiologists, it cannot be performed universally, despite the fact that it is the criterion standard for the confirmation of lateralizable aldosterone excess.



• Adrenal venous sampling probably has its greatest utility in the setting of either totally normal adrenal imaging despite biochemical evidence for PH or settings in which bilateral adrenal pathology is present on imaging, with the biochemistry suggesting the presence of a functional aldosteronoma. The test also has utility in resolving the exact etiology in cases of PH where discordance exists between the biochemical findings and the radiologic findings as regards to whether the PH is due to IAH or an aldosteronoma.



• One series reported that 41% of patients with a normal adrenal CT who had biochemical evidence of PH actually had lateralizable disease, while 49% with bilateral micronodules on CT also had lateralizable disease. Even in cases where only a single adrenal nodule was found on imaging, when adrenal sampling was performed, it only confirmed lateralizable disease in 51-66% of cases.

• Baseline and post-ACTH stimulation, preferably by continuous infusion at 50mcg/h for the duration of the sampling study, blood samples are obtained simultaneously from both adrenal veins as well as periphery veins, and the samples are assayed for aldosterone and cortisol.

• The accuracy of the test exceeds 95% when the procedure is technically successful. The ratio of aldosterone concentrations between the right and left adrenal veins generally exceeds 10:1 if autonomous unilateral secretion of aldosterone is present on either side. 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.

• To ensure that the catheters are adequately placed during the test, simultaneous cortisol levels need to be assayed, and aldosterone-to-cortisol ratios need to be computed.

• The procedure is not without risks. Adrenal and iliac venous thrombosis, adrenal hemorrhage, and adrenal insufficiency are among the potential complications. Ideally, adrenal venous sampling should be performed in all patients with PH in whom the biochemical and imaging studies are inconclusive regarding the presence of lateralizable, surgically correctable disease.

• Magnetic resonance imaging

• 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.

• If the screening (CT and/or MRI) of a patient with PH is completely normal, a treatment trial of aldosterone antagonists for 6-12 months is generally recommended, after which the imaging studies should be repeated. Treatment with glucocorticoids may also be considered for GRA (if GRA is suspected).

• NP-59 iodocholesterol scintigraphy

• Although fairly difficult to set up and not routinely available, this test is useful in 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.

• The test results are improved by 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 a few 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.

• Adrenal phlebography

• This procedure attempts to invasively visualize the venous patterns encircling adrenocortical adenomas.

• The procedure has fallen into disrepute because of the risk of adrenal infarction.

Other Tests

• Because of the different adrenocortical zones involved in idiopathic hyperplasia, as compared to adenomas, assays of plasma 18-hydroxycorticosterone (18-OHB) or plasma and/or urine 18-oxo-cortisol (18-oxo-F)/18-hydroxy-cortisol may be of diagnostic use. Aldosteronomas are typically associated with 18-OHB levels greater than 100 ng/dL. Similarly, GRA (type 1 familial hyperaldosteronism), though a hyperplastic disease, is also associated with an increased production of these 18-oxo/hydroxy derivatives. This is presumed to be the case because the zona fasciculata is predominantly hyperplastic in this condition. This distinct biochemistry has also been observed in PAH but not in RRAs.



• Fludrocortisone suppression test
• • This test works on the same principle as the sodium chloride infusion or oral salt loading test for confirming a diagnosis of PH. It has become far less popular in recent times because it requires hospitalization of the patient and it requires 4-5 days to complete. U-Aldo excretion is normally suppressed to less than 12 mcg/d, and the plasma aldosterone level is less than 8 ng/dL at the time of completion of the test in healthy patients. In patients with PH, neither the urinary aldosterone level or the plasma aldosterone level suppresses to the thresholds noted above.
  
  
  
  • Fludrocortisone is administered orally at a dose of 0.1-0.2 mg every 6 hours along with supplemental sodium chloride and potassium supplements. In the healthy individual, following this stimulation, the plasma aldosterone level is typically suppressed to less than 8 ng/dL with a corresponding urinary aldosterone excretion of less than 12 mcg/d.
     
• Dexamethasone suppression test
• • This test is only relevant in the setting of possible familial hyperaldosteronism. Customarily, in patients with PH, dexamethasone is associated with a transient reduction of plasma and urinary aldosterone levels, though not into the reference range. In the subset of patients with GRA, small doses of dexamethasone (1-2 mg/d) induce full normalization in both plasma and urinary aldosterone levels. This is invariably associated with improvement in the HTN of 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 postdexamethasone challenge.
  
  
  
  • Two major variants of familial PH exist. Type 1 familial PH (also called GRA) is associated with improvement in HTN using low-dose dexamethasone. Type 2 familial PH is not dexamethasone suppressible.
     
• Metoclopramide (Reglan) test
• • This is a promising noninvasive test for distinguishing between aldosteronomas and 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 secretion in vivo. This response is retained in patients with aldosteronomas and in patients with low-renin HTN but not in patients with IAH.
  
  
  
  • Following a 10-mg intravenous injection of metoclopramide, serum aldosterone levels increase significantly in patients with aldosteronoma but remain either unchanged or paradoxically reduced in patients with IAH.
     
• Therapeutic trial of spironolactone (Aldactone)
• • This procedure is no longer used as a diagnostic test for PH because easier and more rapid alternatives exist.
  
  
  
  • The therapeutic trial involves spironolactone administered orally at a dose of 100 mg 4 times per day for 5 weeks. A positive test is characterized by a decrease in diastolic blood pressure (DBP) of at least 20 mm Hg.
     
• ACTH stimulation test
• • This test uses the standard 250-mcg intravenous injection.
  
  
  
  • In adenomatous disease, a robust aldosterone response is typically observed.
  
  
  
  • In IAH, the aldosterone surge is considerably feebler. The test is no longer used because the discriminant value of the test is rather poor.
     
• Angiotensin-II infusion test
• • This test involves evaluating the response of PRA and serum aldosterone to a continuous angiotensin-II infusion. The response characteristics are similar to those observed in the posture tests (see Lab Studies), with an appropriate increase in aldosterone level observed in IAH but not in aldosteronomas.
  
  
  
  • It is less popular because of the need for continuous infusion and close hemodynamic monitoring.

Histologic Findings

Histologic findings are variable, depending on the type of PH. Typical aldosteronomas are characterized by adenomatous tissue, usually with zona fasciculata–type morphology. Most of these tumors are small (<3 cm in diameter). Most of the cells are composed of lipid-laden cells arranged in acini or cords. Associated focal and/or diffuse hyperplasia often occurs.

RRAs are characterized by zona glomerulosa–type morphology, but the only other distinctive features are predictable unique biochemical features.

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 PAH, diffuse hyperplasia, which is unilateral and has zona fasciculata morphology, is typically observed.

PH syndrome rarely occurs in the setting of adrenal carcinoma or with the typical features of adrenal carcinoma, including mitotic figures, local invasion, and lymph node metastases.

TREATMENT

Section 6 of 11  

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Medical Care

Medical management is the treatment of choice for the IAH variant of primary hyperaldosteronism (PH).

Among the major goals of therapy are (1) normalization of blood pressure, (2) normalization of serum potassium and other deranged electrolytes levels, and (3) normalization of serum aldosterone levels. Evidence exists to show that chronic hyperaldosteronism in and of itself in the absence of elevated blood pressure (eg, as occurs in secondary hyperaldosteronism) is associated with increased risk for cardiac injury including ischemic and fibrotic injury. Furthermore, studies show that patients with PH are more likely to have left ventricular hypertrophy, stroke, and acute coronary syndromes than patients with similar degrees of hypertension from other causes.

Aldosterone antagonism, by both spironolactone and eplerenone, in patients with heart failure who have secondary hyperaldosteronism has been demonstrated to confer survival benefit.

• 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, ACTH, and angiotensin-II. Nifedipine is the most extensively studied of these medications; however, while causing a significant improvement in patients with HTN, it does not address the pathophysiology of the condition. The PRA, aldosterone levels, plasma volume, and serum potassium concentrations remain essentially unchanged while using nifedipine.

• ACE inhibitors and angiotensin receptor blockers (ARBs) are also potential treatment options.

• Mineralocorticoid antagonists, such as spironolactone, achieve remarkable blood pressure control and normalization of the above-mentioned parameters, particularly in patients with aldosteronomas. The salutary effects of spironolactone appear to be mainly due to the effects 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 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 new selective antialdosterone agent that may fulfill this promise, as it is a specific aldosterone receptor antagonist without the additional antiandrogen effects associated with spironolactone.

• Other less ideal medical treatment options include other potassium-sparing diuretics, such as triamterene and amiloride. Amiloride acts at the level of the distal convoluted tubule (DCT) but does not bind to mineralocorticoid receptors.

• Medical 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.

• In the subgroup of patients with GRA, the treatment of choice is to use the lowest possible dose of glucocorticoid 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.

Surgical Care

Surgery is the treatment of choice for the lateralizable variants of PH, including typical aldosteronomas, RRAs, and PAH.

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

• An adrenalectomy can be performed either via a formal laparotomy or, increasingly commonly, by a laparoscopic technique. The laparoscopic option now makes it possible to offer surgical therapy to relatively frail patients who would be unable to withstand formal laparotomies. Ongoing studies are systematically evaluating the place of adrenal-conserving operations versus total unilateral adrenalectomy in these patients.

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

• About 60-70% of patients are rendered normotensive following curative surgery for aldosteronomas when evaluated 1 year postoperatively. The percentage of patients who remain normotensive 5 years postoperatively is about 53%. Resolution of hypertension following adrenalectomy invariably occurs in the setting of absent family history of hypertension and/or preoperative use of two or fewer antihypertensives. Virtually all patients with an aldosteronoma, however, have significant reductions in aldosterone secretion, blood pressure, and correction of hypokalemia following surgery.



• Adrenalectomy has very little utility in the setting of IAH. In reported cases where this had been done unintentionally, the effects on blood pressure, hypokalemia, and aldosterone hypersecretion have been found to be 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 have had HTN for more than 5 years prior to surgery, and in those who did not respond preoperatively to spironolactone.

• Other possibilities to consider are an incomplete resection of the adenoma with remaining remnant hyperplastic tissue or the possibility that the patient may have coexistent essential HTN (which is a prevalent condition). The coexistence of hypertensive nephrosclerosis in some of these patients is also a distinct possibility. The coexistence of other secondary causes of HTN also needs to be considered; renal artery stenosis is an important consideration.

• Prior to surgery, patients should receive at least 8-10 weeks of medical therapy, both to decrease blood pressure and to correct the metabolic syndromes that are often associated with PH. Postoperatively, metabolic profiles should be closely monitored. Most patients do not develop permanent hypomineralocorticoidism and, thus, 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 ACTH suppression by exogenous steroids (see Image 3). 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.

• A few reports of using percutaneous injection of ethanol or acetic acid into aldosteronomas as a treatment modality exist, usually in patients for whom surgery is contraindicated. This technique is neither popular nor well validated. Furthermore, it requires the technical expertise of a highly skilled interventional radiologist.

Diet

• A low-salt diet, though helpful in achieving blood pressure control in this condition, may be associated with false-negative results on biochemical testing.
• A high-salt diet makes achievement of blood pressure control more difficult and may cause false-positive results on biochemical testing.

MEDICATION

Section 7 of 11  

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• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

In nonsurgical PH, medical therapy is the treatment of choice. The first choice for most variants of nonsurgical PH is spironolactone, which is used both to achieve normoaldosteronism and to assist with blood pressure control. In patients who are unable to tolerate spironolactone, other potassium-sparing diuretics, such as amiloride and triamterene, can be used.

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 causing significant improvement in patients with HTN, they do not address the pathophysiology. PRA, aldosterone levels, plasma volume, and serum potassium concentrations remain essentially unchanged, despite nifedipine use.

Drug Category: Aldosterone antagonists

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

Drug Category: Potassium-sparing diuretics

These agents are used as second-line medication for treatment of PH 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.

FOLLOW-UP

Section 8 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Complications

• Specific complications are related to the complications of chronic HTN (eg, myocardial infarction, cerebrovascular disease, congestive heart failure) and those related to the specific therapy (eg, drug reactions, surgical complications).

MISCELLANEOUS

Section 9 of 11  

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• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

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

MULTIMEDIA

Section 10 of 11  

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• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Primary hyperaldosteronism. Potential causes of primary hyperaldosteronism.
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Media file 2:  Primary hyperaldosteronism. Effects of main antihypertensives on the renin-angiotensin system.
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Media file 3:  Primary hyperaldosteronism. Transitional zone adrenocortical steroids.
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Media file 4:  Primary hyperaldosteronism. Algorithm for screening of potential primary hyperaldosteronism.
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Media file 5:  Primary hyperaldosteronism. Algorithm for confirmation of primary hyperaldosteronism.
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Media file 6:  Primary hyperaldosteronism. Algorithm for distinguishing subtypes of primary hyperaldosteronism.
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REFERENCES

Section 11 of 11

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• Introduction
• Clinical
• Differentials
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• Miscellaneous
• Multimedia
• References

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