Hypertension resulting from mineralocorticoid excess can be categorized based on levels of renin and aldosterone ( Box 14.1 ). Aldosterone, deoxycorticosterone, and cortisol are the three major mineralocorticoid receptor ligands. This chapter reviews the clinical presentation, diagnostic evaluation, and treatment of these three types of renin-independent mineralocorticoid excess states.
Low Renin and High Aldosterone
Primary Aldosteronism
Aldosterone-producing adenoma (APA)—35% of cases
Bilateral idiopathic hyperplasia (IHA)—60% of cases
Primary (unilateral) adrenal hyperplasia—2% of cases
Aldosterone-producing adrenocortical carcinoma—<1% of cases
Familial hyperaldosteronism (FH)
Glucocorticoid-remediable aldosteronism (FH type I)—<1% of cases
FH type II (APA or IHA)—<2% of cases
FH type III (associated with the germline mutation in the KCNJ5 potassium channel)—<1% of cases
Ectopic aldosterone-producing adenoma or carcinoma—<0.1% of cases
Low Renin and Low Aldosterone
Hyperdeoxycorticosteronism
Congenital adrenal hyperplasia
11β-Hydroxylase deficiency
17α-Hydroxylase deficiency
Deoxycorticosterone-producing tumor
Primary cortisol resistance
Apparent Mineralocorticoid Excess (AME)/11β-Hydroxysteroid Dehydrogenase Deficiency
Genetic
Acquired
Licorice or carbenoxolone ingestion
Cushing syndrome
Cushing Syndrome
Exogenous glucocorticoid administration—most common cause
Endogenous
ACTH-dependent—85% of cases
Pituitary
Ectopic
ACTH-independent—15% of cases
Unilateral adrenal disease
Bilateral adrenal disease
Bilateral macronodular adrenal hyperplasia (rare)
Primary pigmented nodular adrenal disease (rare)
High Renin and High Aldosterone
Renovascular hypertension
Diuretic use
Renin-secreting tumor
Malignant-phase hypertension
Coarctation of the aorta
ACTH, Adrenocorticotropin hormone, AME, apparent mineralocorticoid excess; APA, aldosterone-producing adenoma; FH, familial hyperaldosteronism; IHA, idiopathic hyperaldosteronism.
Primary Aldosteronism
Hypertension, suppressed plasma renin activity (PRA), and increased aldosterone excretion characterize the syndrome of primary aldosteronism, first described in 1955. Aldosterone-producing adenoma (APA) and bilateral idiopathic hyperaldosteronism (IHA) are the most common subtypes of primary aldosteronism (see Box 14.1 ). Somatic mutations account for about half of APAs and include mutations in genes encoding components of: the Kir 3.4 (GIRK4) potassium channel (KCNJ5); the sodium/potassium and calcium ATPases (ATP1A1 and ATP2B3); and a voltage-dependent C-type calcium channel (CACNA1D). A much less common form, unilateral hyperplasia or primary adrenal hyperplasia (PAH), is caused by micronodular or macronodular hyperplasia of the zona glomerulosa of predominantly one adrenal gland. Familial hyperaldosteronism (FH) is also rare, and three types have been described (see later).
In the past, clinicians would not consider the diagnosis of primary aldosteronism unless the patient presented with spontaneous hypokalemia, and then the diagnostic evaluation would require discontinuation of antihypertensive medications for at least 2 weeks. This diagnostic approach resulted in predicted prevalence rates of less than 0.5% of hypertensive patients. However, it is now recognized that most patients with primary aldosteronism are not hypokalemic and that screening can be completed while the patient is taking antihypertensive drugs with a simple blood test that yields the ratio of plasma aldosterone concentration (PAC) to PRA. Use of the PAC/PRA ratio as a case-detection test, followed by aldosterone suppression for confirmatory testing, has resulted in much higher prevalence estimates for primary aldosteronism; 5% to 10% of all patients with hypertension.
Clinical Presentation
The diagnosis of primary aldosteronism is usually made in patients who are in the third to sixth decade of life. Few symptoms are specific to the syndrome. Patients with marked hypokalemia may have muscle weakness and cramping, headaches, palpitations, polydipsia, polyuria, nocturia, or a combination of these. Periodic paralysis is a very rare presentation in Caucasians, but it is not an infrequent presentation in patients of Asian descent. For example, in a series of 50 patients with APA reported from Hong Kong, 21 (42%) presented with periodic paralysis. Another rare presentation is tetany associated with the decrease in ionized calcium with marked hypokalemic alkalosis. The polyuria and nocturia are a result of hypokalemia-induced renal concentrating defect, and the presentation is frequently mistaken for prostatism in men. There are no specific physical findings. Edema is not a common finding because of the phenomenon of mineralocorticoid escape, described earlier. The degree of hypertension is typically moderate to severe and may be resistant to usual pharmacologic treatments. In the first 262 cases of primary aldosteronism diagnosed at Mayo Clinic (1957 to 1986), the highest blood pressure was 260/155 mm Hg; the mean (± standard deviation [SD]) was 184/112 ± 28/16 mm Hg. Patients with APA tend to have higher blood pressures than those with IHA.
Hypokalemia is frequently absent, so all patients with hypertension are candidates for this disorder. In other patients, the hypokalemia becomes evident only with the addition of a potassium-wasting diuretic (e.g., hydrochlorothiazide, furosemide). Deep-seated renal cysts are found in up to 60% of patients with chronic hypokalemia. Because of a reset osmostat, the serum sodium concentration tends to be high-normal or slightly above the upper limit of normal. This clinical clue is very useful in the initial assessment for potential primary aldosteronism.
Several studies have shown that patients with primary aldosteronism are at higher risk than other patients with hypertension for target-organ damage of the heart and kidney. Chronic kidney disease is common in patients with long standing primary aldosteronism. When matched for age, blood pressure, and duration of hypertension, patients with primary aldosteronism have greater left ventricular mass measurements than patients with other types of hypertension (e.g., pheochromocytoma, Cushing syndrome, essential hypertension). In patients with APA, the left ventricular wall thickness and mass were markedly decreased 1 year after adrenalectomy. A case-control study of 124 patients with primary aldosteronism and 465 patients with essential hypertension (matched for age, sex, and systolic and diastolic blood pressure) found that patients presenting with either APA or IHA had a significantly higher rate of cardiovascular events (e.g., stroke, atrial fibrillation, myocardial infarction) than the matched patients with essential hypertension. A negative effect of circulating aldosterone on cardiac function was found in young nonhypertensive subjects with GRA who had increased left ventricular wall thickness and reduced diastolic function compared with age- and sex-matched controls.
Diagnostic Investigation
The diagnostic approach to primary aldosteronism can be considered in three phases: case-detection tests, confirmatory tests, and subtype evaluation tests.
Case-Detection Tests
Spontaneous hypokalemia is uncommon in patients with uncomplicated hypertension; when present, it strongly suggests associated mineralocorticoid excess. However, several studies have shown that most patients with primary aldosteronism have baseline serum levels of potassium in the normal range. Therefore, hypokalemia should not be the major criterion used to trigger case detection testing for primary aldosteronism. Patients with hypertension and hypokalemia (regardless of presumed cause), treatment-resistant hypertension (poor control on three antihypertensive drugs), severe hypertension (≥160 mm Hg systolic or ≥100 mm Hg diastolic), hypertension, and an incidental adrenal mass, or onset of hypertension at a young age should undergo screening for primary aldosteronism ( Fig. 14.1 ).
In patients with suspected primary aldosteronism, screening can be accomplished (see Fig. 14.1 ) by paired measurements of PAC and PRA in a random morning ambulatory blood sample (preferably obtained between 8.00 and 10.00 am ). This test may be performed while the patient is taking antihypertensive medications (with some exceptions, discussed later) and without posture stimulation. Marked hypokalemia reduces the secretion of aldosterone, and it is optimal to restore the serum level of potassium to normal before performing diagnostic studies.
It may be difficult to interpret data obtained from patients treated with a mineralocorticoid receptor antagonist (spironolactone and eplerenone). These drugs prevent aldosterone from activating the receptor, resulting sequentially in sodium loss, a decrease in plasma volume, and an elevation in PRA, which will reduce the utility of the PAC/PRA ratio. For this reason, spironolactone and eplerenone should not be initiated until the evaluation is completed and the final decisions about treatment are made. However, there are rare exceptions to this rule. For example, if the patient is hypokalemic despite treatment with spironolactone or eplerenone, then the mineralocorticoid receptors are not fully blocked and PRA or PRC should be suppressed in such a patient with primary aldosteronism. In this unique circumstance, the evaluation for primary aldosteronism can proceed despite treatment with mineralocorticoid receptor antagonists. However, in most patients already receiving spironolactone, therapy should be discontinued for at least six weeks. Other potassium-sparing diuretics, such as amiloride and triamterene, usually do not interfere with testing unless the patient is on high doses.
Angiotensin-converting-enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have the potential to falsely elevate the PRA. Therefore, the finding of a detectable PRA level or a low PAC/PRA ratio in a patient taking one of these drugs does not exclude the diagnosis of primary aldosteronism. However, an undetectably low PRA level in a patient taking an ACE inhibitor or ARB makes primary aldosteronism likely, and the PRA is suppressed (<1.0 ng/mL per hour) in almost all patients with primary aldosteronism.
The PAC/PRA ratio, first proposed as a case-detection test for primary aldosteronism in 1981, is based on the concept of paired hormone measurements. The PAC is measured in nanograms per deciliter, and the PRA in nanograms per milliliter per hour. In a hypertensive hypokalemic patient, secondary hyperaldosteronism should be considered if both PRA and PAC are increased and the PAC/PRA ratio is less than 10 (e.g., renovascular disease). An alternative source of mineralocorticoid receptor agonism should be considered if both PRA and PAC are suppressed (e.g., hypercortisolism). Primary aldosteronism should be suspected if the PRA is suppressed (<1.0 ng/mL per hour) and the PAC is increased. At least 14 prospective studies have been published on the use of the PAC/PRA ratio in detecting primary aldosteronism. Although there is some uncertainty about test characteristics and lack of standardization (see later discussion), the PAC/PRA ratio is widely accepted as the case-detection test of choice for primary aldosteronism.
It is important to understand that the lower limit of detection varies among different PRA assays and can have a dramatic effect on the PAC/PRA ratio. As an example, if the lower limit of detection for PRA is 0.6 ng/mL per hour and the PAC is 16 ng/dL, then the PAC/PRA ratio with an “undetectable” PRA would be 27; however, if the lower limit of detection for PRA is 0.1 ng/mL per hour, the same PAC level would yield a PAC/PRA ratio of 160. Thus, the cutoff for a “high” PAC/PRA ratio is laboratory dependent and, more specifically, PRA assay dependent. In a retrospective study, the combination of a PAC/PRA ratio greater than 30 and a PAC level greater than 20 ng/dL had a sensitivity of 90% and a specificity of 91% for APA. At Mayo Clinic, the combination of a PAC/PRA ratio of 20 or higher, and a PAC level of at least 15 ng/dL is found in more than 90% of patients with surgically confirmed APA. In patients without primary aldosteronism, most of the variation occurs within the normal range. A high PAC/PRA ratio is a positive screening test result, a finding that warrants further testing.
It is critical for the clinician to recognize that the PAC/PRA ratio is only a case-detection tool, and all positive results should be followed by a confirmatory aldosterone suppression test to verify autonomous aldosterone production before treatment is initiated. In a systematic review of 16 studies with 3136 participants, the PAC/PRA cutoff levels used varied between 7.2 and 100. The sensitivity for APA varied between 64% and 100%, and the specificity between 87% and 100%. However, the description of the reference standard and the attribution of diagnosis at the end of the studies were incomplete, and there was a lack of standardization concerning the origin of the study cohort, ongoing antihypertensive medications, use of high-salt versus low-salt diet, and circumstances during blood sampling. The authors concluded that none of the studies provided any valid estimates of test characteristics (sensitivity, specificity, and likelihood ratio at various cutoff levels). In a study of 118 subjects with essential hypertension, neither antihypertensive medications nor acute variation of dietary sodium affected the accuracy of the PAC/PRA ratio adversely; the sensitivities on and off therapy were 73% and 87%, respectively, and the specificities were 74% and 75%, respectively. In a study of African American and Caucasian subjects with resistant hypertension, the PAC/PRA ratio was elevated (>20) in 45 of 58 subjects with primary aldosteronism and in 35 of 207 patients without primary aldosteronism (sensitivity, 78%; specificity, 83%).
The measurement of PRA is time-consuming, shows high interlaboratory variability, and requires special preanalytic prerequisites. To overcome these disadvantages, a monoclonal antibody against active renin is being used by several reference laboratories to measure the plasma renin concentration (PRC) instead of PRA. However, few studies have compared the different methods of testing for primary aldosteronism, and these studies lack confirmatory testing. It is reasonable to consider a positive PAC/PRC test if the PAC is greater than 15 ng/dL and the PRC is below the lower limit of detection for the assay.
Confirmatory Tests
An increased PAC/PRA ratio is not diagnostic by itself, and primary aldosteronism must be confirmed by demonstration of inappropriate aldosterone secretion. The list of drugs and hormones capable of affecting the RAA axis is extensive, and a “medication-contaminated” evaluation is frequently unavoidable in patients with poorly controlled hypertension despite a three-drug program. Calcium channel blockers and α1-adrenergic receptor blockers do not affect the diagnostic accuracy in most cases. It is impossible to interpret data obtained from patients receiving treatment with mineralocorticoid receptor antagonists (e.g., spironolactone, eplerenone) when the PRA is not suppressed (see earlier). Therefore, treatment with a mineralocorticoid receptor antagonist should not be initiated until the evaluation has been completed and the final decisions about treatment have been made. Aldosterone suppression testing can be performed with orally administered sodium chloride and measurement of urinary aldosterone or with intravenous sodium chloride loading and measurement of PAC.
Oral Sodium Loading Test
After hypertension and hypokalemia have been controlled, patients should receive a high-sodium diet (supplemented with sodium chloride tablets if needed) for 3 days, with a goal sodium intake of 5000 mg (equivalent to 218 mEq of sodium or 12.8 g sodium chloride). The risk of increasing dietary sodium in patients with severe hypertension must be assessed in each case. Because the high-salt diet can increase kaliuresis and hypokalemia, vigorous replacement of potassium chloride may be needed, and the serum level of potassium should be monitored daily. On the third day of the high-sodium diet, a 24-hour urine specimen is collected for measurement of aldosterone, sodium, and creatinine. To document adequate sodium repletion, the 24-hour urinary sodium excretion should exceed 200 mEq. Urinary aldosterone excretion of more than 12 μg/24 hours in this setting is consistent with autonomous aldosterone secretion. The sensitivity and specificity of the oral sodium loading test are 96% and 93%, respectively.
Intravenous Saline Infusion Test
The intravenous saline infusion test has also been used widely for the diagnosis of primary aldosteronism. Normal subjects show suppression of PAC after volume expansion with isotonic saline; subjects with primary aldosteronism do not show this suppression. The test is done after an overnight fast. Two liters of 0.9% sodium chloride solution is infused intravenously with an infusion pump over 4 hours with the patient recumbent. Blood pressure and heart rate are monitored during the infusion. At the completion of the infusion, blood is drawn for measurement of PAC. PAC levels in normal subjects decrease to less than 5 ng/dL, whereas most patients with primary aldosteronism do not suppress to less than 10 ng/dL. Postinfusion PAC values between 5 and 10 ng/dL are indeterminate and may be seen in patients with IHA. Historically, the saline infusion test has been performed in the supine position and the false-negative rate has been excessive; preliminary data suggest that if the saline infusion test is performed in the seated position the accuracy is improved.
Fludrocortisone Suppression Test
In the fludrocortisone suppression test, fludrocortisone acetate is administered for 4 days (0.1 mg every 6 hours) in combination with sodium chloride tablets (2 g three times daily with food). Blood pressure and serum potassium levels must be monitored daily. In the setting of low PRA, failure to suppress the upright 10 am PAC to less than 6 ng/dL on day 4 is diagnostic of primary aldosteronism. Increased QT dispersion and deterioration of left ventricular function have been reported during fludrocortisone suppression tests. Most centers no longer use this test.
Subtype Studies
After case-detection and confirmatory testing, the third management issue guides the therapeutic approach by distinguishing APA and PAH from IHA and GRA. Unilateral adrenalectomy in patients with APA or PAH results in normalization of hypokalemia in all cases; hypertension is improved in all cases and is cured in 30% to 60% of patients. In IHA and GRA, unilateral or bilateral adrenalectomy seldom corrects the hypertension. IHA and GRA should be treated medically. APA is found in approximately 35% of cases and bilateral IHA in approximately 60% (see Box 14.1 ). APAs are usually small hypodense adrenal nodules (<2 cm in diameter) on computed tomography (CT) and are golden yellow in color when resected. IHA adrenal glands may be normal on CT or may show nodular changes. Aldosterone-producing adrenal carcinomas are almost always larger than 4 cm in diameter and have an inhomogeneous phenotype on CT.
Adrenal Computed Tomography
Primary aldosteronism subtype evaluation may require one or more tests, the first of which is imaging of the adrenal glands with CT. If a solitary unilateral hypodense (HU < 10) macroadenoma (>1 cm) and normal contralateral adrenal morphology are found on CT in a young patient (<35 years) with severe primary aldosteronism, unilateral adrenalectomy is a reasonable therapeutic option ( Fig. 14.2 ). However, in many cases, CT shows normal-appearing adrenals, minimal unilateral adrenal limb thickening, unilateral microadenomas (≤1 cm), or bilateral macroadenomas. In these cases, additional testing is required to determine the source of excess aldosterone secretion.
Small APAs may be labeled incorrectly as IHA on the basis of CT findings of bilateral nodularity or normal-appearing adrenals. Also, apparent adrenal microadenomas may actually represent areas of hyperplasia, and unilateral adrenalectomy would be inappropriate. In addition, nonfunctioning unilateral adrenal macroadenomas are not uncommon, especially in older patients (>40 years). Unilateral PAH may be visible on CT, or the PAH adrenal may appear normal on CT. In general, patients with APAs have more severe hypertension, more frequent hypokalemia, and higher levels of plasma aldosterone (>25 ng/dL) and urinary aldosterone (>30 μg/24 hours), and are younger (<50 years), compared with those who have IHA. Patients fitting these descriptors are considered to have a “high probability of APA” regardless of the CT findings, and 41% of patients with a “high probability of APA” and a normal adrenal CT scan prove to have unilateral aldosterone hypersecretion.
Adrenal CT is not accurate in distinguishing between APA and IHA. In one study of 203 patients with primary aldosteronism who were evaluated with both CT and adrenal venous sampling, CT was accurate in only 53% of patients; based on the CT findings, 42 patients (22%) would have been incorrectly excluded as candidates for adrenalectomy, and 48 (25%) might have had unnecessary or inappropriate surgery. In a systematic review of 38 studies involving 950 patients with primary aldosteronism, adrenal CT/magnetic resonance imaging (MRI) results did not agree with the findings from adrenal venous sampling in 359 patients (38%); based on CT/MRI, 19% of the 950 patients would have undergone noncurative surgery, and 19% would have been offered medical therapy instead of curative adrenalectomy. Therefore, adrenal venous sampling is essential to direct appropriate therapy in patients with primary aldosteronism who have a high probability of APA and are seeking a potential surgical cure.
Adrenal Venous Sampling
Adrenal venous sampling (AVS) is the criterion standard test to distinguish between unilateral and bilateral disease in patients with primary aldosteronism. AVS is an intricate procedure because the right adrenal vein is small and may be difficult to locate and cannulate; the success rate depends on the proficiency of the angiographer. A review of 47 reports found that the success rate for cannulation of the right adrenal vein in 384 patients was 74%. With experience and focusing the expertise to one or two radiologists at a referral center, the AVS success rate can be as high as 96%.
The five keys to a successful AVS program are: (1) appropriate patient selection, (2) careful patient preparation, (3) focused technical expertise, (4) defined protocol, and (5) accurate data interpretation. A center-specific, written protocol is mandatory. The protocol should be developed by an interested group of endocrinologists, hypertension specialists, internists, radiologists, and laboratory personnel. Safeguards should be in place to prevent mislabeling of the blood tubes in the radiology suite and to prevent sample mix-up in the laboratory.
At Mayo Clinic, we use continuous cosyntropin infusion during AVS (50 μg/hour starting 30 minutes before sampling and continuing throughout the procedure) for the following reasons: (1) to minimize stress-induced fluctuations in aldosterone secretion during nonsimultaneous AVS; (2) to maximize the gradient in cortisol from adrenal vein to inferior vena cava (IVC) and thus confirm successful sampling of the adrenal veins; and (3) to maximize the secretion of aldosterone from an APA. The adrenal veins are catheterized through the percutaneous femoral vein approach, and the position of the catheter tip is verified by gentle injection of a small amount of nonionic contrast medium and radiographic documentation. Blood is obtained from both adrenal veins and from the IVC below the renal veins and assayed for aldosterone and cortisol concentrations. To be sure that there is no cross-contamination, the IVC sample should be obtained from the external iliac vein. The venous sample from the left side typically is obtained from the common phrenic vein immediately adjacent to the entrance of the adrenal vein. The cortisol concentrations from the adrenal veins and IVC are used to confirm successful catheterization; the adrenal vein/IVC cortisol ratio is typically greater than 10:1.
Dividing the right and left adrenal vein PAC values by their respective cortisol concentrations corrects for the dilutional effect of the inferior phrenic vein flow into the left adrenal vein; these are termed cortisol-corrected ratios ( Figs. 14.3A and 14.3B ). In patients with APA, the mean cortisol-corrected aldosterone ratio (i.e., the ratio of PAC/cortisol from the APA side to that from the normal side) is 18:1. A cutoff point of 4:1 for this ratio is used to indicate unilateral aldosterone excess. In patients with IHA, the mean cortisol-corrected aldosterone ratio is 1.8:1 (high side to low side), and a ratio of less than 3.0:1 suggests bilateral aldosterone hypersecretion. Therefore, most patients with a unilateral source of aldosterone have cortisol-corrected aldosterone lateralization ratios greater than 4.0, and ratios greater than 3.0 but less than 4.0 represent a zone of overlap. Ratios no higher than 3.0 are consistent with bilateral aldosterone secretion. The test characteristics of adrenal vein sampling for detection of unilateral aldosterone hypersecretion (APA or PAH) are 95% sensitivity and 100% specificity. At centers with experience with AVS, the complication rate is 2.5% or less. Complications can include symptomatic groin hematoma, adrenal hemorrhage, and dissection of an adrenal vein. However, adrenocortical function remains intact in most patients who experience AVS-related adrenal hemorrhage.
Some centers and clinical practice guidelines recommend that AVS should be performed in all patients who have the diagnosis of primary aldosteronism. The use of AVS should be based on patient preference, patient age, clinical comorbidities, and the clinical probability of finding an APA. A more practical approach is the selective use of AVS (see Fig. 14.2 ).
As more aldosterone-specific imaging agents are developed, it is hoped that an accurate and widely available noninvasive subtype test will be available.
Familial Hyperaldosteronism
Glucocorticoid-Remediable Aldosteronism: Familial Hyperaldosteronism Type 1
GRA (FH type 1) was first described in a single family in 1966. Twenty-six years later the causative CYP11B1/CYP11B2 chimeric gene was discovered. GRA is a form of hyperaldosteronism in which the hypersecretion of aldosterone can be reversed with physiologic doses of glucocorticoid. It is rare, as illustrated by a study of 300 consecutive patients with primary aldosteronism; only two patients were diagnosed with GRA (prevalence = 0.66%) (see Box 14.1 ). GRA is characterized by early-onset hypertension that is usually severe and refractory to conventional antihypertensive therapies, aldosterone excess, suppressed PRA, and excess production of 18-hydroxycortisol and 18-oxycortisol. Mineralocorticoid production is regulated by adrenocorticotropin hormone (ACTH) instead of by the normal secretagogue, angiotensin II. Therefore, aldosterone secretion can be suppressed by glucocorticoid therapy. In the absence of glucocorticoid therapy, this mutation results in overproduction of aldosterone and the hybrid steroids 18-hydroxycortisol and 18-oxycortisol, which can be measured in the urine to make the diagnosis.
Genetic testing is a sensitive and specific means of diagnosing GRA and obviates the need to measure the urinary levels of 18-oxycortisol and 18-hydroxycortisol or to perform dexamethasone suppression testing. Genetic testing for GRA should be considered for patients with primary aldosteronism who have a family history of primary aldosteronism, onset of primary aldosteronism at a young age (<20 years), or a family history of strokes at a young age.
Familial Hyperaldosteronism Type 2
FH-2 is autosomal dominant and may be monogenic. The hyperaldosteronism in FH-2 does not suppress with dexamethasone, and GRA mutation testing is negative. FH-2 is more common than FH-1, but it still accounts for fewer than 6% of all patients with primary aldosteronism. The molecular basis for FH-2 is unclear, although a recent linkage analysis study showed an association with chromosomal region 7p22.
Familial Hyperaldosteronism Type 3
FH-3 was first described in a single family in 2008. This initial report included a father and two daughters who all presented with refractory hypertension before seven years of age and all three were treated with bilateral adrenalectomy. The adrenal glands showed massive hyperplasia. Three years later the causative germline mutation in this family was discovered: a point mutation in and near the selectivity filter of the potassium channel KCNJ5. This KCNJ5 mutation produces increased sodium conductance and cell depolarization, triggering calcium entry into glomerulosa cells, the signal for aldosterone production and cell proliferation. Other families with early onset hyperaldosteronism have also been identified to have germline point mutations in the KCNJ5 gene. In families in Europe with FH (GRA excluded), a new germline G151E KCNJ5 mutation was found in two patients with primary aldosteronism from Italy and they presented a remarkably milder clinical and biochemical phenotype. In four families with early onset primary aldosteronism, germline G151R KCNJ5 mutations were found in two with severe hyperplasia requiring surgery; two kindreds had G151E mutations and mild primary aldosteronism.
Somatic Mutations in KCNJ5, ATP1A1, ATP2B3, and CACNA1D Genes
Somatic mutations in KCNJ5, ATP1A1, ATP2B3, and CACNA1D are found in approximately 50% of resected aldosterone-producing adenomas. In a study of 474 unselected patients with aldosterone-producing adenomas, somatic heterozygous KCNJ5 mutations were present in 38%, CACNA1D mutations in 9.3%, ATP1A1 mutations in 5.3%, and ATP2B3 mutations in 1.7%. A metaanalysis that included 1636 patients with primary aldosteronism who had somatic KCNJ5 mutations showed that more pronounced hyperaldosteronism, young age, female gender, and larger tumors are the phenotypic features of APA patients with KCNJ5 mutations. In addition, patients with KCNJ5 mutations were more frequently female and diagnosed younger, compared with CACNA1D mutation carriers or noncarriers. However, the presence of one of these somatic mutations does not affect diagnosis or treatment.
Additional somatic APA mutations have been identified in three other genes: ATP1A1 and ATP2B3, encoding Na + /K + -ATPase 1 and Ca ++ -ATPase 3, respectively; and, CACNA1D, encoding a voltage-gated calcium channel. In a subsequent study, somatic APA mutations in ATP1A1, ATP2B3, and KCNJ5 were present in 6.3%, 0.9%, and 39.3% of 112 APAs, respectively. In addition, germline mutations in CACNA1D have now been reported in two children with primary aldosteronism.
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