Hypertension, suppressed plasma renin activity (PRA), and increased aldosterone secretion characterize the syndrome of primary aldosteronism. Aldosterone-producing adenoma (APA) and bilateral idiopathic hyperaldosteronism (IHA) are the two most common subtypes of primary aldosteronism (Table 10–2). 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, is caused by micronodular or macronodular hyperplasia of the zona glomerulosa of predominantly one adrenal gland. Unilateral hyperplasia is referred to as primary adrenal hyperplasia (PAH). Familial hyperaldosteronism (FH) is also rare and three types have been described: FH types 1, 2, and 3.
TABLE 10–2Adrenocortical causes of hypertension. |Favorite Table|Download (.pdf) TABLE 10–2 Adrenocortical causes of hypertension.
Low Renin and High Aldosterone
Aldosterone-producing adenoma (APA) ≈35% of cases
Bilateral idiopathic hyperplasia (IHA) ≈60% of cases
Unilateral (primary) 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
Congenital adrenal hyperplasia
Primary cortisol resistance
Apparent Mineralocorticoid Excess (AME)/11β-Hydroxysteroid Dehydrogenase Deficiency
Type 1 AME
Type 2 AME
Licorice or carbenoxolone ingestion (type 1 AME)
Cushing syndrome (type 2 AME)
Exogenous glucocorticoid administration—most common cause
ACTH-dependent ≈85% of cases
ACTH-independent ≈15% of cases
Unilateral adrenal disease
Bilateral adrenal disease
Bilateral macronodular adrenal hyperplasia (rare)
Primary pigmented nodular adrenal disease (rare)
FH type 1, or glucocorticoid-remediable aldosteronism (GRA), is caused by a chimeric gene duplication that results from unequal crossing over between the promoter sequence of CYP11B1 gene (encoding 11β-hydroxylase) and the coding sequence of CYP11B2 (encoding aldosterone synthase). This chimeric gene contains the 3′ ACTH-responsive portion of the promoter from the 11β-hydroxylase gene fused to the 5′ coding sequence of the aldosterone synthase gene. The result is ectopic expression of aldosterone synthase activity in the cortisol-producing zona fasciculata. Thus, mineralocorticoid production is regulated by ACTH instead of the normal secretagogue, angiotensin II. Aldosterone secretion can be suppressed by glucocorticoid therapy.
FH type 2 (FH-2) refers to the familial occurrence of APA or IHA or both. 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 3% of all patients with primary aldosteronism. The molecular basis for FH-2 is unclear, although a linkage analysis study showed an association with chromosomal region 7p22.
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 age 7 years 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 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 discontinuing antihypertensive medications for at least 2 weeks. The spontaneous hypokalemia/no antihypertensive drug 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 case-detection testing can be completed with a simple blood test (plasma aldosterone concentration [PAC]-to-plasma renin activity [PRA] ratio) while the patient is taking most antihypertensive drugs. Using the PAC-PRA ratio as a case-detection test, followed by aldosterone suppression confirmatory testing, has resulted in much higher prevalence estimates (5%-10% of all patients with hypertension) for primary aldosteronism.
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. The polyuria and nocturia are a result of a 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 mineralocorticoid escape. The degree of hypertension is usually moderate to severe and may be resistant to usual pharmacologic treatments. Although not common, primary aldosteronism may present with hypertensive urgencies. Patients with APA tend to have higher blood pressures than those with IHA. Hypokalemia is frequently absent; thus, all patients with hypertension are candidates for this disorder. In other patients, the hypokalemia only becomes evident with addition of a potassium-wasting diuretic (eg, hydrochlorothiazide, furosemide). Aldosterone excess also leads to a mild metabolic alkalosis because of increased urinary hydrogen excretion mediated both by hypokalemia and by the direct stimulatory effect of aldosterone on distal renal tubule acidification. Because of a reset osmostat, the serum sodium concentration tends to be high-normal or slightly above the upper limit of normal—this clinical finding is very useful when initially assessing the potential for primary aldosteronism.
Several studies have shown that patients with primary aldosteronism may be at higher risk than other patients with hypertension for target organ damage of the heart and kidney. When matched for age, blood pressure, and duration of hypertension, patients with primary aldosteronism have greater left ventricular mass by echocardiographic measurements than patients with other types of hypertension (eg, pheochromocytoma, Cushing syndrome, or essential hypertension). In patients with APA, the left ventricular wall thickness and mass decreases markedly 1 year after adrenalectomy. Patients presenting with either APA or IHA have a significantly higher rate of cardiovascular events (eg, stroke, atrial fibrillation, and myocardial infarction) than matched patients with essential hypertension who have similar degrees of hypertension duration and control.
The diagnostic approach to primary aldosteronism can be considered in three parts: (A) case-detection tests, (B) confirmatory tests, and (C) subtype evaluation tests.
Spontaneous hypokalemia is uncommon in patients with uncomplicated hypertension and, when present, strongly suggests associated mineralocorticoid excess. However, most patients with primary aldosteronism have baseline serum levels of potassium in the normal range. Therefore, hypokalemia is not and should not be the only criterion used to determine whom to test for primary aldosteronism. Patients with hypertension and hypokalemia (regardless of presumed cause), treatment-resistant hypertension (three antihypertensive drugs and poor control), severe hypertension (≥150 mm Hg systolic or ≥100 mm Hg diastolic), hypertension and an incidental adrenal mass, and onset of hypertension at a young age (eg, <30 years) should undergo case-detection testing for primary aldosteronism (Figure 10–4). In addition, primary aldosteronism should be tested for when considering a secondary hypertension evaluation (eg, when testing for renovascular disease or pheochromocytoma).
When to consider testing for primary aldosteronism and use of the plasma aldosterone concentration to plasma renin activity ratio as a case-finding tool (BP, blood pressure; PAC, plasma aldosterone concentration; PRA, plasma renin activity; PRC, plasma renin concentration).
In patients with suspected primary aldosteronism, case detection can be accomplished by measuring a morning (preferably between 8 am and 10 am) ambulatory paired random PAC and PRA (see Figure 10–4). This test may be performed while the patient is taking most antihypertensive medications and without posture stimulation. Hypokalemia reduces the secretion of aldosterone, and it is optimal in patients with hypokalemia 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 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 6 weeks. Other potassium-sparing diuretics, such as amiloride and triamterene, usually do not interfere with testing unless the patient is on high doses.
ACE-inhibitors and angiotensin receptor blockers (ARBs) have the potential to falsely elevate PRA. Therefore, in a patient treated with an ACE inhibitor or ARB, the finding of a detectable PRA level or a low PAC-PRA ratio does not exclude the diagnosis of primary aldosteronism. However, a very useful clinical point is that when a PRA level is undetectably low in a patient taking an ACE inhibitor or ARB, primary aldosteronism is likely. A second important clinical point is that PRA is suppressed (<1.0 ng/mL/h) in almost all patients with primary aldosteronism, regardless of concurrent medications.
The PAC-PRA ratio is based on the concept of paired hormone measurements. For example, in a hypertensive hypokalemic patient: (a) secondary hyperaldosteronism should be considered when both PRA and PAC are increased and the PAC-PRA ratio is less than 10 (eg, renovascular disease); (b) an alternate source of mineralocorticoid receptor agonism should be considered when both PRA and PAC are suppressed (eg, hypercortisolism); and, (c) primary aldosteronism should be suspected when PRA is suppressed (<1.0 ng/mL/h) and PAC is increased (Figure 10–5). Although there is some uncertainty about test characteristics and lack of standardization, 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/h and the PAC is 18 ng/dL, then the PAC-PRA ratio would be 30; however, if the lower limit of detection for PRA is 0.1 ng/mL/h and the PAC is 18 ng/dL, then the PAC-PRA ratio would be 180. Thus, the cutoff for a high PAC-PRA ratio is laboratory dependent and, more specifically, PRA assay dependent. At Mayo Clinic, a PAC (in ng/dL)-PRA (in ng/mL/h) ratio of 20 or more and PAC of at least 15 ng/dL are 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. The sensitivity and specificity of the PAC-PRA ratio in the diagnosis of primary aldosteronism are approximately 80% and 75%, respectively. A high PAC-PRA ratio with a PAC of at least 15 ng/dL is a positive case-detection test result, a finding that warrants further testing. Other initial case-detection strategies include measurement of isolated plasma renin activity or 24-hour urinary aldosterone excretion.
Use of the plasma aldosterone concentration-to-plasma renin activity ratio to differentiate among different causes of hypertension and hypokalemia (DOC, deoxycorticosterone; OHSD, hydroxysteroid dehydrogenase; PAC, plasma aldosterone concentration; PRA, plasma renin activity; SI units, International System of Units). (Adapted with permission from Young WF Jr, Hogan MJ. Renin-independent hypermineralocorticoidism. Trends Endocrinol Metab. 1994 Apr;5(3):97-106.)
An increased PAC-PRA ratio is not diagnostic by itself, and primary aldosteronism must be confirmed by demonstrating lack of normal suppressibility of aldosterone secretion. The list of drugs and hormones capable of affecting the renin-angiotensin-aldosterone axis is extensive, and frequently, a medication-contaminated evaluation is unavoidable. 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 (eg, spironolactone, eplerenone) when PRA is not suppressed. 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 are 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 12.8 g sodium chloride or 218 mEq of sodium). The risk of increasing dietary sodium in patients with severe hypertension must be assessed in each case. Because the high sodium 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 more than 12 μg/24 h 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 for the confirmation 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 risks associated with rapid intravenous volume expansion should be assessed in each case. The test is done after an overnight fast. Two liters of 0.9% sodium chloride solution are infused intravenously with an infusion pump over 4 hours into the recumbent patient. 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; most patients with primary aldosteronism do not suppress to less than 10 ng/dL; post-saline infusion PAC values between 5 and 10 ng/dL are indeterminate and can be seen in patients with IHA.
Following case detection and confirmatory testing, the third management step 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; hypertension is improved in all and is cured in approximately 30% to 60% of them. 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% of cases (see Table 10–2). APAs are usually hypodense nodules (<2 cm in diameter) on CT and are golden yellow in color on cut section. IHA adrenal glands may be normal on CT or show nodular changes. Aldosterone-producing adrenal carcinomas are almost always greater than 4 cm in diameter and have a suspicious imaging phenotype on CT. Patients with aldosterone-producing adrenocortical carcinomas usually have severe aldosterone excess with serum potassium concentrations frequently less than 2.0 mEq/L.
Adrenal CT—Primary aldosteronism subtype evaluation may require one or more tests, the first of which is imaging the adrenal glands with CT (Figure 10–6). This imaging test is usually ordered as CT of the abdomen limited to the adrenal glands with 2-mm contiguous cuts. Although contrast enhancement is not necessary, contrast administration results in improved discrimination between normal adrenal cortex and the small lipid-rich cortical adenoma. When a solitary unilateral hypodense (Hounsfield units [HU] <10) macroadenoma (>1 cm) and normal contralateral adrenal morphology are found on CT in a young patient (adrenal incidentalomas are uncommon in patients <35 years) with primary aldosteronism, unilateral adrenalectomy is a reasonable therapeutic option (Figure 10–7). However, in most cases, CT may show normal-appearing adrenals, minimal unilateral adrenal limb thickening, unilateral microadenomas (<1 cm), bilateral macroadenomas, or a large (eg, >2 cm) unilateral macroadenomas that would be atypical for primary aldosteronism. In these cases, when the patient wants to pursue the surgical treatment option for primary aldosteronism, additional testing is required to determine the source of excess aldosterone secretion (Figure 10–8). 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 individuals more than 35 years of age. 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, higher plasma (>30 ng/dL) and urinary (>30 μg/24 h) levels of aldosterone than those with IHA.
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 (AVS), CT was accurate in only 53% of patients; based on CT findings, 42 patients (22%) would have been incorrectly excluded as candidates for adrenalectomy and 48 (25%) might have had unnecessary or inappropriate surgery. Therefore, AVS is essential to direct appropriate therapy in patients older than 35 years of age with primary aldosteronism who have a high probability of APA and who seek a potential surgical cure. However, it is important to recognize that the surgical option is not mandatory in patients with APA—pharmacologic therapy with a mineralocorticoid receptor antagonist is the medication equivalent of adrenalectomy (discussed later).
Adrenal venous sampling—AVS is the criterion standard test to distinguish between unilateral and bilateral disease in patients with primary aldosteronism who want to pursue surgical management for their hypertension. 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. 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/h started 30 minutes before sampling and continued throughout the procedure) for the following reasons: (a) to minimize stress-induced fluctuations in aldosterone secretion during nonsimultaneous AVS; (b) to maximize the gradient in cortisol from adrenal vein to inferior vena cava (IVC) and thus confirm successful sampling of the adrenal veins; and, (c) 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 (see Figure 10–8). Blood is obtained from both adrenal veins and the IVC below the renal veins and assayed for aldosterone and cortisol concentrations. To be sure 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 more than 10:1.
Dividing the right and left adrenal vein PACs by their respective cortisol concentrations corrects for the dilutional effect of the inferior phenic vein flow into the left adrenal vein; these are termed cortisol-corrected ratios (see Figure 10–8). In patients with APA, the mean cortisol-corrected aldosterone ratio (APA-side PAC/cortisol:normal adrenal PAC/cortisol) is 18:1. A cutoff of the cortisol-corrected aldosterone ratio from high side to low side more than 4:1 is used to indicate unilateral aldosterone excess (see Figure 10–8). In patients with IHA, the mean cortisol-corrected aldosterone ratio is 1.8:1 (high side:low side); a ratio less than 3:1 is suggestive of bilateral aldosterone hypersecretion. Therefore, most patients with a unilateral source of aldosterone will have cortisol-corrected aldosterone lateralization ratios greater than 4.0; ratios greater than 3.0 but less than 4.0 represent a zone of overlap. Ratios no more than 3.0 are consistent with bilateral aldosterone secretion. The test characteristics of AVS for detecting unilateral aldosterone hypersecretion (APA or PAH) have sensitivity of 95% and specificity of 100%. However, since all patients who undergo AVS are not sent to surgery, the true diagnostic sensitivity of AVS is unknown. 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.
Some centers and clinical practice guidelines recommend that AVS should be performed in all patients who have the diagnosis of primary aldosteronism. However, a more practical approach is to consider the use of AVS based on patient preferences, patient age, clinical comorbidities, and clinical probability of finding an APA (see Figure 10–6).
Glucocorticoid-remediable aldosteronism—familial hyperaldosteronism type 1—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-oxocortisol and 18-hydroxycortisol or to perform dexamethasone suppression testing. Genetic testing for GRA should be considered for primary aldosteronism patients with a family history of primary aldosteronism or onset of primary aldosteronism at a young age (eg, <20 years), or in primary aldosteronism patients who have a family history of strokes at a young age. Cerebrovascular complications (eg, hemorrhagic stroke) associated with intracranial aneurysms affect approximately 20% of all patients with GRA—a frequency of cerebral aneurysm similar to that found in adult polycystic kidney disease.
Familial hyperaldosteronism type 2—FH type 2 is autosomal dominant and may be monogenic. All hypertensive first degree relatives of patients with primary aldosteronism should be advised to have case detection testing for primary aldosteronism.
Familial hyperaldosteronism type 3—FH type 3 typically presents in childhood or adolescence with hypertension, which may be mild or severe. When hypertension is severe, spontaneous hypokalemia is more likely to be present. FH-3 is caused by germline mutations in the potassium channel KCNJ5. Germline mutation testing is available and should be considered in patients with familial hyperaldosteronism and in patients who present with primary aldosteronism in childhood or adolescence.
Subtype evaluation of primary aldosteronism. For patients who want to pursue a surgical treatment for their hypertension, adrenal venous sampling is frequently a key diagnostic step. See text for details (APA, aldosterone-producing adenoma; AVS, adrenal venous sampling; CT, computed tomography; IHA, idiopathic hyperaldosteronism; PAH, primary adrenal hyperplasia). (Adapted with permission from Young WF Jr, Hogan MJ. Renin-independent hypermineralocorticoidism. Trends Endocrinol Metab. 1994 Apr;5(3):97-106.)
A 30-year-old woman had a 7-year history of hypertension and hypokalemia. Her blood pressure was not well controlled despite a four-drug program that included a calcium channel blocker, ACE-inhibitor, thiazide diuretic, and a β-adrenergic blocker. To correct her hypokalemia, she took 420 mEq of potassium per day. The case-detection test for primary aldosteronism was positive, with a plasma aldosterone concentration (PAC) of 34 ng/dL and low plasma renin activity (PRA) at less than 0.6 ng/mL/h (PAC-PRA ratio >56). The confirmatory test for primary aldosteronism was also positive, with 24-hour urinary excretion of aldosterone of 77 μg on a high-sodium diet (urinary sodium, 205 mEq/24 h). A. Adrenal CT axial image showing a 15-mm low-density mass (arrow) within the right adrenal gland. She underwent laparoscopic right adrenalectomy. B. Right adrenal gland (6.2 g, 6.1 cm × 3.7 cm × 1.4 cm) with a 1.8-cm cortical adenoma arising from the surface. C. Cut sections of the yellow adrenal cortical adenoma forming a 1.8 cm × 1.7 cm × 1.3 cm nodule. The postoperative plasma aldosterone concentration was less than 1.0 ng/dL. Hypokalemia was resolved. Four years after surgery, her blood pressure was normal without the aid of antihypertensive medications.
A 48-year-old man had a 7-year history of hypertension that was not optimally controlled on four antihypertensive drugs (β-adrenergic blocker, peripheral α1-antagonist, angiotensin receptor blocker, and a thiazide diuretic). He was not hypokalemic. Resistant hypertension prompted case-detection testing for primary aldosteronism with a plasma aldosterone concentration (PAC) of 15 ng/dL and low plasma renin activity (PRA) at less than 0.6 ng/mL/h (PAC-PRA ratio >25). The confirmatory test for primary aldosteronism was also positive, with 24-hour urinary excretion of aldosterone of 16 μg on a high-sodium diet (urinary sodium, 356 mEq/24 h). A. Adrenal CT split section axial images show a 12-mm thickening (large arrow) in the inferior aspect of the left adrenal gland and a tiny nodule (small arrow) in the right adrenal gland. The patient wanted to pursue a surgical approach to the resolution of or improvement in hypertension. B. Adrenal venous sampling images showing the catheter in the right and left adrenal veins. The delicate venous architecture is demonstrated. C. Adrenal venous sampling lateralized aldosterone secretion to the right adrenal gland, and a 3-mm yellow cortical adenoma was found at laparoscopic right adrenalectomy. The postoperative plasma aldosterone concentration was less than 1.0 ng/dL. One year after surgery, his blood pressure was in the normal range with the aid of one antihypertensive medication. (Reproduced with permission from Young WF. Endocrine hypertension: then and now. Endocr Pract. 2010 Sep-Oct;16(5):888-902.)
The treatment goal is to prevent the morbidity and mortality associated with hypertension, hypokalemia, and cardiovascular damage. The cause of the primary aldosteronism helps to determine the appropriate treatment. Normalization of blood pressure should not be the only goal in managing a patient who has primary aldosteronism. In addition to the kidney and colon, mineralocorticoid receptors occur in the heart, brain, and blood vessels. Excessive secretion of aldosterone is associated with increased risk of cardiovascular disease and morbidity. Therefore, normalization of circulating aldosterone or mineralocorticoid receptor blockade should be part of the management plan for all patients with primary aldosteronism. However, clinicians must understand that most patients with longstanding primary aldosteronism have some degree of renal insufficiency that is masked by the glomerular hyperfiltration associated with aldosterone excess. The true degree of renal insufficiency may only become evident after effective pharmacologic or surgical therapy.
A. Surgical treatment of aldosterone-producing adenoma and unilateral hyperplasia
Unilateral laparoscopic adrenalectomy is an excellent treatment option for patients with APA or PAH (unilateral hyperplasia). Although blood pressure control improves in nearly 100% of patients postoperatively, average long-term cure rates of hypertension after unilateral adrenalectomy for APA range from 30% to 60%. Persistent hypertension following adrenalectomy is correlated directly with having more than one first-degree relative with hypertension, use of more than two antihypertensive agents preoperatively, older age, increased serum creatinine level, and duration of hypertension.
Laparoscopic adrenalectomy is the preferred surgical approach and is associated with shorter hospital stays and less long-term morbidity than the open approach. Because APAs are small and may be multiple, the entire adrenal gland should be removed. To decrease the surgical risk, hypokalemia should be corrected with potassium supplements and/or a mineralocorticoid receptor antagonist preoperatively. The mineralocorticoid receptor antagonist and potassium supplements should be discontinued postoperatively. PAC should be measured 1 to 2 days after the operation to confirm a biochemical cure. Serum potassium levels should be monitored weekly for 4 weeks after surgery and a generous sodium diet should be followed to avoid the hyperkalemia of hypoaldosteronism that may occur because of the chronic suppression of the renin-angiotensin-aldosterone axis. In approximately 5% of APA patients, clinically significant hyperkalemia may develop after surgery, and short-term fludrocortisone supplementation may be required. Typically, the component of hypertension that was associated with aldosterone excess resolves in 1 to 3 months postoperatively.
B. Pharmacologic treatment
IHA should be treated medically. In addition, patients with APAs may be treated medically if the medical treatment includes mineralocorticoid receptor blockade. A sodium-restricted diet (<100 mEq of sodium per day), maintenance of ideal body weight, tobacco avoidance, and regular aerobic exercise contribute significantly to the success of pharmacologic treatment. No placebo-controlled randomized trials have evaluated the relative efficacy of drugs in the treatment of primary aldosteronism. Spironolactone, available as 25-, 50-, and 100-mg tablets, has been the drug of choice to treat primary aldosteronism for more than 4 decades. The initial dosage is 12.5 to 25 mg/d and is increased to 400 mg/d, if necessary, to achieve a high-normal serum potassium concentration without the aid of oral potassium chloride supplementation. Hypokalemia responds promptly, but hypertension may take as long as 4 to 8 weeks to correct. After several months of therapy, this dosage often can be decreased to as little as 25 to 50 mg/d; dosage titration is based on a goal serum potassium level in the high-normal range. Serum potassium and creatinine should be monitored frequently during the first 4 to 6 weeks of therapy (especially in patients with renal insufficiency or diabetes mellitus). Spironolactone increases the half-life of digoxin, and for patients taking this drug, the dosage may need to be adjusted when treatment with spironolactone is started. Concomitant therapy with salicylates should be avoided because they interfere with the tubular secretion of an active metabolite and decrease the effectiveness of spironolactone. Spironolactone is not selective for the mineralocorticoid receptor. For example, antagonism at the androgen receptor may result in painful gynecomastia, erectile dysfunction, and decreased libido in men; agonist activity at the progesterone receptor results in menstrual irregularity in women.
Eplerenone is a steroid-based antimineralocorticoid that acts as a competitive and selective mineralocorticoid receptor antagonist. It has a marked reduction in progestational and antiandrogenic actions compared with spironolactone. Eplerenone is available as 25- and 50-mg tablets. For primary aldosteronism, it is reasonable to start with a dose of 25 mg twice daily (twice daily because of the shorter half-life of eplerenone compared to spironolactone) and titrated upward for a target high-normal serum potassium concentration without the aid of potassium supplements. Potency studies with eplerenone show 50% less milligram per milligram potency when compared with spironolactone. As with spironolactone, it is important to follow blood pressure, serum potassium, and serum creatinine levels closely.
Patients with IHA frequently require a second antihypertensive agent to achieve adequate blood pressure control. Hypervolemia is a major reason for resistance to drug therapy, and low doses of a thiazide (eg, 12.5-50 mg of hydrochlorothiazide daily) or a related sulfonamide diuretic are effective in combination with the mineralocorticoid receptor antagonist. Because these agents often lead to further hypokalemia, serum potassium levels should be monitored.
Before initiating treatment, GRA should be confirmed with genetic testing. In the GRA patient, chronic treatment with physiologic doses of a glucocorticoid normalizes blood pressure and corrects hypokalemia. The clinician should avoid iatrogenic Cushing syndrome with excessive doses of glucocorticoids, especially with the use of dexamethasone in children. The smallest effective dose of shorter acting agents, such as prednisone or hydrocortisone, should be prescribed in relation to body surface area (eg, hydrocortisone, 10-12 mg/m2/d). Target blood pressure in children should be guided by age-specific blood pressure percentiles. Children should be monitored by pediatricians with expertize in glucocorticoid therapy, with careful attention paid to preventing retardation of linear growth by overtreatment. Treatment with mineralocorticoid receptor antagonists in these patients may be just as effective and avoids the potential disruption of the hypothalamic-pituitary-adrenal axis and risk of iatrogenic side effects. In addition, glucocorticoid therapy or mineralocorticoid receptor blockade may even have a role in normotensive GRA patients.
Patients with FH-3 should be treated with mineralocorticoid receptor blockade. Some of these patients have severe aldosterone excess, and the daily required dosage of spironolactone or eplerenone is not feasible lifelong, and bilateral adrenalectomy may need to be considered in selected cases.
Primary aldosteronism is uncommon in pregnancy with fewer than 40 patients reported in the medical literature, and most patients have had APA. Primary aldosteronism can lead to intrauterine growth retardation, preterm delivery, intrauterine fetal demise, and placental abruption. Case detection testing for primary aldosteronism in the pregnant woman is the same as for nonpregnant patients: morning blood sample for the measurement of aldosterone and plasma renin activity or renin mass measurement. If spontaneous hypokalemia in present in the woman with high aldosterone and suppressed renin, confirmatory testing is not needed. In the normokalemic woman with a positive case detection test, confirmatory testing should be pursued. However, the captopril stimulation test is contraindicated in pregnancy, and the saline infusion test may not be well tolerated. One option is measurement of sodium and aldosterone in a 24-hour urine collection on an ambient sodium diet.
Subtype testing with abdominal MRI without gadolinium is the test of choice. Adrenal imaging with CT, iodocholesterol scintigraphy, and adrenal venous sampling should be avoided in pregnancy.
Primary aldosteronism in pregnancy is fascinating in that the degree of disease may be improved or aggravated by pregnancy. In some women with primary aldosteronism, the high blood levels of pregnancy-related progesterone are antagonistic at the mineralocorticoid receptor and partially block the action of aldosterone—these patients have an improvement in the manifestations of primary aldosteronism during pregnancy. In other pregnant women, increased expression of luteinizing hormone-chorionic gonadotropin receptor and gonadotropin-releasing hormone receptor have been documented in APAs and the degree of hyperaldosteronism is aggravated by the increased pregnancy-related blood levels of human chorionic gonadotropin.
The type of treatment for primary aldosteronism in pregnancy depends on how difficult it is to manage the hypertension and hypokalemia. If the patient is in the subset of patients who have a remission in the degree of primary aldosteronism, then surgery or treatment with a mineralocorticoid antagonist can be avoided until after delivery. However, if hypertension and hypokalemia are marked, then surgical and/or medical intervention is indicated. Unilateral laparoscopic adrenalectomy during the second trimester can be considered in those women with confirmed primary aldosteronism and a clear-cut unilateral adrenal macroadenoma (>10 mm).
Spironolactone crosses the placenta and is a United States Federal Drug Association (FDA) pregnancy category C drug because feminization of newborn male rats has been documented. However, there is only one human case in the medical literature where treatment with spironolactone in pregnancy led to ambiguous genitalia in a male infant—this occurred in a woman treated with spironolactone for polycystic ovarian disease pre-pregnancy and through the fifth week of gestation. Eplerenone is an FDA pregnancy category B drug. Therefore, for those pregnant women who will be managed medically, the hypertension should be treated with standard antihypertensive drugs approved for use during pregnancy. Hypokalemia, if present, should be treated with oral potassium supplements. For those patients with refractory hypertension and/or hypokalemia, the addition of eplerenone may be cautiously considered.