Adrenocortical Adenoma: Adenoma, which is found in approximately 60% of patients with primary aldosteronism, was once considered to be the most common abnormality. However, with the current use of PA:PRA ratios for case detection, IHA is now the most common subtype (63%). This change in subtype prevalence is almost certainly related to the less florid clinical and biochemical manifestations of IHA compared with APA, together with the current ability of sensitive screening methods to detect patients with IHA.

Adrenal adenomas occur somewhat more frequently in the left than in the right adrenal.2,45 Adenomas usually measure less than 2 cm in diameter, and have a golden yellow color (Fig. 12-3). On light microscopy, four cell types have been identified: small and large hybrid cells with features of both zona glomerulosa and zona fasciculata cells, and others with zona glomerulosa or zona fasciculata characteristics.⁴⁶ Electron microscopy has shown that most of the mitochondria possess tubular cristae similar to those found in the cells of the zona glomerulosa. If the patient has been exposed to spironolactone therapy, spironolactone bodies may be seen.^46,47 It is interesting to note that zona glomerulosa hyperplasia often accompanies APA in the surrounding cortex.⁴⁶ In unusual circumstances, multiple adenomas or an adenoma with associated macronodular hyperplasia or smaller satellite nodules can be found. These findings, which are similar to those of multiple endocrine neoplasia, have suggested that genetic mutations affecting regulation of adrenocortical cell growth and differentiation may serve as the basis for at least some cases of primary aldosteronism.⁴⁸ It is interesting that a patient with bilateral adenomas with two types of adenoma cells associated with both primary aldosteronism and Cushing’s syndrome has also been reported.⁴⁹

Idiopathic Hyperaldosteronism: In IHA, the zona glomerulosa usually demonstrates diffuse or focal hyperplasia with normal ultrastructure but may be macroscopically normal.47,50 Associated nodules may be microscopic or may be as large as 2 cm in diameter, and their ultrastructure is typical of clear cells of zona fasciculata origin. In keeping with this observation, in vitro the nodules produce cortisol but not aldosterone. Immunohistochemistry for aldosterone synthase has demonstrated intense staining in the zona glomerulosa and outer zona fasciculata in IHA. The compact cells in APA also stain for aldosterone synthase.⁵¹

Adrenal pathologic findings may be important to the outcome resulting from unilateral adrenalectomy. Ito and colleagues⁵² studied 37 patients with primary aldosteronism: 23 had unilateral solitary adenomas (Group 1), 3 had unilateral multiple adenomas (Group 2), and 11 had adenomas with multiple macroscopic or microscopic nodules (Group 3). Postoperative changes in the renin-angiotensin-aldosterone system were similar, but marked differences in blood pressure responses were noted, as half of Group 3 remained hypertensive at 1 year. The authors suggested that adrenal nodules might result from long-standing hypertension. Glands with nodules almost invariably show arteriopathy of the capsular vessels, which may lead to focal ischemia and atrophy, with the better perfused cells becoming hyperplastic, leading to nodule formation.⁵³

Adrenal Carcinoma: Adrenal carcinoma is a rare cause of primary aldosteronism. Histologically, carcinomas may be difficult to distinguish from adenomas, but almost invariably, carcinomas are larger (>3 cm in diameter) and include areas of necrosis and pleomorphic nuclei.⁴⁶ Calcification, commonly found in carcinomas, may be detected by magnetic resonance imaging (MRI), computed tomography (CT) scanning, or ultrasonography.

Clinical Presentation of Primary Aldosteronism: The clinical features of primary aldosteronism have been extensively described (Table 12-2).^58–62 Most patients are asymptomatic. Some are discovered to be hypokalemic on routine investigation of hypertension, whereas others may have symptoms of hypokalemia such as muscle weakness, very occasional muscle paralysis, or more commonly, polyuria, polydipsia, nocturia (secondary to nephrogenic diabetes insipidus), paresthesias, and, rarely, tetany.⁶³ Chinese patients have a high prevalence of hypokalemic periodic paralysis.⁶⁴

Conn et al.⁶⁵ found an intriguing sex difference in the prevalence of paresthesias and tetany in patients with primary aldosteronism; that is, females are more likely than males to develop paresthesias or to present with tetany. Tetany results from reduced ionized calcium accompanied by hypokalemic alkalosis. Plasma total calcium and magnesium levels are normal, however, and treatment consists of potassium repletion, not administration of calcium or magnesium.

Malignant hypertension originally was thought not to occur in primary aldosteronism.² However, this was found to be erroneous, and many cases have now been reported.^66,67 The diagnosis of primary aldosteronism can be missed in malignant hypertension because PRA may not be suppressed. On the other hand, normotensive aldosteronism has been documented.^68,69 Normotensive primary aldosteronism is most likely to occur in families with familial hyperaldosteronism (FH-I or FH-II), as affected individuals may be detected at an early, preclinical stage of the disease process by means of genetic family screening programs.⁷⁰

In primary aldosteronism, the normal circadian pattern of blood pressure appears to be preserved with nocturnal dipping,⁷¹ but the magnitude of the nighttime decrease is reduced.⁷² However, blood pressure variability may be reduced in primary aldosteronism compared with essential hypertension,⁷³ possibly as a result of protection of baroreflex function, or as a consequence of the salt-loaded state with extracellular fluid volume expansion.

Originally, primary aldosteronism was thought to be a relatively benign disorder with low morbidity and mortality. Studies conducted during the past decade, however, have provided new insights into the role of aldosterone in tissue damage (inflammation, fibrosis, and remodeling) (Fig. 12-4).⁷⁴ Many studies have shown that patients with primary aldosteronism are at higher risk than other patients with hypertension for target organ damage, especially involving the heart, kidneys, and blood vessels (Table 12-3).^75–83 When matched for age, blood pressure, and duration of hypertension, patients with primary aldosteronism have greater left ventricular mass measurements compared with other patients with hypertension.⁷⁷ In patients with APA, both left ventricular wall thickness and mass regress markedly within a year of unilateral adrenalectomy. Patients who present with APA or IHA have an increased number of cardiovascular events when compared with an age-, gender- and blood pressure–matched population with essential hypertension.⁷⁵ In primary aldosteronism, a striking increase in the relative risks for stroke (4.2%), myocardial infarction (6.5%), and atrial fibrillation (12.1%) has been noted.⁷⁵ Patients with primary aldosteronism have enhanced diastolic dysfunction when compared with hypertensive individuals without increased aldosterone production. Circulating aldosterone also produced a negative effect on various parameters of cardiac structure and function even in nonhypertensive subjects with GRA compared with age- and gender-matched control subjects.⁸³ After matching for age, body mass index, cholesterol, triglycerides, and glucose levels, arterial wall stiffness was found to be increased in primary aldosteronism compared with essential hypertension.⁷⁹ Hyperaldosteronism has been associated with widespread tissue fibrosis and increased remodeling of resistance vessels.⁷⁴

Patients with primary aldosteronism have increased renal dysfunction compared with those with essential hypertension. In the relatively large Primary Aldosteronism Prevalence in Hypertensives (PAPY) Study from Italy, patients with APA or IHA had higher urinary microalbumin excretion compared with those with essential hypertension.80,81 Also, prevalence of the metabolic (insulin resistance) syndrome is increased in patients with primary aldosteronism compared with those with essential hypertension.⁸²

General Considerations: In 2008, The Endocrine Society published a clinical guideline on the detection, diagnosis, and treatment of primary aldosteronism with specific recommendations for diagnostic workup.⁷ Sequential steps recommended for workup include (1) case detection (screening), (2) confirmation of the diagnosis, and (3) subtype classification.⁷

The approach to the diagnosis of primary aldosteronism differs from center to center. In some centers, the only patients investigated are those with hypokalemia and hypertension. As discussed above, most patients with this syndrome are normokalemic. Thus, a large fraction of patients with primary aldosteronism will not be detected if this approach is taken. In other centers, all hypertensive patients are screened for this diagnosis. Favoring this approach, the cost involved in screening is relatively small compared with the cost of lifelong drug therapy and the potential benefit derived from surgical cure or specific medical treatment.

Clinical criteria and methods for screening for primary aldosteronism are summarized in Fig. 12-5. All patients with the combination of hypertension and hypokalemia (spontaneous or diuretic induced) should be screened. Other recommendations for screening include young patients with hypertension, patients with early onset of cerebrovascular accident (<age 50), patients with a positive family history of early stroke in a first-degree relative, patients with hypertension and adrenal incidentalomas,⁸⁵ those whose blood pressure is difficult to control (resistant hypertension), and those in whom the diagnosis of secondary hypertension is being entertained for other reasons.⁷

Primary hyperaldosteronism is especially common among patients with resistant hypertension. Resistant hypertension is defined as blood pressure that remains above goal despite concurrent use of three antihypertensive agents of different classes, or that requires a minimum of four agents to achieve therapeutic goal.⁸⁶ In evaluations by several different investigators, the prevalence of primary hyperaldosteronism has been consistently reported to be about 20% among subjects with resistant hypertension.⁸⁶ In support of hyperaldosteronism as a common cause of resistant hypertension, aldosterone antagonists have been shown to provide significant additional blood pressure reduction when added to existing multidrug regimens in patients whose blood pressure remains uncontrolled.⁸⁶

At Mayo Clinic, an average of 12 patients per annum were diagnosed with primary aldosteronism from 1960 to 1991. However, with intensive screening, the number of patients with this diagnosis increased 10-fold over the subsequent 8 years.⁵⁸ In the past, the tipoff for thinking of the disease was the measurement of serum potassium in a hypertensive patient. The presence of hypokalemia (serum potassium <3.6 mmol/L) in an untreated hypertensive patient demanded further investigation of the renin-angiotensin-aldosterone system. As was previously discussed, it is also worthwhile to investigate patients who have diuretic-induced hypokalemia.⁸⁷ It is worth keeping in mind that circulating potassium levels may be elevated by red blood cell hemolysis and/or by the use of a tourniquet with muscle pumping.⁸⁸ In an otherwise hypokalemic patient, normokalemia may be induced by low sodium intake because urinary potassium excretion is directly related to the distal nephron sodium load in conditions of mineralocorticoid excess.^89,90 If 24-hour urinary sodium excretion is less than 100 mmol, hypokalemia may be provoked by increasing sodium intake (e.g., NaCl 6 g/day for 5 days) and then repeating the serum potassium measurement. Under these circumstances, some patients with normokalemic primary aldosteronism will become frankly hypokalemic. Twenty years ago, plasma or serum potassium was thought to have a sensitivity of 75% to 90% in the diagnosis of primary aldosteronism.^15,91 Current data from centers employing aldosterone:PRA ratios for case detection suggest that this figure should be reduced to less than 50%. The precise prevalence of normokalemic primary aldosteronism in an untreated hypertensive population is currently unknown but now appears to be much higher than was previously appreciated. Bravo and associates⁹² reported 80 patients with primary aldosteronism, 27.5% of whom had normal serum potassium. In another study,⁶⁶ 11% of patients with primary aldosteronism were normokalemic. Many other laboratories have confirmed these findings.^15,85 Thus, even before the aldosterone:renin ratio was introduced as the screening test of choice, between 7% and 38% of patients with primary aldosteronism had basal circulating potassium levels greater than 3.6 mmol/L. After screening with the ratio was introduced, 60% to 70% of patients with primary aldosteronism were reported as being normokalemic.

In general, hypokalemia secondary to mineralocorticoid excess is associated with inappropriate renal loss of potassium (kaliuresis). The degree of kaliuresis depends on daily potassium intake, but potassium excretion usually exceeds 30 mmol/24 hour in hypokalemic patients with primary aldosteronism (Fig. 12-6). In addition, enhanced distal nephron sodium-hydrogen exchange leads to increased hydrogen ion excretion, usually as ammonium ion, which is responsible for the relatively mild metabolic alkalosis observed in these patients. Although it is not understood, some patients with GRA have alkalosis but are persistently normokalemic.

In primary aldosteronism, plasma sodium levels usually are in the upper part of the normal range or are slightly elevated owing to resetting of the hypothalamic osmostat. As with other biochemical parameters, this abnormality may be more marked in patients with an adenoma than in those with hyperplasia.⁶⁶ Total exchangeable sodium is increased in patients with primary aldosteronism caused by an adenoma but is usually normal in those with idiopathic adrenal hyperplasia.³² A similar situation exists for total exchangeable potassium, with reduced levels in patients with an adenoma but not in those with hyperplasia.³² Whether differences also occur between IHA and the angiotensin-responsive variety of adenoma (which biochemically mimics IHA in other ways, including responsiveness of aldosterone to angiotensin II and normalcy of “hybrid steroid” [18-hydroxy-cortisol and 18-oxo-cortisol] levels⁹³) has yet to be determined.

Assessment of the Renin-Angiotensin-Aldosterone Axis:

Establishment of the Diagnosis of Primary Aldosteronism: Instead of proceeding directly from a positive screening test to subtype classification, it is strongly recommended that patients undergo one of four aldosterone suppression tests (see below) to definitively confirm or exclude the diagnosis of primary aldosteronism (Table 12-5).⁷ Three of these are salt-loading tests that can be conducted by increasing dietary sodium intake, infusing saline, or administering exogenous mineralocorticoid, or through combinations of these approaches. The rationale behind these tests is that in normal subjects, volume expansion with saline suppresses plasma aldosterone, whereas in primary aldosteronism, further volume expansion does not have the same suppressive action on aldosterone secretion. The fourth test depends on inhibition of aldosterone secretion by an ACE inhibitor. Detailed methods for performing these tests have been reviewed recently.⁷ At present, evidence is insufficient to allow recommendation of any one of these tests over any of the others.⁷ It has been recommended that pharmacologic agents with minimal or no effect on the renin-angiotensin-aldosterone system (see Table 12-4; discussed above) be employed to control blood pressure during confirmatory testing, if possible. Whether or not medications that affect the renin-angiotensin-aldosterone system are discontinued, however, spironolactone and eplerenone clearly interfere with these tests and must be discontinued 5 to 6 weeks before testing in all cases.

Diagnosis of Primary Aldosteronism During Pregnancy: The diagnosis of primary aldosteronism during pregnancy may be problematic because of the high circulating levels of progesterone, which inhibits the renal collecting duct effect of aldosterone on sodium transport. For example, administration of exogenous aldosterone 500 µg during the last month of pregnancy did not affect urinary sodium or potassium excretion, whereas the same dose administered postpartum induced marked sodium reabsorption and increased potassium excretion.⁸⁸

Primary Aldosteronism Subtype Classification: After the diagnosis of primary aldosteronism has been confirmed using one of the four confirmatory tests discussed above, unilateral disease (usually due to APA) needs to be differentiated from bilateral disease (usually due to hyperplasia), rare aldosterone-producing carcinomas, and the extremely rare tumors responsible for ectopic production of aldosterone (see Table 12-1).

Adrenal Venous Sampling: Adrenal venous sampling is considered the “gold standard” for differentiation of unilateral from bilateral disease.7,58,123 Adrenal vein catheterization is technically difficult, and even an experienced radiologist may be unable to enter the right adrenal vein because of its exit at a right angle directly into the inferior vena cava. Complications may occur (especially adrenal hemorrhage or extravasation of contrast medium into the adrenal parenchyma, which can lead to loss of function), but these are uncommon if adrenal venography is avoided. For this reason, adrenal venography is contraindicated except that a small amount of contrast medium usually can be infused safely to localize the catheter tip.

On the side of the tumor, aldosterone:cortisol ratios measured in blood collected from the adrenal veins are significantly higher than those found in the inferior vena cava, whereas on the contralateral side, aldosterone secretion from the zona glomerulosa is suppressed. Hence, the aldosterone:cortisol ratios on the side contralateral to an APA are not higher than peripheral124,125 (see example in Fig. 12-7). Because of the problems involved in adrenal vein catheterization, it is critical to measure both aldosterone and cortisol to determine whether the catheter is placed correctly in the adrenal vein. Some authors have administered ACTH to try to improve the test.⁸⁵ This approach overcomes the problems of intermittent aldosterone secretion and differences in endogenous ACTH when left and right adrenal vein samples are being obtained at different times. Also, ACTH has been thought to selectively stimulate aldosterone production from APAs compared with hyperplastic tissue. Others, however, have found that ACTH infusion leads to overproduction of aldosterone by the contralateral gland, in addition to stimulation of aldosterone secretion from the APA, leading to a false-positive diagnosis of IHA. Even if it is not possible to enter the right adrenal vein, interpretation of aldosterone:cortisol ratios in the left adrenal vein and in the inferior vena cava sometimes can still provide enough information to localize the side of unilateral aldosterone secretion from an APA.¹²⁴

Fig. 12-8 depicts the ratios of plasma aldosterone (A) to cortisol (C) from the raw values of the adrenal venous sampling example in Fig. 12-7. Commonly employed criteria for the diagnosis of unilateral aldosterone hypersecretion (Table 12-6) are as follows: (1) unilateral hypersecretion is confirmed when the A:C ratios from the high side are more than fourfold greater than those on the contralateral low side; (2) unilateral hypersecretion is not present when the A:C ratios are less then threefold greater on the high side than those on the low side; (3) A:C values between 3 and 4 (high to low side) are considered indeterminate.⁷

Young and coworkers123,125 have reviewed their experience at the Mayo Clinic with adrenal venous sampling (AVS). In a prospective study of 34 patients with primary aldosteronism, 15 had a normal CT scan or minimal thickening of one adrenal limb, 6 had unilateral microadenomas, 9 had bilateral nodules, and 4 had atypical unilateral macroadenomas. Both adrenal veins were catheterized in 33 of 34 patients. Six (40%) of the patients with normal or minimal thickening on CT scan had unilateral adrenal aldosterone production. All 6 patients with microadenomas had unilateral production. Four of 9 patients with bilateral adrenal masses had a unilateral source of aldosterone, as did 3 of the 4 with atypical macroadenomas. These results, if validated by operative pathologic findings and the therapeutic benefit of unilateral adrenalectomy, indicate that a highly significant number of patients would have erroneous diagnoses if based entirely on CT findings.¹²⁵ Young⁵⁸ suggested that the age of the patient should be taken into account when one is considering the need for AVS. Thus, if a unilateral hypodense nodule is seen on CT scanning in a patient with confirmed primary aldosteronism and the patient is younger than 40 years, the Mayo Clinic would proceed directly to surgery. If, however, the patient is older than 40, AVS would be performed.

Adrenal Scintigraphy: ¹³¹I-labeled or ⁷⁵Se-6-seleno-methylnorcholesterol can be used to image the adrenals and to distinguish between APA and IHA. However, these tests have largely been supplanted by the adrenal venous sampling procedure. Dexamethasone pretreatment and an improved scanning agent, [I¹³¹I]-iodomethyl-19-norcholesterol, have improved the accuracy of diagnosis compared with that of the initially used [¹³¹I]19-iodocholesterol.^126–129 Previous treatment with spironolactone may interfere with this test (this medication should be stopped for 6 weeks). The dose of dexamethasone employed has usually been greater than that required to suppress ACTH (i.e., 1 mg four times daily). Lugol’s iodine solution or saturated solution of potassium iodide (SSKI) should be given before radioisotope administration to block thyroid uptake.

The criteria used to make the distinction between APA and IHA are important. In one study of 30 patients with APA and 20 patients with IHA, the authors analyzed [¹³¹I]-iodomethyl-19-norcholesterol uptake at 5 days and found that nearly one half of the patients with APA had bilateral uptake, and that nearly one fourth of patients with IHA had marked asymmetrical uptake.¹²⁶ Thus, this test would not have been useful in distinguishing APA from IHA. The authors suggested that it was necessary to observe the pattern of adrenal imaging and that, during dexamethasone administration, early unilateral or early bilateral (i.e., <5 days) uptake was the primary indication of the diagnosis.¹²⁶

In reviewing the literature, Young and Klee¹³⁰ suggested that the accuracy (i.e., percentage of correct diagnoses) of iodocholesterol scintigraphy was 72% versus 73% for CT scanning and 95% for adrenal venous sampling in which both adrenal veins were correctly sampled. In other reports, however, less satisfactory results for adrenal scintigraphy were reported. Pagny and coworkers,¹²⁹ in 160 patients with primary aldosteronism, found that scintigraphy was accurate in only 53% of 51 examinations, whereas CT scanning was accurate in 82% of 85 examinations. However, scintigraphic scanning does have the potential advantage over other imaging techniques of correlating function with anatomic abnormality.

Adrenal carcinomas causing Cushing’s syndrome usually fail to take up iodocholesterol by the tumor or by the suppressed normal adrenals. However, in mineralocorticoid excess associated with adrenal carcinoma, uptake of iodocholesterol has been reported in both the primary tumor and its metastases.¹³¹

Surgical Treatment: In a patient with APA who is a candidate for surgery, the recommended treatment is unilateral laparoscopic adrenalectomy.⁷ Treatment for patients with spironolactone before surgery is often useful, because patients tend to have a smoother perioperative course with better control of blood pressure and plasma potassium levels, and treatment can result in significant improvement in clinical status (including reductions in left ventricular mass and improved left ventricular function) and fitness for surgery. Relatively low doses of spironolactone (12.5 to 50 mg daily) are usually sufficient for reducing blood pressure, provided that several weeks is provided to afford a therapeutic response. Low doses are less likely to induce side effects (gynecomastia, reduced libido, menstrual irregularity, and hyperkalemia) that are common among patients treated with much higher doses.

Laparoscopic adrenalectomy is now the standard approach for the removal of adrenal tumors. Terachi and colleagues¹³⁷ reported on a series of 100 such operations (APA, 41 patients; Cushing’s syndrome, 15; nonfunctioning adenoma, 22; myelolipoma, 3; pheochromocytoma, 7; complicated adrenal cyst, 3). The mean ± standard deviation (SD) operative time was 240 ± 76 minutes. Only three operations had to be converted to open surgery. The authors concluded that laparoscopic adrenalectomy via the transperitoneal anterior approach is as efficacious as open surgery but is associated with shorter convalescence.¹³⁷ Similar results have been reported by Rutherford and associates¹³⁸ in a series of 67 successful adrenalectomies, but the operation times were considerably shorter (124 ± 47 minutes).

Nakada and colleagues¹³⁹ compared unilateral adrenalectomy versus enucleation of the adenoma (22 unilateral vs. 26 enucleation). Both methods had similar effects on blood pressure, plasma potassium, PRA and plasma aldosterone, cortisol, and ACTH. However, 5 years after surgery, the enucleation group showed significantly greater PRA and plasma aldosterone responses to sodium deprivation and diuretics than did patients who underwent unilateral adrenalectomy. On this basis, they suggest that enucleation may be preferred. However, this approach has the potential to result in suboptimal correction of primary aldosteronism because it relies on the assumption that the removed adenoma is the correct and sole source of aldosterone excess.¹⁴⁰ As was noted earlier, multiple satellite nodules and/or hyperplastic tissue surrounding the extirpated adenoma can contribute to continuing hypersecretion of aldosterone.

Following surgery for APA, blood pressure usually decreases progressively over a period of weeks to months. In the report of Itoh and associates¹⁴¹ of 60 patients with primary aldosteronism, 60% were normotensive at 1 month after surgery and 76% by the second year. By the fifth year, 70% remained normotensive. This is very similar to the 69% long-term cure rate for unilateral adrenalectomy for APA based on 694 cases from 20 reports. Itoh and associates¹⁴¹ found that the best predictor of blood pressure at 2 months was the duration of hypertension before surgery. At 6 months and 1 year, the adrenal histology was predictive. By the fifth year, the most important predictor was a family history of hypertension.¹⁴¹ Comparison of surgery versus long-term spironolactone suggests that surgery for APA is more likely to lead to normalization of blood pressure.¹⁴² Furthermore, patients undergoing surgery for APA consistently report marked improvement in quality of life to a degree that is more apparent than with spironolactone.

Factors associated with resolution of hypertension in the postoperative period include having one or no first-degree relatives with hypertension and preoperative use of two or fewer antihypertensive agents.¹⁴³ Other factors that may play a role include duration of hypertension less than 5 years, higher preoperative PAC:PRA ratio, higher urinary aldosterone secretion, and preoperative response to spironolactone.⁷ The most common reasons for persistent hypertension after adrenalectomy are coexistent essential hypertension and older age and/or longer duration of hypertension.⁷

Medical Treatment: A low-sodium diet (less than 80 mEq of sodium per day) is a useful adjunct to pharmacologic therapy. After spironolactone treatment is initiated, correction of hypokalemia is rapid, but blood pressure control may take several weeks. The response of the renin-angiotensin-aldosterone system to treatment with spironolactone may help in difficult diagnostic problems to distinguish between APA and IHA. In patients with APA treated with spironolactone, no increase in plasma or urinary aldosterone was noted, even though normalization of plasma potassium and an increase in PRA occurred.¹⁴⁴ In contrast, in IHA, a twofold to threefold increase was noted in both plasma and urinary aldosterone. In patients who developed adverse effects on spironolactone, the drug of choice is eplerenone (50 mg twice daily). Eplerenone is a mineralocorticoid receptor antagonist that is less potent than spironolactone and usually needs to be given as 50 mg twice daily. Unlike spironolactone, eplerenone does not interfere with the androgen receptor.^145–147 Therefore, eplerenone may be the drug of choice in men in need of long-term mineralocorticoid receptor blocker therapy. Amiloride (2.5 to 20 mg daily), an aldosterone-independent antagonist of renal tubule (cortical collecting duct) sodium transport, also may be employed. The antihypertensive effect is generally less potent than that of spironolactone.

Patients with IHA should be treated medically. Of 99 patients with IHA treated by unilateral or bilateral adrenalectomy, only 19 (19%) were cured.85,148–151 The usual approach to medical treatment of IHA is to start with spironolactone or eplerenone. Despite improvement in electrolyte status, the blood pressure response is often suboptimal, and additional drugs are required. These may include amiloride and calcium channel blocking agents such as nifedipine.

The effects of calcium channel blocking drugs have been reported in both APA and IHA. In 10 patients with primary aldosteronism (five with APA, five with IHA), nifedipine, given as both short- and long-term (4 weeks) treatment, lowered blood pressure, normalized serum potassium, and reduced plasma aldosterone in both groups.¹⁵² These results contrasted with those of nitrendipine given to three patients with APA and three with IHA for 4 weeks (40 to 60 mg/d).¹⁵³ Opocher and colleagues¹⁵⁴ studied the effects of verapamil infusion on aldosterone levels in 11 patients with primary aldosteronism (five with IHA, six with APA). These investigators found that aldosterone levels decreased in IHA but not in APA. The lack of effect of calcium channel blocking drugs in APA on aldosterone has been observed by others.¹⁵⁵

The mechanism of action of calcium channel blocking drugs in primary aldosteronism is unclear. Given the sensitivity of the adrenal zona glomerulosa to angiotensin II in IHA and the key role of an angiotensin II–induced increase in intracellular calcium in stimulating aldosterone secretion, it might be anticipated that the drugs might affect aldosterone secretion in IHA. Kramer and associates¹⁵⁶ suggested an alternative mechanism that could be relevant to both IHA and APA. Extracellular fluid volume expansion leads to the secretion of an endogenous inhibitor of sodium-potassium adenosine triphosphatase (Na/K-ATPase), high levels of which have been found in primary aldosteronism. Ouabain, a known inhibitor of Na/K-ATPase, when administered to normal subjects not only inhibits the enzyme but also increases peripheral vascular resistance. These investigators found that this effect could be blocked by nifedipine.

ACE inhibitors have been shown to be effective in IHA. Enalapril lowered blood pressure and aldosterone secretion and improved plasma potassium levels.¹⁵⁷ As was already discussed, this effect may be due to blockade of the intra-adrenal renin-angiotensin system in IHA.

Drugs that block the synthesis of aldosterone have also been investigated. Trilostane, an inhibitor of 3β-hydroxysteroid dehydrogenase (3β-HSD), has been shown to lower blood pressure in both APA and IHA.¹⁵⁸ However, very little experience with the long-term use of this compound has been documented. The adrenolytic drug mitotane is of value in aldosterone-secreting carcinomas.¹⁵⁹ In the future, inhibitors of aldosterone synthase may become available.

In GRA, exogenous glucocorticoid is highly effective in controlling hypertension. It is not necessary to completely suppress ACTH to achieve normal blood pressure, and the lowest dose that maintains normal blood pressure should be given.⁷ Treatment leads within 2 weeks to a return of plasma potassium, aldosterone, and PRA levels to normal with reduction of blood pressure. Spironolactone, amiloride, and triamterene are alternatives or can be added to improve blood pressure control.

Liddle’s Syndrome: The principal cells of the cortical collecting tubule contribute to net sodium reabsorption and serve as the primary site of potassium secretion in the kidney. Aldosterone, after combining with the cytosolic mineralocorticoid receptor, increases both the number of open sodium channels in the apical membrane of principal cells and the number of basolateral Na/K-ATPase pumps.234,235 The reabsorption of cationic sodium makes the lumen electronegative, thereby creating a favorable gradient for the secretion of potassium into the lumen. Normally, increased intracellular sodium downregulates the activity of the apical sodium ion channels, while increased export of intracellular sodium (via increased basolateral Na/K-ATPase pump activity) ensures that apical sodium channels remain open.²³⁶ Amiloride closes apical sodium channels, leading to natriuresis and potassium retention.²³⁷ The amiloride-sensitive epithelial sodium channel (ENaC) consists of three subunits: α, β, and γ. In Liddle’s syndrome, activity of ENaC is enhanced as the result of varying mutations in a short segment of the cytoplasmic tail of the β or γ subunits.^238–243 Expression of mutated genes in the Xenopus oocyte is associated with a significant increase in apical sodium reabsorption and loss of inhibition of ENaC activity by increased levels of intracellular sodium.^236,238,241 Some of the defects also prevent downregulation of ENaC through the loss of interaction with an intracellular protein lipase, leading to an increase in the number of open channels in the apical membrane.^244,245

Patients with Liddle’s syndrome typically present in youth, with excess sodium retention, hypertension, and varying degrees of hypokalemia. These effects are not mediated by increased levels of circulating aldosterone or other mineralocorticoids. The syndrome is transmitted in autosomal dominant fashion,246,247 and in one kindred, the average serum potassium of 18 affected family members was 3.6 mEq/L.²⁴⁶ Thus, hypokalemia is not a necessary component of the diagnosis of Liddle’s syndrome. The differential diagnosis includes other mineralocorticoid excess syndromes in which aldosterone secretion is low, such as the two hypertensive forms of congenital adrenal hyperplasia (17α-hydroxylase and 11β-hydroxylase deficiency), congenital apparent mineralocorticoid excess syndrome, DOC-producing adrenal tumors, ectopic ACTH secretion, licorice or carbenoxolone ingestion, and familial glucocorticoid resistance. The lack of hyperandrogenism in Liddle’s syndrome helps to differentiate it from 11β-hydroxylase deficiency and familial glucocorticoid resistance, and the normal urinary cortisol:cortisone ratio helps rule out congenital apparent mineralocorticoid excess syndrome, licorice ingestion, and ectopic ACTH secretion. Additionally, patients with Liddle’s syndrome do not respond to spironolactone therapy,²⁴⁶ because increased sodium reabsorption is not mediated by aldosterone or other mineralocorticoids. The lack of response also distinguishes it from 11β-HSD2 deficiency. Therapy for Liddle’s syndrome involves the use of potassium-sparing diuretics such as amiloride or triamterene,^239,246 which directly close apical membrane sodium channels in principal cells.