Primary Aldosteronism: A Practical Approach to Diagnosis and Treatment

Abstract

Primary aldosteronism (PA) may account for as many as 10%–14% of hypertension cases. The plasma aldosterone concentration/plasma renin activity ratio is a simple screening test for PA that should be performed in all patients with refractory/severe hypertension, spontaneous or provoked (by diuretics) hypokalemia, or a requirement for excessive potassium supplementation to maintain normokalemia. PA can be confirmed by a fludrocortisone suppression test or 24‐hour urine collection for aldosterone. Confirmatory testing should be followed by high‐resolution computerized tomography of the adrenal glands to distinguish bilateral hyperplasia or an adenoma. A solitary tumor greater than 1 cm in size in a younger patient is an indication for surgery; all other (nondiagnostic) findings should be followed by bilateral adrenal venous sampling (if available) to identify a unilateral cause of PA. Treatment for a later alizing positive study is surgical; spironolactone or another mineralocorticoid receptor antagonist is the treatment of choice for a nonlateralizing study. If adrenal venous sampling is not readily available, patients may be successfully treated pharmacologically.

Primary aldosteronsim (PA) is a syndrome that results in increased production of the mineralocorticoid hormone aldosterone. A number of distinct lesions can result in PA (Table). Whatever the cause, the ultimate consequence of PA is the same—aldosterone production is excessive, no longer under the control of the renin‐angiotensin system and not necessarily responsive to the inhibitory effects of low serum potassium levels. Increased production of aldosterone generally results in suppressed plasma renin activity, metabolic alkalosis, a potassium‐losing diathesis (sometimes leading to hypokalemia; ≤3.5 mEq/L), and hypertension, but these findings are variable. The increase in blood pressure can be severe and resistant to conventional antihypertensive therapy.

Table TABLE.

DIFFERENTIAL DIAGNOSIS OF PRIMARY ALDOSTERONISM*

Subtype	Prevalence**	Features
Aldosterone‐producing adenoma	60%	Benign lesions presenting as a solitary mass <2 cm in size. Blood pressure and biochemical changes are more pronounced than in IHA. Adrenalectomy is recommended.
Idiopathic hyperaldosteronism	30%	Radiographic studies reveal bilateral adrenal gland hyperplasia or are normal. May actually be found to be more common than APA as the screening for PA becomes routine. Should be managed medically.
Glucocorticoid‐remediable aldosteronism	1%–3%	Autosomal dominant genetic defect that allows adrenocorticotropic hormone to be the sole regulator of aldosterone production. Patients are generally normokalemic and present at an earlier age than those with the other variants. Management is medical, and refractory patients may require exogenous glucocorticoids to inhibit aldosterone production.
Unilateral adrenal hyperplasia	1%–2%	A rare variant (also known as primary adrenal hyperplasia) that radiographically resembles IHA, but is unilateral. However, the biochemical presentation resembles APA and should be treated as if it were an APA. The importance of achieving this subclassification by stimulatory tests is not known.
Angiotensin‐responsive aldosterone‐producing adenoma	Unknown	Presents radiographically as an APA if visible; otherwise, has probably been mistaken for IHA in the past, as postural studies resemble those of IHA. Should be treated as APA if diagnosed; however, the importance of achieving this subclassification beyond APA is not known.
Adrenal carcinoma	<1%	Presents as a solitary mass >3 cm in size. Calcifications may rarely be present. Hypokalemia may be severe. Treated surgically, with adjuvant chemotherapy a consideration.
Ectopic aldosterone‐secreting tumor	Rare	Data are limited.
*May be present in as many as 10%–14% of all hypertensives, although not all data report this high an incidence.
** Approximate percentage of total population with primary aldosteronism. IHA=idiopathic hyperaldosteronism; APA=aldosterone‐producing adenoma; PA=primary aldosteronism

PA was traditionally thought to occur in fewer than 2% of patients with hypertension, but in recent years, with the development of refined diagnostic techniques and the realization that hypokalemia is not requisite, its prevalence has been estimated in some studies ¹ , ² to be as high as 10%–14% of unselected hypertensives. PA may thus be the most prevalent form of secondary hypertension. Further, targeted pharmacologic therapy or surgery is highly effective in lowering blood pressure and preventing target‐organ damage in these patients, highlighting the importance of early detection and specific treatment.

The objective of this article is to present the clinician with a simplified and practical approach to the detection and treatment of PA (Fig.); more exhaustive reviews of PA can be found elsewhere. ³ , ⁴ , ⁵ , ⁶ , ⁷ , ⁸ It should be emphasized that screening and even confirmatory testing can generally be accomplished prior to subspecialty referral.

Figure.

Diagnosis and management of primary aldosteronism. FST=fludrocortisone suppression test (positive if PAC >5 ng/dL); PAC=plasma aldosterone concentration; PRA=plasma renin activity; HRCT=high‐resolution computerized tomography. *24‐Hour urine collection is positive if aldosterone is >12 µg/dL. **If possible, hold angiotensin‐converting enzyme inhibitors, calcium channel antagonists, and diuretics.

WHO SHOULD BE SCREENED?

On the basis of findings of a high prevalence of PA in normokalemic patients with resistant hypertension, the criteria for screening hypertensive patients for PA have been broadened. Any patient with severe or resistant hypertension—inadequately controlled blood pressure in a patient prescribed three or more antihypertensive medications in adequate doses—with no other obvious secondary cause should be considered for screening (Fig.). In particular, patients with spontaneous hypokalemia (serum potassium concentration of ≤3.5 mEq/L) or inappropriate hypokalemia (serum potassium concentration of =3.0 mEq/L) while on conventional doses of diuretics or who require excessive doses of potassium replacement therapy should be screened for PA. ⁸ An important point to be underscored is that hypokalemia is not a universal finding in patients with PA. Indeed, a recent study ⁹ revealed that only 29% of 69 patients with documented PA were hypokalemic.

PLASMA ALDOSTERONE CONCENTRATION TO PLASMA RENIN ACTIVITY RATIO (PAC/PRA)

The PAC/PRA (in ng/dL/ng/ml/hr) is regarded by most experts to be the screening test of choice for PA (Fig.). ³ , ⁴ , ⁶ , ⁷ , ⁹ , ¹⁰ , ¹¹ , ¹² This test should be performed in the morning after the patient has been ambulatory. ⁶ A ratio greater than 20 ¹¹ , ¹³ with a PAC of at least 15 ng/dL should prompt confirmatory testing. A ratio greater than 70 with a PAC of ≥15 and a PRA ≤1ng/ml/hr is virtually diagnostic of PA. ⁵

The test can be performed in patients taking all antihypertensive medications, except spironolactone. However, some argue that β‐adrenergic receptor antagonists can suppress PRA and lead to false positive results. ⁹ , ¹⁴ If the initial PAC/PRA ratio is close to 20 in a patient in whom there is a strong clinical suspicion of PA who has concomitant hypokalemia or is receiving potentially interfering medications (angiotensin‐converting enzyme [ACE] inhibitors can raise PRA and suppress PAC; ¹⁴ diuretics can raise PRA; and calcium channel antagonists can suppress PAC ¹⁵ , ¹⁶ ), the test should be repeated after correction of serum potassium and withdrawal (if it can be done safely) of the interfering agents for at least 2 weeks. Spironolactone should be withheld for at least 6 weeks prior to testing. α‐Adrenergic receptor antagonists do not alter the PAC/PRA, and thus may be utilized as substitute antihypertensive agents in patients preparing to be retested. ¹¹

CONFIRMATORY TESTING

A PAC/PRA of 20–70 with a PAC of 15 ng/dL is suggestive of PA and should be followed by a confirmatory study. The rationale for confirmatory testing is to demonstrate that aldosterone secretion is at least partially autonomous (not dependent on renin‐angiotensin stimulation). A simple approach is to perform a fludrocortisone suppression test (FST) or a 24‐hour urine collection for aldosterone while the patient is consuming a high‐salt diet (at least 5 g of sodium daily ⁴ or 2^1/8 teaspoons of table salt [at least 500 mg of sodium may be found in an 8‐oz serving of tomato juice, a 2‐oz serving of bloody Mary mix, one hamburger, one hot dog, or one slice of pizza]). The FST is accomplished by prescribing fludrocortisone (0.1 mg orally every 6 hours) for 3 days and determining the PAC on the fourth day. If the PAC is not suppressed (remains at >5 ng/dL), the diagnosis of PA is confirmed. ⁵ , ¹⁷ This test can be performed on an outpatient basis. The serum potassium level should be kept within the normal range by supplementation, if required. ⁵

The alternative confirmatory test for PA is a 24‐hour urine collection for aldosterone in a patient consuming a high‐salt diet (high salt intake will usually suppress aldosterone secretion). The collection for urinary aldosterone and sodium should begin on the third day of the high‐salt diet. The patient may require potassium replacement during this time, as during the FST. The 24‐hour urinary excretion of sodium should exceed 200–250 mEq ⁸ , ¹⁸ to demonstrate the adequacy of the salt load, and the aldosterone excretion rate should be greater than 12 µg/24 hours ⁷ , ¹⁸ to confirm PA. Either confirmatory test is suitable, and can be selected according to patient and physician preferences.

SUBTYPE DIFFERENTIATION

The most important distinction to be made is between the two most common causes of PA—aldosterone‐producing adenoma (APA) and idiopathic hyperaldosteronism (IHA, also known as bilateral adrenal hyperplasia). APA is usually treated surgically and IHA is treated medically. The algorithm presented here will allow the proper therapy to be instituted for these conditions without complicated diagnostic procedures and without a requirement for referral to a specialized center.

There are several rare subtypes of aldosteronism that require more complicated diagnostic studies. Unilateral adrenal hyperplasia (primary adrenal hyperplasia) and angiotensin‐responsive aldosterone‐producing adenoma subtypes may be discerned by postural studies and angiotensin II infusions. ¹⁹ , ²⁰ These tests should be undertaken only at specialized centers that have established diagnostic protocols. Rarely, PA may be due to adrenal carcinoma. This entity is suspected when high‐resolution computerized tomography (HRCT) reveals a solitary mass of >3 cm, particularly if the mass is calcified. ⁴

Glucocorticoid‐remediable aldosteronism is an autosomal dominant defect caused by an unequal crossing‐over between the aldosterone synthase and 11 β‐hydroxylase genes. The regulatory element of the 11 β‐hydroxylase gene is fused to the aldosterone synthase gene, placing the production of aldosterone under the exclusive control of ACTH. ²¹ This subtype of PA can be discerned by performing a dexamethasone suppression test (see below).

HRCT

To avoid unnecessary surgery, it is imperative that a biochemical diagnosis of PA (by aldosterone and renin determinations) be established prior to the performance of imaging studies, since 3%–7% of patients over the age of 50 will have nonfunctioning adrenal nodules (“incidentalomas”). ¹³ Therefore, only patients with biochemically confirmed aldosterone excess should undergo HRCT to detect an adrenal lesion. ²² The most useful finding on HRCT is a unilateral adrenal mass >1 cm in size in a patient less than 40 years of age and suspected of having PA (older patients have a higher prevalence of incidentalomas and should undergo adrenal venous sampling [AVS] if surgery is being considered; see below). The treatment of choice in such a patient is laparoscopic adrenalectomy. ¹⁸ This procedure is minimally invasive, safe, and effective in the treatment of PA due to APA. ²³ , ²⁴

Other findings on HRCT, in patients with biochemically confirmed PA, such as normal‐appearing adrenal glands, unilateral enlargement, bilateral adenomas, or unilateral microadenoma (<1 cm in size) are nondiagnostic. For example, normal‐appearing glands may represent IHA, or APA with a nodule too small to be detected. Also, bilateral adenomas may represent IHA, or APA with nonfunctioning contralateral nodules. ¹⁸ When such uncertainty exists, most experts recommend that AVS be performed. ¹⁸ , ²⁵ When successful, AVS unequivocally establishes the presence (or absence) of unilateral aldosterone production, thus clarifying the choice of therapy—medical or surgical. When imaging studies are equivocal or surgery is considered, subspecialty opinion should be sought.

AVS

AVS is the most sensitive test to differentiate APA from IHA. ⁵ , ⁷ , ²⁶ , ²⁷ The aldosterone concentration in both adrenal veins is compared. If one side has a greater concentration than the other (centers have different methods and cut‐offs, but a ratio greater than 10/1 with adequate cortisol levels—demonstrating catheterization of adrenal veins—is generally diagnostic), then APA is diagnosed; otherwise IHA is the diagnosis by default. AVS should be performed in all patients with biochemical markers and equivocal HRCT results, including patients with normal scans or bilateral nodules, and patients over the age of 40 with unilateral nodules. The drawbacks of this procedure are that it is highly operator‐dependent, is not readily available at all centers, and carries a finite risk of venous thrombosis, adrenal hemorrhage, and adrenal insufficiency. ⁷ If AVS cannot be accomplished successfully, medical management is generally recommended (specialty centers differ in success rates; the Mayo Clinic has reported a success rate of 95% ²⁷ ).

Dexamethasone Suppression Test (DST)

This test is useful for identifying patients with glucocorticoid‐remediable aldosteronism (GRA)—a PA subtype that is likely 15 and a PRA. ²⁸ GRA should be suspected in young (first‐third decades) patients with PA, normal HRCT, and a family history of hypertension. The DST results in an attenuation of adrenocorticotropic hormone (ACTH) production, thereby decreasing the production of aldosterone in those with GRA, which is ACTH‐dependent. The DST is performed by prescribing dexamethasone 0.5 mg orally, every 6 hours for 2 days, followed by measuring plasma cortisol (to demonstrate adequate suppression of ACTH) and aldosterone levels on day 3. A PAC level of <4 ng/dL is considered positive and should be followed by confirmatory—genetic—testing. ²⁹ , ³⁰

TREATMENT

Adrenalectomy is indicated in younger patients with confirmed PA and a HRCT that reveals a solitary mass of >1 cm, or in any patient with a lateralizing AVS study. ¹⁸ This population generally has a form of PA that is amenable to surgery—APA, unilateral adrenal hyperplasia, angiotensin‐responsive aldosterone‐producing adenoma, or rarely, adrenal carcinoma. Approximately 53% of patients undergoing adrenalectomy will remain normotensive after 5 years. ⁸ , ²⁰ Medical management is indicated in all other patients, including those who are poor surgical candidates or refuse surgery, have nondiagnostic HRCT scans, refuse or do not have access to AVS, or have undergone technically unsuccessful AVS. Medical therapy is also acceptable and effective for patients with APA, as surgery does not necessarily provide an absolute cure and very few APAs undergo malignant transformation. ¹⁸ , ³¹ It is also reasonable to initiate a trial of medical therapy in patients with equivocal biochemical studies. GRA can be managed as described below, but more severely affected patients may require the addition of corticosteroid therapy to suppress aldosterone secretion. If this is the case, the lowest effective dose of steroids should be prescribed. ⁷

Spironolactone, a synthetic steroid that acts as a nonselective competitive antagonist of aldosterone, ³² is currently the mainstay of medical therapy for PA. ⁶ , ⁷ , ¹⁸ , ²⁵ It has been suggested that aldosterone‐induced cardiac hypertrophy and fibrosis occur independently of blood pressure; ⁵ , ²⁵ thus, an aldosterone receptor antagonist may provide benefits beyond blood pressure lowering in patients treated for PA. This concept was demonstrated in the Randomized Aldactone Evaluation Study (RALES), ³³ in which low‐dose spironolactone was found to be cardioprotective in patients with congestive heart failure (a population different from patients with PA, but with elevated aldosterone levels), without significantly altering blood pressure. However, the side effects of spironolactone are numerous: menstrual abnormalities, sedation, headache, gastrointestinal disturbances, skin rashes, gynecomastia, and impotence; ³² , ³⁴ thus, the initial dose should be low (12.5 mg twice daily). ²⁵ The dose can be titrated upward as tolerated, but should not exceed 50 mg/day in men, as spironolactone competes with dihydrotestosterone for androgen receptors and reduces 17 α‐hydroxylase activity, lowering plasma testosterone levels. ³⁴ If the dose is limited by side effects or if blood pressure is not adequately controlled, other antihypertensive agents may be added. Hydrochlorothiazide has been effectively combined with spironolactone in the management of PA. ³⁵ Calcium channel antagonists and ACE inhibitors are also useful in the medical management of PA. ⁶ , ⁷ , ¹⁵ , ¹⁶ , ¹⁸ Even if tolerated in only very low doses, spironolactone should be part of the regimen in all patients with medically managed PA because of its mineralocorticoid antagonist effects.

Amiloride, a potassium‐sparing diuretic that antagonizes the epithelial sodium channel in the distal tubule, has been advocated as an alternative to spironolactone because of its superior tolerability. ⁷ , ¹⁸ , ²⁵ However, amiloride is not a mineralocorticoid receptor antagonist and thus does not provide the organ protection conferred by spironolactone. The ideal agent for the medical management of PA would selectively antagonize the effects of aldosterone, thereby providing organ protection without the side effects associated with spironolactone use. Eplerenone—a selective aldosterone receptor antagonist currently undergoing phase III clinical trials—appears to exhibit a more favorable pharmacologic profile than spironolactone. ³⁶

CONCLUSION

PA is likely more prevalent than once thought; it is important that it be recognized and adequately treated because conventional antihypertensive therapy may be ineffective and lack pharmacologic specificity. If HRCT is nondiagnostic (all findings other than a >1‐cm unilateral mass in a patient younger than 40) in the context of confirmed PA (PAC/PRA of >70; positive fludrocortisone suppression test; or urinary aldosterone excretion of >12 µg/dL/24 hr following a PAC/PRA of 20–70), the patient should undergo AVS. Successful AVS will distinguish lesions amenable to surgery from those that should be managed medically. If AVS is unavailable, refused, or unsuccessful, the patient should be treated medically with at least a minimal dose of a mineralocorticoid receptor antagonist, along with other antihypertensive agents if necessary. Spironolactone is currently the drug of choice for the pharmacologic management of PA; selective aldosterone receptor antagonists are a new, promising class of agents that may provide more tolerable and effective therapy for PA.

Acknowledgment: This work was supported by NHLBI Training Grant # T32Hl07457.