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PRIMARY ALDOSTERONISM: CAUSE AND ASSESSMENT


What is aldosteronism?

Nonsuppressible (primary) hypersecretion of aldosterone is an uncommon but underdiagnosed cause of hypertension. The classic presenting signs of primary aldosteronism are hypertension and hypokalemia.

Primary aldosteronism refers to excessive secretion of aldosterone by the adrenal cortex, which is usually caused by a cortical adenoma (tumor) or bilateral adreanal hyperplasia. Hyperaldosteronism, in turn, causes excessive sodium and water retention and excessive potassium excretion by the kidneys and GI tracts. A secondary form of the disease occurs in conjuction with heart failure, renal dysfunction, or cirrhosis of the liver. One to 2 percent of cases of hypertension are caused by primary aldosteronism, which can be treated by adrenalectomy.


Severity percent of patients wit haldosterone-secreting adenomas are women, and the incidence of primary aldosteronism is four times higher among blacks than among the general population. Complications include the long-term effects of untreated hypertension - stroke, renal failure, and heart failure.

Many subtypes of primary aldosteronism have been described since Conn's original report of the aldosterone-producing adenoma in 1954. The most common subtypes are:


  1. Aldosterone-producing adenomas
  2. Bilateral idiopathic hyperaldosteronism

Assessment:

1. Excessive thirst (polydipsia) caused by hypermatremia
2. Muscle weakness caused by hypokalemia.
3. Possible paresthesias, tetany, and polyria caused by alkalosis
4. Hypertension.

Less common forms include:

  • Unilateral hyperplasia or primary adrenal hyperplasia (caused by micronodular or macronodular hyperplasia of the zona glomerulosa of predominantly one adrenal gland)
  • Familial hyperaldosteronism type I (glucocorticoid-remediable aldosteronism) and type II (the familial occurrence of aldosterone-producing adenoma or bilateral idiopathic hyperplasia or both)
  • Pure aldosterone-producing adrenocortical carcinomas and ectopic aldosterone-secreting tumors (eg, neoplasms in the ovary or kidney)
  • The subtype-directed treatment of primary aldosteronism will be reviewed here. The clinical manifestations and diagnosis of this disorder and other, less common causes of mineralocorticoid excess are discussed separately.

GOALS OF THERAPY — The treatment goal is to prevent the morbidity and mortality associated with hypertension, hypokalemia, and cardiovascular damage. The cause of primary aldosteronism helps to determine the appropriate treatment. Normalization of blood pressure should not be the only goal. 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 [2-4]. Therefore, normalization of circulating aldosterone or mineralocorticoid receptor blockade should be part of the management plan for all patients with primary aldosteronism.

GENERAL PRINCIPLES — Establishing the correct subtype diagnosis is essential since the treatment of primary aldosteronism is based upon whether the adrenal aldosterone hypersecretion is unilateral (adenoma, unilateral hyperplasia, or carcinoma) or bilateral (idiopathic adrenal hyperplasia or glucocorticoid-remediable aldosteronism).

Surgery is curative only in patients with unilateral disease.
Patients with bilateral idiopathic adrenal hyperplasia are treated with a mineralocorticoid antagonist.
Patients with glucocorticoid-remediable aldosteronism should receive physiologic doses of a glucocorticoid.
Clinical Guidelines — In 2008, The Endocrine Society published evidence-based guidelines for the diagnosis and treatment of primary aldosteronism [5]. Our therapeutic approach outlined here is consistent with the guidelines. The recommendations for case detection and confirmation of primary aldosteronism are reviewed separately.

UNILATERAL ADRENAL ADENOMA OR HYPERPLASIA — A unilateral adrenal adenoma is responsible for the hypersecretion of aldosterone in 30 to 60 percent of cases of primary aldosteronism [2], while unilateral hyperplasia is less common (about 3 percent). Surgery is the preferred therapy in this setting. An alternative is medical therapy with a mineralocorticoid receptor antagonist.

Surgery — Unilateral adrenalectomy in patients with aldosterone-producing adenomas or unilateral hyperplasia induces a marked reduction in aldosterone secretion and correction of the hypokalemia in almost all patients. Hypertension is improved in all and is cured in approximately 35 to 60 percent of patients.

We suggest laparoscopic adrenalectomy over open adrenalectomy because it is associated with shorter hospital stays and fewer complications.

Laparoscopic partial adrenalectomy (removal of an adenoma leaving the remaining adrenal intact) has been tried as a strategy to further reduce surgical morbidity, but it is an inadequate procedure in many cases. This was illustrated in a series of 92 patients with primary aldosteronism undergoing laparoscopic adrenalectomy [13]. Postoperatively, all 63 patients with total adrenalectomy had improved blood pressure and normal plasma aldosterone, while 2 of 29 with partial adrenalectomy had persistent hypertension and high plasma aldosterone. Of the 63 removed adrenal glands, 17 (27 percent) contained multiple nodules along with what was thought to be the hypersecretory adenoma. Thus, we suggest resection of the entire affected adrenal gland.

Preoperatively, hypertension should be controlled and hypokalemia should be corrected with a mineralocorticoid receptor antagonist (eg, spironolactone or eplerenone). The blood pressure response to spironolactone preoperatively often predicts the blood pressure response to unilateral adrenalectomy in patients with aldosterone-producing adenomas.

Postoperative management — Postoperative management after unilateral adrenalectomy should include the following:

Plasma aldosterone should be measured the day after surgery to assess for cure.
Potassium supplements and spironolactone should be discontinued, and, if possible, antihypertensive therapy should be decreased.

Patients should be monitored closely for hyperkalemia, which may result from transient hypoaldosteronism due to chronic suppression of renal renin release and contralateral adrenal gland aldosterone secretion. Serum potassium should be measured during the hospitalization, and as an outpatient, once weekly for four weeks. Occasionally short-term supplementation with fludrocortisone may be needed to treat the hyperkalemia.

Serum creatinine should be followed serially in patients who had renal insufficiency preoperatively. Primary aldosteronism has been associated with renal toxicity [14-16], and improvement of hypertension corrects renal hyperfiltration and may unmask the renal damage. In a long-term study that included 50 patients with primary aldosteronism and 100 patients with essential hypertension, during 30 to 90 days after intervention, the mean glomerular filtration rate decreased in patients with primary aldosteronism by -13.6 mL/min, but only by -2.1 mL/min in patients with essential hypertension, despite similar blood pressure values.

The preferred intravenous fluid after surgery is isotonic saline without potassium (unless the patient is still hypokalemic) and a sodium-rich diet should be suggested after discharge.

Effect on hypertension — Although hypertension is cured in some patients, a lesser degree of hypertension persists in as many as 40 to 65 percent of cases. A number of clinical features help to identify patients who are more likely to experience complete resolution of their hypertension after adrenalectomy, including lack of family history of hypertension, shorter duration of hypertension, preoperative use of two or fewer antihypertensive agents, younger age, higher preoperative ratio of plasma aldosterone concentration to plasma renin activity, and higher urine aldosterone level.

Persistent hypertension may be related to underlying essential hypertension and/or the development of nephrosclerosis after a prolonged period of uncontrolled hypertension. It is also possible that an error in subtype assignment has been made and that the patient has bilateral adrenal hyperplasia, a disorder that should be treated medically, not with unilateral adrenalectomy. As many as one-third of patients thought to have a unilateral lesion on imaging studies have bilateral adrenal hyperplasia on adrenal vein sampling.

A scoring system, the aldosteronoma resolution score (ARS), has been proposed to help identify patients at low or high likelihood of complete resolution of hypertension after adrenalectomy. In a study of 100 patients with primary aldosteronism seen at a single tertiary center, four clinical features provided the best predictive model for complete resolution of hypertension after adrenalectomy. For scoring purposes, each predictor was assigned a weight as follows:

Two or fewer antihypertensive medications (2 points)
Body mass index ≤25 kg/m2 (1 point)
Duration of hypertension ≤6 years (1 point)
Female sex (1 point)

The likelihood of complete resolution of hypertension for patients with ARS scores of 0 to 1, 2 to 3, and 4 to 5 was 27, 46, and 75 percent, respectively. These relationships were validated in a second population of 67 patients from a different tertiary center. Thus, the ARS appears to be a useful tool for informing patients of the likelihood of resolution of hypertension after surgery.

Ablative procedures — Although published data are limited, some centers have advocated percutaneous ablative therapy for unilateral adrenal adenomas, including percutaneous acetic acid injection and radiofrequency ablation.

Percutaneous ablative therapy requires overnight hospitalization. It is also associated with a variety of adverse effects, including abdominal pain, hematuria, pancreatitis, pneumothorax, bleeding, adrenal abscess formation, tumor tracking, and incomplete ablation.

Given the limited experience, uncertain success rate, and potential complications, we cannot recommend adrenal percutaneous ablative therapy.

Medical therapy

Aldosterone antagonists — Although laparoscopic adrenalectomy is more cost-effective over time, the administration of an aldosterone (mineralocorticoid receptor) antagonist is an effective alternative in patients who refuse or are not candidates for surgery. The efficacy of this approach was illustrated in a study of 24 patients with adenomas who were treated medically for at least five years. The following results were reported:

Systolic and diastolic blood pressures decreased from 175/106 to 129/79 mmHg.
The serum potassium concentration increased from 3.0 to 4.3 mEq/L.
Five tumors had increased in size by at least 0.5 cm (as determined by CT scan), but there was no evidence of malignant transformation in any patient.
Dietary sodium restriction (<100 mEq/day), maintenance of ideal body weight, avoidance of alcohol, and regular aerobic exercise contribute to the success of pharmacologic therapy in almost any patient with hypertension.

There have been no placebo-controlled, randomized trials evaluating the relative efficacy of different drugs in the management of primary aldosteronism. Spironolactone has long been the drug of choice; eplerenone represents a newer more expensive alternative with fewer side effects. (See 'Suggested approach' below.)

There are some precautions with the use of spironolactone:

Serum potassium and creatinine should be monitored frequently during the first four to six weeks of therapy, especially in patients with renal insufficiency or diabetes mellitus. The clinical course and circumstances dictate the frequency of subsequent monitoring.

Spironolactone may increase the half-life of digoxin, and for patients taking this drug, the dose may need to be adjusted when treatment with spironolactone is started.

Concomitant therapy with salicylates or nonsteroidal antiinflammatory drugs may interfere with the antihypertensive efficacy of spironolactone (and other antihypertensive medications).

Spironolactone is also a progesterone agonist and androgen receptor antagonist, resulting in side effects such as breast tenderness and menstrual irregularities in women, and impotence, decreased libido, and gynecomastia in men. In a review of 699 patients with primary aldosteronism treated with spironolactone, the incidence of gynecomastia was dose-dependent: 6.9 percent at doses below 50 mg/day and 52 percent at doses above 150 mg/day. Spironolactone may also be associated with minor gastrointestinal symptoms.

Eplerenone is a highly selective mineralocorticoid receptor antagonist. Compared to spironolactone, eplerenone has 0.1 percent of the binding affinity to androgen receptors and less than 1 percent of the binding affinity to progesterone receptors.

Because of its selectivity, eplerenone is associated with a low incidence of endocrine side effects. Eplerenone would be considered the first-line drug over spironolactone if it provided the same degree of blood pressure and potassium control with fewer side effects. However, trials comparing spironolactone and eplerenone in patients with primary aldosteronism have not been published. In addition, eplerenone is substantially more expensive. Thus, until more data become available, it is reasonable to start with spironolactone and, if endocrine side effects are limiting, switch to eplerenone.

For patients with primary aldosteronism, a reasonable starting dose of eplerenone is 25 mg once or twice daily and titrated upward for normokalemia without the aid of potassium supplements. The maximum dose approved by the US Food and Drug Administration for hypertension is 100 mg daily. Eplerenone has 25 to 50 percent less mg per mg potency than spironolactone. Serum potassium and creatinine should be monitored frequently during the first four to six weeks of therapy, especially in patients with renal insufficiency or diabetes mellitus. The clinical course and circumstances dictate the frequency of subsequent monitoring. Eplerenone is now available as a generic, but it remains substantially more expensive than spironolactone.

Potassium-sparing diuretics — Potassium-sparing diuretics that block the aldosterone-sensitive sodium channel in the collecting tubules (amiloride, triamterene) can block the renal effects of aldosterone, lowering the blood pressure and raising the serum potassium concentration. However, these drugs are not recommended for first-line therapy because of persistence of hyperaldosteronism with its possible deleterious cardiovascular effects. (See "Clinical features of primary aldosteronism", section on 'Cardiovascular risk' and "Mechanism of action of diuretics", section on 'Potassium-sparing diuretics'.)

Suggested approach — The goals of medical therapy in patients with unilateral disease who refuse or are not candidates for surgery are correction of hypokalemia, restoration of normal blood pressure, and reversal of the effects of hyperaldosteronism on the heart.

When using spironolactone or, if not tolerated, eplerenone, we suggest the following regimen, which is consistent with the 2008 Endocrine Society guidelines.

Spironolactone is titrated to a normal serum potassium concentration without the aid of potassium supplements. The starting dose is 12.5 to 25 mg daily with food, which increases drug absorption. The dose can be increased every two weeks.

The blood pressure goal is often difficult to achieve with monotherapy, since a lesser degree of hypertension persists after surgery in as many as 40 to 65 percent of patients despite complete correction of the hyperaldosteronism. (See 'Effect on hypertension' above.) If hypertension persists, we add another antihypertensive drug (eg, 12.5 to 25 mg of hydrochlorothiazide or chlorthalidone daily). Amiloride is an alternative for men and women intolerant of both spironolactone and eplerenone. Amiloride dosing may be started at 5 mg twice daily and increased to the dose needed to correct the hypokalemia. If the hypertension persists, a second-step drug should be added. Low doses of a thiazide diuretic (eg, 12.5 to 25 mg of hydrochlorothiazide or chlorthalidone daily) are preferred because hypervolemia is a major reason for resistance to amiloride.

Monitoring — With each medication change, it is important to monitor the effect on both blood pressure and serum potassium. Serum potassium, creatinine, and blood pressure should be monitored frequently during the first four to six weeks of medical therapy (especially in patients with renal insufficiency or diabetes mellitus). Clinical course and circumstances dictate the frequency of monitoring thereafter.

BILATERAL ADRENAL HYPERPLASIA — There are two forms of primary aldosteronism due to bilateral adrenal zona glomerulosa hyperplasia: idiopathic adrenal hyperplasia and the rare glucocorticoid-remediable aldosteronism, which responds to the administration of exogenous glucocorticoid. (See "Approach to the patient with hypertension and hypokalemia" and "Glucocorticoid-remediable aldosteronism".)

Idiopathic adrenal hyperplasia — Idiopathic adrenal hyperplasia is generally a milder disease than adrenal adenoma, with less hypersecretion of aldosterone and less hypokalemia. Such patients should be treated with an aldosterone (mineralocorticoid receptor) antagonist.

Subtotal adrenalectomy has been tried in patients with idiopathic hyperplasia, but only a minority of patients have a clinically significant hypotensive response. However, unilateral adrenalectomy in patients with bilateral adrenal hyperplasia does have the potential to effectively "debulk" the amount of adrenal tissue responsible for aldosterone hypersecretion and may, in selected patients, provide improved blood pressure control.

Optimal treatment of idiopathic adrenal hyperplasia consists of mineralocorticoid receptor blockade with spironolactone or eplerenone as described above for medical therapy of a unilateral adrenal adenoma. The goals of therapy are the same as for unilateral adenoma: normalization of the serum potassium in hypokalemic patients, normalization of the blood pressure, and reversal of the effects of hyperaldosteronism on the heart (which cannot be confirmed clinically).

In patients with bilateral adrenal hyperplasia, quality of life (QOL), as measured by the validated Medical Outcomes Study Short Form 6 General Health Survey (SF-36), improves during treatment with mineralocorticoid receptor antagonists [31]. However, the improvement appears to be more modest and occurs more slowly when compared to historical control patients undergoing unilateral adrenalectomy for unilateral adrenal adenoma.

A thiazide diuretic or an angiotensin converting enzyme (ACE) inhibitor can be added if the hypertension persists. The efficacy of an ACE inhibitor in the low plasma renin state may in part reflect the role of even low concentrations of angiotensin II as an aldosterone secretagogue in adrenal hyperplasia.

Glucocorticoid-remediable aldosteronism — Before initiating treatment for glucocorticoid-remediable aldosteronism, the diagnosis should be confirmed with genetic testing; the mutation in patients with GRA is fusion of the promoter region of the gene for CYP11B1 and the coding sequences of CYP11B2.

Chronic treatment with physiologic doses of a glucocorticoid normalizes blood pressure and corrects hypokalemia. The clinician should be cautious about inducing iatrogenic Cushing's syndrome with excessive doses of glucocorticoids, especially with the use of dexamethasone in children.

SUMMARY AND RECOMMENDATIONS

From a treatment perspective, the two major forms of primary aldosteronism are: unilateral adrenal aldosterone hypersecretion (eg, adenoma, unilateral hyperplasia, or carcinoma) and bilateral aldosterone hypersecretion (eg, idiopathic adrenal hyperplasia and the rare glucocorticoid-remediable aldosteronism).
The goals of therapy for primary aldosteronism due to either unilateral or bilateral adrenal disease are the same and include normalization of the serum potassium in hypokalemic patients, normalization of the blood pressure, which often persists after correction of the hyperaldosteronism, and reversal of the adverse cardiovascular effects of hyperaldosteronism.

For most patients with confirmed unilateral aldosterone hypersecretion (eg, adrenal adenoma or unilateral adrenal hyperplasia), we suggest unilateral adrenalectomy over medical therapy (Grade 2B).

Because of the reduction in postoperative morbidity, hospital stay, and expense compared with open laparotomy, we suggest laparoscopic adrenalectomy by an experienced endocrine surgeon for adrenal adenomas (Grade 2C). Hypokalemia should be corrected with spironolactone preoperatively.

We recommend that most patients with bilateral adrenal hyperplasia be treated with medical therapy, not adrenalectomy (Grade 1B). Blood pressure control is often inadequate with subtotal adrenalectomy, and the risks associated with bilateral adrenalectomy (including the need for lifelong glucocorticoid and mineralocorticoid replacement) outweigh the potential benefits.

For patients with either bilateral adrenal hyperplasia or confirmed unilateral adrenal aldosterone hypersecretion (who refuse or are not candidates for surgery), we recommend an aldosterone antagonist (eg, spironolactone or eplerenone) over other potassium-sparing diuretics (eg, amiloride, triamterene) as our first choice for pharmacologic therapy (Grade 1C).

Of the aldosterone antagonists, we suggest spironolactone as the first line drug (Grade 2C) and switch to eplerenone if side effects are limiting. Eplerenone is a more selective mineralocorticoid receptor antagonist than spironolactone, and may be associated with fewer side effects. However, it is more expensive, and there are no clinical trial data comparing efficacy.

For patients who do not tolerate spironolactone or eplerenone, we switch to a potassium-sparing diuretic, such as amiloride.

Serum potassium, creatinine, and blood pressure should be monitored frequently during the first four to six weeks of medical therapy (especially in patients with renal insufficiency or diabetes mellitus). Clinical course and circumstances dictate the frequency of monitoring thereafter.

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