Approach Considerations
Among the major goals of therapy for primary aldosteronism are (1) normalization of blood pressure, (2) normalization of levels of serum potassium and other electrolytes, and (3) normalization of serum aldosterone levels. [24, 43]
The appropriate treatment for primary aldosteronism depends on its cause. Although hypertension (HTN) is frequently cured after unilateral adrenalectomy in patients with primary aldosteronism secondary to an adrenal aldosteronoma, the mean HTN cure rate is only 19% after unilateral or even bilateral adrenalectomy in patients with idiopathic adrenal hyperplasia (IAH). Therefore, medical management is the treatment of choice for the IAH variant of primary aldosteronism. (See the chart below.)
In patients with an aldosteronoma, medical therapy is used preoperatively to control blood pressure and correct hypokalemia, thus decreasing surgical risk. Medical therapy is also administered to patients with persistent HTN postoperatively, poor surgical candidates, and patients who refuse surgery.
In patients with heart failure who have secondary aldosteronism, aldosterone antagonism by spironolactone and eplerenone has been demonstrated to confer survival benefit. [44, 45]
A prospective study by Adler et al indicated that treatment of primary aldosteronism, either by adrenalectomy or mineralocorticoid antagonist, causes an increase in the insulin response to glucose, as well as a decrease in insulin clearance. Moreover, according to the investigators, this phenomenon does not result from changes in creatinine clearance or plasma cortisol. [46]
Pharmacologic Therapy
Calcium channel blockers
By inhibiting the intracellular calcium flux in the adrenocortical cells, the dihydropyridine calcium channel blockers reduce the production of aldosterone in response to a variety of stimulants, including potassium, corticotropin, and angiotensin-II.
Nifedipine is the most extensively studied of these medications; however, although nifedipine causes a significant improvement in patients with hypertension (HTN), it does not address the pathophysiology of the condition. The plasma renin activity (PRA), aldosterone levels, plasma volume, and serum potassium concentrations remain essentially unchanged while using nifedipine.
Mineralocorticoid antagonists
Mineralocorticoid antagonists, such as spironolactone, are inhibitory ligands to the mineralocorticoid receptor (MR). They achieve remarkable blood pressure control and normalization of plasma volume and serum potassium concentrations, particularly in patients with aldosteronomas. [47]
The salutary effects of spironolactone appear to be due mainly to its impact on salt and water balance rather than to its antagonism of aldosterone in the kidney. The combination of spironolactone and thiazides often provides even better blood pressure control than does spironolactone alone.
Because of the estrogenlike adverse effects of spironolactone, including impotence and gynecomastia, the incentive to develop a similarly effective antialdosterone agent without these adverse effects is considerable. Eplerenone is a selective antialdosterone agent that may fulfill this promise, because it is a specific aldosterone receptor antagonist that does not have the additional antiandrogen effects associated with spironolactone.
Glucocorticoids
In the subgroup of patients with glucocorticoid-remediable aldosteronism (GRA), the treatment of choice is the administration of the lowest possible dose of glucocorticoid that can be used to achieve adequate blood pressure control. Because of the potential adverse effects that can result from even subtle glucocorticoid excess, using short-acting glucocorticoids, such as prednisone and hydrocortisone (rather than dexamethasone), is generally best.
Other
ACE inhibitors and angiotensin receptor blockers (ARBs) are also potential treatment options. Less ideal medical treatment options include potassium-sparing diuretics, such as triamterene and amiloride, that are not mineralocorticoid antagonists. Amiloride acts at the level of the distal convoluted tubule but does not bind to mineralocorticoid receptors.
A few reports of the use of percutaneous injection of ethanol or acetic acid into aldosteronomas as a treatment modality exist; in these cases, the treatment was usually administered to patients for whom surgery was contraindicated. [48] This technique is neither popular nor well validated. Furthermore, it requires the technical expertise of a highly skilled interventional radiologist.
Considerations
Nonsurgical therapy is also a viable treatment option in patients who have lateralizable disease but who are poor surgical candidates because of other coexisting comorbidities. It is also a viable treatment option in the rare setting of bilateral functional adrenal adenomas that would otherwise require bilateral adrenalectomy.
Adrenal Surgery
Surgery is the treatment of choice for the lateralizable variants of primary aldosteronism, including typical aldosteronomas, renin-responsive adenomas (RRAs), and primary adrenal hyperplasia (PAH).
Preoperatively, once the biochemical and anatomic diagnoses are made and confirmed, the patient should be started on a 3- to 5-week course of spironolactone. This serves as an additional diagnostic tool (in confirming the diagnosis of primary aldosteronism) and as a means of predicting the blood pressure response that can be expected postsurgery.
An adrenalectomy can be performed via a formal laparotomy or by using a laparoscopic technique (with performance of the latter becoming increasingly common). The laparoscopic option now makes it possible to offer surgical therapy to relatively frail patients who would be unable to withstand a formal laparotomy. Ongoing studies are systematically evaluating the place of adrenal-conserving operations versus total unilateral adrenalectomy in these patients. [49]
Among the options being studied are (1) partial adrenalectomy, in which a wedge resection of the gland with the adenoma is performed along with aldosteronoma enucleation, and (2) medulla-sparing adrenalectomy, in which an attempt is made to retain the adrenal medullary tissue while removing the cortex.
Outcomes
About 60-70% of patients are rendered normotensive following curative surgery for aldosteronomas when evaluated 1 year postoperatively. Hypertension (HTN) typically does not resolve immediately postoperatively but, rather, over 3-6 months. (Although following surgery, virtually all patients with an aldosteronoma have significant reductions in aldosterone secretion and blood pressure and also demonstrate a correction of hypokalemia. [50, 51, 52, 53, 54] )
A retrospective study of 168 patients with primary aldosteronism who underwent an adrenalectomy found that HTN was cured or controlled in 77% of patients with a unilateral adenoma and in 68% of patients with aldosteronism who had no adenoma, but whose aldosterone-to-cortisol ratio was at least 5 times higher on the dominant side than on the nondominant side. [52]
The percentage of patients who remain normotensive 5 years postoperatively is about 53%. The resolution of HTN following adrenalectomy invariably occurs in the setting of a family history in which HTN is absent and/or when there has been preoperative use of 2 or fewer antihypertensives by the patient.
Adrenalectomy has very little utility in the setting of idiopathic adrenal hyperplasia (IAH). In reported cases in which surgery has unintentionally been performed on patients with IAH, the effects on blood pressure, hypokalemia, and aldosterone hypersecretion have been minimal, further underpinning the necessity of making a correct diagnosis before making a case for adrenalectomy.
Persistence of HTN following apparent surgical treatment of lateralizable disease is most common in patients older than 45 years, in those who had HTN for more than 5 years prior to surgery, and in persons who did not respond preoperatively to spironolactone. [52, 53]
Persistent HTN may be related to resetting of baroreceptors, established hemodynamic changes, structural changes in the blood vessels, or coincidental essential HTN.
Another possibility to consider in persistent HTN is an incomplete resection of the adenoma, with remaining remnant hyperplastic tissue. The coexistence of hypertensive nephrosclerosis in some patients with persistent HTN is also a distinct possibility. The coexistence of other secondary causes of HTN needs to be considered as well; renal artery stenosis is an important consideration.
A study by Pan et al indicated that in patients with primary aldosteronism who are treated with adrenalectomy, the incidence of new-onset atrial fibrillation (NOAF) is lower than in patients with essential hypertension. However, the investigators also reported that lower-dose mineralocorticoid antagonist therapy in study patients with primary aldosteronism did not have a significant impact on NOAF incidence compared with cases of essential hypertension. [55]
Preoperative and postoperative care
Prior to surgery, patients should receive at least 8-10 weeks of medical therapy in order to decrease blood pressure and to correct the metabolic syndromes that are often associated with primary aldosteronism.
Postoperatively, metabolic profiles should be closely monitored. Most patients do not develop permanent hypomineralocorticoidism and therefore do not require fludrocortisone replacement.
For patients who develop hypoaldosteronism, the symptoms may persist for a long time and may be akin to the delay observed in adrenal glucocorticoid recovery following chronic corticotropin suppression by exogenous steroids. However, if significant hyperkalemia develops, potassium supplements should be discontinued, and the patient can be started on furosemide at doses of 80-160 mg daily.
Diet
A low-salt diet, although helpful in achieving blood pressure control in primary aldosteronism, may be associated with false-negative results on biochemical testing.
A high-salt diet makes the achievement of blood pressure control more difficult and may cause false-positive results on biochemical testing.
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Magnetic resonance imaging (MRI) scan in a patient with Conn syndrome showing a left adrenal adenoma.
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Scintigram obtained by using iodine-131-beta-iodomethyl-norcholesterol (NP-59) in a 59-year-old man with hypertension shows fairly intense radionuclide uptake in the right adrenal tumor. At surgery, a Conn tumor was confirmed.
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Effects of main antihypertensives on the renin-angiotensin system.
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Potential causes of primary aldosteronism.
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Transitional zone adrenocortical steroids.
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Algorithm for screening for potential primary aldosteronism.
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Algorithm for confirmation of primary aldosteronism.
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Algorithm for distinguishing subtypes of primary aldosteronism.
Tables
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- Overview
- Presentation
- DDx
- Workup
- Approach Considerations
- Screening (First-Tier) Tests
- Confirmatory (Second-Tier) Tests
- Determination of Primary Aldosteronism Subtype (Third-Tier) Tests
- CT Scanning and MRI
- NP-59 Iodo-methyl-norcholesterol Scintigraphy
- Adrenal Venous Sampling
- Hydroxycorticosterone and Oxocortisol-Hydroxycortisol Assays
- Fludrocortisone Suppression Test
- Dexamethasone Suppression Test
- Metoclopramide (Reglan) Test
- Additional Laboratory Studies
- Angiotensin-II infusion test
- Histological Findings
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- Guidelines
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- Questions & Answers
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