Highlights & Basics
- Primary aldosteronism (PA) is the most common specifically treatable and potentially curable form of hypertension. It accounts for at least 5% of hypertensive patients, with most patients normokalemic.
- Approximately 30% have unilateral forms correctable by unilateral laparoscopic adrenalectomy, and 70% have bilateral forms in which hypertension responds well to aldosterone antagonist medications.
- Optimal detection involves screening all hypertensive patients using the plasma aldosterone/renin ratio, after controlling for factors (including medications) that may confound results.
- In patients with repeatedly elevated aldosterone/renin ratios, definitive confirmation or exclusion of diagnosis involves careful suppression testing with measurement of aldosterone response to fludrocortisone or to salt loading.
- Subtype differentiation for optimal treatment involves genetic testing for familial forms where suspected. If genetic testing is not performed or negative, adrenal CT and adrenal venous sampling should be performed to differentiate unilateral from bilateral forms.
Quick Reference
History & Exam
Key Factors
hypertension
Other Factors
age 20 to 70 years
nocturia, polyuria
lethargy
mood disturbance (irritability, anxiety, depression)
difficulty concentrating
paresthesias, muscle cramps
muscle weakness
palpitations
Diagnostics Tests
1st Tests to Order
plasma potassium
aldosterone/renin ratio
Other Tests to consider
fludrocortisone suppression test
saline infusion testing
oral salt loading
genetic testing
adrenal CT
adrenal venous sampling
adrenal MRI
posture stimulation testing
angiotensin II infusion testing
24-hour urinary hybrid steroids (18-hydroxy- and 18-oxo-cortisol)
dexamethasone suppression testing
Emerging Tests
¹¹ C-Metomidate PET/CT
Treatment Options
ongoing
unilateral PA
surgical candidates
not candidates for surgery
bilateral PA (excluding familial hyperaldosteronism type I)
no adrenal lesion ≥2.5 cm
adrenal lesion ≥2.5 cm
Definition
Classifications
Pathologic classification
- Aldosterone-producing adenoma (APA): a benign adrenocortical tumor of at least 10 mm in diameter autonomously producing aldosterone.Image APAs may be further subclassified according to whether they are angiotensin-unresponsive (as in the classic Conn tumor) or angiotensin-responsive, in which responsiveness is defined as a rise in plasma aldosterone by at least 50% over basal during 2 or 3 hours of upright posture following overnight recumbency or during an infusion of angiotensin II.
- Aldosterone-producing nodule (APN): a benign adrenocortical lesion of less than 10 mm in diameter autonomously producing aldosterone.
- Aldosterone-producing adrenocortical carcinoma (APACC): a malignant adrenocortical tumor autonomously producing aldosterone.
- Other unilateral forms: one adrenal excessively and autonomously producing aldosterone, but with no discrete tumor identified on pathologic exam. Instead, the adrenal is shown to contain either one or multiple aldosterone-producing micronodules (APM or MAPM) that stain positive for CYP11B2 by immunohistochemistry but are not distinguishable from the surrounding cortex by hematoxylin-eosin staining. More rarely, aldosterone-producing diffuse hyperplasia (APDH) shows a broad continuous region of hyperplastic, CYP11B2-positive zona glomerulosa cells.
- Bilateral forms: both adrenals affected by diffuse and/or nodular hyperplasia and excessively and autonomously producing aldosterone; includes both non-glucocorticoid-remediable (idiopathic) and glucocorticoid-remediable forms. Rarely, bilateral hyperplasia is macronodular with autonomous secretion of cortisol more often than of aldosterone.
Functional (treatment-oriented) classification
- Unilateral PA:
- Includes APA, APN, APACC, and unilateral (or primary) adrenal hyperplasia.
- Bilateral PA:
- Non-glucocorticoid-remediable: includes bilateral (idiopathic) adrenal hyperplasia which is rarely macronodular (nonfamilial, familial hyperaldosteronism type II, and familial hyperaldosteronism type III) and bilateral APA.
- Glucocorticoid-remediable (familial hyperaldosteronism type I).
Familial classification
- Familial hyperaldosteronism type I (FH-I; glucocorticoid-remediable; associated with hybrid gene).
- Familial hyperaldosteronism type II (FH-II; nonglucocorticoid-remediable; associated with germ-line mutations of CLCN2).
- Familial hyperaldosteronism type III (FH-III; nonglucocorticoid-remediable; associated with germ-line mutations of KCNJ5).
- Familial hyperaldosteronism type IV (FH-IV; nonglucocorticoid-remediable; associated with germ-line mutations of CACNA1H).
- Apparently nonfamilial PA (without known affected relatives).
Vignette
Common Vignette 1
Common Vignette 2
Other Presentations
Epidemiology
Etiology
Pathophysiology
Images
Aldosterone-producing adenoma
Hybrid CYP11B1/CYP11B2 gene responsible for ACTH-regulated aldosterone overproduction in FH-I
CT showing lesion in right adrenal gland in patient with right aldosterone-producing adenoma
CT showing lesion in right adrenal gland in patient with bilateral adrenal hyperplasia
Adrenal venous sampling results from patient with left aldosterone-producing adenoma
Diagnostic Approach
Screening
- Dietary salt restriction, concomitant malignant or renovascular hypertension, pregnancy (in which high levels of progesterone antagonize aldosterone action at the mineralocorticoid receptor), and treatment with diuretics (including spironolactone), dihydropyridine calcium channel antagonists, angiotensin-converting enzyme (ACE) inhibitors, or angiotensin receptor antagonists can all lead to false-negative ratios by stimulation of renin secretion.[6] [71] [72][74] [75] [76][77] [78]
- Because potassium is a powerful chronic regulator of aldosterone secretion, hypokalemia may also be associated with false-negative ratios.[73]
- False-positives can occur in premenopausal women during the luteal phase of the menstrual cycle, and also in women receiving estrogen-containing contraceptive agents or hormone replacement therapy, but only when renin is measured as direct active renin concentration and not as plasma renin activity.[80] [81] [82]
- False-positives may also be seen in patients with impaired renal function (renin production is reduced, whereas any associated hyperkalemia tends to elevate aldosterone), in advancing age (during which production of renin falls more quickly than that of aldosterone), and in familial hyperkalemic hypertension, also known as pseudohypoaldosteronism type II or Gordon syndrome.[10] [72] [83]
- Treatment with antidepressants of the selective serotonin reuptake inhibitor (SSRI) class lowers the aldosterone/renin ratio, but whether they can cause false-negatives in patients with PA remains uncertain.[84]
Confirmation of diagnosis
Subtype differentiation
- If FH-I is suspected (for example, on the basis of early onset of PA or a family history of early onset hypertension, PA, or stroke), genetic testing of peripheral blood for the hybrid gene should be performed before going on to other tests aimed at subtype differentiation, as a positive genetic test will make them superfluous. Because presence of the hybrid gene is diagnostic for FH-I, testing for it has virtually supplanted the tedious and less reliable biochemical methods of diagnosing this subtype (e.g., demonstration of marked, persistent suppression of plasma aldosterone during several days of dexamethasone administration).[91] [92] [93] The great majority of patients with PA, however, will test negative for the hybrid gene, leaving the more difficult task of separating the unilateral tumorous forms from varieties of bilateral adrenal hyperplasia (BAH). In patients with early onset PA who test negative for the hybrid gene, consideration should be given for genetic testing for mutations in CLCN2, KCNJ5, and CACNA1H for diagnosis of FH-II, FH-III, and FH-IV respectively.[41]
- Adrenal CT scanning is recommended in all patients to confirm subtype and exclude adrenocortical carcinoma.[10] [28] [41] It is usually able to detect aldosterone-producing carcinomas because of their relatively large size (usually >3 cm) but frequently misses aldosterone-producing adenomas (which have an average size of approximately 1 cm).[9] CT may be misleading, as it cannot distinguish aldosterone-producing adenomas from nonfunctioning nodules.[6] [27] [71] [94] [95] Similar limitations apply to adrenal MRI.[96]
- Responsiveness of plasma aldosterone (defined as a rise of at least 50% over basal) during 2 or 3 hours of upright posture following overnight recumbency or during angiotensin II infusion was once considered specific for BAH among patients with PA.[97] [98] However, similar findings are also observed in the angiotensin II-responsive variety of aldosterone-producing adenoma, which accounts for over 50% of aldosterone-producing adenomas in some series.[4] [99] [100] Examination of the aldosterone response to posture in patients with PA is nevertheless worthwhile, as its absence narrows the diagnosis to angiotensin II-unresponsive aldosterone-producing adenoma or FH-I in most cases. Hybrid steroid levels (18-hydroxy- and 18-oxo-cortisol) are elevated in FH-I and angiotensin II-unresponsive aldosterone-producing adenoma, and are useful evidence suggesting one or the other of these two conditions. However, they are not widely available, and because they are normal in both BAH and angiotensin II-responsive aldosterone-producing adenoma, they do not distinguish unilateral from bilateral PA.[92] [99] [100]
- Nuclear imaging using positron emission tomography-computed tomography (PET-CT) with labelled metomidate as a ligand of CYP11B1 and CYP11B2 has been proposed to be a viable alternative to AVS, or as an adjunct to AVS in difficult cases.[105] [106] In this protocol dexamethasone pretreatment is used to suppress adrenocorticotropic hormone and CYP11B1 expression. The short half-life and lack of specificity for CYP11B2 of the currently used isotope limits the widespread application and reliability of this technique, however, work is ongoing to find alternatives.
Risk Factors
History & Exam
Tests
Differential Diagnosis
Essential hypertension (HTN)
Differentiating Signs/Symptoms
- No differentiating signs or symptoms.
Differentiating Tests
- Aldosterone/renin ratio will be normal if performed off interfering medications. May be elevated if patient receiving medications (such as beta-blockers) that cause false positives, in which case test should be repeated after such medications are withdrawn for at least 2 (and preferably 4) weeks.
- A normal ratio in a patient receiving medications that can cause false positives makes primary aldosteronism (PA) highly unlikely.
- In a minority of cases of PA, there is unprovoked hypokalemia.
Thiazide-induced hypokalemia in patient with essential HTN
Differentiating Signs/Symptoms
- History of use of thiazides.
Differentiating Tests
- Aldosterone/renin ratio will be normal after correcting hypokalemia and withdrawing thiazide for at least 6 weeks.[72]
Renal artery stenosis
Differentiating Signs/Symptoms
- Known renal artery stenosis, history of arterial disease elsewhere, or risk factors for atherosclerosis (e.g., smoking, diabetes mellitus, and hyperlipidemia).
Differentiating Signs/Symptoms
- Family history of this syndrome. Hereditary form usually presents in childhood.
- History of excessive consumption of licorice, which can lead to an acquired form.
Hypertensive forms of congenital adrenal hyperplasia
Differentiating Signs/Symptoms
- Family history of congenital adrenal hyperplasia due to 11beta-hydroxylase or 17alpha-hydroxylase deficiency.
- Usually presents in childhood.
- History of either virilization (in the case of 11beta-hydroxylase deficiency) or feminization (in the case of 17alpha-hydroxylase deficiency).
Differentiating Tests
- Although patients are usually hypokalemic and have suppressed renin levels, aldosterone levels are also low and the aldosterone/renin ratio usually is normal.
- In 11beta-hydroxylase deficiency, plasma cortisol and corticosterone are low, whereas basal or adrenocorticotropic hormone stimulated levels of deoxycorticosterone and 11-deoxycortisol are elevated.
Differentiating Signs/Symptoms
- Family history of this syndrome (but can be acquired).
- May be associated with androgenization.
Differentiating Tests
- Although patients are usually hypokalemic and have suppressed renin levels, aldosterone levels are also low and the aldosterone/renin ratio usually is normal.
Ectopic adrenocorticotropic hormone syndrome
Differentiating Signs/Symptoms
- Clinical findings of underlying tumor.
- Clinical findings due to raised cortisol levels (Cushing syndrome) including ecchymoses, muscle weakness, and diabetes mellitus.
Differentiating Tests
- Although patients are usually hypokalemic and have suppressed renin levels, aldosterone levels are also low and the aldosterone/renin ratio usually is normal.
- Evidence of underlying tumor on imaging studies.
Differentiating Signs/Symptoms
- Family history of this syndrome.
- Exacerbation of HTN and development of hypokalemia during pregnancy.
Screening
Screening for PA in people with hypertension
Familial hyperaldosteronism type I (FH-I)
- FH-I progresses through an asymptomatic (including normotensive) phase
- The implications of missing the diagnosis of this condition (which can lead to severe, resistant hypertension and early death from hypertensive stroke) are considerable.
Familial hyperaldosteronism type II (FH-II)
Familial hyperaldosteronism type III (FH-III)
Familial hyperaldosteronism type IV (FH-IV)
Familial hyperaldosteronism of unknown genetic etiology
Treatment Approach
Surgical treatment of PA
Postoperative treatment
Medical treatment of PA
Treatment for familial hyperaldosteronism type I
Treatment for other types of familial hyperaldosteronism
Treatment Options
unilateral PA
surgical candidates
unilateral laparoscopic adrenalectomy
Comments
- Unilateral adrenalectomy in carefully selected patients after a full workup provides a high chance of biochemical cure of primary aldosteronism (PA; 70% cured and 100% improved, as judged by postoperative fludrocortisone suppression testing), including cure of hypokalemia in all patients in whom it was present preoperatively.[107] [115] [116] [117] Hypertension is cured in 50% to 60% of fully worked-up patients, and improved in all remaining patients.[115] [116] [117] Less than 20% of patients require equivalent or increased medication doses after surgery.[104]
- Almost always, the entire adrenal is removed - even when an apparent adenoma is seen on CT scanning or on visualization of the gland.
- Laparoscopic adrenalectomy is associated with shorter hospital stays and fewer complications.[118]
- Immediately before surgery, potassium supplementation should be withdrawn, aldosterone antagonists discontinued, and other antihypertensive therapy reduced, if appropriate.
- Postoperative intravenous fluids should be given as normal saline without potassium chloride. A generous sodium diet should be recommended to avoid the hyperkalemia due to chronic contralateral adrenal gland suppression.[6] In rare instances, temporary fludrocortisone therapy may be required.
- Successful removal of an aldosterone-producing adenoma during pregnancy has been rarely reported.[120] Although case reports suggest the optimal time for surgery is during the middle trimester, it is clearly preferable when possible to postpone surgery in patients found to have an aldosterone-producing adenoma during pregnancy until after delivery.
preoperative aldosterone antagonists
Primary Options
- spironolactone
12.5 to 50 mg orally once daily or in 2 divided doses, higher doses have been reported, maximum 200 mg/day
- spironolactone
Secondary Options
- amiloride
2.5 to 15 mg orally once daily or in 2 divided doses, higher doses have been reported, maximum 40 mg/day
- amiloride
- eplerenone
25 to 100 mg orally once daily or in 2 divided doses, maximum 100 mg/day
- eplerenone
Comments
- For surgical candidates with severe hypertension and left ventricular hypertrophy (LVH) pre-surgery, spironolactone is the drug of first choice, with amiloride or eplerenone (in countries where available as a subsidized treatment for primary aldosteronism) reserved mainly for those who develop sex-steroid-related adverse effects.
- Overtreatment can cause volume contraction with prerenal failure, raising creatinine levels and causing life-threatening hyperkalemia.
- In patients with reduced renal glomerular function, concurrent administration of a low-dose potassium-wasting diuretic can be helpful to avoid hyperkalemia, but potassium and creatinine levels should still be carefully monitored.[6]
- Hyperkalemia is more likely in patients who have renal dysfunction or are taking other potassium-retaining agents such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin-II receptor antagonists, or nonsteroidal anti-inflammatory drugs (NSAIDs).
- Spironolactone can be associated with sex-steroid-related adverse effects, including gynecomastia and loss of libido, menstrual irregularities, and aggravation of breast fibrocystic change.[122] The incidence is dose-related. At 12.5 to 50 mg daily, the incidence of gynecomastia is approximately 10% to 15%.[107] [123]
postoperative aldosterone antagonists
Primary Options
- amiloride
2.5 to 10 mg orally once daily or in 2 divided doses
- amiloride
- spironolactone
12.5 to 25 mg orally once daily or in 2 divided doses
- spironolactone
- eplerenone
25 to 50 mg orally once daily or in 2 divided doses
- eplerenone
Comments
- Twenty percent of patients diagnosed with unilateral primary aldosteronism (PA) preoperatively show evidence of ongoing PA after surgery. If residual hypertension is due to aldosterone excess, it may respond well to aldosterone antagonist medication, but, as aldosterone levels have been reduced by surgery, caution is required.
- Eplerenone (in countries where available as a subsidized treatment for PA) is another option for patients in whom spironolactone is poorly tolerated and where amiloride is unable to achieve sufficient aldosterone blockade. Normality of the ratio, which depends on renin becoming unsuppressed, is the best guide to whether or not adequate blockade of aldosterone is being achieved.
- The lowest recommended dose should usually be used at introduction.
- Overtreatment can cause volume contraction with prerenal failure, raising creatinine levels and causing life-threatening hyperkalemia.
- In patients with reduced renal glomerular function, concurrent administration of a potassium-wasting diuretic in low dosage can be helpful to avoid hyperkalemia, but potassium and creatinine levels should still be carefully monitored.[6]
- Hyperkalemia is more likely in patients who have renal dysfunction or are taking other potassium-retaining agents such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin-II receptor antagonists, or nonsteroidal anti-inflammatory drugs (NSAIDs).
not candidates for surgery
aldosterone antagonists
Primary Options
- amiloride
2.5 to 15 mg orally once daily or in 2 divided doses, higher doses have been reported, maximum 40 mg/day
- amiloride
- spironolactone
12.5 to 50 mg orally once daily or in 2 divided doses, higher doses have been reported, maximum 200 mg/day
- spironolactone
- eplerenone
25 to 100 mg orally once daily or in 2 divided doses, maximum 100 mg/day
- eplerenone
Comments
- Indicated in patients with unilateral primary aldosteronism (PA) who prefer medical treatment or are not candidates for surgery.
- Because of its less potent aldosterone antagonist action and its much lower propensity to induce adverse effects, amiloride may be the drug of first choice in many patients, particularly those with milder degrees of hypertension, biochemical disturbance, and target organ effects (e.g., echocardiographically demonstrated LVH).
- Side-effects from amiloride are rare. Spironolactone can be associated with sex-steroid-related adverse effects, including gynecomastia and loss of libido, menstrual irregularities, and aggravation of breast fibrocystic change.[122] The incidence is dose-related. At 12.5 to 50 mg daily, the incidence of gynecomastia is approximately 10% to 15%.[107] [123]
- Amiloride and spironolactone can also be used in combination to minimize the dose of spironolactone and the risk of sex-steroid-related adverse effects.
- Eplerenone (in countries where available as a subsidized treatment for PA) is another option for patients in whom spironolactone is poorly tolerated and where amiloride is unable to achieve sufficient aldosterone blockade. Normality of the ratio, which depends on renin becoming unsuppressed, is the best guide to whether or not adequate blockade of aldosterone is being achieved.
- Overtreatment can cause volume contraction with prerenal failure, rising creatinine levels, and life-threatening hyperkalemia. In patients with reduced renal glomerular function, concurrent administration of a potassium-wasting diuretic in low dosage can be helpful to avoid hyperkalemia, but potassium and creatinine levels should still be carefully monitored.[6]
- Hyperkalemia is more likely in patients who have renal dysfunction or are taking other potassium-retaining agents such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin-II receptor antagonists, or nonsteroidal anti-inflammatory drugs (NSAIDs).
- Amiloride, spironolactone, and eplerenone have a slow onset of antihypertensive action. Benefit may not be apparent for 2 weeks, even months. If necessary, other antihypertensive agents with more rapid onset of action could be employed during this period, and then later reduced or withdrawn.
bilateral PA (excluding familial hyperaldosteronism type I)
no adrenal lesion ≥2.5 cm
aldosterone antagonists
Primary Options
- amiloride
2.5 to 15 mg orally once daily or in 2 divided doses, higher doses have been reported, maximum 40 mg/day
- amiloride
- spironolactone
12.5 to 50 mg orally once daily or in 2 divided doses, higher doses have been reported, maximum 200 mg/day
- spironolactone
- eplerenone
25 to 100 mg orally once daily or in 2 divided doses, maximum 100 mg/day
- eplerenone
Comments
- Lesions ≥2.5 cm should be considered for removal based on their malignant potential. Some centers use higher cutoffs of 3.0 cm or even 4.0 cm, but this increases the risk of missing a malignant lesion. CT should be repeated in 3 to 6 months and then annually to recognize growth which would suggest malignancy.
- Because of its less potent aldosterone antagonist action and its much lower propensity to induce adverse effects, amiloride may be the drug of first choice in many patients, particularly those with milder degrees of hypertension, biochemical disturbance, and target organ effects (e.g., echocardiographically demonstrated LVH).
- Side-effects from amiloride are rare. Spironolactone can be associated with sex-steroid-related adverse effects, including gynecomastia and loss of libido, menstrual irregularities, and aggravation of breast fibrocystic change.[122] The incidence is dose-related. At 12.5 to 50 mg daily, the incidence of gynecomastia is approximately 10% to 15%.[107] [123]
- Amiloride and spironolactone can also be used in combination to minimize the dose of spironolactone and the risk of sex-steroid-related adverse effects.
- Eplerenone (in countries where available as a subsidized treatment for primary aldosteronism [PA]) is another option for patients in whom spironolactone is poorly tolerated and where amiloride is unable to achieve sufficient aldosterone blockade. Normality of the ratio, which depends on renin becoming unsuppressed, is the best guide to whether or not adequate blockade of aldosterone is being achieved.
- Overtreatment can cause volume contraction with prerenal failure, rising creatinine levels, and life-threatening hyperkalemia. In patients with reduced renal glomerular function, concurrent administration of a potassium-wasting diuretic in low dosage can be helpful to avoid hyperkalemia, but potassium and creatinine levels should still be carefully monitored.[6]
- Hyperkalemia is more likely in patients who have renal dysfunction or are taking other potassium-retaining agents such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin-II receptor antagonists, or nonsteroidal anti-inflammatory drugs (NSAIDs).
- Amiloride, spironolactone, and eplerenone have a slow onset of antihypertensive action. Benefit may not be apparent for two weeks, even months. If necessary, other antihypertensive agents with more rapid onset of action could be employed during this period, and then later reduced or withdrawn.
laparoscopic adrenalectomy
Comments
- It is sometimes appropriate to consider the option of unilateral adrenalectomy in patients with bilateral forms of primary aldosteronism (PA) because both spironolactone and amiloride have been tolerated poorly even at low doses, or the dose of spironolactone required to control hypertension has produced adverse effects.
- For rare patients with marked, bilateral adrenal hyperplasia and severe, bilateral PA (including those with severe forms of familial hyperaldosteronism type III), bilateral adrenalectomy (often in 2 stages, to gauge the effect of unilateral adrenalectomy first) may be required to control hypertension and biochemical manifestations of PA.[16] [47]
- The aim of adrenalectomy is to reduce the mass of adrenal tissue that is excessively and autonomously producing aldosterone, and thereby bring about improvements in BP levels and marked reductions in the doses of aldosterone antagonist medications required to control hypertension. BP responses under these circumstances are much less predictable than in patients with unilateral PA.
- Laparoscopic adrenalectomy is associated with shorter hospital stays and fewer complications.[118]
- Immediately before surgery, potassium supplementation should be withdrawn, aldosterone antagonists temporarily discontinued, and other antihypertensive therapy reduced, if appropriate.
- Postoperative intravenous fluids should be given as normal saline without potassium. A generous sodium diet should be recommended to avoid the hyperkalemia due to chronic contralateral adrenal gland suppression.[6] In rare instances, temporary fludrocortisone therapy may be required. Plasma potassium levels should be monitored at least twice daily for the first 2 days.
- Successful removal of an aldosterone-producing adenoma during pregnancy has been rarely reported.[120] Although case reports suggest that the optimal time for surgery is during the middle trimester, it is clearly preferable to postpone surgery in patients with PA during pregnancy until after delivery where possible.
pre- and postoperative aldosterone antagonists
Primary Options
- amiloride
2.5 to 15 mg orally once daily or in 2 divided doses, higher doses have been reported, maximum 40 mg/day
- amiloride
- spironolactone
12.5 to 50 mg orally once daily or in 2 divided doses, higher doses have been reported, maximum 200 mg/day
- spironolactone
- eplerenone
25 to 100 mg orally once daily or in 2 divided doses, maximum 100 mg/day
- eplerenone
Comments
- It is highly desirable that hypertension and hypokalemia be controlled preoperatively. This usually involves treatment with an aldosterone antagonist. If not tolerated, other antihypertensive agents can be used.
- Recommencement of aldosterone antagonist medication postoperatively can usually be deferred for several weeks. The lowest recommended dose should be used initially, and electrolyte and renal function carefully monitored.
- Overtreatment can cause volume contraction with prerenal failure, rising creatinine levels, and life-threatening hyperkalemia. In patients with reduced renal glomerular function, concurrent administration of a potassium-wasting diuretic in low dosage can be helpful to avoid hyperkalemia.[6]
- Hyperkalemia is more likely in patients who have renal dysfunction or are taking other potassium-retaining agents such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin-II receptor antagonists, or nonsteroidal anti-inflammatory drugs (NSAIDs).
- Spironolactone can be associated with sex-steroid-related adverse effects, including gynecomastia and loss of libido, menstrual irregularities, and aggravation of breast fibrocystic change.[122] The incidence is dose-related. At 12.5 to 50 mg daily, the incidence of gynecomastia is approximately 10% to 15%.[107] [123]
- Eplerenone (in countries where available as a subsidized treatment for primary aldosteronism) is another option for patients in whom spironolactone is poorly tolerated and where amiloride is unable to achieve sufficient aldosterone blockade. Normality of the ratio, which depends on renin becoming unsuppressed, is the best guide to whether or not adequate blockade of aldosterone is being achieved.
adrenal lesion ≥2.5 cm
unilateral laparoscopic adrenalectomy
Comments
- Lesions of this size should be considered for removal based on their malignant potential. Some centers use higher cutoffs of 3.0 cm or even 4.0 cm, but this increases the risk of missing a malignant lesion.
- Laparoscopic adrenalectomy is associated with shorter hospital stays and fewer complications.[118] Open adrenalectomy may be required, however, in the case of very large lesions.
- Immediately before surgery, potassium supplementation should be withdrawn, aldosterone antagonists discontinued, and other antihypertensive therapy reduced, if appropriate.
- Postoperative intravenous fluids should be given as normal saline without potassium chloride. A generous sodium diet should be recommended to avoid the hyperkalemia due to chronic contralateral adrenal gland suppression.[6] In rare instances, temporary fludrocortisone therapy may be required.
- Successful removal of an aldosterone-producing adenoma during pregnancy has been rarely reported.[120] Although case reports suggest that the optimal time for surgery is during the middle trimester, it is clearly preferable to postpone surgery in patients with primary aldosteronism during pregnancy until after delivery where possible.
pre- and postoperative aldosterone antagonists
Primary Options
- amiloride
2.5 to 15 mg orally once daily or in 2 divided doses, higher doses have been reported, maximum 40 mg/day
- amiloride
- spironolactone
12.5 to 50 mg orally once daily or in 2 divided doses, higher doses have been reported, maximum 200 mg/day
- spironolactone
- eplerenone
25 to 100 mg orally once daily or in 2 divided doses, maximum 100 mg/day
- eplerenone
Comments
- Where possible, hypertension and hypokalemia should be controlled preoperatively, ideally with an aldosterone antagonist.
- Postoperatively, residual hypertension usually responds well to recommencement of aldosterone antagonist medication. This is usually deferred for several weeks. The lowest recommended dose should be used initially.
- Overtreatment can cause volume contraction with prerenal failure, raising creatinine levels, and life-threatening hyperkalemia. In patients with reduced renal glomerular function, concurrent administration of a potassium-wasting diuretic in low dosage can be helpful to avoid hyperkalemia.[6]
- Hyperkalemia is more likely in patients who have renal dysfunction or are taking other potassium-retaining agents such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin-II receptor antagonists, or nonsteroidal anti-inflammatory drugs (NSAIDs).
- Spironolactone can be associated with sex-steroid-related adverse effects, including gynecomastia and loss of libido, menstrual irregularities, and aggravation of breast fibrocystic change.[122] The incidence is dose-related. At 12.5 to 50 mg daily, the incidence of gynecomastia is approximately 10% to 15%.[107] [123]
- Eplerenone (in countries where available as a subsidized treatment for primary aldosteronism) is another option for patients in whom spironolactone is poorly tolerated and where amiloride is unable to achieve sufficient aldosterone blockade. Normality of the ratio, which depends on renin becoming unsuppressed, is the best guide to whether or not adequate blockade of aldosterone is being achieved.
familial hyperaldosteronism type I
adults
glucocorticoids
Primary Options
- dexamethasone
0.125 to 0.5 mg orally once daily
- dexamethasone
- prednisone
2.5 to 5 mg orally once daily
- prednisone
Comments
- The risk of Cushingoid adverse effects is minimal because the required doses are low.[133] However, patients should still be monitored for clinical development of Cushingoid features. Periodic dual energy-ray absorptiometry (DXA) bone scanning should be performed to monitor the development of osteoporosis.
- Treatment should be avoided in children because of the potential to impair growth.
- For pregnant patients, low-dose glucocorticoids have been used successfully to control hypertension. Prednisone and hydrocortisone are thought to be preferable to dexamethasone. Alternatives to glucocorticoids are any of the recognized pregnancy-safe antihypertensives.
aldosterone antagonists
Primary Options
- amiloride
2.5 to 15 mg orally once daily or in 2 divided doses, higher doses have been reported, maximum 40 mg/day
- amiloride
- spironolactone
12.5 to 50 mg orally once daily or in 2 divided doses, higher doses have been reported, maximum 200 mg/day
- spironolactone
- eplerenone
25 to 100 mg orally once daily or in 2 divided doses, maximum 100 mg/day
- eplerenone
Comments
- Aldosterone antagonists are an alternative way to control hypertension in patients with familial hyperaldosteronism type I (FH-I).
- They may be used in patients who wish to avoid or have been unable to tolerate glucocorticoid treatment, or in whom such treatment is otherwise contraindicated.
- Because of its less potent aldosterone antagonist action and its much lower propensity to induce adverse effects, amiloride may be the drug of first choice in many patients, particularly those with milder degrees of hypertension, biochemical disturbance, and target organ effects (e.g., echocardiographically demonstrated LVH). Amiloride and spironolactone can also be used in combination to minimize the dose of spironolactone and the risk of sex-steroid-related adverse effects.
- Eplerenone (in countries where available as a subsidized treatment for primary aldosteronism) is another option for patients in whom spironolactone is poorly tolerated and where amiloride is unable to achieve sufficient aldosterone blockade. Normality of the ratio, which depends on renin becoming unsuppressed, is the best guide to whether or not adequate blockade of aldosterone is being achieved.
- Overtreatment can cause volume contraction with prerenal failure, rising creatinine levels, and life-threatening hyperkalemia. In patients with reduced renal glomerular function, concurrent administration of a potassium-wasting diuretic in low dosage can be helpful to avoid hyperkalemia.[6]
- Hyperkalemia is more likely in patients who have renal dysfunction or are taking other potassium-retaining agents such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin-II receptor antagonists, or nonsteroidal anti-inflammatory drugs (NSAIDs).
- Spironolactone can be associated with sex-steroid-related adverse effects, including gynecomastia and loss of libido, menstrual irregularities, and aggravation of breast fibrocystic change.[122] The incidence is dose-related. At 12.5 to 50 mg daily, the incidence of gynecomastia is approximately 10% to 15%.[107] [123]
children (pre- and peripubertal)
amiloride
Primary Options
- amiloride
2.5 to 7.5 mg orally once daily or in 2 divided doses
- amiloride
Comments
- Although glucocorticoids are highly effective in controlling hypertension and hypokalemia (where present) in familial hyperaldosteronism type I (FH-I), they may impair growth in children and their use should therefore be avoided in that patient group.
- Amiloride is a potassium-sparing diuretic and effective against hypertension and hypokalemia in patients with primary aldosteronism of all forms, including FH-I.[122] Although spironolactone is more effective in this respect than amiloride, its propensity to induce sex-steroid-related adverse effects and, in particular, to interfere with sexual development, renders its use in children undesirable.
- Overtreatment with amiloride can cause volume contraction with prerenal failure, rising creatinine levels, and life-threatening hyperkalemia. In patients with reduced renal glomerular function, concurrent administration of a potassium-wasting diuretic in low dosage can be helpful to avoid hyperkalemia.[6]
- Hyperkalemia is more likely in patients who have renal dysfunction or are taking other potassium-retaining agents such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin-II receptor antagonists, or nonsteroidal anti-inflammatory drugs (NSAIDs).
eplerenone
Primary Options
- eplerenone
consult specialist for guidance on dose
- eplerenone
Comments
- Eplerenone is a mineralocorticoid receptor antagonist that appears to be more selective for the receptor than spironolactone, and is, therefore, less likely to produce sex-steroid-related adverse effects such as gynecomastia and loss of libido, menstrual irregularities, and aggravation of breast fibrocystic change.[136] It may also be less likely to interfere with sexual development in children. Hence, it may be particularly suited for adult patients who have demonstrated intolerance to spironolactone because of sex-steroid-related adverse effects, or in children with primary aldosteronism (PA; including those with familial hyperaldosteronism type I).
- Eplerenone is already available and being used in clinical practice. However, indications for its use in different countries vary, and in some countries it is not approved for government-subsidized use in PA. Furthermore, data regarding its safety and efficacy in children with PA are lacking. Hence, it should remain a second-line option in this clinical context.
Emerging Tx
Aldosterone synthase inhibitors
Prevention
Primary Prevention
Secondary Prevention
Follow-Up Overview
Prognosis
Patients undergoing unilateral adrenalectomy for unilateral PA
Patients undergoing treatment with aldosterone antagonist medications
Patients with FH-I undergoing treatment with glucocorticoid medications
Monitoring
- BP, plasma electrolytes, and aldosterone and renin levels should be monitored every 6 to 12 months for clinical and biochemical evidence of recurrence (if cured postoperatively) or worsening (if improved but not cured) of PA. Patients should have an adrenal CT scan performed at 1 year postoperatively, and at 1- to 3-year intervals thereafter. This is because it has become apparent from careful postoperative follow-up of patients that some have a natural history of the disease in which the remaining adrenal slowly increases in size and becomes nodular, and which may turn out to be in a different class genetically. Occasionally, a new adenoma that may or may not be secreting aldosterone requires removal on size criteria alone (e.g., ≥2.5 cm, although some centers use higher cutoffs of 3.0 cm or even 4.0 cm), with preservation of an apparently normal limb of the adrenal if possible.
- Electrolytes and renal function should be monitored regularly (e.g., every 3 to 6 months), watching for development of hyperkalemia (more likely in patients who have renal dysfunction or are taking other potassium-retaining agents such as angiotensin-converting enzyme [ACE] inhibitors, angiotensin-II receptor antagonists, or nonsteroidal anti-inflammatory drugs [NSAIDs]), hyponatremia, and uremia. Renin levels can be used to guide doses of treatment, provided that the method is sound and results are not confounded by the use of other medications. In all patients with PA treated medically, CT of the adrenals should be performed annually at first and, if no nodular growth is seen, every 3 to 4 years, indefinitely.
- Hypertension is readily controlled by administering glucocorticoids in low doses. Control can be assessed by clinic, home, and ambulatory BP monitoring, and by periodic (e.g., yearly) echocardiographic assessments of left ventricular mass index and diastolic function. Patients should also be monitored for the development of glucocorticoid-induced osteoporosis by dual-energy x-ray absorptiometry (DXA) performed every 2 to 3 years.
Complications
Citations
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Key Articles
Referenced Articles
Guidelines
Diagnostic
Summary
Recommendations on the management of primary aldosteronism.Published by
Endocrine Society
Published
2016
Summary
A position statement and consensus outlining subtype differentiation, treatment, and complications of primary aldosteronism.Published by
Working Group on Endocrine Hypertension of the European Society of Hypertension
Published
2020
Summary
A position statement and consensus outlining the genetics, prevalence, and diagnosis of primary aldosteronism.Published by
Working Group on Endocrine Hypertension of the European Society of Hypertension
Published
2020
Treatment
Summary
This guideline provides a comprehensive overview of the management approach for primary aldosteronism.Published by
National Comprehensive Cancer Network
Published
2023
Summary
Recommendations on the treatment of primary aldosteronism.Published by
Endocrine Society
Published
2016
Summary
Diagnosis and treatment of primary aldosteronism.Published by
The Japan Endocrine Society
Published
2021
Summary
Clinical practice guidelines for the management of primary aldosteronism.Published by
Italian Society of Arterial Hypertension (SIIA)
Published
2020
Credits
Patient Instructions
- Lifestyle modification (including maintenance of a healthy weight, regular exercise, avoidance of alcohol excess, dietary salt restriction, and smoking cessation). Dietary salt restriction may reduce the dose of aldosterone blocking drug required.
- Self-monitoring of BP is usually appropriate.
- Importance of medication compliance.