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Hyperaldosteronism Treatment & Management

  • Author: George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London); Chief Editor: Stephen Kemp, MD, PhD  more...
 
Updated: Dec 10, 2015
 

Approach Considerations

Surgical excision of the affected adrenal gland is recommended for all patients with hyperaldosteronism who have a proven aldosterone-producing adenoma (APA). After surgical removal of an APA (aldosteronoma), a period of hypoadrenalism can occur. If this is not recognized, clinically significant hyponatremia and hyperkalemia may result.

Severe hypokalemia may require intravenous (IV) correction if the potassium concentration is less than 2.5 mmol/L or if the patient is clinically symptomatic. Once the potassium level is stable, sodium restriction and oral potassium supplements may be used as effectively as, or in addition to, potassium-sparing diuretics.

Spironolactone is the most effective drug for controlling the effects of hyperaldosteronism, though it may interfere with the progression of puberty. Newer drugs that possess greater specificity for the mineralocorticoid receptor than spironolactone does are becoming available.

Alternative medications for patients in whom aldosterone antagonists are contraindicated include amiloride and triamterene, as well as calcium channel antagonists and alpha-adrenergic antagonists (especially alpha1 -specific agents such as prazosin and doxazosin); in patients with angiotensin II–responsive disease, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are indicated.

Patients receiving medical treatment for hyperaldosteronism must be transferred to a physician with experience in managing such cases (eg, an endocrinologist, a cardiologist, or a nephrologist).

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Pharmacologic Therapy

Idiopathic hyperaldosteronism

Although bilateral adrenalectomy (see below) corrects hypokalemia in patients with idiopathic hyperaldosteronism (IHA), it has not been shown to be effective at controlling blood pressure, with cure rates less than 20%. This may be because this condition is typically insidious in its onset, allowing time for chronic hypertension to cause secondary damage. Furthermore, bilateral adrenalectomy commits the patient to lifelong replacement therapy with glucocorticoids and mineralocorticoids.

Control of hypokalemia and hypertension in IHA can be achieved with sodium restriction (to < 2 g/day) and administration of spironolactone or amiloride, but additional antihypertensives are often needed to achieve good control in this patient group. Pediatric drug doses are outlined in the Table below.

Table 2. Drugs Used in the Management of Idiopathic Hyperaldosteronism in Children (Open Table in a new window)

Drug Class Pediatric Dose
Spironolactone Aldosterone antagonist 0-10 kg: 6.25 mg/dose PO q12h



11-20 kg: 12.5 mg/dose PO q12h



21-40 kg: 25 mg/dose PO q12h



>40 kg: 25 mg PO q8h



Potassium canrenoate Aldosterone antagonist 3-8 mg/kg IV qd; not to exceed 400 mg
Amiloride Potassium-sparing diuretic 0.2 mg/kg q12h
Triamterene Potassium-sparing diuretic 2 mg/kg/dose q8-24h
Nifedipine Dihydropyridine calcium channel antagonist 0.25-0.5 mg/kg PO q6-8h
Amlodipine Calcium channel antagonist 0.05-0.2 mg/ day PO
Doxazosin Alpha1 -specific adrenergic antagonist 0.02-0.1 mg/day; not to exceed 4 mg
Prazosin Alpha1 -specific adrenergic antagonist 0.005 mg/kg test dose, then 0.025-0.1 mg/kg/dose q6h; not to exceed 0.5 mg/dose

 

Spironolactone is generally considered first-line therapy for patients with BAH at doses ranging between 25-400 mg/d (usually 12,5-50 mg/d). It is a nonselective, competitive mineralocorticoid receptor antagonist that is structurally similar to progesterone and metabolized in the liver to active metabolites. Additionally, spironolactone also acts as an antagonist of the androgen receptor, a weak antagonist of the glucocorticoid receptor, and an agonist of the progesterone receptor. These receptor-mediated actions also result in the associated adverse effects of spironolactone including hyperkalemia, hyponatremia, gynecomastia, impotence, menstrual disturbances and breast tenderness in women, hirsutism, and decreased libido. It should be used with caution in peripubertal children.[19, 20]

Gynecomastia is one of the major side effects of spironolactone in men and occurs in a dose-dependent manner in approximately 7% of cases with doses of less than 50 mg/d and as many as 50% of cases with doses of more than 150 mg/d. Spironolactone-mediated inhibition of central sympathetic nervous system activity has been suggested to be an important mechanism underlying its antihypertensive effects in patients with resistant hypertension.[24, 41]

Patients unable to tolerate spironolactone can be treated with eplerenone, a more expensive but selective mineralocorticoid receptor blocker with fewer antiandrogenic effects. Eplerenone is derived from spironolactone and considered a selective mineralocorticoid receptor antagonist with limited crossreactivity for the androgen and progesterone receptors, thus lacking many of the significant sexually-related adverse effects known to be associated with the use of spironolactone. However, eplerenone has a low affinity for the mineralocorticoid receptor and is less efficient than spironolactone with respect to BP lowering in patients with mild-to-moderate hypertension; thus, higher doses of eplerenone are needed to achieve the same effect as spironolactone (usually 25-50 mg twice daily).

The difference in response is likely due to pharmacologic differences, as metabolites of spironolactone are biologically active and have relatively long half-lives, whereas eplerenone has a relatively short half-life of approximately 4 hours, and its metabolites are inactive.[21]

Hyperkalemia is probably considered the most concerning adverse effect of mineralocorticoid receptor antagonist therapy, with a rate of 2-12%. In medically treated patients, it can occur late in therapy, often following years of mineralocorticoid receptor blocker administration, and may require either a decrease in the dose or addition of diuretics.[20]

Canrenone is an active metabolite of spironolactone with a long half-life, which is currently available only in Europe. Canrenone has been shown to improve diastolic function in patients with primary hypertension independently of effects on BP and LV mass regression, suggesting a direct myocardial effect. Both canrenone and potassium canrenoate, its open E-ring water soluble congener, might be considered, in that they possibly have fewer sex steroid-related side effects.

Amiloride and triamterene may be used instead of spironolactone. They have a direct effect on the renal tubule, impairing sodium reabsorption in exchange for potassium and hydrogen.

Familial hyperaldosteronism type I (GRA)

In adult patients with familial hyperaldosteronism (FH) type 1 (FH-I), or glucocorticoid-remediable aldosteronism (GRA), control of hypertension can be achieved through treatment with physiologic doses of dexamethasone. In general, the lowest dose of glucocorticoid that normalizes the BP should be used (for example, 0.125–0.5 mg of dexamethasone or 2.5–5 mg of prednisolone per day), to avoid the risk the of Cushingoid side-effects. In children, however, dexamethasone is best avoided because of its adverse effects on growth and bone density. Hydrocortisone has a short half-life (a typical dose is 10-12 mg/m2) and is a better choice but is not as efficient at reducing mineralocorticoid levels. Amiloride may be a preferred option because it avoids the potential problems of growth retardation associated with the use of glucocorticoids and potential adverse effects resulting from blockade of sex steroid receptors by spironolactone.

For children receiving long-term treatment with glucocorticoids, consultation with a pediatric endocrinologist is mandatory. GRA is associated with intracranial aneurysm and hemorrhagic stroke, and screening for intracranial aneurysms in patients with proven GRA is recommended. Amiloride and spironolactone have also been used as monotherapy for treating GRA.

Familial hyperaldosteronism type II

Patients with FH-II should be regularly observed, and treatment should be started when they develop hypertension. Treatment is with the same agents as for IHA. In the event that patients develop an adenoma, adrenal venous sampling should be considered to confirm lateralization of aldosterone hypersecretion before surgical removal.

In cases where gradient is lacking, medical treatment is recommended, with regular monitoring. Because patients with FH-II are not at increased risk of carcinoma, nonsurgical management may be worth considering.

Familial hyperaldosteronism type III

The clinical spectrum of FH-III widely varies. Hence, some patients may benefit from medical treatment, whereas others require bilateral adrenalectomy due to resistance to aggressive antihypertensive therapy, including aldosterone receptor blockade and amiloride.

Patients with APAs and gain of function mutations in CACNA1D can respond to treatment with a calcium channel blocker. Approved calcium channel blockers are weak antagonists of wild type CaV1.3, although potent and specific CaV1.3 inhibitors have been identified.[42] This type of compound might be useful in patients with KCNJ5 mutations because the latter leads to aldosterone production through increased calcium influx.[14] Data have shown that a number of dihydropyridine calcium channel blockers also have mineralocorticoid receptor antagonist activity at high doses, suggesting that these agents may target multiple mechanisms in control of hypertension.

Medical treatment of hypertension-perspectives

The development of second-generation potent aldosterone synthase inhibitors that exhibit selectivity for CYP11B2 over CYP11B, thus not affecting the glucocorticoid axis, is currently under investigation.[43]

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Adrenalectomy and Adenomectomy

Surgical excision of the affected adrenal gland is recommended for all patients with hyperaldosteronism who have a proven APA. Compared with an open approach, laparoscopic adrenalectomy significantly reduces operative morbidity, substantially shortens the hospital stay, and reduces blood loss. The risk of operative complications is related directly to the experience of the surgeon. Some surgeons prefer a posterior retroperitoneoscopic approach, especially for patients with smaller tumors (< 6 cm), prior abdominal surgery and lower BMI. Furthermore, recent data suggest that robotic procedures are associated with shorter hospital stay and less morbidity than laparoscopic adrenalectomy.[1]

Ensuring good control of BP and replenishment of potassium levels preoperatively is important. The literature on adults indicates that 30-60% of patients are cured when cure of hypertension is defined as BP lower than 140/90 mm Hg without antihypertensive medications. Most patients (80%–95%) experience an improvement in BP control. These rates are likely to be even better in children who have fewer independent factors that predispose to hypertension. BP typically normalizes or shows maximal improvement 1-6 months postoperatively, although it can continue to decrease for as long as 1 year after surgery. Hypokalemia resolves and aldosterone levels normalize in more than 98% of patients who undergo adrenalectomy for an APA.

Persistent hypertension despite control of hyperaldosteronism may be the result of misdiagnosis of unilateral aldosterone hypersecretion, coexistent essential hypertension, hypertensive vascular damage secondary to the hyperaldosteronism, or, rarely, another cause of secondary hypertension. Pheochromocytoma and renal artery stenosis have been reported in association with APA.

Postoperative hypoaldosteronism is common. Potassium replacement may produce hyperkalemia in this period. Patients may need supplementation with mineralocorticoids for several months after successful surgery. Immediate postoperative declines in blood pressure may not be sustained.

Imaging-guided ablation of the adrenal glands (radiofrequency or chemical ablation using ethanol or acetic acid) is an alternative minimally invasive therapy for aldosteronomas and other functioning adrenal tumors. The indications for imaging-guided ablation as opposed to surgical management include lack of fitness for surgery owing to multiple comorbid medical conditions, unresectable tumors, tumors that have already been treated with multiple debulking procedures and patient refusal of surgery.[44] A limited number of cases of isolated adenomectomy with preservation of the remaining normal adrenal tissue have been reported. However, subtotal adrenalectomy may not be appropriate in patients with primary hyperaldosteronism because unilateral adrenal hyperplasia accounts for 14-17% of all cases of unilateral PA, whereas the prevalence of cortical adenoma within cortical hyperplasia is estimated to be 6-24%.[2]

A limited number of cases of isolated adenomectomy with preservation of the remaining normal adrenal tissue have been reported. Transcatheter arterial ablation with high-concentration ethanol injection of APA has been reported.

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Diet

As noted (see above), patients being evaluated for hyperaldosteronism should have a high sodium intake. In adults, a daily sodium intake of 10 g or more is recommended; this amount can be reduced proportionately for children, depending on their size. Regular monitoring of potassium is important when sodium intake is increased in patients with suspected hyperaldosteronism because this measure may unmask hypokalemia.

Medical management of patients with established hyperaldosteronism should include salt restriction. This should include not adding salt to cooking and not having salt on the table. Ideally, patients should receive less than 2 g of sodium chloride per day. Problems with compliance may occur because this degree of restriction is often unpalatable to children.

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Activity

Patients with significant hypertension should be advised to avoid strenuous activity until blood pressure is under control because such activity may further exacerbate their problem.

Postoperative activity is governed by the type of surgery performed. Patients should avoid bathing or wetting their wounds until they have healed. Patients who have undergone laparotomy must avoid heavy lifting for 6 weeks after their operation. Patients who have undergone laparoscopic adrenalectomy need only restrict their activity while they are sore or until the wound heals.

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Consultations

Once screening indicates a possible diagnosis of hyperaldosteronism, referral to an endocrinologist is recommended for further assessment and management. Numerous causes of primary hyperaldosteronism in children and adolescents can be managed medically.[45]

Patients with severe or long-standing hypertension may require assessment by a cardiologist because hyperaldosteronism may lead to myocardial fibrosis. This problem is more likely to occur in adults, in whom the duration of disease is much greater.

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Long-Term Monitoring

Follow-up requirements depend on the cause of the hyperaldosteronism. Patients who are treated medically need regular follow-up to ensure adequacy of blood pressure control and treatment of hypokalemia. In children, doses must be adjusted as patients grow.

In cases of familial hyperaldosteronism, genetic counseling, provided at an age-appropriate level, is also important.

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Contributor Information and Disclosures
Author

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) Professor and Chair, First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children's Hospital, Greece; UNESCO Chair on Adolescent Health Care, University of Athens, Greece

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) is a member of the following medical societies: American Academy of Pediatrics, American College of Physicians, American Pediatric Society, American Society for Clinical Investigation, Association of American Physicians, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research, American College of Endocrinology

Disclosure: Nothing to disclose.

Coauthor(s)

Amalia Sertedaki, PhD Research Associate, Molecular Endocrinology Laboratory, Division of Endocrinology, Diabetes and Metabolism, First Department of Pediatrics, Aghia Sophia Children's Hospital, University of Athens Medical School, Greece

Disclosure: Nothing to disclose.

Eleni Magdalini Kyritsi, MD, PhD Clinical Resident in Endocrinology, Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, "Aghia Sophia" Children's Hospital, University of Athens Medical School, Greece

Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD Former Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas for Medical Sciences College of Medicine, Arkansas Children's Hospital

Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Acknowledgements

Antony Lafferty, MB ChB, FRACP Senior Lecturer of Pediatric Endocrinology, Monash University Department of Pediatrics, National Institutes of Health, Bethesda, MD, and Princess Margaret Hospital for Children, Perth, Western Australia

Antony Lafferty, MB ChB, FRACP is a member of the following medical societies: Endocrine Society

Disclosure: Nothing to disclose.

Lynne Lipton Levitsky, MD Chief, Pediatric Endocrine Unit, Massachusetts General Hospital; Associate Professor of Pediatrics, Harvard Medical School

Lynne Lipton Levitsky, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Diabetes Association, American Pediatric Society, Endocrine Society, Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Pfizer Grant/research funds P.I.; Tercica Grant/research funds Other; Eli Lily Grant/research funds PI; NovoNordisk Grant/research funds PI; NovoNordisk Consulting fee Consulting; Onyx Heart Valve Consulting fee Consulting

Thomas A Wilson, MD Professor of Clinical Pediatrics, Chief and Program Director, Division of Pediatric Endocrinology, Department of Pediatrics, The School of Medicine at Stony Brook University Medical Center

Thomas A Wilson, MD is a member of the following medical societies: Endocrine Society, Pediatric Endocrine Society, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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Steroid biosynthetic pathway.
Physiologic regulation of the renin-angiotensin-aldosterone axis.
Table 1. Factors affecting interpretation of ARR results
False Negative Results
Factor Aldosterone Renin ARR
Medications      
K-sparing diuretics ↑↑
K-wasting diuretics (Non-K-sparing diuretics, such as thiazides, induce renal potassium losses and reduce plasma potassium concentrations, leading to decreased aldosterone secretion.) →↑ ↑↑
ACE inhibitors ↑↑
Angiotensin receptor blockers ↑↑
DHPs (It is a shared opinion that dihydropyridinic calcium channel blockers do not significantly affect aldosterone secretion, mainly causing an increase in PRA, which rarely gives false negatives.) →↓
Other conditions
Hypokalemia →↑
Sodium-restricted diet ↑↑
Pregnancy ↑↑
Renovascular hypertension ↑↑
Malignant hypertension ↑↑
False Positive Results
Beta-adrenergic blockers ↓↓
Central alpha-2 agonists (eg, clonidine, alpha-methyldopa) ↓↓
NSAIDS ↓↓
Other conditions
Potassium loading →↓
Sodium-loaded diet ↓↓
Advancing age ↓↓
Renal dysfunction →↑
PHA-2
Luteal phase of menstrual cycle PRA: Unchanged
Antihypertensive Medications With Minimal Effect on the ARR
Prazosin, doxazosin, terazosin   ←→
Verapamil, hydralazine   ←→
Other medications
Renin inhibitors (Renin inhibitors raise the ARR if renin is measured as PRA [false positive] and lower it if measured as DAR concentration [false negative.]) ↑↓ ↑↓
SSRIs
OCPs (OCPs have little effect on ARR when renin is measured as PRA. Use of immunometric measurements of DAR rather than PRA may give false positive results. Subdermal etonogestrel has no effect on ARR.) ↓DAR
Liddle syndrome Normal
 



ARR, aldosterone-renin ratio; NSAIDs, non-steroidal anti-inflammatory drugs; K, potassium; ACE, angiotensin converting enzyme; ARBs, angiotensin II type 1 receptor blockers; DHPs, dihydropyridines; PHA-2, pseudohypoaldosteronism type 2; PRA, plasma renin activity; DAR, direct active renin; OCPs, oral contraceptive agents; SSRIs, selective serotonin reuptake inhibitors



Table 2. Drugs Used in the Management of Idiopathic Hyperaldosteronism in Children
Drug Class Pediatric Dose
Spironolactone Aldosterone antagonist 0-10 kg: 6.25 mg/dose PO q12h



11-20 kg: 12.5 mg/dose PO q12h



21-40 kg: 25 mg/dose PO q12h



>40 kg: 25 mg PO q8h



Potassium canrenoate Aldosterone antagonist 3-8 mg/kg IV qd; not to exceed 400 mg
Amiloride Potassium-sparing diuretic 0.2 mg/kg q12h
Triamterene Potassium-sparing diuretic 2 mg/kg/dose q8-24h
Nifedipine Dihydropyridine calcium channel antagonist 0.25-0.5 mg/kg PO q6-8h
Amlodipine Calcium channel antagonist 0.05-0.2 mg/ day PO
Doxazosin Alpha1 -specific adrenergic antagonist 0.02-0.1 mg/day; not to exceed 4 mg
Prazosin Alpha1 -specific adrenergic antagonist 0.005 mg/kg test dose, then 0.025-0.1 mg/kg/dose q6h; not to exceed 0.5 mg/dose
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