Hyperaldosteronism

Normal aldosterone physiology

Aldosterone participates in the homeostasis of circulating blood volume and serum potassium concentration; these, in turn, feed back to regulate aldosterone secretion by the zona glomerulosa of the adrenal cortex. Aldosterone secretion is stimulated by an actual or apparent depletion in blood volume detected by stretch receptors and by an increase in serum potassium ion concentrations; it is suppressed by hypervolemia and hypokalemia.

The mechanisms regulating aldosterone secretion are complex, involving the zona glomerulosa of the adrenal glands, the juxtaglomerular apparatus in the kidneys, the cardiovascular system, the autonomic nervous system, the lungs, and the liver (see the image below). The major factors stimulating aldosterone production and release by the zona glomerulosa are angiotensin II and the serum potassium concentration. The juxtaglomerular apparatus is the principal site of regulation of angiotensin II production.

ACTH stimulates aldosterone secretion in an acute and transient fashion but does not appear to play a significant role in the long-term regulation of mineralocorticoid secretion. The major inhibitors of the zona glomerulosa include circulating atrial natriuretic peptide (ANP) and, locally, dopamine. Although ANP levels are clearly increased in hyperaldosteronism, neither ANP nor dopamine has been implicated as a primary cause of clinically disordered aldosterone secretion.

Metoclopramide has been shown to increase aldosterone secretion, suggesting that dopamine may tonically inhibit aldosterone release. The physiologic roles of adrenomedullin and vasoactive intestinal peptide (VIP) on aldosterone secretion remain to be clarified, although both of these neuropeptides are produced in rat zona glomerulosa.

The synthesis of prorenin, its conversion to renin, and its systemic secretion are stimulated by blood volume contraction detected by stretch receptors, beta-adrenergic stimulation of the sympathetic nervous system, and prostaglandins I2 and E2. These processes are inhibited by volume expansion and ANP.

Renin converts angiotensinogen, a proenzyme synthesized in the liver, into the decapeptide angiotensin I, which is then converted in the lungs into the octapeptide angiotensin II by angiotensin-converting enzyme (ACE). Angiotensin II is both a stimulator of aldosterone secretion and a potent vasopressor. Angiotensin II is metabolized to angiotensin III, a heptapeptide that is also a stimulator of aldosterone secretion.

The synthesis and secretion of prostaglandins I2 and E2 and the normal function of the stretch receptors are dependent on the intracellular ionized calcium concentration. Renal prostaglandin secretion is stimulated by catecholamines and angiotensin II. The complex regulation of aldosterone synthesis and secretion provides several points at which disturbance in the regulation of aldosterone secretion may occur.

Aldosterone is synthesized from cholesterol in a series of 6 biosynthetic steps (see the image below). Only the last 2 steps are specific to aldosterone synthesis; the first 4 also apply to cortisol synthesis by the zona fasciculata. Consequently, a defect in one of the specific aldosterone synthetic enzymes does not lead to hypercortisolism and secondary ACTH-mediated adrenal hyperplasia.

The enzyme aldosterone synthase is encoded by the gene CYP11B2 and has 11β-hydroxylase, 18-hydroxylase, and 18-hydroxydehydrogenase activity. This gene is located on human chromosome arm 8q24.3-tel, close to the gene CYP11B1, which encodes 11β-hydroxylase, the enzyme that catalyzes the final step of cortisol synthesis. Mutations in these genes can result in a number of disorders of aldosterone synthesis (see Differentials).[4]

Aldosterone action on target tissues (eg, the distal renal tubule, sweat glands, salivary glands, and epithelium of the large intestine) is mediated via a specific mineralocorticoid receptor. Mineralocorticoid receptors exhibit equal affinity for mineralocorticoids and cortisol, yet the aldosterone receptors in the distal tubule and elsewhere are protected from cortisol-mediated activation by 11β-hydroxysteroid dehydrogenase type 2, which locally converts cortisol to inactive cortisone.

Primary aldosteronism

The term primary hyperaldosteronism (or primary aldosteronism [PA]) refers to a renin-independent increase in the secretion of aldosterone. This condition is principally a disease of adulthood, with its peak incidence in the fourth to sixth decades of life.

More than 90% of cases of PA are due either to an aldosterone-producing adenoma (APA), which accounts for around 35% of cases (30-40%), or to idiopathic hyperaldosteronism (IHA), which accounts for around 60% of cases (almost all of which are bilateral). Unilateral adrenal hyperplasia (UAH) is a rare cause of PA, accounting for 1-2% of cases. About 1% of patients present with adrenocortical carcinomas that are purely aldosterone-secreting and are usually large at the time of diagnosis; 1% present with familial hyperaldosteronism, and 1% present with an ectopic aldosterone-producing adenoma or carcinoma.[5]

Unilateral adrenal hyperplasia accounts for 14-17% of all cases of unilateral PA. The prevalence of cortical adenoma within cortical hyperplasia is estimated to be 6-24%. The clinical presentation and outcome of patients with unilateral primary hyperaldosteronism are similar regardless of the histopathologic diagnosis. Unilateral adrenocortical hyperplasia is rare.[6]

APAs (sometimes referred to as aldosteronomas) are usually benign encapsulated adenomas that are less than 2 cm in diameter. Most cases are solitary, although in as many as one third of cases, evidence exists of nodularity in the same adrenal gland, suggesting that the condition has arisen in a previously hyperplastic gland.

Patients with IHA have bilateral thickening and variable nodularity of their adrenal cortex. A wide spectrum of severity exists for this disorder, which may go undetected for long periods with no hypokalemia and only mild hypertension. It has been suggested that IHA arises as a result of an undetected adrenal cortex–stimulating factor. Alternatively, the disorder may arise as a result of an activating mutation in an adrenal cortex–specific gene. Neither hypothesis has been proven.

Inherited forms of primary hyperaldosteronism account for only 1% of cases but are more likely to occur during childhood years. These forms include familial hyperaldosteronism (FH) types I, II, and III.

Familial hyperaldosteronism type I

FH type I (FH-I), also referred to as glucocorticoid-remediable aldosteronism (GRA), may be detected in asymptomatic individuals during screening of the offspring of affected individuals, or patients may present in infancy with hypertension, weakness, and failure to thrive due to hypokalemia. FH-I is inherited in an autosomal dominant manner and has a low frequency of new mutations.

The first clinical description of GRA appeared in 1966, and the genetic mechanism was discovered in 1992. FH-I arises as a result of unequal crossing over of highly related CYP11B1 (the 11β-hydroxylase gene) and CYP11B2 (the aldosterone synthase gene) during meiosis, producing an anti-Lepore-type fusion product.[7, 8] This genetic rearrangement causes the expression of CYP11B2 to be placed under the control of the CYP11B1 promoter and the aldosterone synthesis to be abnormally regulated by ACTH rather than by the renin-angiotensin system.

The result is ACTH-dependent aldosterone production and production of 17-hydroxylated analogues of 18-hydroxycortisol under ACTH regulation from ectopic enzyme expression in the zona fasciculata. Bilateral hyperplasia of the zona fasciculata occurs, and high levels of novel 18-hydroxysteroids appear in the urine. Adenoma formation is rare, but patients do have a significant increase in incidence of cerebrovascular aneurysms, for which they require screening.

Familial hyperaldosteronism type II

FH type II (FH-II) is a non–glucocorticoid-suppressible inherited form of hyperaldosteronism that was first recognized as a distinct entity by Gordon et al, though cases had previously been described in the 1980s. Like FH-I, it is inherited in an autosomal dominant manner. In contrast to FH-I, some FH-II kindreds exhibit a high rate of adenoma formation.

The mechanism and gene locus have not yet been identified, though CYP11B and the renin and angiotensin II receptor genes have been excluded. However, linkage has been established for a number of families to band 7p22.[9, 10] It has also been speculated that FH-II is not a single disorder.

Familial hyperaldosteronism type III

FH-III is a rare autosomal dominant form of PA characterized by early-onset hypertension, nonglucocorticoid-remediable hyperaldosteronism, and hypokalemia. Germline heterozygous missense mutations of the KCNJ5 gene, encoding Kir3.4, a member of the inwardly rectifying K+ channel family, have been identified as a cause of FH-III. Thus far, 4 mutations (G151R, G151E, T158A, and I157S) have been reported in 6 families.[11, 12, 13]

The clinical phenotype of patients harboring the above mutations ranges from severe PA and hypertension refractory to medical treatment that requires bilateral adrenalectomy, to mild or moderate hypertension responsive to medical therapy. In some patients, adrenal hyperplasia has been described.

Various studies from different centers report a prevalence of somatic KCNJ5 mutations in sporadic APAs ranging from 30-65%.[11, 14, 15, 16] There are 2 recurrent mutations, G151R and L168R, reported by all studies, whereas there is one report of a 3-nucleotide deletion, the delI157.[17]

The affected residues of both the germline and the somatic mutations are in or near the selectivity filter of the Kir3.4 potassium channel and are highly conserved among different species. Electrophysiologic studies demonstrate that these mutations result in loss of channel selectivity, with increased Na+ conductance leading to membrane depolarization. In zona glomerulosa cells, membrane depolarization leads to opening of voltage activated Ca2+ channels, with activation of the calcium-signalling pathway, the major mediator of aldosterone production.

APAs with KCNJ5 mutations are more prevalent in females than males and in younger patients. They are also associated with higher preoperative aldosterone levels. They are not related with the tumor size, but they are related with higher aldosterone levels and lower K+ concentrations.

Transcriptome and real-time polymerase chain reaction (PCR) analyses demonstrate that APAs with KCNJ5 mutations exhibit increased expression of the CYP11B2 gene and its transcriptional regulator NR4A2, thus increasing aldosterone production. It has also been found that APAs with and without KCNJ5 mutations display slightly different gene expression patterns.[16] Another study reports KCNJ5 mRNA levels higher in the APAs with KCNJ5 mutations and significantly higher in APA than cortisol-producing adenomas and pheochromocytomas.[15]

Somatic mutations in ATP1A1 (gene that encodes the alpha-1 [catalytic] subunit of the Na+/K+ ATPase, a member of the P-type ATPase family), ATP2B3 (gene that encodes the plasma membrane calcium transporting ATPase 3 [PMAC3], another member of the P-type ATPase family), or CACNA1D (gene that encodes Cav1.3, the alpha subunit of an L-type voltage-gated calcium channel) are present in approximately 6%, 1% and 8% of all cases of an aldosterone-producing adenoma, respectively. More recently, de novo germline mutations in CACNA1D were reported in 2 children with a previously undescribed syndrome that featured PA and neuromuscular abnormalities.[18]

Secondary hyperaldosteronism

Secondary hyperaldosteronism is a collective term for a diverse group of disorders characterized by physiologic activation of the renin-angiotensin-aldosterone (R-A-A) axis as a homeostatic mechanism designed to maintain serum electrolyte concentrations or fluid volume. In the presence of normal renal function, it may lead to hypokalemia.

Secondary hyperaldosteronism can be divided into 2 categories, 1 with associated hypertension and 1 without. The former category includes renovascular hypertension, which results from renal ischemia and hypoperfusion leading to activation of the R-A-A axis. The most common causes of renal artery stenosis in children are fibromuscular hyperplasia and neurofibromatosis. Hypokalemia may occur in as many as 20% of patients.

Plasma renin activity (PRA) levels are often in the reference range, but elevated levels of PRA may be detected after provocation with a single dose of captopril 1 mg/kg. Renal ischemia is also thought to underlie the secondary hyperaldosteronism observed in malignant hypertension.

Hyperreninemia and secondary aldosteronism have also been reported in patients with pheochromocytoma, apparently as a result of functional renal artery stenosis. Renin-producing tumors are very rare, and very high levels of PRA (up to 50 ng/mL/h) are noted, frequently with an increased prorenin-to-renin ratio. The tumors are generally of renal origin and include Wilms tumors and renal cell carcinomas.

Hyperkalemia due to chronic renal failure also causes secondary hyperaldosteronism. Low sodium-to-potassium ratios can be measured in saliva and stool. Cyclosporine-induced hypertension in solid organ transplant patients may also involve a component of hyperaldosteronism.

Secondary hyperaldosteronism in the absence of hypertension occurs as a result of homeostatic attempts to maintain the sodium concentration or circulatory volume or to reduce the potassium concentration. Clinical conditions in which it may arise include diarrhea, excessive sweating, low cardiac output states, and hypoalbuminemia due to liver or renal disease or nephrotic syndrome. Secondary hyperaldosteronism may also occur developmentally in newborn infants (see below).

Increased mineralocorticoid dependency in the young

The mineralocorticoid dependency of sodium reabsorption is increased during infancy and childhood, peaking in the neonatal period before decreasing progressively with advancing age. This increase occurs because the reabsorption of sodium and water by the proximal tubule is least efficient in early life, resulting in an increased sodium and water load at the level of the distal renal tubule.

Because sodium and water resorption from the distal tubule is mediated by the R-A-A axis, the PRA is approximately 10-fold to 20-fold higher in a newborn infant than in an adult. Consequently, neonates show relative increases in aldosterone production rates (>300 µg/m2/day vs 50 µg/m2/day in an adult) and plasma aldosterone concentrations (80 pg/dL vs 16 pg/dL). These increases in early life explain why young infants exhibit profound clinical symptoms of hyperaldosteronism that gradually improve with advancing age.

The following is a summary of etiologies of hyperaldosteronism and conditions that mimic hyperaldosteronism:

Causes of primary hyperaldosteronism include the following:

• APA - High aldosterone, low PRA

• IHA - Responds to posture (bilateral adrenal hyperplasia)

• Primary adrenal hyperplasia - Responds to posture (unilateral disease)

• Chronic stress-induced hyperaldosteronism[19]

• FH-I (GRA) - Sustained suppression of aldosterone (< 4 ng/dL) with dexamethasone

• FH-II/FH-III - Familial (probably autosomal dominant)

Causes of secondary hyperaldosteronism include the following:

• Edema disorders (eg, cardiac failure and nephrotic syndrome) - High aldosterone, nonsuppressed PRA (>2 ng/mL)

• Renovascular hypertension

• Renin-producing tumors

• Pregnancy[20]

Causes of conditions that mimic aldosterone excess include the following:

• Congenital adrenal hyperplasia (11β-hydroxylase deficiency and 17α-hydroxylase deficiency) - Low aldosterone, low PRA, elevated steroid intermediates

• Primary glucocorticoid resistance - High glucocorticoid secretion unsuppressed by dexamethasone

• Deoxycorticosterone-secreting tumors - Elevated deoxycorticosterone levels

• Syndrome of apparent mineralocorticoid excess

• Liddle syndrome

• Gain of function mutation of mineralocorticoid receptor[21]

• Licorice ingestion

• Carbenoxolone

Hypokalemia may be precipitated by a diet that is rich in sodium or the concomitant administration of drugs that produce kaliuresis (including diuretics and carbenoxolone). Taking carbenoxolone or eating large quantities of licorice may result in hypokalemia because of the blockade of the target tissue enzyme that protects the aldosterone receptor from the relatively higher levels of circulating cortisol (apparent mineralocorticoid excess).

Primary hyperaldosteronism is a rare condition in children. The youngest child reported with an aldosterone-secreting adenoma was aged 3 years. Earlier use of hypokalemia as a diagnostic requirement, as advocated by some authorities, may have led to underrecognition of the contribution of primary hyperaldosteronism to hypertension.

The prevalence rate for PA in hypertensive patients varies between studies, ranging from 4.6% to 16.6% in reports using confirmatory tests to diagnose PA.[22] Patients with PA also make up 17-23% of the treatment-resistant hypertensive population.[23, 24, 25, 26, 27]

Most of the hyperaldosteronism observed in the general population is sporadic, with most cases due to bilateral adrenal hyperplasia. APAs are likely to be diagnosed earlier than IHA because they are more likely than IHA to produce early symptomatic hypertension and hypokalemia. APAs account for 40% of cases of primary hyperaldosteronism.

It is possible that the distinction between adenoma and hyperplasia is not as clear as was once assumed. In one third of cases, associated hyperplasia or nodules of the adjacent zona glomerulosa is present, implying that the adenoma may have arisen in previously hyperplastic tissue.

Inherited forms of primary hyperaldosteronism (ie, FH-I [GRA], FH-II, and a very rare form known as FH type III [FH-III]) account for approximately 1% of cases of primary hyperaldosteronism, though they are more likely to occur during childhood and adolescent years than other forms of primary hyperaldosteronism are.

Studies of secondary hyperaldosteronism have found that approximately 15% of adults who attend hypertension clinics have elevated PRA. Reliable figures for children are not readily available.

Age-, sex-, and race-related demographics

Because the 2 causes that account for about 99% of cases of primary hyperaldosteronism have a peak age of onset in adulthood, the less common causes account for a larger percentage of children with hyperaldosteronism. For this reason, children with apparent hyperaldosteronism should be evaluated for evidence of congenital defects of the R-A-A axis and inherited forms of hypermineralocorticoidism.

Data on adults suggest that hyperaldosteronism has a female preponderance. Equivalent information is not available for children, in whom primary hyperaldosteronism due to inherited syndromes is likely to represent a greater proportion of cases.

The literature on adults demonstrates that blacks are at significantly greater risk for hypertension-related morbidity and mortality than whites are. They are also more likely to develop low-renin hypertension, though no studies indicate that the prevalence of primary hyperaldosteronism is significantly higher in blacks.

The age of the patient and the duration of disease before diagnosis are the 2 most important prognostic factors. Adult studies have shown that hypertension is cured in 30-60% of cases and significantly improved in 40-70% of cases, postoperatively (see Treatment).[5, 28] This figure is likely to be higher in children because disease duration is shorter and the prevalence of other causes of hypertension is lower.

Primary hyperaldosteronism can result in substantial morbidity and mortality as a result of hypertensive vascular complications (hypertrophy followed by sclerosis of intimal smooth muscle), renal complications (sclerosis), and cardiac complications (hypertrophy followed by dilatation). Through early recognition and treatment of hypertension, these complications can be avoided in children.

A study by Lai et al indicated that patients with autosomal dominant polycystic kidney disease (ADPKD) have a high prevalence of PA and that ADPKD patients with PA have an increased overall risk of cardiovascular disease. Surrogate markers showed a greater indication of atherosclerosis in these patients than in ADPKD patients with normal plasma aldosterone levels. The study included 27 hypertensive ADPKD patients, nine of whom (33%) had PA.[29]

Appropriate medical or surgical intervention in PA results in long-term reduction in blood pressure and left ventricle (LV) mass via LV inward remodeling (eg, through a reduction in LV diameters and volume).[30] Moreover, a significant decrease in urinary albumin excretion at 6 months after treatment has been reported in patients with PA and associated microalbuminuria. Both adrenalectomy and mineralocorticoid receptor antagonists (MRAs) can reverse the intrarenal hemodynamic pattern that leads to the decline in glomerular filtration rate and increased proteinuria.[13, 31] Furthermore, surgical or medical management of PA results in improvement in the metabolic complications of PA, such as plasma glucose control, and quality of life as well.

A study by Rossi et al found that patients with PA caused by an aldosterone-producing adenoma had, following adrenalectomy, a long-term atrial fibrillation–free survival rate comparable to that of optimally treated primary hypertension patients. However, medically treated patients with IHA had a lower long-term rate. The study’s median follow-up period was 11.8 years. The report’s results, according to the investigators, demonstrate the importance that early identification of PA patients requiring adrenalectomy has in the prevention of incident atrial fibrillation.[32]

The Aldosteronoma Resolution Score (ARS) is currently the most accurate prediction model for complete resolution of hypertension after adrenalectomy, taking into account 4 preoperative clinical parameters: body mass index (BMI) of 25 kg/m2 or higher, female sex, duration of preoperative hypertension 6 years or longer, and number of preoperative antihypertensive medications (≤2). Each parameter receives a score of 1, with the exception of number of preoperative medications, which is scored by 2 points due to its relative significance in the prediction model. A score of 0-1 predicts a low likelihood of resolution, whereas patients with ARS scores of 4-5 have a high likelihood of resolution of hypertension after adrenalectomy.

Moreover, data suggest that the TT genotype of the CYP11B2 gene encoding aldosterone synthase predicts resolution of hypertension in patients undergoing adrenalectomy for aldosterone-producing adenoma.

Patients with GRA must undergo assessment of their cerebral circulation because this disorder is associated with a significant risk of cerebral vascular aneurysms. Provided that hypertension is well treated, morbidity and mortality should not be increased significantly.

Hypokalemia is more frequently observed in patients with adenomas, though it should not be considered a diagnostic feature of primary hyperaldosteronism, as was once thought. Patients with adenomas are more likely to develop this complication, as are patients who have milder disease but receive treatment with diuretics for their hypertension before the hyperaldosteronism is diagnosed.

Hypokalemic patients may experience neuromuscular symptoms such as weakness or paralysis, constipation, and polyuria and polydipsia because of an associated renal concentrating defect. Hypokalemia also impairs insulin secretion and can promote the development of diabetes mellitus.

Although cardiac fibrosis has been reported in adults with primary hyperaldosteronism, no such reports exist in children, possibly because of the shorter duration of disease at the time of diagnosis. Cardiac fibrosis has also been reported in rats treated with excessive amounts of mineralocorticoids, especially if hyperglycemia is also present. This effect can be ameliorated with amiloride. The role of aldosterone in diabetic heart disease has been questioned, and trials of mineralocorticoid antagonists in this condition have been initiated.

Patients with mild hyperaldosteronism must learn how to avoid foods that are high in sodium; such foods will exacerbate their hypertension and increase their tendency to develop hypokalemia.

Patients also should be informed that medications can lead to hyperkalemia and hypotension, particularly in the presence of intercurrent illness, and should be advised to see their pediatrician if these conditions develop.

Primary hyperaldosteronism may be asymptomatic, particularly in its early stages. When symptoms are present, they may be related to hypertension (if severe), hypokalemia, or both.

The spectrum of hypertension-related symptoms includes the following:

• Headaches

• Facial flushing

• If hypertension is severe, weakness, visual impairment, impaired consciousness, and seizures (hypertensive encephalopathy)

Hypokalemia can be precipitated by non–potassium-sparing diuretics or sodium loading. Symptoms of hypokalemia include the following:

• Constipation

• Polyuria and polydipsia (because of impaired renal concentrating ability)

• Weakness

• If the serum potassium is low enough, paralysis and disturbances of cardiac rhythm[3]

Hyperglycemia or frank diabetes mellitus is possible because insulin secretion is a potassium-dependent process that may be impaired by hypokalemia.

If secondary hyperaldosteronism is suspected as the cause of hypertension, the history should include questions about flushing, diaphoresis, anxiety attacks, and headaches (pheochromocytoma) and about hematuria and abdominal fullness (Wilms tumor or other renal tumor), in addition to the above symptoms.[33, 34]

For patients in whom secondary hyperaldosteronism is suggested, questions should be specifically directed at potential causes (eg, the presence and duration of swelling, the child’s exercise tolerance).

Information should be sought about a family history of essential hypertension and familial syndromes, including the following:

• Neurofibromatosis (associated with renal artery stenosis and pheochromocytoma)

• Multiple endocrine neoplasia (MEN) type 2 – This includes MEN 2A (parathyroid adenoma, medullary thyroid carcinoma [MTC], and pheochromocytoma) and MEN 2B (mucosal neuromas of eyelids, lips, and tongue with a long thin face, pheochromocytoma, and MTC)

• von Hippel-Lindau syndrome - Cerebellar hemangioblastoma; renal and pancreatic cysts and carcinoma; hemangiomas of the retina, liver, and adrenal glands; and pheochromocytomas

In any child or adolescent with significant hypertension, a thorough investigation into the cause is warranted. Hypermineralocorticoidism should be considered in any patient with associated hypokalemia, though it should not be excluded in the absence of hypokalemia. In patients with significant hypertension, blood pressure should be measured several times, preferably with an automated device after a supine rest.

Examination of the hypertensive patient should include the following:

• General examination – Be alert for dysmorphic features (eg, MEN 2B), evidence of neurofibromatosis type 1 (NF-1; ie, café-au-lait lesions, axillary freckling, short stature, and evidence of disease in parents), and features of Cushing syndrome (ie, obesity, short stature, striae, and hirsutism)

• Neck examination – Assess for a thyroid mass (MTC associated with MEN 2)

• Cardiovascular examination - Assess left ventricular muscle mass and exclusion of murmurs and pulse differential (eg, coarctation of the aorta); check for abdominal bruits (renal artery stenosis) and peripheral edema (secondary hyperaldosteronism)

• Abdominal examination – Look for masses (Wilms tumor), hepatomegaly (cardiac failure or liver disease), splenomegaly, and ascites

• Neurologic examination - Examine the eyes, and assess visual acuity (severe hypertension may interfere with vision); examine the eye grounds (looking for retinal angiomas [von Hippel-Lindau syndrome]); be alert for hypertensive retinopathy, which is of prognostic significance, including arterial narrowing, hemorrhages, cotton-wool spots, and papilledema; assess for Lisch nodules of the iris (NF-1)

• Strength assessment - Evaluation for weakness, focal neurologic signs, or impaired conscious state in a patient with severe hypertension, which requires urgent treatment and central nervous system (CNS) imaging to exclude infarction or hemorrhage

• Skin examination - In patients who have secondary hyperaldosteronism, look for evidence of NF-1

The main complications of primary hyperaldosteronism are hypertension and hypokalemia.

Hypertension due to hyperaldosteronism can damage many organs and organ systems, including the heart (hypertrophy and myocardial fibrosis), the blood vessels (vascular remodeling with medial and intimal hypertrophy and acceleration of atherogenesis), the eyes (arterial narrowing, retinal ischemia, and papilledema), the kidneys (progressive deterioration with nephrosclerosis), and the brain (hemorrhage).

When patients with untreated PA are compared with patients who have essential hypertension, the risk of previous myocardial infarction or acute coronary syndrome is increased approximately 2.5-fold, cerebrovascular event or transient ischemic attack is increased approximately 3–4-fold, sustained cardiac arrhythmia is increased approximately 5-fold, and peripheral arterial disease is increased approximately 3-fold.[27] Renal disease is also increased in patients with PA. The frequency of 24-hour microalbuminuria in patients with PA (both APA and IHA) is twice that of patients with essential hypertension. Renal insufficiency has been reported to occur in 7-29% of patients with PA, and proteinuria has been reported in 8-24%.[31]

Aggressive blood pressure control and early diagnosis and treatment of the underlying hyperaldosteronism minimize the risk.

Hypokalemia initially results in weakness, constipation, and polyuria; when it is more severe, it may cause cardiac arrhythmias. Patients receiving cardiac drugs are at greater risk for this complication. Hypokalemia also impairs insulin secretion and can promote the development of diabetes mellitus. Of note, hypokalemia should not be considered a diagnostic feature of primary hyperaldosteronism. In some studies, only a minority of patients with PA (9-37%) had hypokalemia.[28] Thus, normokalemic hypertension constitutes the most common presentation of the disease; hypokalemia is probably present in only the more severe cases.

Patients with adenomas are more likely to develop this complication, as are patients who have milder disease but receive treatment with diuretics for their hypertension before the hyperaldosteronism is diagnosed.

Evaluation of a patient in whom hyperaldosteronism is suggested has several distinct stages. The finding of hypertension, hypokalemia, or both most commonly precipitates the decision to screen. The presence of these 2 features together has a 50% predictive value.

Screening for PA is recommended for patients with Joint National Commission (JNC) stage 2 (>160–179/100–109 mm Hg), stage 3 (>180/110 mm Hg), or drug-resistant hypertension (defined as systolic BP >140 and diastolic BP >90 despite treatment with 3 hypertensive medications); hypertension and spontaneous or diuretic-induced hypokalemia; hypertension with adrenal incidentaloma; or hypertension and a family history of early onset hypertension or cerebrovascular accident at a young age (< 40 y); and all hypertensive first-degree relatives of patients with PA. Additionally, in patients younger than 20 years or those with a family history of PA or stroke at a young age (< 40 y), or with an onset at a young age (eg, < 20 y), genetic testing for glucocorticoid-remediable aldosteronism is suggested.[25, 28]

The first step in the workup entails confirming that hyperaldosteronism is present and, if it is not present, excluding other conditions that produce a similar picture. The next step involves differentiating primary causes of hyperaldosteronism from secondary causes.

Aldosterone-to-renin ratio

The aldosterone-to-renin ratio (ARR)—that is, the ratio of plasma aldosterone (expressed in ng/dL) to plasma renin activity (PRA, expressed in ng/mL/h)—is the most sensitive means of differentiating primary from secondary causes of hyperaldosteronism. It can be obtained under random conditions of sodium intake.

The principle behind this test is that as aldosterone secretion rises, PRA (which measures the rate of production of angiotensin I from endogenous angiotensinogen) in ex vivo testing should fall because of sodium retention. This negative feedback response should occur when the aldosterone levels are supraphysiologic for that individual patient, and PRA may fall well before plasma aldosterone is clearly increased.

Values obtained in the upright position (ie, with the patient standing for 2 h) are more sensitive than supine test results. Patients should be encouraged not to restrict salt intake and hypokalemia should be corrected before testing because low potassium suppresses aldosterone secretion. Most authors recommend an ARR of 20-40, whereas an ARR of at least 35 has 100% sensitivity and 92.3% specificity in diagnosing PA. Some investigators require elevated aldosterone levels in addition to elevated ARR for a positive screening test for PA (usually aldosterone >15 ng/dL). Against a formal cut-off level for aldosterone are the findings of several studies, indicating that 36–48% of individuals with PA have plasma aldosterone levels between 9–16 ng/dL and approximately 20% of individuals with unilateral autonomous adrenal aldosterone production have levels less than 15 ng/dL.[5, 25, 27, 28]

The most important factors that can interfere with the diagnostic reliability of the ARR test are drugs and renal impairment (Table below).[25, 28, 35] Beta blockers can reduce PRA, leading to a falsely elevated ARR, and dihydropyridine calcium antagonists (eg, nifedipine) can reduce aldosterone levels, potentially leading to a falsely normal ARR in some patients with primary hyperaldosteronism. Diuretics tend to induce secondary hyperaldosteronism. Spironolactone, an aldosterone receptor antagonist, can raise plasma renin levels.

Table 1. Factors affecting interpretation of ARR results (Open Table in a new window)

 

Spironolactone or eplerenone, along withdiuretics, should be withheld for 6 weeks before testing.

If necessary to maintain hypertension control, patients should be treated with other antihypertensive medications that have lesser effects on the ARR (ie, verapamil slow-release, hydralazine [with verapamil slow-release, to avoid reflex tachycardia], prazosin, doxazosin, terazosin). See Table above. It is a shared opinion that dihydropyridinic calcium channel blockers do not significantly affect aldosterone secretion, causing mainly an increase in PRA, which rarely gives false negatives.[36, 37]

Βeta-blockers, ACE inhibitors, selective serotonin reuptake inhibitors, and oral contraceptives have been shown to influence the results of the test. Ideal testing conditions involve discontinuation of such medications 2 weeks prior.

Patients should also eliminate products derived from licorice root because these can interfere with 11beta-hydroxysteroid dehydrogenase, producing a state of apparent mineralocorticoid excess.

Renal impairment can lead to a high ARR in patients without primary hyperaldosteronism because fluid retention suppresses PRA and hyperkalemia stimulates aldosterone secretion.

Renin assays should be sufficiently sensitive to measure levels as low as 0.2–0.3 ng/mL/h (DRC 2 mU/L).

Recent data suggest that the random urinary aldosterone-to-creatinine ratio (UACR) might enable the diagnosis of PA in concordance with the 24-hour urinary aldosterone level (Uald-24 h). The thresholds with the best sensitivity for a specificity of 90.6% of the UACR were 3 ng/mg and that of the Uald-24 h was 20.3 mcg, in a single study.[38]

After a positive screening test result, subsequent testing is directed at confirming aldosterone secretory autonomy and differentiating an APA, for which surgery is currently the first-line treatment, from idiopathic hyperaldosteronism (IHA), which is usually treated medically. The possibility of GRA, which accounts for approximately 1% of cases of primary hyperaldosteronism, should be kept in mind.

Tests for confirming autonomous aldosterone secretion

Currently, US and Japanese guidelines recommend confirmatory testing in the work-up of PA; however, no test is seen as the criterion standard because of insufficient evidence.

The saline infusion test can confirm autonomous aldosterone secretion. Other tests described include the measurement of urine aldosterone excretion during oral salt loading and the fludrocortisone suppression test. All tests rely on the principle that a lack of suppression of aldosterone excretion with an intravascular expansion is indicative of aldosterone production.

Saline infusion test

Patients stay in the recumbent position for at least 1 hour before and during the infusion of 2 liters of 0.9% saline intravenously (IV) over 4 hours, starting at 8:00–9.30 AM. Blood samples for renin, aldosterone, cortisol and plasma potassium are measured at time 0 and after 4 hours, with blood BP and heart rate monitored throughout the test. Postinfusion plasma aldosterone levels less than 5 ng/dL make the diagnosis of PA unlikely. In individuals without primary hyperaldosteronism, plasma aldosterone levels should fall to less than 10 ng/dL. Plasma aldosterone values higher than 10 ng/dL confirm primary hyperaldosteronism and levels 5-10 ng/dL may be considered borderline.

Cortisol levels are taken to exclude an adrenocorticotropic hormone (ACTH)–mediated rise in aldosterone. The modified saline infusion test, performed after dexamethasone administration (0.5 mg every 6 h for 2 consecutive days) to eliminate any ACTH effect on aldosterone secretion, has been shown to have higher sensitivity compared with the classic saline infusion test in one study.[39] Consider the risks of fluid expansion or hypokalemia in susceptible patients.

Oral salt loading test

Patients should increase their sodium intake to more than 6 g/d for 3 days with diet and sodium chloride tabs. Potassium supplementation and daily potassium measurements are required for patients with hypokalemia. Patients perform 24-hour urine collection starting on day 3 for sodium and aldosterone. Potassium supplementation and daily potassium measurements are required for patients with hypokalemia. A 24-hour urinary aldosterone excretion of more than 12 mcg/d is consistent with PA, whereas 24-hour urinary sodium of 200 mEq/24 h indicates adequate intake. This test should not be performed in patients with uncontrolled hypertension, congestive heart failure, or arrhythmias. Renal insufficiency may confound the interpretation of the results (false negative).

Captopril test

The captopril test has also been used for screening. Its use is based on the principle that inhibition of angiotensin II production should not affect the autonomous secretion of aldosterone in PA. Patients receive 25–50 mg of oral captopril after sitting or standing for 1 h. Plasma aldosterone concentration, renin, and cortisol levels are measured before captopril administration and 1 or 2 hours after. Plasma aldosterone concentration is suppressed by 30% or more if primary hyperaldosteronism is not present. ARR is more than 30–50, plasma aldosterone concentration remains elevated (≥8.5 ng/dL), and renin remains suppressed in primary hyperaldosteronism. Differences may be seen between patients with APA and those with IHA, in that some decrease in aldosterone levels is occasionally seen in IHA. High rates of false negative or equivocal results have been reported, although this test is considered safer in patients at risk of volume overload.

Fludrocortisone suppression test

The fludrocortisone suppression test uses fludrocortisone (0.1 mg every 6 h) and salt loading.[40, 41] Patients receive 0.1 mg oral fludrocortisone every 6 hours for 4 days, together with slow-release potassium chloride supplements (every 6 h at doses sufficient to keep plasma potassium close to 4 mmol/L). Serum potassium is measured four times daily. High-sodium diet plus sodium chloride tabs are administered (30 mmol 3 times daily with meals) to maintain a urinary sodium excretion rate of at least 3 mmol/kg body weight. On day 4, plasma cortisol is measured at 7 or 8 AM and 10 AM, and plasma aldosterone concentration and renin are measured at 10 AM, with the patient in the seated position.

Upright plasma aldosterone higher than 6 ng/dL on day 4 at 10 AM confirms PA, provided that PRA is suppressed to less than 1 ng/mL/h, plasma potassium levels are normal and 10 AM plasma cortisol concentration is lower than the value obtained at 7 AM (to exclude a confounding ACTH effect). The test should not be performed in patients with uncontrolled hypertension, congestive heart failure, or arrhythmias, whereas false negative results may be obtained in renal insufficiency.

The use of the combined fludrocortisone-dexamethasone suppression test (FDST), which involves the co-administration of dexamethasone 2 mg at midnight, has been recently applied by some investigators to eliminate the stimulatory input of ACTH on aldosterone secretion, thus increasing substantially the sensitivity and specificity of the FDST and enabling the detection of milder forms of primary hyperaldosteronism.[21, 34, 37, 36, 42, 43]

Tests for differentiating aldosterone-producing adenoma from other primary hyperaldosteronism

Postural testing

Postural testing is best performed after overnight recumbency. An IV catheter is inserted at 7 AM, and baseline aldosterone, cortisol, and PRA values are obtained at 8 AM. After 2 hours of ambulation, these values are obtained again.

Typically, APAs are unresponsive to angiotensin II, and a fall in aldosterone over 2 hours is observed in parallel with reduced circadian ACTH and cortisol release. In IHA, however, a rise in aldosterone is observed, during walking compared with lying down, because upright posture stimulates renin secretion. Cortisol levels are used to validate the test; a rise in cortisol release suggests an ACTH surge, which invalidates the test. Of note, 30–50% of APAs respond to upright posture and 20% of bilateral adrenal hyperplasia are unresponsive. A diagnostic accuracy of 85% is reported.

18-hydroxycorticosterone level

Levels of 18-hydroxycorticosterone are typically elevated (>100 ng/dL) in patients with APAs and are significantly lower in patients with IHA. Although a diagnostic accuracy of 82% is reported, 18-hydroxycorticosterone levels have been noted to parallel the severity of hyperaldosteronism, and levels of aldosterone and clinical severity are greater in APAs than in IHA.

Hybrid steroid levels (18-OHF and 18-oxoF) are high (3–30 times normal) in with FH-I, normal to mildly elevated in FH-II (3–4 times normal, as in sporadic PA), and mildly to extremely high in FH-III (3–100 times normal).

Dexamethasone suppression test

In cases of bilateral aldosterone secretion or when the diagnosis is suspected on the basis of the family history, GRA can be excluded by means of a 4-day dexamethasone suppression test (using a dosage of 0.5 mg every 6 h).

The aldosterone, renin, and cortisol levels can be measured before suppression testing, after 2 days of testing, and after 4 days of testing. In patients without GRA, aldosterone levels typically fall by approximately 50% and return to the reference range by the end of testing; however, persistent suppression of aldosterone levels to less than 4 ng/dL is reported in patients with GRA. Plasma cortisol suppression (ie, < 5 mcg/dL) is used as an index of the dexamethasone effect. Compared with direct genetic testing, this test achieves a sensitivity of 92% and a specificity of 100% for the diagnosis of GRA.

Biochemically unique, markedly elevated levels of 18-oxocortisol and 18-hydroxycortisol (>100 nmol/day) are also observed in GRA and have been shown to be better than the dexamethasone suppression test for the diagnosis of GRA.

Mutation analysis for the hybrid gene that gives rise to GRA can now be accomplished by means of Southern blotting or a long polymerase chain reaction (PCR) technique. This study is likely to supersede the time-intensive dexamethasone suppression test.

In patients with FH-II, suppression of plasma aldosterone concentration may vary in response to glucocorticoid suppression test (partial, transient, blunted reduction or unresponsive).[44]

FH-III is a distinct disorder characterized by a paradoxical increase of aldosterone after ACTH suppression in some patients, while others demonstrate no response.

Of interest, data have shown that the titer of circulating autoantibodies directed against the second loop of the angiotensin 1 receptor (AT1AA), as well as the serum levels of parathyroid hormone, were both higher in patients with APA than those with IHA or essential hypertension, with only a small overlap between values for patients with APA and IHA.[45, 46] Hence, the determination of those parameters may provide helpful additional information for the diagnostic discrimination between these conditions.

The sensitivity and specificity of adrenal imaging with 1.25-3 mm cuts for APA is 78% and 75%, respectively. Findings may range from normal-appearing or slightly enlarged adrenal glands suggestive of bilateral adrenal hyperplasia, to small, homogeneous, hypodense nodules characteristic of APAs or, rarely, large, dense heterogeneous masses suggestive of ACC (almost always >4 cm in diameter).

In one large series, the mean APA size was 1.8 cm; however, 19% of these tumors were smaller than 1 cm. Aldosteronomas are typically lipid-rich and commonly appear as homogeneous lesions with a low Hounsfield number consistent with this high lipid content. Reported data show that if imaging alone was used for localization, 14.6% of patients would have undergone inappropriate adrenalectomy, whereas 19.1% would have been inappropriately excluded from surgery. Furthermore, in 3.9% of patients, the wrong adrenal might have been removed.

Of note, many APAs are too small to be detected and nonfunctioning incidentalomas may be mistakenly identified as causative.[5, 27, 28] Hence, the primary role of CT is to the exclude the presence of ACC. In addition, CT is also useful in defining the adrenal anatomy and localizing the right adrenal vein in preparation for adrenal venous sampling (AVS) as it enters into the inferior vena cava, thus aiding cannulation of the vein during AVS.

When a solitary adrenal mass is identified on a CT scan from a child or young adult with hyperaldosteronism, it is very likely to be the cause of the hyperaldosteronism because the prevalence of nonfunctioning adrenal adenomas is very low in childhood.

The interest in adrenal cortical scintigraphy has been renewed by the use of the new hybrid single photon emission tomography (SPET)/CT technology. Hybrid imaging permits correct localization of findings by incorporating anatomical and functional information.

The NP-59 (6b-131) iodomethyl-19-norcholesterol scan, performed with dexamethasone suppression, was a helpful diagnostic tool in the detection and lateralization of PA. SPET/CT can identify small adenomas (0.8-1.5 cm) even in patients with chronic renal disease where the biochemical diagnosis of PA is difficult. A study by Di Martino et al suggested that NP-59 testing can be used to localize primary hyperaldosteronism preoperatively when there are contraindications to adrenal venous sampling or the results of sampling are inconclusive. Basing the NP-59 test value on pathologic outcomes resulted in a sensitivity and positive predictive value of 90.9% and 83.3%, respectively. Basing the test’s performance on postoperative blood pressure control resulted in a 91.6% value for both sensitivity and positive predictive value.[47]

Lately, 11C-metomidate PET-CT with and without dexamethasone suppression has been found to be a sensitive and specific noninvasive alternative to AVS.[48]  A literature review by Chen Cardenas et al indicated that as a PET-scan tracer, 11C-metomidate provides a potentially useful means of identifying PA and detecting adrenocortical masses. The investigators found it to be highly specific for adrenocortical tissue and to correlate with enzyme activity.[49]

AVS is the criterion standard test to differentiate unilateral (APA or UAH) from bilateral disease in patients with PA; however, it requires considerable skill. It can be performed as an outpatient procedure, although younger children may need general anesthesia. Ideally, the procedure should be performed in centers with appropriate expertise. Adrenal veins are often small, and the right vein tends to be difficult to cannulate.

According to a consensus statement from an international panel of experts, AVS is not necessarily required in patients older than 40 years with marked PA and a clear unilateral adrenal adenoma and a normal contralateral adrenal gland on computed tomography imaging, in patients with unacceptable high risk of adrenal surgery (eg, multiple comorbidities in elderly patients), in patients suspected of having an adrenocortical carcinoma, or in patients with proven FH-I or with FH-III.[45]

ACTH may be infused into a peripheral vein (at a dosage of 50 mcg/h, starting 30 minutes before sampling) to mask the effects of confounding ACTH peaks during sampling. To reduce the risk of adrenal hemorrhage, adrenal venography is avoided.

If cosyntropin stimulation is not used, AVS is best performed in the morning after an hour of supine rest, to avoid false positive results due to diurnal fluctuation in ACTH concentrations. Additional measures, such as use of benzodiazepines and local anesthesia before venipuncture, should be taken to minimize emotional and pain-related stress.

Hypokalemia should be adequately corrected before AVS. MRAs and amiloride should be withdrawn for 4-6 weeks before AVS. Particularly, the former may allow a rise in renin secretion, which can stimulate aldosterone secretion from the unaffected contralateral adrenal gland, thus minimizing the lateralization. Peripheral α1-adrenergic receptor blockers and the long-acting dihydropyridine or nondihydropyridine calcium-channel blockers (verapamil) are recommended because of their minimal effect on renin secretion.

If cosyntropin stimulation is not used, then bilateral simultaneous AVS should be performed.

An adrenal vein cortisol-to-inferior vena cava cortisol ratio (selectivity index/SI) is used to confirm adequate cannulation of adrenal veins. The cut-off value for the SI should be 2 or higher for AVS performed under unstimulated conditions and 3 or higher for AVS performed during cosyntropin stimulation.

The lateralization index (LI), calculated from the PAC and plasma cortisol concentration (PCC) in both adrenal veins and defined as the ratio of the higher (dominant) over the lower (nondominant) PAC/PCC ratio is used for the assessment of lateralization of aldosterone hypersecretion. Although data on LI cut-off values are controversial, LI cutoff of 4 during cosyntropin stimulation and of 2 for unstimulated AVS have been recommended as the criteria to document lateralization of aldosterone excess. AVS studies using cosyntropin stimulation are considered equivocal when the LI is 2-4.

Adrenal venous sampling is not without risk and can lead to damage of the adrenal gland if not performed correctly. The major complications include adrenal vein rupture, infarction, thrombosis, groin hematoma, and adrenal hemorrhage, whereas associated complete and permanent adrenal insufficiency have been only occasionally reported. Even in experienced centers, the complication rate averages 0.5-2.5%. Similarly, failure to cannulate the right adrenal vein (≤ 20% of cases) can lead to an incorrect diagnosis of unilateral disease when, in fact, both glands are affected.

Unlike cortisol-producing adrenocortical tumors, in which the remaining ipsilateral and contralateral glands are commonly atrophic, APAs may show hyperplasia of the zona glomerulosa in the nontumorous cortex, either forming a broad zone locally or thickening the entire cortex, with tongues of glomerulosa like cortex extending inward from the subcapsular region.

This appearance has been reported in as many as one third of patients with APAs and suggests that the tumor has arisen from within an area that was hyperplastic, though to date, neither an external stimulus nor an intrinsic defect has been found.

IHA is a disease of the zona glomerulosa with a variable macroscopic appearance that can range from hyperplasia with micronodules and macronodules to hyperplasia without nodules to normal-appearing zona glomerulosa with micronodules. The glands may be normal in weight or heavy.

The normal microscopic appearance of the zona glomerulosa is of small discontinuous subcapsular nests of cells. In hyperplasia, the zona glomerulosa may contain continuous bands of cells that may be visibly thickened, either forming a continuous sheet or focally extending as tongues into the adjacent cortex. This process may be focal or diffuse and may vary from one part of the gland to another, requiring multiple sections.

GRA, or familial hyperaldosteronism (FH) type I (FH-I), results from the formation of a hybrid gene that leads to ACTH-mediated mineralocorticoid synthesis by the zona fasciculata. Histologically, evidence suggests hyperplasia of this zone in addition to the zona glomerulosa.

FH type II (FH-II) has been linked to a locus on chromosome 7p22. Histologically, evidence suggests adrenocortical hyperplasia or hypertrophy and the presence of adenomas.

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, such as eplerenone, 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).

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, eplerenone, 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)

 

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 MRA 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.[25, 26]

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.[31, 50]

Patients who are 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 is considered a selective MRA 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.[27]

Hyperkalemia is probably considered the most concerning adverse effect of MRA 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 the addition of diuretics.[26]

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 it 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 the blockade of sex steroid receptors by spironolactone or eplerenone.

For children receiving long-term treatment with glucocorticoids, consultation with a pediatric endocrinologist is mandatory. GRA is associated with intracranial aneurysms 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 the 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.[51] This type of compound might be useful in patients with KCNJ5 mutations because the latter leads to aldosterone production through increased calcium influx.[18] Data have shown that a number of dihydropyridine calcium channel blockers also have MRA activity at high doses, suggesting that these agents may target multiple mechanisms in the 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.[52]

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.[5]

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 (40-70%) 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.

A retrospective study by Araujo-Castro et al of patients with PA found that the reduction in blood pressure at median 23.6-month follow-up in patients who underwent adrenalectomy was similar to that in individuals treated with MRAs. However, the surgery patients experienced a greater reduction in the number of antihypertensive pills taken and a greater increase in serum potassium levels.[53]

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. Retrospective studies, while limited in size and length of follow-up, suggest that in patients with unilateral hyperfunctioning adrenal nodules (primarily, aldosterone-producing adenomas), radiofrequency ablation delivers outcomes comparable to those of laparoscopic adrenalectomy, with reduced morbidity and speedier recovery.[54]

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.[55] 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%.[6]

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.

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.

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.

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.[56]

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.

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.

Aldosterone antagonists are indicated for the treatment of hyperaldosteronism. Hypokalemia and hypertension are also addressed with medications as needed.

Class Summary

Aldosterone antagonists are used to lower the blood pressure, normalize serum potassium, and minimize postoperative hypoaldosteronism.

Spironolactone (Aldactone)

Spironolactone is the agent most commonly used to treat hyperaldosteronism because it directly antagonizes aldosterone effects at the distal tubule.

Eplerenone (Inspra)

Weaker than spironolactone but with very little cross-reactivity with the androgen receptor. The drug usually is given twice a day.

Class Summary

Management of hypokalemia associated with hyperaldosteronism when spironolactone is contraindicated.

Triamterene (Dyrenium)

Triamterene inhibits reabsorption of sodium ions in exchange for potassium and hydrogen ions at the segment of the distal tubule that is under the control of adrenal mineralocorticoids (especially aldosterone). This activity is not directly related to aldosterone secretion or antagonism, and it is a result of a direct effect on the renal tubule.

The fraction of filtered sodium reaching this distal tubular exchange site is relatively small, and the amount that is exchanged depends on the level of mineralocorticoid activity; thus, the degree of natriuresis and diuresis produced by inhibition of the exchange mechanism is necessarily limited.

Increasing the amount of available sodium and the level of mineralocorticoid activity by using more proximally acting diuretics increases the degree of diuresis and potassium conservation. Triamterene may occasionally cause increases in serum potassium, which can result in hyperkalemia. It does not produce alkalosis, because it does not cause excessive excretion of titratable acid and ammonium.

Amiloride

Amiloride is an antikaliuretic drug with weak natriuretic, diuretic, and antihypertensive activity. It decreases the enhanced urinary excretion of magnesium that occurs when a thiazide or loop diuretic is used alone. It exerts a potassium-conserving effect in patients receiving kaliuretic diuretic agents.

Class Summary

Treatment of hypertension should be designed to lower blood pressure and reduce other risk factors of coronary heart disease. Pharmacologic therapy should be individualized on the basis of the patient’s age, race, known pathophysiologic variables, and concurrent conditions. Treatment should be aimed not only at lowering blood pressure safely and effectively but also at preventing or reversing hyperlipidemia, glucose intolerance, and left ventricular hypertrophy.

Nifedipine (Adalat, Procardia XL, Nifedical XL, Nifediac CC)

Nifedipine is a calcium channel blocker that produces vasodilation with antianginal and antihypertensive effects. It is available in both short-acting and sustained-release preparations.

Nifedipine acts by blocking postexcitation release of calcium ions into cardiac and vascular smooth muscle, thereby inhibiting the activation of adenosine triphosphatase (ATPase) on myofibril contraction. The overall effect is reduced intracellular calcium levels in cardiac and smooth muscle cells of the coronary and peripheral vasculature, resulting in dilatation of coronary and peripheral arteries.

Amlodipine (Norvasc)

Amlodipine is a calcium channel blocker that produces vasodilation with antianginal and antihypertensive effects. It acts by blocking the postexcitation release of calcium ions into cardiac and vascular smooth muscle, thereby inhibiting the activation of ATPase on myofibril contraction. The overall effect is reduced intracellular calcium levels in cardiac and smooth muscle cells of the coronary and peripheral vasculature, resulting in dilatation of coronary and peripheral arteries.

Diltiazem (Cardizem, Cardizem CD, Dilacor XR, Tiazac)

During depolarization, diltiazem inhibits calcium ions from entering the slow channels and voltage-sensitive areas of vascular smooth muscle and myocardium. It is a nondihydropyridine appropriate for prophylaxis of variant angina.

Nicardipine (Cardene)

Nicardipine relaxes coronary smooth muscle and produces coronary vasodilation, which, in turn, improves myocardial oxygen delivery and reduces myocardial oxygen consumption.

Verapamil (Calan, Calan SR, Covera HS, Isoptin, Verelan)

Verapamil is a nondihydropyridine that is appropriate for prophylaxis of variant angina. During depolarization, verapamil inhibits the entry of calcium ions into slow channels or voltage-sensitive areas of the vascular smooth muscle and myocardium.

Doxazosin (Cardura, Cardura XL)

Doxazosin is an alpha1-adrenergic antagonist, which causes vasodilation of veins and arterioles. These effects result in decreased peripheral resistance and blood pressure.

Prazosin (Minipress)

Prazosin is a postsynaptic alpha1-adrenergic antagonist. It causes vasodilation of veins and arterioles. These effects result in decreased peripheral resistance and blood pressure.

Frequency and requirement for follow-up depends 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 with familial hyperaldosteronism, genetic counseling is also important at an age-appropriate level.

Severe hypokalemia may require intravenous correction if the potassium is less than 2.5 mmol/L or the patient is clinically symptomatic. Once 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, although it may interfere with the progression of puberty. Newer drugs with greater specificity for the mineralocorticoid receptor than spironolactone are becoming available.

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

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