Pediatrics

Primary aldosteronism

OVERVIEW: What every practitioner needs to know about Primary Aldosteronism

Primary aldosteronism is a group of disorders, originally described by JW Conn, in which there is a non-suppressible secretion of aldosterone and hypertension. Aldosterone is a salt-retaining hormone synthesized by the adrenal gland that is regulated by multiple factors, with the renin-angiotensin system and serum potassium being the major factors. Additional minor regulators include adrenocorticotropic hormone (ACTH), atrial natriuretic factor, and dopamine.

Are you sure your patient has Primary Aldosteronism? What are the typical findings for this disease?

The major symptoms associated with primary aldosteronism are hypertension and hypokalemia. However, it has been reported that hypokalemia does not occur in the majority of patients with primary aldosteronism, with the prevalence ranging only from 9% to 37% in adults. Therefore, normokalemic hypertension is the typical presentation, with the more severe cases having hypokalemia as a presenting symptom. Various symptoms associated with hypokalemia include muscle weakness with various types of paresthesias, tiredness, thirst, polyuria, and nocturia.

It is known that primary aldosteronism occurs in greater than 10% of hypertensive adult patients. Although primary aldosteronism is considered rare in children, the high prevalence in the general adult population suggests that the disease may develop in the pediatric population prior to its presentation of hypertension and vascular damage in adulthood.

The Endocrine Society recommends evaluation of hypertension in those patients who appear to be at risk for primary aldosteronism. However, these guidelines are more applicable to adults rather than the pediatric population, and are based on adult definitions of hypertension. In adults, patients who appear at risk for primary aldosteronism include patients with moderate/severe hypertension (systolic blood pressure (SBP) >160 mmHg, diastolic blood pressure (DBP) > 100 mmHg), resistant hypertension (those with SBP > 140 mmHg, DBP > 90 mmHg despite treatment with 3 anti-hypertensive medications), hypertensive patients with spontaneous or diuretic-induced hypokalemia, and hypertension with adrenal incidentalomas.

What other disease/condition shares some of these symptoms?

Endocrinologic diseases that could present similarly to primary aldosteronism include:

  1. 11β-hydroxylase deficiency: 11β-hydroxylase catalyzes the conversion of deoxycorticosterone to corticosterone, and 11-deoxycortisol to cortisol in the adrenal gland. Deficiency in this enzyme leads to an accumulation of precursor products, resulting in not only increased mineralocorticoid activity, but also hyperandrogenism. Hypertension is common, but is a less consistent feature than virilization. Elevated blood pressure is usually not identified until later in childhood or adolescence, although its appearance at 3 months of age has been documented.

  2. Apparent mineralocorticoid excess (AME): This is a rare inherited form of hypertension caused by 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) deficiency. The syndrome is caused by nonfunctional mutations in the HSD11B2 gene located on chromosome 16q22. The enzyme inactivates 11-hydroxy steroids to their inactive keto-form, thus protecting the non-selective mineralocorticoid receptor (MR) from glucocorticoids. In patients with AME, compromised 11β-HSD2 activity at the mineralocorticoid target organs allows for activation of the MR receptor by cortisol, which has higher circulating levels than aldosterone. Clinical presentations of AME are similar to a mineralocorticoid excess state, however, without a measurable mineralocorticoid level. The ratio of cortisol to its 11-keto metabolite or cortisone provides the biochemical diagnosis. Interestingly, clinical manifestations resembling AME can be found in patients who take an excessive amount of licorice or carbenoxolone. Both of these share an active ingredient, a glycyrrhetinic acid derivative, that can competitively inhibit 11β-HSD2 activity.

  3. 17α-hydroxylase deficiency: 17α-hydroxylase catalyzes the conversion of pregnenolone and progesterone to their 17-hydroxy forms (17-hydroxypregnenolone and 17-hydroxyprogresterone) in the adrenal gland. Deficiency in this enzyme leads to decreased biosynthesis of androgens and cortisol production, and increased synthesis of mineralocorticoid precursors. As a result, varying degrees of hypertension and hypokalemia are seen, as well as undervirilization in 46, XY males and sexual infantilism in 46, XX females.

  4. Pheochromocytomas: These are catecholamine-producing tumors that arise from chromaffin cells of the sympathetic ganglia and adrenal medulla. Symptoms of this tumor are related to excessive catecholamine action, with hypertension being the most common clinical symptom. The peak incidence occurs in adulthood in the third to fourth decade. However, about 10% to 20% occur in children, with the median age at presentation between 9.5 and 12.5 years. Additionally, it has been found that 1% to 2% of children with hypertension are reported to have a pheochromocytoma.

  5. Liddle’s syndrome: This is a very rare autosomal dominant disease that is due to genetic mutations found in chromosome 16p12 (SCNN1B and SCNN1G). These mutations result in arterial hypertension, with other biochemical findings including hypokalemia, and suppression of renin, aldosterone and angiotensin II.

  6. Primary glucocorticoid resistance: This is another very rare disorder that is caused by inactivating mutations of the glucocorticoid receptor gene. The mode of inheritance can be either autosomal recessive or dominant. It is characterized by an elevated ACTH and cortisol, with resultant hypertension due to cortisol’s action on the mineralocorticoid receptor. However, there is a lack of Cushing’s features on physical exam due to nonfunctional glucocorticoid receptors.

  7. Thyroid disorders: Hypertension can be associated with both hyper- and hypothyroidism. Hypertension from hypothyroidism is thought to be due to extracellular volume expansion. In hyperthyroidism, the increased cardiac output and stroke volume are the underlying factors leading to hypertension, usually associated with a wide pulse pressure.

What caused this disease to develop at this time?

The major causes of primary aldosteronism are as follows:

1. Aldosterone-producing adenomas: These are often small tumors, less than 2 centimeters in diameter.

2. Bilateral adrenal hyperplasia: This is usually due to micronodular or macronodular hyperplasia.

3. Unilateral adrenal hyperplasia: This is sometimes referred to as primary adrenal hyperplasia, and is typically due to micronodular or macronodular hyperplasia of the zona glomerulosa of one adrenal gland.

4. Adrenal carcinoma: Although a very rare cause of primary aldosteronism, these tumors are usually greater than 4 centimeters at the time of diagnosis. Histological examination typically shows extension of the tumor into the adrenal capsule or a high mitotic index.

5. Familial hyperaldosteronism: There are two forms of familial hyperaldosteronism (FH), both of which are inherited in an autosomal dominant fashion. FH-I is also known as Glucocorticoid Remediable Aldosteronism, with aldosterone secretion under the control of ACTH rather than angiontensin II. As a result, this form of aldosteronism is able to be suppressed by dexamethasone administration. FH-II is more common than FH-I; however, aldosterone production is not able to be suppressed by steroids, and symptoms are clinically indistinguishable from other forms of primary aldosteronism.

In adults, current estimates are that aldosterone-producing adenomas account for about 35% of cases of primary aldosteronism, while bilateral adrenal hyperplasia accounts for approximately 60%. Due to its uncertain prevalence in the pediatric population, the estimated percentage of each is unknown.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

The Endocrine Society’s Clinical Guidelines recommends the use of the plasma aldosterone-renin ratio (ARR) as an initial screening test in patients with hypertension who are at increased risk for primary aldosteronism. However, this should be used as a detection test only, and warrants repeat testing if the initial results are not conclusive or are difficult to interpret. Established ARR cut-off values in adults range between 20 to 40, although the variability of assays between laboratories makes it difficult to provide firm recommendations. Additionally, normal potassium levels are often associated with primary aldosteronism; therefore, using hypokalemia as a screening test may lead to underestimation of hyperaldosteronism as a cause.

Confirmatory testing is indicated if the ARR is abnormal. This testing can be done by one of the four tests listed below; however, cut-off values and interpretation have been established only in adults.

1. Oral sodium loading test: Patient should increase sodium intake (to > 200 mmol or 6 grams/day in adults) for 3 days, with subsequent measurement of a 24-hour urine aldosterone sample from the morning of day 3 or day 4. Primary aldosteronism is very likely if a patient has a urinary aldosterone level > 12 mcg/24 hours.

2. Saline infusion test: Patient should stay recumbent for > 1 hour both before and during a 2-liter normal saline infusion that runs over 4 hours. At 0 and 4 hours, blood samples for renin, aldosterone, cortisol, and plasma potassium should be drawn. Primary aldosteronism is very likely if a patient has an aldosterone level > 10 ng/dL post-infusion.

3. Fludrocortisone suppression test: The patient receives 0.1 mg fludrocortisone every 6 hours and KCl supplements for 4 days. Serum potassium is monitored carefully throughout. On day 4, plasma aldosterone and renin are measured in the morning. Primary aldosteronism is confirmed if the patient’s upright aldosterone level is > 6 ng/dL.

4. Captopril challenge test: The patient receives 25-50 mg of captopril after sitting or standing for > 1 hour. Blood samples for renin, aldosterone and cortisol are measured at 0, 1 and 2 hours. Primary aldosteronism is likely if a patient has an elevated aldosterone level, with a suppressed renin level.

Additionally, of importance in the pediatric population, the Endocrine Society recommends that genetic testing for FH-I should be considered in patients with onset of confirmed primary aldosteronism earlier than 20 years of age, as well as in patients with a family history of primary aldosteronism or of strokes at a young age.

Would imaging studies be helpful? If so, which ones?

Once the diagnosis of primary aldosteronism is suspected from the ARR and a follow-up confirmatory test, an adrenal CT scan is the next step in further determining the underlying cause. The Endocrine Society does not recommend magnetic resonance imaging due to less spatial resolution than computed tomography. Imaging is the initial study necessary in subtype testing as well as to aid in excluding potential adrenocortical carcinoma or other large masses.

Some potential disadvantages of this method of imaging are the inability to reliably identify microadenomas or distinguish incidentolomas from other types of adenomas. As a result, further testing may be necessary. If imaging does not reveal an aldosterone-producing adrenal carcinoma (usually larger than 4 cm in diameter as seen on CT scan), treatment depends upon several factors, including patient preference and whether the patient is a candidate for surgery.

Confirming the diagnosis

Please refer to Figure 1 for the Primary Aldosteronism Algorithm.

Figure 1.

Primary Aldosteronism Algorithm

If you are able to confirm that the patient has Primary Aldosteronism, what treatment should be initiated?

If there is no concern for adrenal carcinoma based on imaging results, treatment for primary aldosteronism will depend on whether or not the patient wishes to pursue surgical versus medical management of the condition.

If surgical treatment is an option and preferred, distinguishing between unilateral versus bilateral adrenal disease is important prior to intervention. This is accomplished by adrenal vein sampling (AVS). This test should only be performed by a skilled and experienced angiographer. When done in such a manner, this method leads to a high success rate in distinguishing unilateral from bilateral adrenal disease.

If unilateral disease is confirmed by AVS, a unilateral adrenalectomy is the recommended course of action, performed by laparoscopy. This treatment is recommended by the Endocrine Society, given that it can potentially eliminate the need for medication and reduce potential medication adverse effects.

However, if a patient is found to have bilateral adrenal disease or if surgery is not indicated, recommended or unable to be performed, medical management is recommended. Treatment with a mineralocorticoid receptor antagonist is recommended as first-line therapy for this patient group.

The major mineralocorticoid receptor antagonists used are spironolactone and eplerenone, with spironolactone being the first-line agent in adults. Spironolactone is typically started at 12.5 to 25 mg per day in adults, with reported recommended doses in children with this disorder being 100-400 mg/m2/day in 1 to 2 divided doses. Eplerenone is typically started at 25 mg once or twice daily in adults. In children, however, dosing recommendations have not been established. In 2008, the FDA reported that a 10-week study in hypertensive pediatric patients taking eplerenone, with doses up to 100 mg per day, failed to have a blood pressure lowering effect. But a recent study in 2010 showed that high-dose eplerenone (50 mg twice per day) produced a statistically significant reduction in blood pressure in hypertensive pediatric patients. Additionally, the Endocrine Society states that eplerenone may be preferred in affected children, and in patients who may be concerned about growth retardation and anti-androgen effects such as gynecomastia.

If a patient is found to have FH-I based on genetic testing, treatment is aimed at suppressing ACTH secretion rather than targeting aldosterone inhibition directly. The treatment of choice is a long-acting glucocorticoid such as prednisone or dexamethasone, administering the lowest dose possible that can normalize the patient’s blood pressure and serum potassium. Ideally, this medication should be taken at bedtime to suppress the early morning ACTH rise. In children, a more physiologic glucocorticoid such as hydrocortisone is preferred due to its less harmful effects on growth.

What are the adverse effects associated with each treatment option?

Reported side effects with treatment options are noted below and broken down by system:

Spironolactone

Cardiovascular: vasculitis

Central nervous system: ataxia, confusion, drowsiness, drug fever, fatigue, headache, lethargy

Dermatologic: eosinophilia, maculopapular or erythematous cutaneous eruptions, urticaria

Endocrine and metabolic: gynecomastia (men 9%), breast pain (men 2%), hyperkalemia (serious, 2%), dehydration, hyperchloremic metabolic acidosis in decompensated hepatic cirrhosis, hyponatremia, impotence, irregular menses, amenorrhea, postmenopausal bleeding

Gastrointestinal: anorexia, cramps, diarrhea, gastritis, nausea, ulceration, vomiting, xerostomia

Hematologic: agranulocytosis

Hepatic: cholestatic/hepatocellular toxicity

Renal: increased BUN, renal dysfunction, renal failure

Miscellaneous: anaphylactic reaction, breast cancer, deepening of the voice

Eplerenone

>10%:

Endocrine and metabolic: hyperkalemia ([HF post-MI: K >5.5 mEq/L: 16%; K ≥6 mEq/L: 6%] [HTN: K >5.5 mEq/L at doses ≤100 mg: ≤1%; doses >100 mg: 9%]), hypertriglyceridemia (1% to 15%, dose related)

1% to 10%:

Central nervous system: dizziness (3%), fatigue (2%)

Endocrine and metabolic: hyponatremia (2%, dose-related), breast pain (males <1% to 1%), gynecomastia (males <1% to 1%), hypercholesterolemia (<1% to 1%)

Gastrointestinal: diarrhea (2%), abdominal pain (1%)

Genitourinary: abnormal vaginal bleeding (<1% to 2%)

Renal: creatinine increased (HF post-MI: 6%), albuminuria (1%)

Respiratory: cough (2%)

Miscellaneous: flu-like syndrome (2%)

<1%, postmarketing, and/or case reports:

Angioneurotic edema, increased BUN, increased liver function tests, rash, increased uric acid

Glucocorticoids

Cardiovascular: edema, hypertension

Central nervous system: headache, vertigo, seizures, euphoria, psychosis, pseudotumor cerebri, insomnia, nervousness

Dermatologic: acne, skin atrophy

Endocrine and metabolic: hypothalamic-pituitary-adrenal (HPA) suppression, growth suppression, glucose intolerance, hypokalemia, alkalosis, Cushing's syndrome

Gastrointestinal: peptic ulcer, nausea, vomiting

Neuromuscular and skeletal: muscle weakness, osteoporosis, decreased bone mineral density, fractures

Ocular: cataracts, increased intraocular pressure (IOP), glaucoma

Miscellaneous: immunosuppression, anaphylactoid reactions (rare)

What are the possible outcomes of Primary Aldosteronism?

Quality studies documenting improved quality of life and morbidity and mortality have not been documented in primary aldosteronism. Medical management appears to be effective at controlling blood pressure in patients with primary aldosteronism. However, these medications are associated with side effects, as discussed above, to varying degrees.

What is the evidence?

Conn, JW, Louis, LH. "Primary aldosteronism, a new clinical entity". Ann Intern Med. vol. 44. 1956. pp. 1-15.

Mulatero, P, Stowasser, M, Loh, KC. "Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents". J Clin Endocrinol Metab. vol. 89. 2004. pp. 1045-50.

Funder, JW, Carey, RM, Fardella, C. "Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline". J Clin Endocrinol Metab. vol. 93. 2008. pp. 3266-81.

Martinez-Aguayo, A, Aglony, M, Campino, C. "Aldosterone, plasma renin activity, and aldosterone/renin ratio in a normotensive healthy pediatric population". Hypertension. vol. 56. 2010. pp. 391-6.

Nimkarn, S, New, MI. "Steroid 11beta-hydroxylase deficiency congenital adrenal hyperplasia". Trends Endocrinol Metab. vol. 19. 2008. pp. 96-9.

Mimouni, M, Kaufman, H, Roitman, A. "Hypertension in a neonate with 11 beta-hydroxylase deficiency". Eur J Pediatr. vol. 143. 1985. pp. 231-3.

Wilson, R, Nimkarn, S, New, M. "Apparent mineralocorticoid excess". Trends Endocrinol Metab. vol. 12. 2001. pp. 104-11.

Farese, RV, Biglieri, EG, Shackleton, CH. "Licorice-induced hypermineralocorticoidism". N Engl J Med. vol. 325. 1991. pp. 1223-7.

Marshall, I, Nimkarn, S.

Mircescu, H, Wilkin, F, Paquette, J. "Molecular characterization of a pediatric pheochromocytoma with suspected bilateral disease". J Pediatr. vol. 138. 2001. pp. 269-73.

Dubois, R, Chappuis, J. "[Pheochromocytoma: pediatric features]". Arch Pediatr. vol. 4. 1997. pp. 1217-25.

Stenson, PD, Mort, M, Ball, EV. "The Human Gene Mutation Database: 2008 update". Genome Med. vol. 1. 2009. pp. 13.

Sutherland, D, Ruse, J, Laidlaw, J. "Hypertension, increased aldosterone secretion and low plasma renin activity relieved by dexamethasone". Can Med Assoc J. vol. 95. 1966. pp. 1109-19.

New, MI, Geller, DS, Fallo, F, Wilson, RC. "Monogenic low renin hypertension". Trends Endocrinol Metab. vol. 16. 2005. pp. 92-97.

Kaplan, NM. "The current epidemic of primary aldosteronism: causes and consequences". J Hypertens. vol. 22. 2004. pp. 863-9.

Young, WF, Stanson, AW, Thompson, GB. "Role for adrenal venous sampling in primary aldosteronism". Surgery. vol. 136. 2004. pp. 1227-35.

http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterial/pediatricadvisorycommitte/ucm166852.pdf.

Li, JS, Flynn, JT, Portman, R. "The efficacy and safety of the novel aldosterone antagonist eplerenone in children with hypertension: a randomized, double-blind, dose-response study". J Pediatr. vol. 157. pp. 282-7.

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