Primary Aldosteronism

How to Cite This Chapter: Rodríguez-Gutiérrez R, Gonzalez-Gonzalez JG, Castillo-Gonzalez DA, Bautista-Orduño KG, Słowińska-Srzednicka J, Płaczkiewicz-Jankowska E. Primary Aldosteronism. McMaster Textbook of Internal Medicine. Kraków: Medycyna Praktyczna. Accessed August 07, 2020.
Last Updated: May 30, 2018
Last Reviewed: August 7, 2019
Chapter Information

Definition, Etiology, PathogenesisTop

Primary aldosteronism is caused by aldosterone hypersecretion that is relatively independent from regulators of its secretion (renin-angiotensin system, intravascular volume, and potassium concentration) and is not suppressed by sodium administration. Aldosterone acts in the distal renal tubule, increasing [Na+] concentration and water reabsorption as well as excretion of K+ and H+. Excess aldosterone classically leads to the development of hypertension and hypokalemia.

Causes and types of primary aldosteronism:

1) The most common causes and types:

a) Unilateral aldosterone-producing adenoma (30%-40% of patients), which develops as a result of monoclonal hyperplasia. Aldosterone production is independent from angiotensin II and shows a correlation with circadian fluctuations in plasma adrenocorticotropic hormone (ACTH) levels.

b) Bilateral idiopathic hyperaldosteronism or idiopathic hyperplasia (60-70% of patients).

2) Infrequent causes and types:

a) Unilateral adrenal hyperplasia (micronodular or macronodular).

b) Familial aldosteronism: Type I is caused by a mutation in the CYP11B2 gene, encoding aldosterone synthase, and in the CYP11B1 gene, encoding 11-beta-hydroxylase. The mutation results in the formation of a chimeric gene, which causes aldosterone synthesis in the ACTH-dependent zona fasciculata of the adrenal cortex. In such patients, administration of dexamethasone (reducing ACTH levels) suppresses aldosterone hypersecretion, which is why this type is also called glucocorticoid-remediable aldosteronism. Type II refers to familial aldosterone-producing adenoma, bilateral idiopathic hyperplasia, or both; aldosteronism is not ACTH-dependent and the underlying genetic defect has not been yet identified, but it most likely involves the CYP11B2 gene. Type III is caused by a germline mutation of the potassium channel KCNJ5 gene and is associated with severe adrenal hyperplasia and severe manifestations of aldosteronism.

c) Aldosterone-secreting adrenocortical carcinoma.

d) Ectopic aldosterone-producing tumors (eg, ovarian tumors or renal cancers).

In ~50% of patients with aldosterone-secreting adrenal adenoma, somatic mutations of the KCNJ5 gene have been found, which make the potassium channels less selective and allow the flow of sodium ions followed by calcium ions into the cells of the zona glomerulosa of the adrenal cortex. This leads to increased aldosterone synthesis. Patients with adrenal adenoma and confirmed KCNJ5 mutations have particularly severe symptoms of aldosteronism.

Clinical Features and Natural HistoryTop

The major clinical finding is hypertension, although most patients are asymptomatic.

The inappropriate production of aldosterone causes hypertension, sodium retention, hypervolemia, and increased hydrogen and potassium excretion, leading to symptoms of hypokalemia. This has been described as the triad of hypertension, hypokalemia, and metabolic alkalosis. However, nowadays only a minority of patients (10%-40%) are reported to have hypokalemia at the time of diagnosis (probably because of diagnosis made earlier in the natural course of the disease). Currently it is also rare to see treatment-resistant hypertension, which often could be severe and accompanied by other symptoms, including muscle weakness, hypomagnesemia, polyuria, excessive thirst, paresthesia, cramps, and tetany (symptoms of a significant potassium deficit and alkalosis). Blood volume is normal. (At early stages blood volume is increased due to sodium and water retention; this is followed by spontaneous diuresis and normalization of the extracellular fluid volume, called an “aldosterone escape,” which is probably associated with increased secretion of atrial natriuretic peptide [ANP].) Excess aldosterone, acting synergistically with angiotensin II, causes necrosis, fibrosis, and proliferation of myocytes; myocardial hypertrophy; vascular remodeling and fibrosis; and impaired endothelial function; in the kidney this results in damage to small and intermediate arteries and the development of nephropathy (particularly in the case of increased sodium intake). As a result, there is an increase in the risk of cardiovascular morbidity and mortality in such patients when compared with patients with the same blood pressure (BP) and primary hypertension. In addition, metabolic syndrome and type 2 diabetes mellitus are more prevalent in patients with primary aldosteronism, which further increases their cardiovascular risk. Finally, aldosterone may increase glomerular filtration rate, albumin excretion, and renal perfusion pressure independent of systemic pressure.


Perform studies to detect primary aldosteronism in:

1) Patients with moderate (>160-179/100-109 mm Hg) or severe (>180/110 mm Hg) hypertension.

2) Patients with refractory hypertension (>140/90 mm Hg despite treatment with a maximum dose of 3 antihypertensive drugs including a diuretic).

3) Patients with hypertension and idiopathic or spontaneous low-dose diuretic-induced hypokalemia.

4) Patients with hypertension and incidentally diagnosed adrenal tumor (incidentaloma).

5) Patients with hypertension and first-degree relatives diagnosed with primary aldosteronism or with a family history of early-onset hypertension or cerebrovascular hemorrhage at a young age (<40 years).

Diagnostic Tests

1. Basic biochemical tests may reveal:

1) Hypokalemia (may be absent in bilateral adrenal hyperplasia, more often found in patients with adenoma). Serum potassium levels should be measured after discontinuation of drugs that affect sodium-potassium metabolism and renin-angiotensin-aldosterone (RAA) system activity (see below) and during periods of normal dietary sodium and potassium intake; the higher the sodium intake, the greater the likelihood of hypokalemia. In some patients hypokalemia appears during antihypertensive treatment with low-dose diuretics.

2) Increased urinary excretion of potassium in patients with hypokalemia (>30 mmol/d).

3) Normal serum sodium levels approaching the upper limit of normal (ULN) or mild hypernatremia (<150 mEq/L).

4) Mild metabolic alkalosis.

2. Hormone tests (initial tests): Blood samples for measurements of plasma renin activity (PRA) and plasma aldosterone concentration (PAC) should be collected in the morning (8:00). Correction of potassium deficit before performing the RAA system hormone studies is recommended. It was traditionally thought that any drugs affecting sodium-potassium metabolism and the RAA system should be discontinued; it is now recommended to continue most of them with the exception of mineralocorticoid receptor antagonists (eg, eplerenone and spironolactone), which should be discontinued for 4 to 6 weeks unless there is hypokalemia, as this indicates that the system is not completely blocked. Tests may be done while patients are treated with angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs) and direct renin inhibitors, which usually increase PRA and decrease the PAC/PRA ratio (consequently, a negative result would not exclude the diagnosis of primary aldosteronism). However, low PRA and a high PAC/PRA ratio despite pharmacotherapy is a strong predictor of aldosteronism. When making the decision about testing, it is important to take into account that discontinuing drugs and changing treatment regimens can worsen hypertension and increase the risk of adverse events such as arrhythmias, heart failure, and hypertensive crisis. If the patient requires treatment with other antihypertensive drugs because of high BP, this must be taken into consideration when interpreting test results.

1) Low baseline (resting) PRA and high baseline (resting) serum aldosterone levels:

a) PRA <0.77 nmol/L/h (1.0 ng/mL/h).

b) PAC >416 pmol/L (15 ng/dL).

c) Aldosterone-renin ratio (ARR) (aldosterone in ng/dL to PRA in ng/mL/h) >20 to 40 (depending on assay).

2) PRA and serum aldosterone levels in dynamic conditions (confirmatory tests, done in specialized settings only):

a) No increase in PRA and aldosterone levels after stimulating the RAA system using a 3-day low-sodium diet (up to 20-30 mmol/d; eg, a rice and fruit diet) followed by 3 to 4 hours in a standing position, or alternatively 20 to 40 mg furosemide followed by 2 to 3 hours in a standing position. Under normal conditions, the increase in PRA and aldosterone levels after 2 to 3 hours in a standing position is 2- or 3-fold, whereas a sodium-restricted diet or administration of furosemide results in a multiple-fold increase.

b) Aldosterone levels are not reduced when the RAA system is suppressed by a 3-day sodium-rich diet (confirmed by urinary sodium excretion >200 mmol/24 h; primary aldosteronism confirmed by urinary aldosterone excretion >39 nmol/24 h [12-14 microg/24 h]); the captopril test (25 mg orally after remaining in a standing position for ≥1 hour; primary aldosteronism confirmed by no decrease [>30%] in serum aldosterone after 2 hours in a sitting position); or the 0.9% saline suppression test using 0.9% saline as a 4-hour IV infusion at a rate of 500 mL/h (monitor BP and serum potassium; a high sodium load may be dangerous as it can precipitate hypertensive crisis in patients with hypertension and severe hypokalemia in patients with primary aldosteronism; primary aldosteronism is confirmed by serum aldosterone levels >277 pmol/L [10 ng/dL]).

After confirming the diagnosis of primary aldosteronism, it is critical to distinguish a unilateral aldosterone-producing adenoma from bilateral idiopathic hyperplasia, as treatment options differ. This is usually done in specialized settings. Adenomas usually have higher aldosterone secretion rates resulting in higher levels of hypertension, hypokalemia (<3.2 mEq/L), aldosterone >25 ng/dL, and PAC/PRA ratios >30.

3. Imaging studies: Computed tomography (CT) allows the visualization of adrenal tumors >8 to 10 mm in diameter; enlargement of one segment of an adrenal gland >6 to 7 mm or of the whole adrenal gland >10 mm is considered abnormal. A result <10 Hounsfield units and assessment of the rate of washout of IV contrast allows for differentiating adrenal adenoma (rapid washout) from adrenal carcinoma (usually >4 cm), metastatic lesions, and pheochromocytoma. However, it should be noted that in some studies CT was accurate in only half of the cases (eg, patients with clearly visualized adenoma may still have bilateral idiopathic hyperplasia and absence of a mass does not exclude an adenoma). Magnetic resonance imaging (MRI) has similar sensitivity and specificity to CT and is useful in differentiating aldosterone-secreting adenomas from nonfunctioning tumors. Adrenal scintigraphy using a 131I-labeled cholesterol analogue is helpful in detecting aldosterone-secreting tumors >1.5 cm in diameter.

4. Adrenal vein catheterization with aldosterone sampling: The limitations of imaging studies dictate the need for further localization of excess aldosterone production, especially if the treatment of choice is surgery and the patient is >35 years (in younger patients the probability of adrenal incidentalomas is low; in such cases biochemical tests and CT are sufficient). Aldosterone levels on the side of the tumor are 4 to 5 times higher than contralaterally. This study is performed in specialized centers only.

Diagnostic Criteria

Diagnosis is based on results of diagnostic tests (see above).

Familial aldosteronism should be suspected in patients who developed hypertension and aldosteronism in early childhood, or in the case of a family history of aldosteronism in relatives who suffered cerebrovascular accidents at a young age. In familial aldosteronism type I, administration of dexamethasone causes suppression of aldosterone secretion.

Differential Diagnosis

1. Other causes of mineralocorticoid-related hypertension (aldosterone and nonaldosterone mineralocorticoids): Table 5.1-2.

2. Other causes of hypokalemia.

3. Secondary aldosteronism caused by long-term activation of the RAA system (high PRA and high serum angiotensin II levels), which stimulates the zona glomerulosa of the adrenal cortex to hypersecrete aldosterone. The most frequent causes include sodium loss, hypovolemia, treatment with high doses of laxatives or diuretics, cirrhosis with ascites, heart failure, myocardial infarction, nephrotic syndrome, renal artery stenosis, renin-secreting tumors, malignant hypertension (regardless of etiology), and estrogen use (as replacement therapy or oral contraceptives; these increase angiotensinogen synthesis).

4. Activating mutation of the mineralocorticoid receptor that becomes apparent during pregnancy (the receptor is stimulated by progesterone).


1. Treatment goals: Prevent adverse outcomes associated with excess aldosterone. Include normalization of BP and serum potassium levels and prevention of cardiovascular damage.

2. Recommend maintaining an appropriate body weight, moderate physical exercise, and sodium-restricted diet (<100 mmol/d; the same applies to patients planned for surgical resection of adenoma).

Surgical Treatment

Unilateral laparoscopic adrenalectomy is the treatment of choice in aldosterone-producing adenomas.


1. Mineralocorticoid receptor blockers are indicated before resection of an aldosterone-secreting adenoma; they are also used in patients with contraindications to surgery and in bilateral adrenal hyperplasia (idiopathic or familial).

1) Spironolactone is administered with meals. Start from 12.5 to 50 mg bid, and when necessary titrate up to 100 mg bid (use a dose that ensures normal serum potassium levels without the need for supplementation; after several months the dose may be reduced even to 25 mg bid). Adverse effects include gynecomastia (at doses >150 mg/d), erectile dysfunction, menstrual disorders caused by inhibition of androgens and progestagens, nausea, vomiting, and diarrhea.

2) Eplerenone 25 mg bid (dose may be increased to 100 mg/d); this causes fewer adverse effects than spironolactone. After a few months of treatment, you may try to taper down the dose provided that good BP control is maintained.

2. Other potassium-sparing diuretics: In case of spironolactone intolerance and unavailability of eplerenone, use amiloride 5 mg bid, up to 20 mg/d.

3. ACEIs are used in patients with bilateral adrenal hyperplasia when BP normalization cannot be achieved using mineralocorticoid receptor blockers.

4. Glucocorticoids are used in patients with familial aldosteronism type I. The most frequently used agent is dexamethasone 0.5 to 0.75 mg/d.


Surgical resection of aldosterone-secreting adenoma leads to complete resolution of signs and symptoms in 35% to 70% of patients. If the disease is undiagnosed or inappropriately treated, the excess aldosterone, especially with a concomitant high salt intake, not only causes hypokalemia and hypertension but also has direct adverse cardiovascular effects and may lead to nephropathy.



Table 5.1-2. Causes of mineralocorticoid-dependent hypertension (aldosterone-related and non–aldosterone-related)

Cause of hypertension


Key clinicala and hormonal features

Primary aldosteronism



↓↓ PRA

↑↑ Aldosterone

Congenital adrenal hyperplasia: 17-alpha-hydroxylase deficit



↓↓ PRA

↓ Aldosterone

↓ Cortisol

Congenital adrenal hyperplasia: 11-beta‑hydroxylase deficit




↓ Aldosterone

DOC-secreting adrenal tumors


Adrenal tumor

↓↓ PRA

↓ Aldosterone

Apparent mineralocorticoid excess

11-beta‑HSD2 deficit


Excessive thirst


↓↓ PRA

↓↓ Aldosterone

↑ Cortisol or cortisone metabolites

a Apart from hypertension.

↓, decrease; ↑, increase; 11-beta-HSD2, 11-beta-hydroxysteroid dehydrogenase isozyme 2; DOC, 11-deoxycorticosterone; PRA, plasma renin activity

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