Primary Aldosteronism

How to Cite This Chapter: Kobza A, Prebtani APH, 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. https://empendium.com/mcmtextbook/chapter/B31.II.11.3.?utm_source=nieznany&utm_medium=referral&utm_campaign=social-chapter-link Accessed December 02, 2021.
Last Updated: May 18, 2020
Last Reviewed: April 6, 2021
Chapter Information

Definition, Etiology, PathogenesisTop

Primary aldosteronism (PA) 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 at the distal renal tubule by increasing the reabsorption of Na+ and water and by increasing the excretion of K+ and H+. Excess aldosterone classically leads to the development of hypertension and often, but not always, to hypokalemia.

Causes of PA:

1) Most common causes:

a) Aldosterone-producing adenoma (APA), also known as Conn syndrome (30%-40% of patients).

b) Bilateral adrenal hyperplasia (BAH)/idiopathic hyperaldosteronism (IHA) (60%-70% of patients).

2) Less common causes:

a) Unilateral adrenal hyperplasia (UAH).

b) Familial aldosteronism: Type I is caused by the fusion of 2 genes that creates a chimeric gene sensitive to adrenocorticotropic hormone (ACTH) in 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 (GRA). Type II refers to a familial aldosterone-producing adenoma, bilateral idiopathic hyperplasia, or both. In such cases the aldosteronism is not ACTH-dependent. The underlying genetic defect has not been identified yet, 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 (ACC).

Clinical Features and Natural HistoryTop

The major clinical finding is hypertension. Hypokalemia and metabolic alkalosis are present in up to 50% of patients. Rarely, patients may have symptoms of hypokalemia and alkalosis, such as muscle weakness, polyuria, excessive thirst, paresthesia, cramps, and tetany.

Patients are typically euvolemic. Edema is uncommon due to an “edema escape” phenomenon, which is probably associated with a compensatory increased secretion of atrial natriuretic peptide (ANP) to maintain proper fluid balance.

Over time, excess aldosterone causes necrosis, fibrosis, and proliferation of myocytes; myocardial hypertrophy; vascular remodeling and fibrosis; and impaired endothelial function. In the kidney it results in damage to small and intermediate arteries and in the development of nephropathy (particularly in the case of increased sodium intake). As a result, there is a greater risk of cardiovascular and renal morbidity and mortality in patients with PA when compared with patients with the same blood pressure due to essential hypertension. In addition, PA is an independent risk factor for the development of metabolic syndrome and type 2 diabetes mellitus, which further increases cardiovascular risk.

DiagnosisTop

Perform screening in:

1) Patients with refractory hypertension (>140/90 mm Hg) despite treatment with a maximum dose of 3 antihypertensive drugs, including a thiazide/thiazide-like diuretic (and preferably a dihydropyridine calcium channel blocker [DHP-CCB]), or patients requiring ≥4 drugs for adequate BP control.

2) Patients with hypertension and spontaneous hypokalemia ([K+] <3.5 mmol/L) or easily provoked hypokalemia ([K+] <3.0 mmol/L) with a low-dose diuretic.

3) Patients with hypertension and discovered adrenal incidentaloma.

4) Patients with hypertension aged <20 years or patients with hypertension and first-degree relatives diagnosed with PA or a family history of early-onset hypertension or hemorrhagic stroke at a young age (<40 years).

Diagnostic Tests

1. Basic biochemical tests may reveal:

1) Hypokalemia (may be absent in up to 40% of cases).

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

4) Mild metabolic alkalosis.

2. Screening hormone tests: The aldosterone-to-renin ratio (ARR) is the preferred screening test, with a low renin level being the most important factor, together with an inappropriately high aldosterone level, to suspect PA.

The test should be performed after the patient has been ambulatory for 2 hours and is done in the upright position. Hypokalemia should be corrected and sodium should not be restricted prior to testing. If possible, agents that significantly affect the results (aldosterone antagonists, diuretics) should be stopped 4 to 6 weeks prior to the blood testing. Interpretation of the ARR depends on the assay and units used (Table 6.1-1). If the results are not diagnostic and BP can be controlled with medications that are less likely to affect testing, it is recommended that there is a 2-week withdrawal of interfering medications (eg, beta-blockers, angiotensin-converting enzyme inhibitors [ACEIs], angiotensin receptor blockers [ARBs], DHP-CCBs, centrally acting alpha2 agonists).

Medications that can cause false-negative and false-positive results: Table 6.1-2.

Medications that are less likely to affect testing and that can be used instead are alpha1 adrenergic blockers, such as doxazosin, terazosin, prazosin; long-acting nondihydropyridine calcium channel blockers, such as diltiazem or verapamil; and/or hydralazine.

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; therefore, this has to be done cautiously in those at high risk.

The diagnosis can be made without further testing if there is spontaneous hypokalemia, plasma renin below detection levels, and plasma aldosterone concentration (PAC) >20 ng/dL (540 pmol/L) or if the ARR is >1400 pmol/L/ng/mL/h (or >270 pmol/ng) with a PAC >440 pmol/L.

Confirmatory testing is recommended for all other patients as described below.

3. Confirmatory testing: Perform one of the following to confirm the diagnosis of PA. All tests aim to suppress aldosterone.

1) Saline loading tests (perform either):

a) Administer 2 L of normal saline IV over 4 hours with the patient in a recumbent position. This test is contraindicated in the presence of severe uncontrolled hypertension or congestive heart failure. PA is defined as a postinfusion PAC >280 pmol/L. If PAC is <140 pmol/L, PA is unlikely. Values in between are considered indeterminate.

b) Administer >200 mmol/d of oral sodium (ie, equivalent to >5 g/d of sodium, >12 g/d of sodium chloride, or >2 tsp/d of salt) for 3 days. PA is defined as a 24-hour urinary aldosterone >33 nmol/d (measured from the morning of day 3 to the morning of day 4). If the result is <28 nmol/d, PA is unlikely.

2) Captopril suppression test: Administer 25 to 50 mg of captopril orally after the patient has been sitting or standing for 1 hour. While seated, renin and PAC should be measured at time 0 and 1 to 2 hours after ingestion. PA is unlikely if PAC is suppressed by >30% after captopril ingestion. In patients with PA, PAC remains elevated while the renin level remains suppressed.

After confirming the diagnosis of PA, if surgery is an option, it is critical to distinguish a unilateral lesion from BAH/IHA, as treatment options differ. This is usually done in specialized centers.

4. Imaging studies (only to be done after biochemical confirmation due to a high chance of finding an incidentaloma that may be nonfunctional): Computed tomography (CT) allows the visualization of adrenal tumors or abnormal enlargement of 1 segment of an adrenal gland. The patient may still have an APA even if no adrenal tumor is found on CT. If a lesion is found on imaging, it may be a nonfunctioning lesion (eg, nonfunctioning incidentaloma), especially in the elderly; functional lesion lateralization requires adrenal vein sampling (AVS) (see below). The density of the mass (measured in Hounsfield units [HU]; a mass <10 HU favors a benign pathology), size of the mass, 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. A CT scan is always recommended as the initial study in patients with PA, as it helps exclude large masses that may represent an adrenocortical carcinoma and aids the surgeon where appropriate. Usually magnetic resonance imaging (MRI) has no advantage over CT in subtype evaluation of PA, as it is more expensive and has a lower spatial resolution than CT.

5. Adrenal vein catheterization with aldosterone sampling (AVS): This is a procedure typically performed by experienced interventional radiologists at specialized centers and the gold standard in distinguishing between unilateral and bilateral causes of PA in patients where surgical treatment is feasible and desired. This procedure involves using a catheter to sample blood from both adrenal veins and a peripheral vein. Cortisol concentrations from the adrenal and peripheral veins are used to confirm successful catheterization of the adrenal veins (as the cortisol concentration is higher in the adrenal veins). Aldosterone concentrations from the 2 adrenal veins are then compared; aldosterone levels on the side of the tumor are much higher than on the contralateral side in unilateral disease.

6. Genetic testing for familial aldosteronism: 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 had hemorrhagic stroke at a young age.

Diagnostic Criteria

Diagnosis is based on a positive ARR (value depends on assay) with or without confirmatory testing, as needed.

Subtype classification is done based on CT scan findings with or without AVS, if indicated, and with or without genetic testing, if indicated (as described above).

Differential Diagnosis

1. Other causes of mineralocorticoid-related hypertension (aldosterone and nonaldosterone mineralocorticoids): Table 6.1-3.

2. Other causes of hypokalemia.

3. Other causes of secondary hypertension.

TreatmentTop

Treatment goal: To normalize BP and serum potassium levels in order to prevent cardiovascular and renal morbidity.

Lifestyle Measures

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 APA and unilateral adrenal hyperplasia.

Pharmacotherapy

1. Potassium oral supplementation (may be tapered down once a mineralocorticoid receptor antagonist [MRA] is initiated and potassium level is adequate).

2. MRAs are indicated before the resection of an APA or UAH; as long-term management in patients with contraindications to surgery or those who do not want surgery; and in BAH/IHA, as they are most effective.

1) Spironolactone: Start with a dose of 12.5 to 50 mg bid and titrate up to a dose where potassium supplementation is not required to maintain normal levels (up to a max of 100 mg bid). Note that after several months the dose may need to be reduced again, even to low levels such as 25 mg bid. Adverse effects include gynecomastia (at doses >150 mg/d), erectile dysfunction, menstrual disorders caused by inhibition of androgens and progestogens, nausea, vomiting, and diarrhea.

2) Eplerenone is an alternative agent. It is more expensive but causes fewer adverse effects than spironolactone, as it is more specific. Start with doses of 25 mg bid. The dose may be increased to 100 mg/d initially and then titrated down once good BP control is achieved.

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

4) ACEIs/ARBs, DHP-CCBs can be added to MRAs (or to another potassium-sparing diuretic) if hypertension persists. Beta-blockers are not very effective in this case.

5) Glucocorticoids are used in patients with GRA in addition to the above-listed drugs. The most frequently used agent is dexamethasone 0.5 to 0.75 mg/d.

PrognosisTop

Surgical resection of an APA or UAH leads to complete resolution of hypertension in 35% to 70% of patients as well as to normalized potassium levels in almost all 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 a direct adverse effect on cardiovascular and renal morbidity.

Many patients may have underlying essential hypertension even after resection of an APA or UAH and should be treated as per usual hypertension practices.

TablesTop

Table 6.1-1. Interpretation of the ARR

Renin measurement methods and units

Weak positive screening result

Strong positive screening result

Plasma renin activity (ng/mL/h)

ARR 550-750

ARR >750

Renin concentration (mIU/L)

ARR 60-90

ARR >90

Renin concentration (ng/L)

ARR 100-144

ARR >144

ARR, aldosterone-to-renin ratio.

Table 6.1-2. Effects of medical states, other drugs, and antihypertensive agents on the ARR

False-positive results

– Aging

– CKD

– Beta-blockers

– Central alpha2 agonists (clonidine, methyldopa)

– NSAIDs

– Birth control pills

False-negative results

– Hypokalemia

– Pregnancy

– Diuretics

– ACEIs

– ARBs

– Ca2+ blockers (DHP)

– Direct renin inhibitors

Neutral

– Alpha1 blockers (doxazosin, terazosin, prazosin)

– Long-acting nondihydropyridine calcium channel blockers (verapamil and diltiazem)

– Hydralazine

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARR, aldosterone-to-renin ratio; CKD, chronic kidney disease; DHP, dihydropyridine; NSAID, nonsteroidal anti-inflammatory drug.

Table 6.1-3. Causes of mineralocorticoid-dependent hypertension

Low renin, high aldosterone

Low renin, low aldosterone

High renin, high aldosterone

Primary aldosteronism

– Congenital adrenal hyperplasia: 17alpha-hydroxylase or 11beta‑hydroxylase deficit

– Apparent mineralocorticoid excess (11beta‑HSD2 deficit), genetic or acquired (eg, black licorice)

– DOC-secreting adrenal tumor

– Liddle syndrome

– Exogenous mineralocorticoid (eg, fludrocortisone)

– Cushing syndrome

– Primary cortisol resistance

– Renal artery stenosis

– Malignant hypertension

– Coarctation of the aorta

– Renin-secreting tumors (reninoma)

– High doses of diuretics

– Ectopic nonrenal renin-producing tumors

 

11beta‑HSD2, 11beta-hydroxysteroid dehydrogenase type 2; DOC, 11-deoxycorticosterone.

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