Primary Aldosteronism

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. It is one of the most common causes of secondary hypertension and often remains underdiagnosed.

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 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 (BP) due to primary 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/resistant hypertension (>140/90 mm Hg) despite treatment with a maximum dose of 3 antihypertensive drugs, including a thiazide or 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 a discovered adrenal incidentaloma.

4) Patients with hypertension aged <20 years.

5) Patients with hypertension and first-degree relatives diagnosed with PA or a family history of early-onset hypertension <40 years of age, or those with 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).

3) Mild metabolic alkalosis.

4) Creatinine should be measured to assess kidney function.

2. Screening hormone tests: The first task is to decide which situations warrant such screening. The presence of significant hypokalemia (especially unexplained), hypertension that is resistant to treatment, young age, and lack of associated risk factors (obesity, diabetes) are all increasing the probability of PA. A scoring tool, SToP-PA, may assist in this decision, with a score of ≥5 points being considered a threshold for further testing. In this tool, which is constructed to be very sensitive towards the recognition of potential PA, potassium concentration <3.0 mEq/L warrants 5 points (<4 mEq/L, 3 points); systolic BP >165 mm Hg, 4.5 points (>135 mm Hg, 3.5 points); use of >3.6 defined daily doses (DDD) of antihypertensive medications, 5.5 points (3 points for ≥0.9 DDD). An additional point is awarded if the patient is male and another one for end-organ damage. A low body mass index (BMI; <21 kg/m²) warrants 4.5 points, and a BMI <25 kg/m², 2.5 points.

Renin, aldosterone, and the aldosterone-to-renin ratio (ARR) are the preferred screening tests, often used in conjunction with potassium and creatinine measurements. A low renin level, together with an inappropriately high aldosterone level and a high ARR, are the most important factors to suspect PA. Therefore, all the 3 parameters need to be taken into account in addition to the clinical data (severity of hypertension, number of drugs, end-organ damage) and potassium level for estimating the pretest probability of PA. Since aldosterone levels vary from day to day, if the suspicion is high, aldosterone testing should be repeated along with renin, potassium, and creatinine measurements.

The test should be performed in the upright position, after the patient has been ambulatory for 2 hours. Hypokalemia should be corrected and sodium should not be restricted prior to testing. Testing can be done while the patient is on medications, but if the results are inconclusive and if possible, agents that significantly affect the results (aldosterone antagonists, diuretics) should be stopped 4 to 6 weeks prior to the repeat blood testing and other interfering medications should be withdrawn for 2 weeks (eg, beta-blockers, angiotensin-converting enzyme inhibitors [ACEIs], angiotensin receptor blockers [ARBs], DHP-CCBs, centrally acting alpha2 agonists). Other common interfering drugs include nonsteroidal anti-inflammatory drugs (NSAIDs) and oral contraceptive pills.

During the washout, BP can be controlled with medications that are much less likely to affect testing, which include alpha1-adrenergic blockers such as doxazosin, terazosin, prazosin; long-acting non–dihydropyridine calcium channel blockers such as diltiazem or verapamil; and/or hydralazine.

Interpretation of the ARR depends on the assay and units used (Table 1).

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

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, caution is needed in those at high risk.

The diagnosis can be made without further confirmatory testing if there is spontaneous hypokalemia, plasma renin below detection levels, and plasma aldosterone concentration (PAC) >555 pmol/L (>20 ng/dL), or if the ARR is >270 pmol/ng (>1400 pmol/L/ng/mL/h) with a PAC >440 pmol/L and a low renin level, or if no spontaneous hypokalemia but a low renin level and a PAC >831 pmol/L are observed. PA is unlikely if the aldosterone level is <139 pmol/L, even with a low renin level.

Mild cortisol cosecretion (or mild autonomous cortisol secretion [MACS]) without overt Cushing syndrome may occur in patients with APAs (≥1 cm). It is important to screen for this condition by measuring baseline serum dehydroepiandrosterone sulfate (DHEAS) and ACTH levels and performing a 1-mg overnight bedtime dexamethasone suppression test to look for cortisol suppression (cortisol level < 50 nmol/L following dexamethasone is normal). MACS can affect the interpretation of adrenal vein sampling (AVS) if adrenalectomy is pursued in individuals with this condition. The patient may need glucocorticoid coverage postoperatively due to cortisol suppression in the contralateral adrenal gland.

Confirmatory testing for PA as described below can be recommended for certain patients, although recent data show that it may not be that accurate (false negatives), especially if the pretest probability is high.

3. Confirmatory testing: All tests aim to suppress aldosterone.

1) Salt loading tests (perform either):

a) Oral: 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. Hypokalemia should be corrected prior to the test. Since sodium loading typically increases kaliuresis and hypokalemia, potassium level should be monitored daily and replacement of potassium chloride should be given if needed. 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 less likely.

b) IV: Administer 2 L of normal saline IV over 4 hours with the patient in a recumbent or supine position. 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. Newer data indicate that the seated test is more accurate and sensitive than that performed in a recumbent or supine position. Here, PA is defined as a postinfusion PAC >222 pmol/L. If PAC is <171 pmol/L, PA is unlikely. Values in between are considered indeterminate. Cortisol levels are also measured in the seated test before and after infusion to avoid false-positive elevation in aldosterone concentration at the end of the infusion. These tests are contraindicated in the presence of severe uncontrolled hypertension or congestive heart failure.

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; functioning lesion lateralization requires 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 allow 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 and interventional radiologist 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: 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 possible and wanted, with or without IV ACTH stimulation. Cortisol concentrations from the adrenal and peripheral veins are used to confirm successful catheterization of the adrenal veins (as 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.

In persons aged <35 years with confirmed PA, hypokalemia, aldosterone levels >831 pmol/L (>30 ng/dL), unilateral adrenal adenoma (>1-2 cm) on CT, and normal morphology of the contralateral adrenal gland, there is no need for AVS before qualifying for surgery.

6. Molecular/nuclear imaging for PA subtyping: The future holds promise for molecular/nuclear imaging to subtype PA (to see if there is a functioning lesion/APA), which may obviate the need for AVS. These include ⁶⁸Ga-pentixafor positron emission tomography with computed tomography (PET-CT) and ¹¹C-metomidate PET-CT scans.

7. Genetic testing for familial aldosteronism: Familial aldosteronism should be suspected in patients who developed hypertension and PA 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 low renin, inappropriately high aldosterone, and high ARR (value depends on assay) levels with or without confirmatory testing, as needed.

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

Differential Diagnosis

1. Other causes of mineralocorticoid-related hypertension (secondary aldosteronism and non-aldosterone–mediated mineralocorticoid excess): Table 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 diet with a restricted amount of sodium <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. If cortisol cosecretion is documented, it is important to cover the patient perioperatively with stress doses of glucocorticoids and taper them after surgery. Aldosterone levels should be checked the day after surgery, and potassium supplements and MRAs should be stopped; other antihypertensive agents can be stopped or tapered with close monitoring of BP and potassium levels. Some patients may have transient (rarely permanent) hypoaldosteronism requiring liberal sodium intake, fluids, and fludrocortisone therapy for the first few weeks.

In very selective cases, noncurative unilateral adrenalectomy can be considered in BAH/IHA if MRA therapy has not been fully effective or is associated with major adverse effects.

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. Renin levels can be used to guide if the mineralocorticoid receptor blockade is adequate. If renin levels remain low or suppressed, the dose of the MRA can be titrated up as needed while monitoring potassium and creatinine levels.

1) Spironolactone: Start with a dose of 12.5 to 25 mg daily 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 a dose of 25 mg once daily. The dose may be increased to 100 mg/d (divided bid) 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 once daily to bid, up to 20 mg/d.

4) ACEIs/ARBs, DHP-CCBs, thiazide-like diuretics 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.

6) Future medical therapies in development include aldosterone synthase inhibitors such as baxdrostat.

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. Observational and small prospective studies show improvement in clinical cardiovascular and renal outcomes with treatment, especially with surgery for APA or UAH.

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 primary hypertension even after resection of an APA or UAH and should be treated as per usual hypertension practices.

TablesTop