Primary Aldosteronism: Screening and Management

Definition and pathophysiology

Primary aldosteronism (PA), also termed primary hyperaldosteronism or Conn syndrome, comprises disorders in which aldosterone secretion is inappropriately increased, relatively autonomous from angiotensin II and plasma potassium, and resistant to suppression by sodium loading. It is the most common form of secondary hypertension.

Aldosterone acts principally through the mineralocorticoid receptor (MR). After entering target cells, it binds the MR, which translocates to the nucleus and induces expression of aldosterone-responsive genes. Although the kidney is a major target—where MR activation promotes sodium transport—MRs are also present in cardiac myocytes, vascular smooth muscle, endothelial cells, macrophages, neurons and other tissues. This distribution helps explain why PA produces cardiovascular injury beyond its effects on blood pressure and potassium balance.

The principal sporadic subtypes are:

• Aldosterone-producing adrenal adenoma

• Bilateral adrenal hyperplasia

• Primary or unilateral adrenal hyperplasia

• Rare aldosterone-producing adrenal carcinoma

• Less commonly, ectopic aldosterone production

Familial forms include familial hyperaldosteronism type 1, formerly termed glucocorticoid-remediable aldosteronism, and other familial forms associated with adrenal adenoma or bilateral adrenal hyperplasia. A family history is therefore important, particularly in patients with early-onset hypertension or premature cerebrovascular disease.

PA is associated with cardiac hypertrophy, myocardial fibrosis, diastolic dysfunction and heart failure. Compared with patients with primary hypertension matched for age, sex and blood pressure, affected patients have more frequent stroke, nonfatal myocardial infarction and atrial fibrillation, as well as greater cardiovascular mortality. Metabolic syndrome and diabetes are also more prevalent.

Epidemiology and clinical significance

The reported prevalence depends on the population studied and the intensity of screening. PA occurs in approximately 10% of patients with hypertension and in approximately 20% of those with resistant hypertension. It is also more frequent with increasing blood pressure severity.

Hypokalaemia is highly suggestive when present, particularly if spontaneous or diuretic-induced, but it is absent in most diagnosed patients. Reliance on hypokalaemia alone therefore misses a substantial proportion of cases.

The cardiorenal and cerebrovascular consequences of unrecognized PA make early case detection clinically important. Current European recommendations advise screening adults with confirmed hypertension by measuring renin and aldosterone, although the strongest indications arise in patients with resistant or severe hypertension and associated clinical features.

Clinical presentation and symptoms

The usual clinical manifestation is hypertension, often severe or resistant to treatment. Some patients have controlled blood pressure only while taking four or more antihypertensive agents.

Possible clinical settings suggesting PA include:

• Grade 2 or 3 hypertension

• Resistant hypertension

• Sustained blood pressure above 150/100 mm Hg on repeated measurements

• Hypertension requiring at least four antihypertensive drugs despite control

• Hypertension with spontaneous or diuretic-induced hypokalaemia

• Hypertension with an adrenal incidentaloma

• Hypertension associated with sleep apnoea

• Hypertension with atrial fibrillation in the absence of an underlying structural cardiac explanation

• Early-onset hypertension or cerebrovascular accident at a young age in the patient or family

• Hypertensive first-degree relatives of patients with PA

Patients with hypokalaemia may develop weakness, muscle cramps or, in severe cases, periodic paralysis. Nevertheless, many patients are normokalaemic and have no distinctive symptoms attributable to aldosterone excess.

Cardiovascular complications may dominate the presentation or emerge during evaluation. These include cardiac hypertrophy, myocardial fibrosis, diastolic dysfunction, heart failure, atrial fibrillation, stroke and myocardial infarction.

Evaluation and physical examination

Assessment begins with confirmation and characterization of hypertension, including treatment burden and the adequacy of blood-pressure control. The medication history is essential because many antihypertensive agents influence renin, aldosterone or the aldosterone-to-renin ratio (ARR).

The history should specifically address:

• Previous spontaneous or diuretic-induced hypokalaemia

• Resistant or severe hypertension

• Adrenal incidentaloma

• Sleep-disordered breathing or sleep apnoea

• Atrial fibrillation

• Early-onset hypertension or stroke in relatives

• Known PA in first-degree relatives

• Age at hypertension onset

• Use of medications that affect ARR interpretation

Physical examination should document blood pressure and assess the consequences and associated conditions of hypertension. The source material does not provide a specific examination phenotype or a defined set of physical signs unique to PA.

Screening with the aldosterone-to-renin ratio

Principles

The recommended screening test is the ARR, calculated from plasma aldosterone and either plasma renin activity or direct renin concentration. Both components should be considered individually because the ratio can be misleading when renin is profoundly suppressed or affected by medication.

Screening is most reliable when patients are potassium replete and have unrestricted dietary salt intake. Hypokalaemia should be corrected before testing because it may reduce aldosterone secretion and obscure the diagnosis.

ARR thresholds vary according to the units used and the local laboratory method. An ARR greater than 20 is commonly used as a positive screening threshold in some settings, whereas a threshold of 30 is also frequently used when aldosterone is expressed in nanograms per decilitre and plasma renin activity in nanograms per millilitre per hour. These values cannot be transferred between laboratories without considering the measurement units and assay characteristics.

Medication effects

ARR is influenced by antihypertensive therapy, sodium intake, posture, time of day and sample handling. Important interfering drugs include:

• Beta-blockers

• Centrally acting agents such as clonidine and methyldopa

• Renin–angiotensin system blockers

• Diuretics

• Mineralocorticoid receptor antagonists

• Non-steroidal anti-inflammatory drugs

• Angiotensin-converting enzyme inhibitors

• Angiotensin receptor blockers

• Dihydropyridine calcium-channel blockers

Two practical approaches are acceptable when the patient is already receiving treatment for hypertension.

The first is to perform ARR testing without changing the baseline regimen and interpret the result in relation to the drugs being taken. This avoids deterioration in blood-pressure control and reduces barriers to screening, but interpretation may require specialist input.

The second is to withdraw interfering drugs before testing whenever this is clinically feasible. One source recommends stopping MRAs for at least four weeks, especially in patients with mild hypertension, and withdrawing other interfering agents for approximately two weeks. Another guideline table specifies withdrawal of aldosterone antagonists for four to six weeks. These intervals should therefore be interpreted in accordance with the relevant guideline and local practice.

Long-acting calcium-channel blockers and alpha-receptor antagonists have little effect on ARR and can be used as alternatives. Centrally acting sympatholytic agents may be used when necessary, although they can slightly increase false-positive results through renin suppression.

MRAs should not be withdrawn when this would be unsafe, such as in severe hypokalaemia or severe hypertension associated with marked hyperaldosteronism. Available evidence indicates that ARR accuracy is only marginally affected in this situation, particularly when PA is florid.

Sodium intake should be assessed, preferably with 24-hour urinary sodium or a morning urinary sodium-to-creatinine ratio. In women, the menstrual-cycle phase may also influence interpretation.

Interpreting suppressed renin

When renin is below the assay’s measurable range, an ARR may not be calculable. The serum aldosterone concentration then becomes particularly important:

• Aldosterone below 10 ng/dL makes overt PA unlikely.

• Aldosterone between 10 and 20 ng/dL generally warrants additional confirmatory testing.

• Suppressed renin, aldosterone above 20 ng/dL and hypokalaemia may be sufficient to establish the diagnosis in the appropriate clinical setting.

Some guideline pathways permit omission of confirmatory testing in patients with hypokalaemia, undetectable renin and aldosterone above 20 ng/dL.

Confirmatory testing

Most patients with a positive ARR undergo a suppression test to confirm or exclude autonomous aldosterone secretion. The available tests include saline loading, oral sodium loading, the fludrocortisone suppression test and the captopril challenge.

Confirmatory testing requires caution in patients with hypokalaemia, heart failure, chronic kidney disease or uncontrolled hypertension. Intravenous saline is often inappropriate in patients with heart failure, chronic kidney disease or uncontrolled hypertension; a captopril test may be used instead when saline loading is considered risky.

The choice of confirmatory test depends on patient preference, cost, local expertise, laboratory procedures and reimbursement arrangements.

Adrenal imaging and subtype diagnosis

Computed tomography and magnetic resonance imaging

After biochemical confirmation, adrenal computed tomography (CT) is recommended to evaluate the adrenal glands and identify a large mass that could represent adrenal carcinoma. CT may show:

• A small, hypodense, unilateral aldosterone-producing adenoma

• Normal-appearing adrenal glands in idiopathic or bilateral hyperaldosteronism

• Nodularity or enlargement of one or both glands in bilateral disease

• Features suggestive of carcinoma, including a mass larger than 4 cm, heterogeneity, internal haemorrhage, calcification, irregular margins or contrast enhancement

CT cannot reliably establish the source of aldosterone excess. Microadenomas measuring 10 mm or less may be missed, while nonfunctioning nodules are common, particularly in older patients. MRI does not improve detection of these abnormalities compared with CT.

Adrenal venous sampling

Because imaging alone may misclassify the functional subtype, adrenal venous sampling (AVS) is recommended before surgery for most patients who are surgical candidates. AVS distinguishes unilateral aldosterone production, which may be surgically curable, from bilateral disease, which requires medical treatment.

The procedure is invasive, technically demanding and dependent on an experienced multidisciplinary team. It is commonly performed in the morning with continuous cosyntropin administration and simultaneous cortisol measurement from adrenal and peripheral venous samples. Lateralization is generally defined using the cortisol-corrected aldosterone ratio between the two adrenal veins; a side-to-side ratio of at least 4:1 is commonly used.

Guideline pathways allow AVS to be omitted in selected younger patients with marked PA and a unilateral adrenal lesion larger than 10 mm on CT. One source specifies an age below 35 years, while another describes direct surgery in selected patients younger than 40 years with a single typical hypodense unilateral nodule. This approach is therefore restricted to carefully selected patients.

Functional imaging with radiolabelled tracers can also contribute to subtype assessment. Newer nuclear imaging methods, including 11C-metomidate PET-CT and gallium-68 pentixafor PET-CT, are being evaluated as potential non-invasive alternatives to AVS.

Steroid profiling

Steroid profiling of adrenal-vein and peripheral samples may help distinguish adenoma from hyperplasia. Peripheral 18-oxocortisol is higher in adenoma than in bilateral hyperplasia, whereas cortisol, corticosterone and dehydroepiandrosterone are lower.

Familial primary aldosteronism and genetic evaluation

A family history should be sought in all patients, with particular attention to early-onset hypertension and premature stroke. Germline genetic testing is recommended when a familial form is suspected, including patients diagnosed at a young age or those with a relevant family history.

Genetic testing is sensitive and specific for familial hyperaldosteronism type 1. Familial hyperaldosteronism type 2 is genetically heterogeneous, and testing is not yet available according to the source material; diagnosis is therefore primarily clinical, based on biochemical findings and family pedigree.

Treatment and management

Management is determined principally by whether aldosterone excess is unilateral or bilateral.

• Unilateral disease may be treated with adrenalectomy.

• Bilateral disease is treated medically and requires lifelong therapy.

• Patients who are older, have important comorbidities or do not wish to undergo surgery may also receive medical therapy despite unilateral disease.

Treatment aims to control blood pressure, correct hypokalaemia and reduce the cardiovascular consequences of aldosterone excess.

Mineralocorticoid receptor antagonists

MRAs are the foundation of medical treatment. Spironolactone is the most widely available and is generally more potent than eplerenone.

• Spironolactone is usually started or maintained in the range of 50–100 mg once daily and may be titrated, if necessary, to 300–400 mg once daily.

• Eplerenone is less potent and requires twice-daily administration, but produces less gynaecomastia and erectile dysfunction in men.

Gynaecomastia and sexual dysfunction may develop in approximately 30% of treated men. Eplerenone is a practical alternative when these adverse effects occur.

Electrolytes require close monitoring during MRA therapy. Patients with PA and hypokalaemia should receive slow-release potassium chloride to maintain plasma potassium, with subsequent adjustment as the aldosterone blockade becomes effective.

Newer non-steroidal MRAs, including finerenone and exarenone, and the aldosterone synthase inhibitor baxdrostat are being evaluated for PA. Their use in PA remains under investigation in the source material.

Unilateral adrenalectomy

Surgical removal of the affected adrenal gland is generally considered for unilateral PA, particularly when the diagnosis of unilateral secretion has been established by AVS or an accepted alternative strategy.

Laparoscopic adrenalectomy is the usual operative approach described in the source material. It is associated with shorter hospital stays, fewer complications and lower costs than open surgery in patients with AVS-proven unilateral disease.

Surgery generally corrects hypokalaemia and may improve or normalize hypertension. In long-term follow-up, blood-pressure cure—defined as blood pressure below 140/90 mm Hg without antihypertensive therapy—occurs in approximately half of patients. Cure is more likely in younger patients, those with a shorter duration of hypertension, patients previously controlled with only one or two drugs, and those with fewer hypertensive first-degree relatives.

After surgery, plasma aldosterone and plasma renin activity are typically reassessed. Potassium supplementation and aldosterone antagonists can then be withdrawn when appropriate. Intravenous saline may be required temporarily because recovery of normal function in the remaining adrenal gland can take several weeks.

Bilateral disease and non-surgical treatment

Surgery is not appropriate for bilateral PA. Such patients require lifelong MRA therapy. The same medical strategy applies to patients with unilateral disease who are not suitable for surgery or who decline an operation.

Familial hyperaldosteronism type 1

Familial hyperaldosteronism type 1 is the familial form responsive to glucocorticoids. Low-dose dexamethasone suppresses adrenocorticotropic hormone and can normalize blood pressure and potassium, generally without clinically important glucocorticoid effects. Low doses can be used during pregnancy according to the source material.

If blood pressure remains elevated despite glucocorticoid treatment, an MRA can be added. Dexamethasone or prednisone is often administered at bedtime, with doses kept low to avoid iatrogenic Cushing syndrome.

Guideline recommendations

Guideline-based screening groups include patients with severe or resistant hypertension, hypokalaemia, adrenal incidentaloma, sleep apnoea, atrial fibrillation without an explanatory structural cardiac cause and suspected familial disease.

The principal diagnostic sequence is:

• Measure aldosterone and renin and calculate the ARR.

• Correct hypokalaemia and account for sodium intake and medication effects.

• Perform confirmatory suppression testing when indicated.

• Obtain adrenal CT after biochemical confirmation.

• Perform AVS in most surgical candidates to establish unilateral or bilateral secretion.

• Select adrenalectomy for appropriate unilateral disease and lifelong MRA therapy for bilateral disease or non-surgical patients.

Prognosis and follow-up

Untreated PA carries greater cardiovascular risk than primary hypertension, including increased rates of cardiac hypertrophy, myocardial fibrosis, diastolic dysfunction, heart failure, stroke, myocardial infarction and atrial fibrillation. Cardiovascular mortality is also higher.

Follow-up should assess:

• Blood-pressure control

• Plasma potassium and other electrolytes during MRA therapy

• Renin and aldosterone status when clinically appropriate

• Resolution or persistence of hypokalaemia

• Need for potassium supplementation

• MRA adverse effects, particularly gynaecomastia and sexual dysfunction

• Cardiovascular complications, including atrial fibrillation and heart failure

• Postoperative biochemical response and the continuing need for antihypertensive therapy

Following successful adrenalectomy, biochemical reassessment is performed soon after surgery, with withdrawal of potassium and MRA therapy when safe. Blood pressure may improve progressively, and the remaining adrenal gland may require several weeks to recover normal function.

For bilateral disease, treatment is lifelong and requires continuing surveillance of electrolytes and blood pressure. The source material does not specify a standardized follow-up interval or a detailed long-term cardiovascular surveillance protocol.