Primary hyperaldosteronism

Primary hyperaldosteronism, sometimes referred to as Conn syndrome, is an excess of aldosterone caused by autonomous overproduction. It is typically due to adrenal hyperplasia (most commonly bilateral) or adrenal adenoma (typically unilateral). Primary hyperaldosteronism is a common cause of secondary hypertension, occurring in > 5–12% of hypertensive patients. High systemic aldosterone levels result in increased renal sodium reabsorption and potassium secretion, which lead to water retention and hypokalemia. Patients are often asymptomatic and found to have hypertension at routine health checks. Hypertension due to primary hyperaldosteronism is often resistant to pharmacotherapy, and patients may have other signs suggestive of secondary hypertension, such as onset before the age of 30 or after the age of 55. If symptoms are present, these are usually manifestations of hypokalemia (e.g., headache, muscle weakness, and polyuria). Initial laboratory values in primary hyperaldosteronism classically show hypokalemia, metabolic alkalosis, high plasma aldosterone concentration (PAC), and low plasma renin activity (PRA). The plasma aldosterone-to-renin ratio is the initial screening test, followed by confirmatory testing. Further subtyping with imaging and/or adrenal venous sampling can determine whether aldosterone hypersecretion is unilateral or bilateral, which guides management. Treatment of unilateral disease consists of surgical resection, whereas bilateral disease is managed medically with aldosterone antagonists (e.g., spironolactone, eplerenone).

• Prevalence: estimated to be between 5 and 12% in hypertensive patients ^[1]
• Sex
  • Aldosterone-producing adrenal adenoma: ♀ > ♂ (2:1)
  • Adrenal hyperplasia ♂ > ♀ (4:1)

Epidemiological data refers to the US, unless otherwise specified.

• Primary hyperaldosteronism (Conn syndrome) is caused by autonomous overproduction of aldosterone in the zona glomerulosa of one or both adrenal glands (see “Hormones of the adrenal cortex”).
• Most commonly due to the following conditions: ^[2]
  • Bilateral idiopathic hyperplasia of the adrenal glands (∼ 60%)
  • Aldosterone-producing adrenal adenoma or aldosteronoma (∼ 30%)
• Less common causes include:
  • Unilateral hyperplasia of one adrenal gland
  • Aldosterone-secreting carcinomas of the adrenal cortex
  • Familial hyperaldosteronism (e.g., FH-I) ^[3]
    • A genetic cause of primary hyperaldosteronism that may respond to different treatment options ^[4]
    • More likely in patients with primary hyperaldosteronism at a young age (< 20 years), a family history of hyperaldosteronism, and/or a family history of early stroke ^[3][5]
  • Ectopic aldosterone production
    • Autonomous aldosterone production that occurs outside the adrenal gland (e.g., aldosterone-producing tumors in the kidneys or ovaries) ^[6]
    • Specialized imaging may be needed to confirm the diagnosis (e.g., PET scan). ^[7]

Autonomous aldosterone secretion and hypertension

• Physiological aldosterone secretion is regulated by the renin-angiotensin-aldosterone system (RAAS) and occurs in response to the detection of low blood pressure in the kidneys (see “Renin-angiotensin-aldosterone system”).
• ↑ Aldosterone → ↑ open Na⁺ channels in principal cells of luminal membrane at the cortical collecting ducts of the kidneys → ↑ Na⁺ reabsorption and retention → water retention → hypertension ^[8]
• Aldosterone escape ^[9]
  • Definition: Evasion of the Na⁺-retaining effects of inappropriately elevated aldosterone levels in conditions such as primary hyperaldosteronism or congestive heart failure
  • Mechanism: sodium and water retention → volume expansion → secretion of atrial natriuretic peptide (ANP) and pressure natriuresis → compensatory diuresis → “escape” from edema formation and hypernatremia

In edematous disorders the aldosterone escape mechanism is impaired, resulting in worsening edema.

Hypokalemia and metabolic alkalosis

• ↑ Na⁺ reabsorption → electronegative lumen → electrical gradient through open K⁺ channels → ↑ K⁺ secretion → hypokalemia
• Hypokalemia → metabolic alkalosis via two mechanisms (both of which decrease extracellular H⁺, thereby increasing extracellular pH):
  • Efflux of K⁺ from intracellular to extracellular space in exchange for H⁺
  • ↑ H⁺ secretion in the kidney in order to enable ↑ K⁺ reabsorption
• Diabetes insipidus: hypokalemia → desensitization of renal tubules to antidiuretic hormone (ADH) → polyuria and polydipsia

• Hypertension
  • Sustained systolic blood pressure > 150 mm Hg or diastolic > 100 mm Hg over three measurements on three different days
  • Systolic blood pressure > 140 mm Hg or diastolic > 90 mmHg AND resistant to three-drug therapy with an adrenergic inhibitor, a vasodilator, and a diuretic
  • See “Secondary hypertension.”
• Features of hypokalemia
  • Fatigue
  • Muscle weakness, cramping
  • Headaches
  • Paresthesia in severe cases due to metabolic alkalosis
  • Polyuria and polydipsia
  • Palpitations
  • Constipation
• Absence of significant edema (due to aldosterone escape)

Primary hyperaldosteronism is characterized by hypokalemia and drug-resistant hypertension.

Approach ^[3]

• Determine whether diagnostic evaluation is warranted. Indications for diagnostic evaluation include:
  • Resistant hypertension despite combination therapy with 3 antihypertensives
  • Family history positive for:
    • First-degree relative with primary hyperaldosteronism
    • Hypertension or cerebrovascular accident at < 40 years of age
  • Hypokalemia ; ^[3][10]
    • Spontaneous or induced by diuretics ^[10]
    • Possibly associated with mild hypernatremia and/or metabolic alkalosis ^[11]
  • Adrenal incidentaloma on prior imaging
  • Sleep apnea ^[3]
• Eliminate confounding factors, e.g.:
  • Correct hypokalemia and encourage normal salt intake prior to testing. ^[3][12]
  • Discontinue agents known to affect renin levels and use an alternative agent. ^[3]
• Perform screening tests: Measure the plasma aldosterone concentration (PAC) and plasma renin activity (PRA) to determine the aldosterone-to-renin ratio (ARR).
  • Positive screening tests
    • Confirm diagnosis (e.g., oral sodium loading test or saline infusion test)
    • Identify subtype and etiology and determine treatment
  • Negative screening tests
    • Consider repeating screening tests if the likelihood of primary hyperaldosteronism remains high.
    • Consider other causes of secondary hypertension.

Agents known to affect renin levels include aldosterone receptor antagonists, ACE inhibitors, and potassium-wasting diuretics. Alternatives include alpha blockers and hydralazine.

Screening: aldosterone-to-renin ratio (ARR) ^[3][12][13]

The aldosterone-to-renin ratio (ARR) is used to screen for primary hyperaldosteronism and differentiate it from other causes of elevated aldosterone (e.g., secondary hyperaldosteronism). ^[14]

• Considerations
  • Compares the plasma aldosterone concentration (PAC) to the plasma renin activity (PRA)
  • Results are easily affected by external factors
  • Low specificity and variable sensitivity : Some sources recommend testing more than once for reliable screening. ^[3][12][13]
• Interpretation
  • ↑ ARR: positive screening result (cutoffs vary) ^[3][15]
  • ↑ PAC: verifies elevated aldosterone and decreases false positive results compared to using ARR alone
  • Example: ARR > 20 (preferably with PAC > 15 ng/dL) suggests elevated aldosterone and suppressed renin.

Patients with primary hyperaldosteronism have elevated aldosterone levels (PAC) that cause decreased renin activity (PRA), resulting in an elevated ARR. [(↑ PAC/↓ PRA) = ↑↑ ARR] ^[3].

Confirmatory studies ^{[3][5][12][13]}

A specialist will order confirmatory testing to verify that aldosterone production is nonsuppressible (i.e., not regulated by the RAAS).

• Test options
  • Oral sodium loading test
    • Ensure high sodium intake for 3 days and collect 24-hour urine aldosterone on the last day.
    • Primary hyperaldosteronism is highly likely if urinary aldosterone > 12 mcg/day.
  • Saline infusion test
    • Draw baseline laboratory studies (e.g., PRA, PAC), infuse normal saline over 4 hours, and draw laboratory studies again.
    • Primary hyperaldosteronism is very probable in patients with aldosterone levels > 10 ng/dL.
  • Others: fludrocortisone suppression test or captopril suppression test
• Interpretation
  • Aldosterone suppression after interventions: primary hyperaldosteronism unlikely. Consider other diagnoses.
  • No aldosterone suppression after interventions: primary hyperaldosteronism confirmed

Determining the subtype

Once hyperaldosteronism is confirmed, imaging helps determine the underlying cause and select treatment.

Adrenal CT ^[3]

Adrenal CT excludes large tumors and helps differentiate possible surgical candidates (e.g., unilateral adenoma) from nonsurgical candidates (e.g., bilateral adrenal hyperplasia). ^[3]

• Indication: recommended as initial imaging modality after confirmatory tests (preferred over MRI)
• Findings ^[3]
  • Bilateral or unilateral adrenal hyperplasia: may appear normal or show nodular changes
  • Aldosterone-producing adrenal adenoma: hypodense nodules < 2 cm
  • Aldosterone-producing adrenal carcinomas: large masses, usually > 4 cm, with potential features of malignancy

Adrenal venous sampling (AVS) ^[3][5]

AVS is the gold standard for biochemically differentiating unilateral aldosterone overproduction from bilateral aldosterone overproduction. ^[3]

• Indications: Both of the following criteria must be met.
  • Adrenal CT suggestive of unilateral hyperaldosteronism
  • Surgical intervention is desired and feasible ^[3]
• Procedure: catheterization of both adrenal veins and a peripheral vein (e.g., IVC) under fluoroscopy followed by a measurement of the aldosterone-to-cortisol ratio of each vein
• Findings ^[3]
  • Unilateral disease: significant difference in the aldosterone-to-cortisol ratio between the right and left adrenal veins
  • Bilateral disease: little to no difference in ratios between the two adrenal gland veins

Additional testing for rare causes of primary hyperaldosteronism

When the underlying cause of primary hyperaldosteronism remains unclear or if specific criteria are met, a specialist may order further testing to evaluate for rare causes, e.g., familial hyperaldosteronism or ectopic aldosterone production (see “Etiology”).

Secondary hyperaldosteronism

• Etiology
  • Renal artery stenosis (e.g., due to atherosclerosis, fibromuscular dysplasia)
  • Renin-secreting tumor
  • Chronic kidney disease
  • Advanced CHF
  • Fibromuscular dysplasia
  • Liver cirrhosis
  • Diuretics
  • Laxative abuse
• Diagnostics: ↑ PAC and ↑ PRA

Pseudohyperaldosteronism

• Etiology
  • Congenital adrenal hyperplasia
  • Exogenous mineralocorticoid
  • Cushing syndrome
  • Liddle syndrome
  • DOC-producing tumor
  • 11β-hydroxysteroid dehydrogenase deficiency
  • Altered aldosterone metabolism
  • Glucocorticoid resistance
  • Excessive licorice ingestion: Excessive consumption of licorice can lead to inhibition of cortisol degradation → hypertension associated with hypokalemia.
• Diagnostics
  • Hypokalemia
  • ↓ PAC and ↓ PRA

The differential diagnoses listed here are not exhaustive.

General principles ^[3]

• Goals of management
  • Reducing blood pressure
  • Limiting end-organ damage
• Unilateral disease or adrenal carcinoma: surgery preferred
• Bilateral disease: medical management preferred

Surgery ^[3][5]

• Indications: confirmed unilateral adrenal hyperaldosteronism in patients with no contraindications to surgery
  • Unilateral aldosterone-producing adenoma (most common)
  • Unilateral adrenal hyperplasia
  • Adrenal carcinoma
• Procedure: laparoscopic unilateral adrenalectomy
• Additional considerations
  • Correct hypokalemia prior to surgery.
  • Monitor for hyperkalemia immediately following the surgery. ^[3]
  • Serial monitoring of blood pressure and ARR on an outpatient basis is recommended. ^[3][5]

Medical management ^[3]

• Indications
  • Bilateral hyperaldosteronism
  • Unilateral hyperaldosteronism in the following situations:
    • When surgery is not desired by the medical team and/or patient
    • Refractory hypertension despite surgery
• First-line: aldosterone receptor antagonists
  • Spironolactone (preferred)
  • Eplerenone
• Other agents
  • Consider additional antihypertensives to decrease the dose of aldosterone antagonists and/or reduce their side effects.
  • Glucocorticoids : indicated only for the treatment of FH-I (rare) ^[3][4]