Primary hyperaldosteronism (Conn syndrome)

Primary hyperaldosteronism, sometimes referred to as Conn syndrome, is an excess of aldosterone caused by autonomous overproduction, usually at the adrenal cortex. It is typically due to adrenal hyperplasia or adrenal adenoma. Primary hyperaldosteronism is one of the common causes of secondary hypertension. High systemic aldosterone levels result in increased sodium reabsorption and potassium secretion in the collecting ducts of the kidney, which leads to the retention of water along with sodium, as well as hypokalemia. Patients are often asymptomatic and found to have hypertension at routine health checks. It will often emerge that the patient's hypertension is resistant to pharmaceutical therapy, and they may have other signs suggestive of secondary hypertension, such as an age of onset below 30 years or above 55 years. If symptoms are present, they typically include headache, muscle weakness, and polyuria. Initial labs in primary hyperaldosteronism classically show a hypertensive patient with hypokalemia, metabolic alkalosis, high plasma aldosterone concentration (PAC) and low plasma renin activity (PRA). Following biochemical confirmation of primary hyperaldosteronism with oral or intravenous sodium loading tests, imaging modalities such as CT and adrenal venous sampling are used to locate the source of autonomous aldosterone secretion. Treatment of primary hyperaldosteronism consists of surgical resection of adrenal adenoma or pharmaceutical therapy with aldosterone antagonists (e.g., spironolactone, eplerenone) in cases of bilateral adrenal hyperplasia.

• 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.

• Hyperaldosteronism 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]
  • Aldosterone-producing adrenal adenoma (Conn syndrome) or aldosteronoma (50–70%)
  • Bilateral idiopathic hyperplasia of the adrenal glands (30%)
• Less common causes include:
  • Unilateral hyperplasia of one adrenal gland
  • Familial hyperaldosteronism
  • Aldosterone-secreting carcinomas of the adrenal cortex
  • Ectopic aldosterone-producing tumors (e.g., in the kidneys, ovaries)

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 principle cells of luminal membrane at the cortical collecting ducts of the kidneys → ↑ Na⁺ reabsorption and retention → water retention → hypertension ^[3]
• Aldosterone escape ^[4]
  • 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 ^[5]

Screening tests

Plasma aldosterone concentration to plasma renin activity (PAC/PRA ratio)

• Indications
  • Hypertension and hypokalemia especially when associated with biochemical findings suggestive of primary hyperaldosteronism
    • Mild hypernatremia
    • Metabolic alkalosis
  • Severe or drug-resistant hypertension
• Results: in primary hyperaldosteronism, aldosterone is increased and renin is decreased
  • ↑ PAC (> 15 ng/dL or 416 pmol/L) and ↓ PRA
  • ↑ PAC/PRA ratio (ratio > 20)
  • Confirmatory testing is considered unnecessary in a patient with the following combination:
    • Spontaneous hypokalemia
    • Undetectable PRA levels
    • PAC > 20 ng/dL

The PAC/PRA ratio is used to detect primary hyperaldosteronism.

Confirmatory tests

Oral sodium loading test

• Procedure
  • High-sodium diet (5000 mg) or oral sodium chloride tablets (2 g taken three times daily) for 3 days
  • Followed by 24-hour urine measurements of aldosterone, sodium (to confirm appropriate sodium loading), and creatinine (to assess adequate urine collection)
• Healthy individuals: RAAS is physiologically suppressed → inhibition of aldosterone secretion
• Primary hyperaldosteronism: failure to suppress aldosterone secretion (high urine aldosterone > 12 mcg/day and urine sodium > 200 mEq)

Saline infusion test

• Procedure: infusion of 2 L of normal saline over 4 hours
• Healthy individuals: RAAS is physiologically suppressed → inhibition of aldosterone secretion to plasma concentration < 5 ng/dL (139 pmol/L)
• Primary hyperaldosteronism: failure to suppress aldosterone secretion (PAC > 10 ng/dL, or 277 pmol/L)

Fludrocortisone suppression test

• Procedure: administration of fludrocortisone (0.1 mg every 6 h) for a duration of 4 days (with simultaneous replacement of sodium chloride and potassium)
• Healthy individuals: RAAS is physiologically suppressed → substantial decrease of aldosterone < 50 ng/mL or ≤ 6 ng/dL (measured in upright position at 10am on day 4)
• Primary hyperaldosteronism: Failure to suppress the aldosterone secretion (serum levels > 50–60 ng/mL or > 6 ng/dL)

Captopril suppression test ^[6]

• Procedure: PRA and PAC are measured at baseline and 2 hours after administration of a single dose of captopril (25–50 mg).
• Healthy individuals: RAAS is physiologically suppressed → inhibition of aldosterone secretion (more than 30% suppression from baseline)
• Primary hyperaldosteronism: failure to suppress the aldosterone secretion (less than 30% suppression from baseline)

Imaging

Adrenal CT

• Initial test to identify the cause of biochemically confirmed primary hyperaldosteronism
• Allows exclusion or detection of carcinoma and differentiation of bilateral adrenal hyperplasia from unilateral adrenal adenoma

Adrenal venous sampling

• Overview
  • Standard for differentiating between unilateral adenoma and bilateral hyperplasia
  • Administered if surgical treatment of primary hyperaldosteronism is desired
• Procedure: PAC measured via catheter in blood from right adrenal vein, left adrenal vein, and inferior vena cava
  • Four-fold increase in PAC compared with the contralateral side is suggestive of unilateral disease
  • Small or no difference in PAC between the two sides (i.e. PAC is bilaterally elevated) is suggestive of bilateral hyperplasia

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.

Bilateral adrenal hyperplasia

• Pharmacotherapy: aldosterone receptor antagonists
  • Eplerenone
  • Spironolactone

Unilateral autonomous aldosterone secretion (e.g., adenoma, unilateral hyperplasia, carcinoma)

• Surgery: adrenalectomy
  • Prior to surgery, hypokalemia should be corrected; with spironolactone and potassium supplementation.
  • Following surgery: monitor for hyperkalemia
• Pharmacotherapy: Aldosterone receptor antagonists may be considered in patients who are poor surgical candidates.