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 and metabolic alkalosis, and high plasma aldosterone concentration (PAC) and low plasma renin activity (PRA) (PAC/PRA ratio increased). 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.

• Autonomous overproduction of aldosterone (a mineralocorticoid) in the zona glomerulosa of one or both adrenal glands (see Physiological effects of adrenal cortex hormones)
  • Bilateral idiopathic hyperplasia of the adrenal glands (most common)
  • Aldosterone-producing adrenal adenoma, or aldosteronoma
  • Less common causes of primary hyperaldosteronism:
    • Unilateral hyperplasia of one adrenal gland
    • Familial hyperaldosteronism
    • Aldosterone-secreting carcinomas of the adrenal cortex
    • Ectopic aldosterone-producing tumors (e.g., in the kidneys or ovaries)

References:^[2][3][4]

Autonomous aldosterone secretion and hypertension

• Under normal conditions, aldosterone secretion is primarily regulated by the renin-angiotensin-aldosterone system (RAAS) and occurs in response to the detection of low blood pressure in the kidneys.
• Autonomous overproduction of aldosterone; increases sodium reabsorption by the kidneys irrespective of blood pressure and renin activity, resulting in hypertension. ↑ 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
• Aldosterone escape
  • The physiological phenomenon that results in a lack of edema formation and frank hypernatremia in primary hyperaldosteronism
  • Probable mechanism: sodium and water retention → volume expansion → secretion of atrial natriuretic peptide (ANP) and pressure natriuresis (other mechanisms may be responsible, although how these operate remains unclear)→ compensatory diuresis → “escape” from edema and formation and frank hypernatremia

Hypokalemia and metabolic alkalosis

• Increased sodium reabsorption leads to hypokalemia: ↑ Na⁺ reabsorption → electronegative lumen → K⁺ follows the electrical gradient through open K⁺ channels → ↑ K⁺ secretion → hypokalemia
• Hypokalemia causes 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) → increased water excretion (polyuria) and excessive thirst (polydipsia)

References:^[4]

• Hypertension
  • Other evidence of the presence of secondary hypertension
• Features of hypokalemia
  • Fatigue
  • Muscle weakness, cramping
  • Headaches
  • Polyuria and polydipsia
  • Palpitations
  • Constipation
• Lack of significant edema (explained by aldosterone escape → see “Pathophysiology” above)
• Paresthesia in severe cases due to metabolic alkalosis

The classic clinical picture of primary hyperaldosteronism: a young patient with hypokalemia and drug-resistant hypertension!

References:^{[3][5][6][7][8]}

Screening tests

• Plasma aldosterone concentration to plasma renin activity (PAC/PRA ratio; aldosterone-to-renin ratio, or ARR)
  • Indicated in patients with:
    • Hypertension and hypokalemia
      • Associated biochemical findings in classic primary hyperaldosteronism
        • Metabolic alkalosis
        • Mild hypernatremia
    • Severe or drug-resistant hypertension (see “Symptoms/clinical findings” above for details)
  • Results
    • ↑ 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, and PAC > 20 ng/dL

Confirmatory tests: several alternatives

• Oral sodium loading test: 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: 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)

Subtype identification: imaging

• Adrenal CT: initial test to identify the cause of primary hyperaldosteronism already confirmed biochemically
  • Allows for carcinoma to be excluded (or detected)
  • Allows bilateral adrenal hyperplasia to be differentiated from unilateral adrenal adenoma
• Adrenal venous sampling
  • Criterion 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
    • Unilateral disease → four-fold increase in PAC compared with the contralateral side
    • Bilateral hyperplasia → small or no difference in PAC between the two sides (i.e. PAC is bilaterally elevated)

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

References:^{[9][1][2][3][5][10][11]}

• Secondary hyperaldosteronism: (↑ PAC and ↑ PRA)
  • Renal artery stenosis
  • Renin-secreting tumor
  • Chronic kidney disease
  • Advanced CHF
  • Liver cirrhosis
  • Diuretics
  • Laxative abuse
• Pseudohyperaldosteronism: other causes of hypertension with hypokalemia (↓ PAC and ↓ PRA)
  • Congenital adrenal hyperplasia
  • Exogenous mineralocorticoid
  • Cushing's syndrome
  • DOC-producing tumor
  • 11-beta-HSD deficiency
  • Altered aldosterone metabolism
  • Liddle's syndrome
  • Glucocorticoid resistance
  • Excessive licorice ingestion: Excessive consumption of licorice can lead to inhibition of cortisol degradation and thus to hypertension associated with hypokalemia.

References:^[12][442;323]

The differential diagnoses listed here are not exhaustive.

Bilateral adrenal hyperplasia

• Aldosterone receptor antagonists (epleronone, spironolactone )

Unilateral autonomous aldosterone secretion (adenoma, unilateral hyperplasia, carcinoma)

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

References:^[1][2][13]