What are the endocrinological causes of hypokalemia?

Endocrinological Causes of Hypokalemia

Primary aldosteronism is the most common endocrinological cause of hypokalemia, occurring in up to 28.1% of all hypertensive patients with hypokalemia. 1

Primary Aldosteronism

• Characterized by inappropriately high aldosterone production that is relatively autonomous from the major regulators of secretion (angiotensin II and potassium) 1
• Results in sodium retention, potassium excretion, and suppressed plasma renin activity 1
• Excessive aldosterone production causes both retention of sodium and excretion of potassium, leading to hypokalemia 2
• Can be caused by:
  • Unilateral adrenal adenoma (approximately 50% of cases) 1
  • Bilateral adrenal hyperplasia (approximately 50% of cases) 1
• Diagnosis involves measuring plasma aldosterone and renin activity, with a plasma aldosterone-to-renin ratio usually greater than 30 in patients with primary hyperaldosteronism 2

Cushing's Syndrome

• Characterized by hypercortisolism which can cause hypokalemia through effects on the renin-angiotensin-aldosterone system 3
• Causes include:
  • ACTH-producing pituitary tumors 2
  • Ectopic ACTH-producing tumors (lung, thyroid, pancreas, bowel) 2, 4
  • Adrenal adenomas or carcinomas 2
  • Exogenous steroid use 3
• Ectopic ACTH secretion is particularly associated with hypokalemia, affecting 57% of patients with this condition 5
• Higher 24-hour urine cortisol excretion significantly correlates with the presence of hypokalemia 5
• Excess cortisol may act as a mineralocorticoid when in excess, possibly by saturating the 11β-hydroxysteroid-dehydrogenase enzyme that normally inactivates cortisol at the renal tubule 5

Other Mineralocorticoid Excess Syndromes

• Congenital adrenal hyperplasia (CAH) can cause hypokalemia and hypertension 2
  • 11β-hydroxylase deficiency: presents with virilization 2
  • 17α-hydroxylase deficiency: presents with incomplete masculinization in males and primary amenorrhea in females 2
• Both forms of CAH can present with hypertension and hypokalemia with low or normal aldosterone and renin levels 2
• Elevated deoxycorticosterone (DOC) and corticosterone levels are characteristic 2

Thyroid Disorders

• Hyperthyroidism can cause hypokalemia through:
  • Increased beta-adrenergic activity leading to intracellular potassium shift 2
  • Increased renal blood flow and glomerular filtration rate 2
• Clinical findings include warm moist skin, heat intolerance, nervousness, tremulousness, and weight loss 2

Diagnostic Approach

• For suspected primary aldosteronism:
  • Measure plasma aldosterone and renin activity 2
  • Calculate aldosterone-to-renin ratio (ARR > 30 is suggestive) 1
  • Confirmatory testing with saline suppression test or salt loading test may be needed 2
• For suspected Cushing's syndrome:
  • Measure 24-hour urine cortisol levels 2
  • ACTH levels help differentiate between ACTH-dependent and ACTH-independent causes 2
• For suspected congenital adrenal hyperplasia:
  • Look for hypertension and hypokalemia with low or normal aldosterone and renin 2
  • Measure DOC and corticosterone levels 2

Management Considerations

• Primary aldosteronism:
  • Unilateral disease: laparoscopic adrenalectomy 2, 1
  • Bilateral hyperplasia: medical management with spironolactone or eplerenone 2, 1
• Cushing's syndrome:
  • ACTH-producing pituitary tumor: transsphenoidal surgery 2
  • Ectopic ACTH-producing tumor: surgical removal if possible 2
  • Adrenal tumor: laparoscopic adrenalectomy for benign tumors 2
  • Medical management with ketoconazole or mitotane if surgery not possible 2

Clinical Pearls

• Always consider endocrine causes of hypokalemia in patients with concurrent hypertension 6
• Hypokalemia due to primary aldosteronism or Cushing's syndrome is often resistant to potassium supplementation alone without addressing the underlying cause 7
• In patients with unexplained hypokalemia and hypertension, measurement of renin, aldosterone, and cortisol concentrations is essential for differential diagnosis 6
• Severe hypokalemia (≤2.5 mEq/L) requires urgent treatment regardless of the cause 7