What causes hypokalemia with hypertension?

Causes of Hypokalemia with Hypertension

Primary aldosteronism is the most common cause of hypokalemia with hypertension, occurring in up to 20% of patients with resistant hypertension and in 28.1% of all hypertensive patients with hypokalemia. 1, 2

Primary Aldosteronism

Primary aldosteronism is defined as a group of disorders characterized by inappropriately high aldosterone production that is relatively autonomous from the major regulators of secretion (angiotensin II and potassium) and cannot be suppressed with sodium loading. 1

Key characteristics include:

• Increased aldosterone production leading to hypertension, cardiovascular damage, and kidney damage 1
• Sodium retention and suppressed plasma renin activity 1
• Increased potassium excretion which, if prolonged and severe, may cause hypokalemia 1
• Hypokalemia is absent in the majority of cases (prevalence increases with decreasing potassium levels) 1, 2

Etiology breakdown:

• ~50% of cases: Unilateral aldosterone production (usually aldosterone-producing adenoma) 1
• ~50% of cases: Bilateral adrenal hyperplasia (idiopathic hyperaldosteronism) 1

Other Causes of Hypokalemia with Hypertension

Medications

• Diuretics (especially thiazide and loop diuretics) 1
• Systemic corticosteroids 1
• Excessive licorice ingestion (causes apparent mineralocorticoid excess) 3

Other Endocrine Disorders

• Cushing's syndrome 1
• Congenital adrenal hyperplasia 1
• Other mineralocorticoid excess syndromes 1
• Glucocorticoid-remediable aldosteronism (familial hyperaldosteronism type-1) 1, 3
• Apparent mineralocorticoid excess syndrome 3
• Liddle's syndrome (genetic disorder causing increased sodium channel activity) 3

Renovascular Disease

• Renovascular hypertension (renal artery stenosis) - causes a high renin state 1, 3

Clinical Indications for Primary Aldosteronism

Screening for primary aldosteronism is recommended in the presence of:

• Resistant hypertension 1
• Hypokalemia (spontaneous or substantial if diuretic-induced) 1
• Incidentally discovered adrenal mass 1
• Family history of early-onset hypertension 1
• Stroke at a young age (<40 years) 1

Diagnostic Approach

1. Screening test: Plasma aldosterone-to-renin ratio (ARR) is the recommended initial screening test 1

   • Most commonly used cutoff: 30 (when plasma aldosterone is reported in ng/dL and plasma renin activity in ng/mL/h) 1
   • Plasma aldosterone concentration should be at least 10 ng/dL to interpret the test as positive 1

2. Pre-test conditions:

   • Patients should have unrestricted salt intake 1
   • Serum potassium should be normalized 1
   • Mineralocorticoid receptor antagonists (spironolactone, eplerenone) should be withdrawn for at least 4 weeks 1
   • Consider the impact of other medications on test results 1

3. Referral: Patients with positive screening should be referred to a hypertension specialist or endocrinologist for further evaluation and treatment 1

Important Clinical Considerations

• The prevalence of primary aldosteronism increases with decreasing potassium levels - up to 88.5% in patients with spontaneous hypokalemia and potassium <2.5 mmol/L 2

• Despite guideline recommendations, screening rates for primary aldosteronism are extremely low - only 1.6% of patients with hypertension and hypokalemia are screened, and only 3.9% of those with severe hypokalemia (<3.0 mEq/L) 4

• Both primary aldosteronism and hypokalemia independently increase the risk of cardiovascular events 2

• Medications that can cause or exacerbate hypokalemia in hypertensive patients include:

  • Diuretics (thiazide and loop diuretics) 1
  • Beta-blockers 1
  • NSAIDs 1
  • Systemic corticosteroids 1

Treatment Considerations

• For primary aldosteronism due to unilateral disease: Laparoscopic adrenalectomy 1
• For bilateral disease: Mineralocorticoid receptor antagonists (spironolactone or eplerenone) 1
• For medication-induced hypokalemia: Consider medication adjustment 1
• For renovascular disease: Medical therapy is recommended for atherosclerotic renal artery stenosis 1