What investigations should be sent to diagnose the cause of persistent hypokalemia?

Diagnostic Approach to Persistent Hypokalemia

The evaluation of persistent hypokalemia should begin with measurement of urinary potassium excretion, blood pressure assessment, and acid-base status determination to identify the underlying cause. 1

Initial Laboratory Investigations

• Serum electrolytes (potassium, sodium, chloride, bicarbonate)
• Urinary potassium excretion:
  • 24-hour urine potassium
  • Spot urine potassium-to-creatinine ratio (K/C ratio)
    • K/C ratio <1.5 suggests non-renal losses
    • K/C ratio >1.5 suggests renal potassium wasting 1
• Acid-base status (arterial blood gas)
• Renal function tests (BUN, creatinine)
• Serum magnesium (hypomagnesemia can cause refractory hypokalemia)

Diagnostic Algorithm Based on Urinary Potassium and Acid-Base Status

1. Low Urinary Potassium Excretion (K/C ratio <1.5)

• With metabolic acidosis: Consider:

  • Lower gastrointestinal losses (diarrhea, laxative abuse)
  • Inadequate potassium intake 1

• With metabolic alkalosis: Consider:

  • Surreptitious vomiting
  • Recent diuretic use (now discontinued)
  • Transcellular shifts (insulin administration, β-adrenergic stimulation) 1

2. High Urinary Potassium Excretion (K/C ratio >1.5)

• With metabolic acidosis: Consider:

  • Diabetic ketoacidosis
  • Renal tubular acidosis (type 1 or 2)
  • Amphotericin B toxicity 1

• With metabolic alkalosis and normal BP: Consider:

  • Current diuretic use (thiazides, loop diuretics)
  • Bartter syndrome
  • Gitelman syndrome
  • Magnesium deficiency 1

• With metabolic alkalosis and hypertension: Consider:

  • Primary hyperaldosteronism
  • Cushing syndrome
  • Renovascular hypertension
  • Apparent mineralocorticoid excess
  • Liddle syndrome
  • Congenital adrenal hyperplasia 1

Additional Targeted Investigations

For Suspected Mineralocorticoid Excess

• Plasma renin activity and aldosterone levels:
  • Low renin, high aldosterone: Primary hyperaldosteronism
  • High renin, high aldosterone: Secondary hyperaldosteronism
  • Low renin, low aldosterone: Apparent mineralocorticoid excess, Liddle syndrome 2

For Suspected Diuretic Use

• Urine diuretic screen 1

For Suspected Endocrine Disorders

• Plasma cortisol levels (for Cushing syndrome)
• Thyroid function tests (hyperthyroidism can cause hypokalemia)
• Urinary cortisol-cortisone ratio (for apparent mineralocorticoid excess) 1

For Suspected Gastrointestinal Losses

• Stool studies (if diarrhea is present)

For Refractory Hypokalemia

• Serum magnesium level (hypomagnesemia can cause refractory hypokalemia) 1

Specialized Testing for Specific Conditions

For Primary Hyperaldosteronism

• Saline suppression test or salt loading test to confirm diagnosis
• Adrenal imaging (CT or MRI)
• Adrenal vein sampling to distinguish between adenoma and bilateral hyperplasia 2

For Cushing Syndrome

• 24-hour urinary free cortisol
• Dexamethasone suppression test 2

Common Pitfalls to Avoid

1. Failing to check magnesium levels - Hypomagnesemia can cause refractory hypokalemia that won't correct until magnesium is repleted 3

2. Not considering medication effects - Many medications can cause hypokalemia, including:

   • Diuretics (most common cause)
   • Laxatives
   • High-dose β-agonists
   • Insulin
   • Certain antibiotics 4

3. Overlooking transcellular shifts - Acute changes in potassium may reflect redistribution rather than total body depletion 5

4. Ignoring acid-base status - The pattern of acid-base disturbance provides crucial diagnostic clues 1

5. Inadequate monitoring - For patients with cardiac disease or on digoxin, more frequent monitoring is essential 3

By systematically evaluating urinary potassium excretion, acid-base status, and blood pressure, the underlying cause of persistent hypokalemia can be identified and appropriate treatment initiated.