What is the appropriate work‑up for chronic hypokalemia?

Work-up for Chronic Hypokalemia

For chronic hypokalemia, begin by measuring 24-hour urine potassium (or spot urine K/Cr ratio), serum magnesium, and assessing acid-base status—these three tests will direct you toward the underlying cause in over 90% of cases.

Initial Laboratory Assessment

Measure the following tests simultaneously:

• 24-hour urine potassium (or spot urine potassium-to-creatinine ratio if 24-hour collection is impractical): A ratio <1.5 mmol/mmol (or <20 mEq/day) indicates extrarenal losses or transcellular shift; ≥1.5 suggests renal potassium wasting 1, 2
• Serum magnesium: Target >0.6 mmol/L (>1.5 mg/dL), as hypomagnesemia is the most common cause of refractory hypokalemia and must be corrected first 1, 3
• Venous blood gas or serum bicarbonate: Determines whether metabolic acidosis or alkalosis is present 2
• Basic metabolic panel: Including sodium, calcium, glucose, creatinine, and eGFR 3

Diagnostic Algorithm Based on Urine Potassium

Low Urine Potassium (<20 mEq/day or K/Cr <1.5)

This pattern indicates appropriate renal potassium conservation, pointing to extrarenal losses or transcellular shift 2, 4:

With metabolic acidosis:

• Lower gastrointestinal losses (diarrhea, laxative abuse, high-output ileostomy/colostomy) 2
• Concealed laxative abuse should be suspected if denied by patient 3

With metabolic alkalosis:

• Surreptitious vomiting (check for low urine chloride <20 mEq/L) 2
• Remote diuretic use (after drug has been discontinued) 3

With normal acid-base status:

• Inadequate dietary intake 1, 4
• Transcellular shift: insulin excess, beta-agonist therapy, thyrotoxicosis, familial/sporadic periodic paralysis 1, 2

High Urine Potassium (≥20 mEq/day or K/Cr ≥1.5)

This indicates inappropriate renal potassium wasting. Further stratify by blood pressure and acid-base status 2:

With Metabolic Alkalosis + Normal Blood Pressure:

• Diuretic use (loop or thiazide): Most common cause—obtain urine diuretic screen if concealed use suspected 1, 3, 4
• Bartter syndrome: Presents with salt-wasting, hypercalciuria, normal blood pressure; genetic testing for SLC12A1, KCNJ1, CLCNKB, BSND, CLCNKA, MAGED2 mutations 3, 5
• Gitelman syndrome: Presents in adolescence/adulthood with hypocalciuria and hypomagnesemia; genetic testing for SLC12A3 mutation 3, 5

With Metabolic Alkalosis + Hypertension:

• Primary aldosteronism: Screen with plasma aldosterone-to-renin ratio (cutoff ≥30 with aldosterone ≥10 ng/dL); affects 8-20% of hypertensive patients 3
• Renovascular hypertension/secondary aldosteronism: Elevated renin and aldosterone 3
• Cushing syndrome: Measure 24-hour urinary free cortisol or overnight dexamethasone suppression test 3, 2
• Congenital adrenal hyperplasia: Low renin, low aldosterone, hypertension; measure 17-hydroxyprogesterone 3, 5
• Apparent mineralocorticoid excess: Measure urinary cortisol-to-cortisone ratio 3, 2
• Liddle syndrome: Low renin, low aldosterone, hypertension; trial of amiloride (responds) vs. spironolactone (does not respond); genetic testing for SCNN1B/SCNN1G mutations 3, 2
• Licorice ingestion: Check for concealed use of herbal supplements or chewing tobacco containing glycyrrhizic acid 3

With Metabolic Acidosis:

• Diabetic ketoacidosis: Elevated glucose, anion gap acidosis 1, 2
• Distal (type 1) renal tubular acidosis: Non-anion gap acidosis, urine pH >5.5, low urinary ammonium 3, 2
• Proximal (type 2) renal tubular acidosis: Non-anion gap acidosis, urine pH <5.5 during acidemia 1

Medication and Dietary Review

Systematically review all medications and substances:

• Potassium-wasting diuretics: Loop diuretics (furosemide, bumetanide, torsemide), thiazides (hydrochlorothiazide, chlorthalidone, indapamide) 1, 3, 4
• Other medications: High-dose penicillin, amphotericin B, aminoglycosides, cisplatin 3
• Substances: Licorice, herbal supplements (alfalfa, dandelion, horsetail, nettle), chewing tobacco 1, 3
• Dietary assessment: Inadequate potassium intake (<3,510 mg/day) 6

Special Diagnostic Considerations

If the cause remains unclear after initial work-up:

• Urine diuretic screen: Essential if concealed diuretic abuse suspected 3, 2
• Thyroid function tests: Rule out thyrotoxic periodic paralysis if presenting with acute paralysis 3, 2
• Genetic testing: Consider for early-onset hypokalemia, family history of tubular disorders, or prenatal polyhydramnios (Bartter/Gitelman/EAST syndrome) 3, 5
• Trial of spironolactone vs. amiloride: Helps differentiate aldosterone-mediated (responds to spironolactone) from ENaC-mediated (responds to amiloride) causes 3, 2

Common Diagnostic Pitfalls

• Failing to check magnesium first: Hypomagnesemia makes hypokalemia resistant to correction and is present in ~40% of hypokalemic patients 1, 3
• Not obtaining urine studies: Serum potassium alone cannot distinguish renal from extrarenal losses 2, 4
• Missing concealed substance use: Directly ask about laxatives, diuretics, licorice, herbal supplements, and eating disorders (bulimia) 3, 5
• Overlooking secondary hyperaldosteronism: Volume depletion from any cause (vomiting, diarrhea, high-output fistulas) activates RAAS and causes renal potassium wasting 1, 5
• Ignoring acid-base status: The combination of potassium level, urine potassium, and acid-base status narrows the differential dramatically 2

Target Potassium Range During Work-up

• General population: Maintain 4.0–5.0 mEq/L 1
• Cardiac disease or heart failure: Strictly maintain 4.0–5.0 mEq/L, as both hypokalemia and hyperkalemia increase mortality 1, 3
• Patients on digoxin: Maintain 4.0–5.0 mEq/L to prevent digitalis toxicity 1, 3