What is the differential diagnosis for hypokalemia?

Differential Diagnosis of Hypokalemia

The differential diagnosis of hypokalemia requires distinguishing between three primary mechanisms: transcellular shifts, inadequate intake, and excessive losses (renal versus gastrointestinal), with the most critical initial step being measurement of urinary potassium excretion and assessment of acid-base status to guide the diagnostic algorithm. 1, 2

Initial Diagnostic Framework

Measure urinary potassium excretion in a freshly-voided urine sample to differentiate renal from non-renal causes. 1 A urinary potassium excretion of ≥20 mEq/day in the presence of serum potassium <3.5 mEq/L indicates inappropriate renal potassium wasting, whereas excretion <20 mEq/day suggests either transcellular shifts, gastrointestinal losses, or prior renal losses that have now ceased. 3, 2

Assess acid-base status simultaneously, as metabolic acid-base disorders provide crucial diagnostic clues. 1 The combination of urinary potassium excretion and acid-base status creates a diagnostic matrix that narrows the differential significantly. 2

Low Urinary Potassium Excretion (<20 mEq/day)

When urinary potassium is appropriately low, consider these three categories:

Transcellular Shifts

• Insulin excess (including treatment of diabetic ketoacidosis) 4, 1
• Beta-agonist therapy (albuterol, other beta-2 agonists) 5, 4
• Thyrotoxicosis (thyrotoxic periodic paralysis) 5
• Metabolic alkalosis (shifts potassium intracellularly) 5
• Catecholamine excess 6

Inadequate Intake

• Severe dietary restriction (rare as sole cause) 1
• Anorexia nervosa 1
• Elderly patients with poor nutrition 5

Prior Renal or Gastrointestinal Losses

• Diarrhea (ongoing or recent) 5, 4
• Vomiting (after cessation) 5, 4
• High-output stomas or fistulas 5, 7
• Laxative abuse (concealed) 8

High Urinary Potassium Excretion (≥20 mEq/day)

When urinary potassium excretion is inappropriately elevated, the acid-base status becomes the critical branch point:

With Metabolic Acidosis (Hyperchloremic)

Measure urinary ammonium (NH4+) excretion to distinguish renal tubular acidosis from other causes. 1

Low NH4+ Excretion (Renal Tubular Acidosis)

• Distal (Type 1) RTA 8, 1
• Proximal (Type 2) RTA 1
• Type 4 RTA (typically causes hyperkalemia, not hypokalemia) 1

High NH4+ Excretion (Non-RTA Causes)

• Diabetic ketoacidosis (during recovery phase) 6, 4
• Ureterosigmoidostomy 1
• Toluene abuse 1

With Metabolic Alkalosis

Assess blood pressure and volume status to distinguish mineralocorticoid excess from volume depletion. 1, 2

Hypertension (Mineralocorticoid Excess)

Measure plasma renin activity and aldosterone levels to differentiate causes. 5, 1

High Aldosterone, High Renin

• Renovascular hypertension 5
• Renin-secreting tumor 5
• Malignant hypertension 5

High Aldosterone, Low Renin

• Primary aldosteronism (adrenal adenoma or bilateral hyperplasia) 5, 1
• Screen when hypertension coexists with spontaneous or diuretic-induced hypokalemia, resistant hypertension, adrenal mass, or family history of early-onset hypertension 5
• Use plasma aldosterone:renin activity ratio ≥30 with plasma aldosterone ≥10 ng/dL for screening 5

Low Aldosterone, Low Renin (Mineralocorticoid-Like Effects)

• Cushing syndrome (measure cortisol) 5, 1
• Exogenous corticosteroids (prednisolone, hydrocortisone) 6
• Licorice ingestion (glycyrrhizic acid) 5, 1
• Liddle syndrome (genetic disorder with ENaC hyperactivity) 1
• 11-beta-hydroxysteroid dehydrogenase deficiency 1

Normotension or Hypotension (Volume Depletion)

Measure urinary chloride to distinguish renal from non-renal sodium losses. 8, 1

High Urinary Chloride (>20 mEq/L) - Renal Salt Wasting

• Diuretic therapy (loop diuretics, thiazides) - most common cause overall 8, 5, 4, 3
• Bartter syndrome (various genetic types) 8
• Gitelman syndrome 8
• Post-obstructive diuresis 1
• Salt-wasting nephropathy 1

Low Urinary Chloride (<20 mEq/L) - Non-Renal Salt Loss

• Vomiting (active, with metabolic alkalosis from gastric acid loss and secondary hyperaldosteronism) 5, 4, 1
• Nasogastric suction 1
• Congenital chloride diarrhea 8
• Villous adenoma of colon 1

Rare Inherited Tubulopathies

Consider genetic testing when clinical presentation suggests inherited tubular disorders, particularly with early onset, family history, or polyhydramnios. 8

Bartter Syndrome Subtypes

• Type 1 (SLC12A1) - prenatal onset, severe polyhydramnios 8
• Type 2 (KCNJ1) - prenatal onset, severe polyhydramnios, deafness risk 8
• Type 3 (CLCNKB) - onset 0-5 years, milder presentation 8
• Type 4a (BSND) - prenatal onset, deafness, CKD risk 8
• Type 4b (CLCNKA + CLCNKB) - prenatal onset, very severe 8
• Type 5 (MAGED2) - transient disease 8

Other Rare Tubulopathies

• Gitelman syndrome (SLC12A3) - presentation in adolescence/adulthood, hypocalciuria 8
• EAST/Sesame syndrome (KCNJ10) 8
• Familial hypokalemic alkalosis with hypercalciuria (CASR) 8

Medication-Induced Hypokalemia

Review all medications systematically, including over-the-counter drugs and supplements. 5, 1

Common Culprits

• Loop diuretics (furosemide, bumetanide, torsemide) 6, 5, 3
• Thiazide diuretics (hydrochlorothiazide) 6, 5, 3
• High-dose penicillin 5
• Amphotericin B 1
• Aminoglycosides 1
• Cisplatin 1

Concealed or Overlooked

• Laxative abuse (often denied by patient) 8
• Diuretic abuse (surreptitious use) 5, 1
• Herbal supplements containing licorice 5

Special Clinical Contexts

Pseudo-Bartter Syndrome

• Cystic fibrosis (salt loss in sweat) 8
• Surreptitious vomiting or diuretic abuse 8

Polyhydramnios in Pregnancy

Severe polyhydramnios is virtually always caused by Bartter syndrome, not other inherited tubular disorders. 8 Proximal tubulopathies and nephrogenic diabetes insipidus do not cause polyhydramnios. 8

Critical Diagnostic Pitfalls

• Failing to check magnesium levels - hypomagnesemia coexists in ~40% of hypokalemic patients and causes renal potassium wasting 6, 5, 7
• Overlooking concealed diuretic or laxative abuse - obtain urine diuretic screen if suspicion exists 8, 5
• Misinterpreting urinary potassium in volume-depleted states - secondary hyperaldosteronism from volume depletion increases renal potassium losses 6, 5
• Not recognizing transcellular shifts - patients may have normal total body potassium despite low serum levels 6, 4
• Ignoring acid-base status - provides essential diagnostic information 1, 2

Diagnostic Algorithm Summary

1. Confirm hypokalemia (serum K+ <3.5 mEq/L) and assess severity 7, 4
2. Obtain ECG to evaluate cardiac manifestations 7
3. Measure urinary potassium excretion (spot or 24-hour) 1, 2
4. Assess acid-base status (venous blood gas) 1, 2
5. Check serum magnesium (target >0.6 mmol/L) 6, 7
6. Review medications thoroughly (including OTC and supplements) 5, 1
7. Measure blood pressure and assess volume status 1, 2
8. If renal losses with metabolic alkalosis and hypertension: measure plasma renin activity and aldosterone 5, 1
9. If renal losses with metabolic alkalosis and normotension: measure urinary chloride 8, 1
10. If renal losses with metabolic acidosis: measure urinary ammonium 1
11. Consider genetic testing if clinical features suggest inherited tubulopathy 8