Causes of Hypokalemia
Hypokalemia results from three primary mechanisms: inadequate intake, excessive losses (renal or gastrointestinal), or transcellular shifts of potassium into cells. 1, 2
Medication-Induced Causes
Diuretic therapy is the most common cause of hypokalemia in clinical practice. 1, 3
- Loop diuretics (furosemide) inhibit sodium and chloride reabsorption in the ascending limb of the loop of Henle, causing significant hypokalemia and metabolic alkalosis 1, 4
- Thiazide diuretics inhibit sodium and chloride reabsorption in the distal tubule, leading to potassium wasting 1, 4, 3
- Beta-agonists cause transcellular potassium shifts into cells and can worsen existing hypokalemia 4
- Insulin excess drives potassium intracellularly, causing transient hypokalemia 4
- High-dose penicillin can contribute to hypokalemia 1
Gastrointestinal Losses
Direct potassium loss through the GI tract is a major contributor to hypokalemia. 1, 4, 5
- Vomiting causes hypokalemia primarily through renal potassium losses driven by metabolic alkalosis and secondary hyperaldosteronism, not through direct loss of potassium in gastric fluid 1
- Diarrhea results in direct potassium loss 1, 5
- High-output fistulas, particularly enterocutaneous fistulas, cause significant potassium depletion 1, 4
The key mechanism with vomiting is that metabolic alkalosis develops when gastric acid is lost, leaving behind bicarbonate in the circulation, which directly increases renal potassium excretion through enhanced activity of the sodium epithelial channel (ENaC) in the cortical collecting duct 1
Renal Losses
Inappropriate renal potassium wasting occurs in several conditions. 1
- Primary hyperaldosteronism causes inappropriate aldosterone production, leading to hypertension with hypokalemia in 8-20% of hypertensive patients 1, 4
- Secondary hyperaldosteronism may occur in patients with high-output stomas, fistulas, or volume depletion 1
- Bartter syndrome causes renal potassium wasting 1, 4
- Gitelman syndrome causes renal potassium wasting 1, 4
- Renal tubular acidosis can be a cause of hypokalemia 6
Magnesium Deficiency
Hypomagnesemia is a critical and often overlooked cause of refractory hypokalemia. 1, 4
- Magnesium deficiency causes renal potassium wasting and makes hypokalemia resistant to correction until magnesium is corrected 1, 4
- Hypomagnesemia frequently coexists with hypokalemia—approximately 40% of hypokalemic patients have concurrent hypomagnesemia 6
- Target magnesium level should be >0.6 mmol/L (>1.5 mg/dL) 1, 6
Inadequate Intake
Dietary potassium deficiency alone rarely causes hypokalemia since the kidney can lower potassium excretion below 15 mmol per day. 7
- However, inadequate intake combined with other factors (diuretics, GI losses) significantly contributes to hypokalemia 2, 8
- The World Health Organization recommends a potassium intake of at least 3,510 mg per day for optimal cardiovascular health 2
Transcellular Shifts
Potassium can shift from extracellular to intracellular compartments without actual body potassium loss. 2, 5
- Thyrotoxicosis leads to transcellular shifts and hypokalemia 6
- Insulin therapy drives potassium into cells 4, 5
- Beta-agonist therapy causes intracellular potassium shifts 4, 5
- Metabolic alkalosis promotes potassium movement into cells 5
Diagnostic Approach
A urinary potassium excretion of 20 mEq or more per day in the presence of serum potassium <3.5 mEq/L suggests inappropriate renal potassium wasting. 3
- Measurement of spot urine for potassium and creatinine, along with evaluation of acid-base status, can be used as an initial diagnostic step 7
- Subsequent evaluations such as spot urinary chloride, blood pressure, serum aldosterone, renin, and cortisol levels may be needed in certain circumstances 7
Critical Pitfall
Failing to address magnesium deficiency when treating hypokalemia is the most common reason for treatment failure. 1, 6