What causes hypokalemia (low potassium levels)?

What Causes Low Potassium (Hypokalemia)

Hypokalemia (serum potassium <3.5 mEq/L) results from three primary mechanisms: decreased intake, excessive losses (renal or gastrointestinal), or transcellular shifts—with diuretic therapy and gastrointestinal losses being the most common culprits in clinical practice. 1, 2, 3

Major Causes by Mechanism

Excessive Renal Losses (Most Common)

Diuretic therapy is the single most frequent cause of hypokalemia in clinical practice. 1, 4, 5

• Loop diuretics (furosemide, bumetanide, torsemide) inhibit sodium and chloride reabsorption in the ascending limb of the loop of Henle, causing significant potassium wasting and metabolic alkalosis 1
• Thiazide diuretics (hydrochlorothiazide) inhibit sodium and chloride reabsorption in the distal tubule, leading to potassium depletion 1
• The magnitude of potassium loss increases with high salt diets, large urine volumes, metabolic alkalosis, and increased aldosterone production 5

Primary aldosteronism causes inappropriate aldosterone production that increases potassium excretion, leading to hypertension with hypokalemia (though hypokalemia is absent in the majority of cases). 6

• Occurs in 8-20% of hypertensive patients 6
• Screen when hypertension coexists with spontaneous or substantial diuretic-induced hypokalemia, resistant hypertension, adrenal mass, or family history of early-onset hypertension 6
• Use plasma aldosterone:renin activity ratio for screening (cutoff value of 30 with plasma aldosterone ≥10 ng/dL) 6

Other renal causes include:

• Secondary hyperaldosteronism from volume depletion (vomiting, high-output fistulas/stomas) 1
• Bartter syndrome and Gitelman syndrome (genetic tubular disorders) 1
• Renal tubular acidosis 7
• Magnesium deficiency causing renal potassium wasting 1

Gastrointestinal Losses

Vomiting causes hypokalemia primarily through renal losses, not direct gastric fluid loss. 1

• The key mechanism is metabolic alkalosis from gastric acid loss, which upregulates sodium epithelial channel (ENaC) activity in the cortical collecting duct, increasing potassium excretion 1
• Volume depletion activates the renin-angiotensin-aldosterone system, causing increased aldosterone secretion that promotes sodium retention and potassium excretion 1
• Increased sodium-bicarbonate delivery to the cortical collecting duct enhances sodium uptake through ENaC with consequent increased potassium excretion 1

Diarrhea directly depletes potassium through colonic losses 1, 2

High-output fistulas (particularly enterocutaneous) cause substantial potassium depletion 1

Medications and Substances

Beyond diuretics, numerous medications cause hypokalemia: 6

Drugs decreasing potassium excretion that paradoxically cause hypokalemia when withdrawn:

• Beta-blockers 6
• NSAIDs 6
• RAAS inhibitors (ACE inhibitors, ARBs, mineralocorticoid receptor antagonists) 6

Drugs causing transcellular shifts:

• Insulin (drives potassium intracellularly) 2, 3
• Beta-agonists (albuterol, terbutaline) 2, 3
• Corticosteroids (mineralocorticoid effects) 7

Other medications:

• Amphotericin B 4
• High-dose penicillin 6
• Aminoglycosides 4

Decreased Intake

Inadequate dietary potassium intake rarely causes hypokalemia alone but contributes when combined with other factors 1, 4

• Normal dietary intake is 50-100 mEq/day 8
• The WHO recommends at least 3,510 mg/day for optimal cardiovascular health 2
• The kidney continues to excrete potassium even during fasting, leading to progressive depletion 9

Transcellular Shifts

Conditions causing potassium to shift from extracellular to intracellular space:

• Acute alkalosis can produce hypokalemia without total body potassium deficit 8
• Thyrotoxicosis causes transcellular shifts 7
• Insulin excess (including treatment of diabetic ketoacidosis) 7, 2
• Refeeding syndrome 4

Magnesium Deficiency

Hypomagnesemia is the most common reason for refractory hypokalemia. 1, 7

• Magnesium deficiency causes dysfunction of potassium transport systems and increases renal potassium excretion 7
• Frequently coexists with hypokalemia and must be corrected before potassium levels will normalize 1
• Target magnesium level >0.6 mmol/L 7

Important Clinical Caveats

Pseudo-hypokalemia must be excluded—this refers to falsely low potassium from improper blood sampling technique or in vitro hemolysis. 6, 8

Acute acidosis can mask hypokalemia by increasing serum potassium concentration into the normal range despite reduced total body potassium. 8

Multiple factors often coexist in any given patient—for example, a patient on diuretics with vomiting and poor oral intake has three simultaneous mechanisms for potassium depletion. 4

Total body potassium deficit is much larger than serum changes suggest—only 2% of body potassium is extracellular, so a serum potassium of 3.0 mEq/L typically represents a total body deficit of 200-300 mEq or more. 8, 5