What are the causes of hypokalemia?

Causes of Hypokalemia

Major Etiologic Categories

Hypokalemia results from three primary mechanisms: inadequate intake (rare as sole cause), excessive losses (renal or gastrointestinal), or transcellular shifts of potassium into cells 1, 2, 3.

Inadequate Intake

• Dietary insufficiency alone rarely causes hypokalemia because the kidneys can reduce potassium excretion to below 15 mEq/day 4.
• Inadequate intake becomes clinically significant only when combined with other factors such as increased losses or impaired renal conservation 5.

Excessive Renal Losses

Diuretic therapy is the most common cause of hypokalemia in clinical practice 6, 7, 5.

• Loop diuretics (furosemide, bumetanide, torsemide) inhibit sodium and chloride reabsorption in the ascending limb of the loop of Henle, causing significant hypokalemia and metabolic alkalosis 7.
• Thiazide diuretics (hydrochlorothiazide) inhibit sodium and chloride reabsorption in the distal tubule, leading to hypokalemia 7.
• Both classes cause hypokalemia through increased distal sodium delivery coupled with aldosterone effects 3.

Primary hyperaldosteronism causes inappropriate aldosterone production, leading to hypertension with hypokalemia in 8-20% of hypertensive patients 7.

• Screen when hypertension coexists with spontaneous or substantial diuretic-induced hypokalemia, resistant hypertension, adrenal mass, or family history of early-onset hypertension 7.
• Use plasma aldosterone:renin activity ratio for screening, with a cutoff value of 30 and plasma aldosterone ≥10 ng/dL 7.

Secondary hyperaldosteronism occurs in volume-depleted states, activating the renin-angiotensin-aldosterone system 7.

• Common in patients with high-output stomas, fistulas, or chronic gastrointestinal losses 7.
• Volume depletion paradoxically increases renal potassium losses through aldosterone-mediated mechanisms 6.

Renal tubular disorders include Bartter syndrome, Gitelman syndrome, and renal tubular acidosis 7.

Medications beyond diuretics:

• Beta-agonists (albuterol) cause transcellular shifts 6, 1.
• High-dose penicillin increases renal potassium excretion 7.
• Corticosteroids (prednisolone, hydrocortisone) cause hypokalemia through mineralocorticoid effects, with hydrocortisone causing more hypokalemia than methylprednisolone at equivalent doses 6.

Gastrointestinal Losses

Vomiting causes hypokalemia primarily through renal losses, not direct gastric fluid loss 7.

• Metabolic alkalosis develops when gastric acid is lost, leaving bicarbonate in circulation 7.
• This alkalosis directly increases renal potassium excretion through enhanced sodium epithelial channel (ENaC) activity in the cortical collecting duct 7.
• Volume depletion activates the renin-angiotensin-aldosterone system, promoting sodium retention and potassium excretion 7.

Diarrhea causes direct potassium loss in stool 7, 2.

High-output fistulas and enterocutaneous fistulas cause significant potassium depletion 7.

Transcellular Shifts

Insulin excess drives potassium into cells, causing transient hypokalemia 6, 1.

• In diabetic ketoacidosis, patients have total body potassium deficits of 3-5 mEq/kg despite initially normal or elevated serum levels 6.

Beta-agonist therapy (albuterol, terbutaline) causes intracellular potassium shift 6, 2.

Thyrotoxicosis leads to transcellular shifts and hypokalemia 6.

Metabolic alkalosis promotes potassium movement into cells 7, 5.

Magnesium Deficiency

Hypomagnesemia is the most common reason for refractory hypokalemia 6, 7.

• Magnesium depletion causes dysfunction of potassium transport systems and increases renal potassium excretion 6.
• Hypokalemia will not correct until magnesium is repleted to >0.6 mmol/L (>1.5 mg/dL) 6, 7.
• Hypomagnesemia frequently coexists with hypokalemia, particularly in patients with gastrointestinal losses or diuretic use 7.

Diagnostic Approach

Initial assessment should include:

• Medication review (diuretics, laxatives, beta-agonists, corticosteroids, insulin) 6, 3.
• Evaluation for gastrointestinal losses (vomiting, diarrhea, fistulas) 4, 3.
• Assessment of volume status with orthostatic vital signs 3.
• Measurement of serum electrolytes including magnesium, calcium, and glucose 6.
• Spot urine potassium and creatinine to calculate fractional excretion 4.

Urinary potassium excretion ≥20 mEq/day with serum potassium <3.5 mEq/L indicates inappropriate renal potassium wasting 5.

Acid-base status helps differentiate causes:

• Metabolic alkalosis suggests vomiting, diuretic use, or mineralocorticoid excess 4, 5.
• Metabolic acidosis suggests renal tubular acidosis, diarrhea, or ureterosigmoidostomy 4.

Blood pressure assessment distinguishes primary from secondary hyperaldosteronism:

• Volume expansion with hypertension suggests primary mineralocorticoid excess 3.
• Volume depletion with normal/low blood pressure suggests secondary hyperaldosteronism or gastrointestinal losses 3.

Common Pitfalls

• Failing to check and correct magnesium first is the most common reason for treatment failure 6.
• Overlooking secondary hyperaldosteronism in volume-depleted patients with gastrointestinal losses 7.
• Not recognizing that vomiting causes hypokalemia primarily through renal losses driven by metabolic alkalosis, not direct gastric fluid loss 7.
• Missing concealed diuretic use or herbal supplements containing licorice (causing mineralocorticoid effects) 7.
• Administering potassium supplementation without addressing the underlying cause leads to persistent hypokalemia 6.