What are the causes of hypokalemia?

Causes of Hypokalemia

Major Etiologic Categories

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

Inadequate Intake

• Dietary potassium deficiency alone rarely causes hypokalemia because the kidneys can reduce potassium excretion to below 15 mEq/day 3
• The WHO recommends at least 3,510 mg potassium daily for optimal cardiovascular health 1

Excessive Renal Losses

Diuretic therapy is the most common cause of hypokalemia in clinical practice 4, 5, 6:

• 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 5
• Thiazide diuretics (hydrochlorothiazide) inhibit sodium and chloride reabsorption in the distal tubule, leading to hypokalemia 5
• Both classes cause urinary potassium wasting proportional to their diuretic effect 4, 5

Primary aldosteronism causes inappropriate aldosterone production, leading to hypertension with hypokalemia in 8-20% of hypertensive patients 5:

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

Secondary hyperaldosteronism occurs with volume depletion from any cause, activating the renin-angiotensin-aldosterone system 5:

• High-output stomas or fistulas cause volume depletion that paradoxically increases renal potassium losses 4, 5
• Correct sodium/water depletion first, as hypoaldosteronism from volume depletion increases renal potassium excretion 4

Renal tubular disorders include Bartter syndrome, Gitelman syndrome, and renal tubular acidosis 4, 5

Medications beyond diuretics that cause renal potassium wasting 5:

• High-dose penicillin
• Certain beta-blockers, NSAIDs, and RAAS inhibitors (paradoxically when withdrawn)

Gastrointestinal Losses

Vomiting causes hypokalemia primarily through renal losses, not direct gastric fluid loss 5:

• Metabolic alkalosis develops when gastric acid is lost, leaving bicarbonate in circulation 5
• This alkalosis directly increases renal potassium excretion through enhanced sodium epithelial channel (ENaC) activity in the cortical collecting duct 5
• Volume depletion activates the RAA system, causing increased aldosterone secretion that promotes potassium excretion 5
• Treating the metabolic alkalosis by restoring chloride helps reduce renal potassium wasting 5

Diarrhea causes direct gastrointestinal potassium losses 5, 2

High-output fistulas cause both direct losses and secondary hyperaldosteronism from volume depletion 4, 5

Transcellular Shifts

Potassium shifts from extracellular to intracellular compartments without total body depletion 4, 3, 2:

• Insulin excess drives potassium into cells 4, 2
• Beta-agonist therapy (albuterol, other sympathomimetics) causes intracellular potassium shift 4, 2
• Thyrotoxicosis causes transcellular shifts 4
• Metabolic alkalosis promotes intracellular potassium movement 5
• Corticosteroids (prednisolone, hydrocortisone) cause hypokalemia through mineralocorticoid effects, with hydrocortisone causing more hypokalemia than methylprednisolone at equivalent doses 4

Magnesium Deficiency

Hypomagnesemia is the most common reason for refractory hypokalemia 4, 5:

• Magnesium depletion causes dysfunction of potassium transport systems and increases renal potassium excretion 4
• Hypomagnesemia frequently coexists with hypokalemia and must be corrected before potassium levels will normalize 4, 5
• Target magnesium level >0.6 mmol/L (>1.5 mg/dL) 4

Diagnostic Approach to Determine Etiology

Measure spot urine potassium and creatinine as the initial diagnostic step 3:

• Urinary potassium excretion ≥20 mEq/day with serum potassium <3.5 mEq/L suggests inappropriate renal potassium wasting 6
• Urinary potassium <15 mEq/day suggests extrarenal losses or inadequate intake 3

Evaluate acid-base status to distinguish causes 3:

• Metabolic alkalosis suggests vomiting, diuretic use, or mineralocorticoid excess 5, 6
• Metabolic acidosis suggests renal tubular acidosis or diarrhea 4

Assess volume status and blood pressure 7:

• Volume depletion with normal/low blood pressure suggests gastrointestinal losses or diuretic use 7
• Volume expansion with hypertension suggests primary mineralocorticoid excess 7
• Measure plasma renin activity and aldosterone levels when mineralocorticoid activity is suspected 7

Check for hidden causes 5:

• Concealed diuretic use 5
• Herbal supplements containing licorice (mineralocorticoid effects) 5
• Laxative abuse 5

Critical Concurrent Factors

Always check magnesium levels immediately in all patients with hypokalemia, as hypomagnesemia makes potassium repletion resistant to correction 4, 5

Evaluate medications systematically 4, 5:

• Diuretics (loop, thiazide)
• Corticosteroids
• Beta-agonists
• Insulin
• Caffeine
• NSAIDs (can affect potassium homeostasis)

Consider tissue destruction as a cause: catabolism, infection, surgery, chemotherapy 4

Investigate constipation, which can increase colonic potassium losses 4