What are the causes of hypokalemia?

Causes of Hypokalemia

Hypokalemia results from three primary mechanisms: inadequate intake, excessive losses (renal or gastrointestinal), or transcellular shifts of potassium from the extracellular to intracellular compartment. 1, 2, 3

Inadequate Dietary Intake

• Dietary potassium deficiency alone rarely causes hypokalemia because the kidneys can reduce potassium excretion to below 15 mmol per day in response to low intake 2, 3
• However, inadequate intake becomes clinically significant when combined with other risk factors such as diuretic use or gastrointestinal losses 1, 3
• Elderly patients with reduced calorie/protein intake, sedentary lifestyle, and deconditioning are particularly susceptible to hypokalemia from inadequate dietary potassium 1

Excessive Renal Losses

Diuretic-Induced Hypokalemia

• Loop diuretics (furosemide, bumetanide, torsemide) cause significant urinary potassium losses through increased distal sodium delivery and secondary aldosterone stimulation 1, 4
• Thiazide diuretics (hydrochlorothiazide) block sodium-chloride reabsorption in the distal tubule, triggering compensatory potassium excretion through ROMK2 channels and aldosterone-sensitive ENaC channels 1, 4
• The risk of diuretic-induced hypokalemia is markedly enhanced when two diuretics are used in combination 1
• Diuretic therapy is the most frequent cause of hypokalemia in clinical practice 1, 4, 3, 5

Primary Hyperaldosteronism

• Excess aldosterone increases distal nephron secretion of potassium into the urine, leading to renal potassium wasting 4, 6
• This condition should be suspected in patients with hypertension and hypokalemia 4

Other Renal Causes

• Polyuric renal failure can lead to excessive urinary potassium losses 7
• Immature renal tubular function in preterm infants (especially those <34 weeks gestation) results in physiologic renal potassium wasting 4

Gastrointestinal Losses

• Diarrhea, vomiting, nasogastric suction, ileostomy, and bowel obstruction are common extrarenal causes of hypokalemia 4, 2, 3, 5
• High-output diarrhea, vomiting, or gastrointestinal fistulas with continuing fluid losses require urgent assessment to prevent further potassium depletion 1
• Gastrointestinal losses are a common cause of hypokalemia alongside diuretic use 3, 5

Transcellular Shifts

Insulin and Glucose

• Insulin promotes cellular uptake of potassium, causing a shift from extracellular to intracellular fluid without changing total body potassium 6
• Enhanced parenteral nutrition can increase endogenous insulin production, promoting potassium shift into cells 4
• Refeeding syndrome, which occurs when nutrition is reintroduced after prolonged starvation, can cause hypokalemia through insulin-mediated transcellular shifts 4

Beta-Agonist Therapy

• Beta-2 agonists (albuterol, other beta-agonists) cause intracellular potassium shift 1, 6
• This mechanism can cause hypokalemia without actual potassium depletion 6

Alkalosis

• Metabolic alkalosis shifts potassium intracellularly, reducing serum potassium levels 1, 6
• Alkalosis enhances distal nephron secretion of potassium into the urine 6

Other Transcellular Shift Causes

• Catecholamines and increased adrenergic activity drive potassium into cells 1, 6
• Aldosterone affects both renal excretion and cellular uptake of potassium 6
• Hyperglycemia can contribute to transcellular shifts 5

Medication-Induced Hypokalemia

• Beta-blockers can affect potassium homeostasis, though they typically decrease potassium excretion 1, 4
• NSAIDs affect potassium homeostasis by causing sodium retention and worsening renal function 1
• Certain medications including some antiarrhythmics and other drugs can cause potassium wasting 4

Magnesium Deficiency

• Hypomagnesemia is frequently present with hypokalemia and must be corrected for successful potassium repletion 1, 4
• Magnesium deficiency causes dysfunction of potassium transport systems and increases renal potassium excretion, making hypokalemia resistant to correction 1
• Approximately 40% of hypokalemic patients have concurrent hypomagnesemia 1

High-Risk Populations

• Elderly patients are particularly susceptible due to reduced glomerular filtration, multi-morbidity, and polypharmacy 1
• Preterm infants may develop hypokalemia due to enhanced demand, electrolyte depletion, inadequate supply, or increased renal losses 4
• Patients with heart failure on multiple medications affecting potassium homeostasis 1

Diagnostic Approach to Determine Etiology

• Urinary potassium >20 mmol/L suggests renal potassium wasting, while urinary potassium <20 mmol/L suggests extrarenal losses 4
• Measurement of spot urine for potassium and creatinine as well as evaluation of acid-base status can be used as an initial step in diagnosis 2
• Metabolic alkalosis together with hypokalemia suggests etiologies such as vomiting, diuretic use, or mineralocorticoid excess 4