What are the causes of hypokalemia?

Etiology of Hypokalemia

Primary Mechanisms of Hypokalemia

Hypokalemia develops through three fundamental mechanisms: inadequate potassium intake, excessive potassium losses (renal or gastrointestinal), or transcellular shifts of potassium from extracellular to intracellular compartments 1, 2, 3.

Inadequate Intake

• Dietary insufficiency alone rarely causes hypokalemia because the kidneys can reduce potassium excretion to below 15 mmol per day, making isolated inadequate intake an uncommon sole cause 3.
• The World Health Organization recommends a minimum potassium intake of 3,510 mg per day for optimal cardiovascular health 1.

Excessive Renal Losses

Diuretic therapy is the most common cause of hypokalemia in clinical practice 4, 5, 2.

• Loop diuretics (furosemide, bumetanide) inhibit sodium and chloride reabsorption in the ascending limb of the loop of Henle, causing significant hypokalemia and metabolic alkalosis 6, 7.
• Thiazide diuretics (hydrochlorothiazide) inhibit sodium and chloride reabsorption in the distal tubule, leading to hypokalemia 6, 8.
• Hypokalemia may develop especially with brisk diuresis, inadequate oral electrolyte intake, when cirrhosis is present, or during concomitant use of corticosteroids, ACTH, licorice in large amounts, or prolonged use of laxatives 7, 8.

Mineralocorticoid excess states:

• Primary hyperaldosteronism causes renal potassium wasting 5, 6.
• Secondary hyperaldosteronism occurs in volume-depleted states, including patients with high-output stomas or fistulas 6.
• Corticosteroids like prednisolone cause hypokalemia through mineralocorticoid effects, with hydrocortisone causing more hypokalemia than methylprednisolone at equivalent doses 4.

Genetic tubular disorders:

• Bartter syndrome and Gitelman syndrome cause renal potassium wasting 6.

Magnesium deficiency:

• Hypomagnesemia causes dysfunction of potassium transport systems and increases renal potassium excretion, making it the most common reason for refractory hypokalemia 4, 5, 6.

Gastrointestinal Losses

Vomiting causes hypokalemia primarily through renal potassium losses driven by metabolic alkalosis and secondary hyperaldosteronism, not through direct loss of potassium in gastric fluid 6.

• Metabolic alkalosis develops when gastric acid is lost through vomiting, 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 6.
• Volume depletion from vomiting activates the renin-angiotensin-aldosterone system, causing increased aldosterone secretion that promotes sodium retention and potassium excretion 6.

Other gastrointestinal causes:

• Diarrhea causes direct potassium losses 6, 2.
• High-output enterocutaneous fistulas can cause significant hypokalemia 6.
• Chronic or frequent vomiting or diarrhea should prompt investigation of serum potassium 9.

Transcellular Shifts

Insulin administration stimulates potassium movement into cells, possibly leading to hypokalemia 10, 1, 2.

• In diabetic ketoacidosis, patients typically have total body potassium deficits of 3-5 mEq/kg body weight despite initially normal or even elevated serum levels 4.
• Intravenously administered insulin has a rapid onset of action, requiring increased attention to hypokalemia and close monitoring of potassium levels 10.

Other transcellular shift causes:

• Beta-agonist therapy can worsen hypokalemia 4, 1, 2.
• Enhanced parenteral nutrition can cause transcellular shifts, leading to hypokalemia through increased endogenous insulin production 5.
• Refeeding syndrome, which occurs when nutrition is reintroduced after prolonged starvation, can cause hypokalemia 5.
• Thyrotoxicosis can cause transcellular potassium shifts 4.

Medication-Induced Causes

Beyond diuretics, multiple medications contribute to hypokalemia:

• Potassium-wasting diuretics and beta-blockers 5.
• NSAIDs can interfere with potassium homeostasis 4.
• Laxative abuse causes prolonged potassium losses 7, 8.

Special Populations and Conditions

Preterm infants:

• May develop hypokalemia due to enhanced demand, electrolyte depletion, inadequate supply, increased renal losses, or immature renal tubular function 5.

Patients with cirrhosis:

• Severe cirrhosis increases the risk of hypokalemia, especially during brisk diuresis 7, 8.

Tissue destruction:

• Catabolism, infection, surgery, and chemotherapy can contribute to hypokalemia 4.

Diagnostic Approach

Urinary potassium measurement distinguishes renal from extrarenal losses:

• Urinary potassium >20 mmol/L suggests renal potassium wasting 5.
• Urinary potassium <20 mmol/L suggests extrarenal losses 5.

Measurement of spot urine for potassium and creatinine, along with evaluation of acid-base status, can be used as an initial step in the diagnosis of hypokalemia 3.

Critical Pitfalls

• Never supplement potassium without checking and correcting magnesium first—this is the most common reason for treatment failure 4.
• Failing to address magnesium deficiency when treating hypokalemia makes potassium repletion difficult until magnesium is corrected 6.
• Overlooking secondary hyperaldosteronism as a cause of hypokalemia in volume-depleted patients 6.
• Hidden medication or substance use, including herbal supplements containing licorice (which causes mineralocorticoid effects) or concealed diuretic use, should be considered 6.