What are the common causes of hypokalemia?

Causes of Hypokalemia

Medication-Induced Causes

Diuretic therapy is the most common cause of hypokalemia in clinical practice. 1, 2

• Loop diuretics (furosemide, bumetanide, torsemide) inhibit sodium and chloride reabsorption in the ascending limb of the loop of Henle, causing significant potassium loss through increased distal sodium delivery and secondary aldosterone stimulation 1, 3
• Thiazide diuretics (hydrochlorothiazide) block sodium-chloride reabsorption in the distal tubule, triggering compensatory potassium excretion through ROMK2 channels and aldosterone-sensitive ENaC channels 1, 3
• Both loop and thiazide diuretics commonly produce metabolic alkalosis alongside hypokalemia 3

Other medications that cause hypokalemia include:

• Beta-agonists (albuterol, other beta-2 agonists) cause intracellular potassium shift 1
• Insulin drives potassium into cells, reducing serum levels 1
• Corticosteroids cause hypokalemia through mineralocorticoid effects, with hydrocortisone causing more hypokalemia than methylprednisolone at equivalent doses 1
• High-dose penicillin can contribute to potassium loss 3
• Laxatives (when abused) produce hypokalemia through gastrointestinal potassium loss, frequently denied by patients 3

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. 3

• Metabolic alkalosis develops when gastric acid is lost through vomiting, leaving behind bicarbonate in the circulation, which directly increases renal potassium excretion through enhanced ENaC activity 3
• Volume depletion from vomiting activates the renin-angiotensin-aldosterone system, causing increased aldosterone secretion that promotes sodium retention and potassium excretion 3

Other gastrointestinal causes:

• Diarrhea results in direct potassium loss from stool 1, 4
• High-output fistulas (particularly enterocutaneous fistulas) cause substantial potassium depletion 1, 3
• High-output stomas lead to both direct potassium loss and secondary hyperaldosteronism from volume depletion 1

Renal Potassium Wasting

Primary aldosteronism causes inappropriate aldosterone production, leading to hypertension with hypokalemia in 8-20% of hypertensive patients 3

• Should be screened when hypertension coexists with spontaneous or substantial diuretic-induced hypokalemia, resistant hypertension, adrenal mass, or family history of early-onset hypertension 3
• Plasma aldosterone:renin activity ratio is used for screening, with a cutoff value of 30 and plasma aldosterone ≥10 ng/dL 3

Inherited tubulopathies:

• Bartter syndrome (multiple genetic subtypes: SLC12A1, KCNJ1, CLCNKB, BSND, CLCNKA + CLCNKB, MAGED2) leads to renal potassium wasting with high urinary chloride, may present prenatally with severe polyhydramnios, and can be associated with deafness or chronic kidney disease 3
• Gitelman syndrome (SLC12A3) causes renal potassium loss that usually manifests in adolescence or adulthood and is characterized by hypocalciuria 3
• EAST/Sesame syndrome (KCNJ10 mutation) is a rare cause with associated neurologic features 3
• Familial hypokalemic alkalosis with hypercalciuria (CASR mutation) presents with hypokalemia, metabolic alkalosis, and elevated urinary calcium 3

Renal tubular acidosis:

• Distal (type 1) renal tubular acidosis causes hypokalemia with metabolic acidosis and low urinary ammonium excretion 3

Transcellular Shifts

Conditions that drive potassium into cells include:

• Insulin excess (including treatment of diabetic ketoacidosis) 1, 4
• Beta-agonist therapy (albuterol, other beta-2 agonists) 1
• Metabolic alkalosis shifts potassium intracellularly 1
• Thyrotoxicosis can lead to transcellular shifts 3
• Catecholamines drive potassium into cells 1

Inadequate Dietary Intake

Reduced calorie/protein intake is particularly common in elderly patients with sedentary lifestyle and deconditioning 1

• Inadequate dietary intake alone rarely causes severe hypokalemia unless combined with other factors 1, 5
• Common in patients with cancer due to anorexia, nausea, or mucositis 5

Magnesium Deficiency

Hypomagnesemia causes renal potassium wasting and makes hypokalemia resistant to correction. 1, 3

• Magnesium depletion causes dysfunction of potassium transport systems and increases renal potassium excretion 1
• Approximately 40% of hypokalemic patients have concurrent hypomagnesemia 1
• Magnesium must be corrected (target >0.6 mmol/L) before potassium levels will normalize 1, 3

Special Populations at High Risk

Elderly patients are particularly susceptible to hypokalemia due to:

• Reduced glomerular filtration 1
• Multi-morbidity and polypharmacy 1
• Reduced dietary intake 1

Patients with cancer develop hypokalemia from:

• Inadequate dietary intake (anorexia, nausea, mucositis) 5
• Chemotherapy-induced vomiting and diarrhea 5
• Tumor-related metabolic abnormalities 5

Diagnostic Approach to Determine Etiology

Measure urinary potassium excretion: A urinary potassium excretion of ≥20 mEq/day in the presence of serum potassium <3.5 mEq/L suggests inappropriate renal potassium wasting 2

Measure urinary chloride concentration: This helps differentiate renal salt-wasting (high chloride >20 mEq/L) from extrarenal losses (low chloride <20 mEq/L) in patients with metabolic alkalosis 3, 6

Consider concealed substance use:

• Hidden diuretic use should be suspected; obtain urine diuretic screen when suspected 3
• Herbal supplements containing licorice can cause mineralocorticoid effects 3
• Concealed laxative abuse is frequently denied by patients 3

Assess volume status: Orthostatic changes in blood pressure and heart rate help determine whether potassium loss is associated with volume depletion (suggesting increased distal sodium delivery) or volume expansion with hypertension (suggesting primary mineralocorticoid excess) 6

Genetic testing is advised for patients with early-onset hypokalemia, family history of tubular disorders, or prenatal findings such as polyhydramnios 3