What are the causes of hypokalemia?

Causes of Low Potassium Levels (Hypokalemia)

Low potassium levels result from three main mechanisms: inadequate intake, excessive losses (renal or gastrointestinal), or shifts of potassium from blood into cells. 1, 2

Primary Mechanisms

Inadequate Intake

• Dietary potassium deficiency alone rarely causes hypokalemia because the kidneys can reduce potassium excretion to below 15 mmol per day 3, 4
• Poor nutritional intake combined with other factors (especially in elderly patients with reduced calorie/protein intake) contributes to hypokalemia 5

Excessive Renal Losses (Most Common)

Diuretic therapy is the single most common cause of hypokalemia in clinical practice 1, 6, 2

• Loop diuretics (furosemide, bumetanide, torsemide) inhibit sodium-chloride reabsorption in the ascending limb of the loop of Henle, causing significant potassium wasting and metabolic alkalosis 5
• Thiazide diuretics (hydrochlorothiazide) block sodium-chloride reabsorption in the distal tubule, triggering compensatory potassium excretion 5
• The risk of diuretic-induced hypokalemia is markedly enhanced when two diuretics are used in combination 1

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 in volume-depleted states, particularly with high-output stomas or fistulas 1, 5

Inherited renal tubular disorders:

• Bartter syndrome causes renal potassium wasting with high urinary chloride; several genetic subtypes present prenatally with severe polyhydramnios and may be associated with deafness or chronic kidney disease 5
• Gitelman syndrome (SLC12A3) causes renal potassium loss that usually manifests in adolescence or adulthood and is characterized by hypocalciuria 5
• EAST/Sesame syndrome (KCNJ10 mutation) is a rare cause with associated neurologic features 5

Other renal causes:

• Distal (type 1) renal tubular acidosis causes hypokalemia with metabolic acidosis and low urinary ammonium excretion 5
• Diabetic ketoacidosis (osmotic diuresis) 1, 4
• High-dose penicillin 5

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 5

• Metabolic alkalosis develops when gastric acid is lost, leaving behind bicarbonate in the circulation 5
• This metabolic alkalosis directly increases renal potassium excretion through enhanced activity of the sodium epithelial channel (ENaC) in the cortical collecting duct 5
• Volume depletion from vomiting activates the renin-angiotensin-aldosterone system, causing increased aldosterone secretion that promotes sodium retention and potassium excretion 5

Other gastrointestinal causes:

• Diarrhea 2, 4
• High-output fistulas (enterocutaneous fistulas) 1, 5
• Laxative abuse (frequently concealed by patients) 5
• Malabsorption 4
• Congenital chloride diarrhea results in non-renal salt loss with low urinary chloride (<20 mEq/L) 5

Transcellular Shifts (Potassium Moves Into Cells)

• Beta-agonist therapy (albuterol, other beta-2 agonists) causes intracellular potassium shift 5, 2
• Insulin excess drives potassium into cells 1
• Metabolic alkalosis shifts potassium intracellularly 5
• Thyrotoxicosis can lead to transcellular shifts 1
• Theophylline can provoke intracellular potassium shifts 1

Magnesium Deficiency

Hypomagnesemia is a critical and frequently overlooked cause of refractory hypokalemia 1, 5

• Magnesium depletion causes dysfunction of potassium transport systems and increases renal potassium excretion 1
• Hypomagnesemia frequently coexists with hypokalemia (approximately 40% of hypokalemic patients have concurrent hypomagnesemia) and must be corrected before potassium levels will normalize 1, 7

Diagnostic Approach

A urinary potassium excretion of 20 mEq or more per day in the presence of low serum potassium (<3.5 mEq/L) suggests inappropriate renal potassium wasting 6

• Measurement of urinary chloride concentration helps differentiate renal salt-wasting (high chloride >20 mEq/L) from extrarenal losses (low chloride <20 mEq/L) in patients with metabolic alkalosis 5
• Spot urine for potassium and creatinine plus evaluation of acid-base status can be used as an initial diagnostic step 3
• When concealed diuretic or laxative abuse is suspected, obtain a urine diuretic screen 5
• Genetic testing is advised for patients with early-onset hypokalemia, family history of tubular disorders, or prenatal findings such as polyhydramnios 5

High-Risk Populations

• Elderly patients are particularly susceptible due to reduced glomerular filtration, multi-morbidity, polypharmacy, and reduced calorie/protein intake 5
• Patients with cardiac disease or heart failure require aggressive investigation even with mild hypokalemia 5
• Patients on digoxin are at increased risk of digitalis toxicity with hypokalemia 1, 5

Common Pitfalls

• Failing to check and correct magnesium first is the single most common reason for treatment failure in refractory hypokalemia 1
• Overlooking secondary hyperaldosteronism as a cause in volume-depleted patients 1
• Not considering concealed diuretic or laxative abuse 5
• Missing hidden medication or substance use, such as herbal supplements containing licorice, which can cause mineralocorticoid effects 5