What are the causes of metabolic alkalosis?

Causes of Metabolic Alkalosis

Metabolic alkalosis results from either loss of hydrogen ions (primarily through gastrointestinal or renal routes) or gain of bicarbonate, with the most common causes being vomiting, diuretic use, volume depletion with hypochloremia, hypokalemia, and mineralocorticoid excess. 1

Pathophysiologic Framework

Metabolic alkalosis requires two components: generation (initial creation of alkalosis) and maintenance (factors preventing renal bicarbonate excretion). 2 Understanding this distinction is critical because treatment must address both aspects.

Generation Mechanisms

• Hydrogen ion loss via gastrointestinal tract: Vomiting or nasogastric suction removes gastric hydrochloric acid 1, 2
• Hydrogen ion loss via kidney: Loop or thiazide diuretics cause urinary potassium and chloride losses 1, 3
• Exogenous base gain: Oral or parenteral bicarbonate, citrate, acetate, or lactate administration 3, 4
• Alkali ingestion: Baking soda (sodium bicarbonate) or calcium carbonate with milk-alkali syndrome 4, 5

Maintenance Mechanisms

The kidney normally excretes excess bicarbonate efficiently, but several factors impair this protective mechanism:

• Volume depletion: Activates sodium reabsorption and increases hydrogen ion secretion 1, 2
• Hypochloremia: Limits the kidney's capacity to excrete bicarbonate 1, 4
• Hypokalemia: Promotes bicarbonate reabsorption and hydrogen ion secretion 1, 2
• Decreased GFR: Reduces filtered bicarbonate load 4, 6
• Aldosterone excess: Increases distal hydrogen ion secretion 1, 4

Clinical Categories

Chloride-Depletion Alkalosis (Saline-Responsive)

• Vomiting or nasogastric suction: Most common cause; characterized by low urine chloride (<20 mEq/L) 2, 4
• Diuretic therapy: Loop diuretics (furosemide) and thiazides cause chloride and potassium wasting 1, 3
• Post-hypercapnic alkalosis: Occurs after rapid correction of chronic respiratory acidosis; kidneys retain bicarbonate during chronic CO2 retention, then when CO2 normalizes rapidly, the elevated bicarbonate persists 1, 4
• Congenital chloride diarrhea: Rare genetic disorder causing chloride loss in stool 4

Mineralocorticoid Excess Syndromes (Saline-Resistant)

• Primary hyperaldosteronism: Aldosterone-producing adenoma or bilateral adrenal hyperplasia; characterized by high urine chloride (>20 mEq/L), hypertension, and hypokalemia 1, 4
• Cushing syndrome: Excess cortisol with mineralocorticoid effects 1, 4
• Bartter syndrome: Genetic defect in chloride transport in the loop of Henle; mimics loop diuretic use 1, 4
• Gitelman syndrome: Genetic defect in sodium-chloride cotransporter in distal tubule; mimics thiazide use 1, 4
• Licorice ingestion: Contains glycyrrhizic acid, which inhibits 11β-hydroxysteroid dehydrogenase, causing apparent mineralocorticoid excess 4, 6

Alkali Administration

• Massive blood transfusion: Citrate in stored blood is metabolized to bicarbonate 4
• Total parenteral nutrition: Acetate is metabolized to bicarbonate 4
• Milk-alkali syndrome: Excessive calcium carbonate intake with absorbable alkali 4
• Surreptitious baking soda ingestion: Often concealed by patients; urine pH >7 and elevated urine anion gap are diagnostic clues 5

Diagnostic Approach

Step 1: Confirm Metabolic Alkalosis

• Arterial pH >7.45 and serum bicarbonate >26 mmol/L 2, 4

Step 2: Assess Volume Status

• Volume depleted: Suggests vomiting, diuretics, or post-hypercapnic state 2
• Volume expanded with hypertension: Suggests mineralocorticoid excess 4

Step 3: Measure Urine Chloride

• <20 mEq/L (saline-responsive): Vomiting, remote diuretic use, post-hypercapnic alkalosis 2, 4
• >20 mEq/L (saline-resistant): Current diuretic use, mineralocorticoid excess, Bartter/Gitelman syndromes 4

Step 4: Additional Tests When Cause Unclear

• Urine pH >7 with high urine anion gap: Suggests surreptitious alkali ingestion 5
• Plasma renin and aldosterone levels: Differentiates primary hyperaldosteronism (low renin, high aldosterone) from secondary causes 2, 4
• 24-hour urine cortisol: Evaluates for Cushing syndrome 4

Common Pitfalls

• Overlooking surreptitious behaviors: Patients may conceal vomiting, laxative abuse, diuretic abuse, or alkali ingestion; maintain high suspicion when history doesn't match clinical picture 5
• Misinterpreting borderline urine chloride: Values near 20 mEq/L can occur with mixed causes; consider timing of diuretic use 5
• Ignoring hypokalemia: Severe hypokalemia (<2.5 mEq/L) both causes and perpetuates metabolic alkalosis; must be corrected for successful treatment 2, 4
• Failing to recognize post-hypercapnic alkalosis: Common in COPD patients after mechanical ventilation; requires time for renal bicarbonate excretion 1

Clinical Significance

Severe metabolic alkalosis (pH ≥7.55) in critically ill patients is associated with significantly increased mortality, affecting multiple organ systems including central nervous system dysfunction, cardiac arrhythmias, decreased oxygen delivery to tissues, and impaired skeletal muscle function. 4, 6