What are the causes of metabolic alkalosis?

Causes of Metabolic Alkalosis

Metabolic alkalosis results from either a net gain of bicarbonate or a loss of hydrogen ions from the extracellular fluid, with the kidney's inability to excrete excess bicarbonate being essential for maintaining the alkalosis. 1, 2

Generation Mechanisms

The initial development of metabolic alkalosis requires one of the following processes:

Gastrointestinal Acid Loss

• Vomiting or nasogastric suction causes loss of hydrochloric acid from gastric secretions, generating metabolic alkalosis through direct hydrogen ion depletion. 3, 1, 2

Renal Acid Loss

• Loop and thiazide diuretics are the most common cause of metabolic alkalosis in hospitalized patients, promoting urinary losses of chloride, sodium, and hydrogen ions while stimulating aldosterone secretion. 3, 1, 4
• Mineralocorticoid excess states (primary hyperaldosteronism, Cushing syndrome, adrenogenital syndrome) enhance distal nephron hydrogen ion secretion, driving bicarbonate generation and potassium wasting. 3, 2, 5
• Bartter syndrome and Gitelman syndrome are genetic salt-losing tubulopathies characterized by impaired salt reabsorption in the thick ascending limb or distal convoluted tubule, resulting in secondary hyperaldosteronism and hypokalemic metabolic alkalosis. 3, 1

Exogenous Alkali Administration

• Excessive oral or parenteral bicarbonate administration can generate metabolic alkalosis, particularly when renal bicarbonate excretion is impaired. 1, 2, 5
• Milk-alkali syndrome from excessive calcium carbonate ingestion (often from antacid overuse) produces metabolic alkalosis combined with hypercalcemia and renal insufficiency. 1
• Metabolism of lactate, acetate, or citrate (found in blood products, parenteral nutrition, or citrate anticoagulation) generates bicarbonate and can contribute to alkalosis. 2, 5

Contraction Alkalosis

• Volume depletion from any cause concentrates existing bicarbonate in a smaller extracellular fluid volume, creating "contraction alkalosis" that is particularly prominent during aggressive diuresis. 3, 1

Maintenance Factors

The kidney normally prevents metabolic alkalosis by excreting excess bicarbonate, so maintenance of alkalosis requires factors that impair renal bicarbonate excretion: 1, 2

• Volume contraction and effective arterial blood volume depletion enhance proximal tubule bicarbonate reabsorption, preventing correction of the alkalosis. 3, 1, 2
• Hypochloremia independently stimulates bicarbonate retention by the kidney, as chloride is required for bicarbonate excretion. 3, 1, 6
• Hypokalemia promotes hydrogen ion secretion and bicarbonate generation in the collecting duct, perpetuating the alkalosis through intracellular acidosis in renal tubular cells. 3, 1, 2
• Reduced glomerular filtration rate decreases the filtered load of bicarbonate, limiting the kidney's capacity to excrete excess base. 1, 2, 5
• Elevated aldosterone levels (primary or secondary) enhance distal sodium reabsorption and hydrogen ion secretion, maintaining bicarbonate generation. 3, 1, 6
• Chronic hypercapnia stimulates renal bicarbonate retention as respiratory compensation, and this elevated bicarbonate persists even if CO₂ levels normalize acutely. 1

Clinical Classification by Urinary Chloride

Measuring urinary chloride concentration provides a practical framework for identifying the underlying cause: 3

Chloride-Responsive Alkalosis (Urinary Cl⁻ <20 mEq/L)

• Vomiting or nasogastric suction 3, 6
• Remote diuretic use (after the diuretic effect has worn off) 3
• Post-hypercapnic alkalosis (after rapid correction of chronic respiratory acidosis) 1
• Chloride-losing diarrhea (rare congenital disorder) 1

Chloride-Resistant Alkalosis (Urinary Cl⁻ >20 mEq/L)

• Active diuretic therapy 3
• Primary hyperaldosteronism or other mineralocorticoid excess states 3, 6
• Bartter syndrome or Gitelman syndrome 3, 1
• Licorice ingestion (contains glycyrrhizic acid, which inhibits 11β-hydroxysteroid dehydrogenase, causing apparent mineralocorticoid excess) 1, 2
• Severe hypokalemia (serum K⁺ <2.0 mEq/L) from any cause 3

Special Considerations

• Severe metabolic alkalosis (arterial pH ≥7.55) in critically ill patients is associated with significantly increased mortality, making prompt identification and treatment essential. 1
• Western dietary patterns with high animal protein and low fruit/vegetable intake can contribute to chronic low-grade metabolic alkalosis through increased net endogenous acid production that paradoxically stimulates compensatory mechanisms. 7
• Cystic fibrosis patients may develop metabolic alkalosis due to excessive sweat chloride losses, particularly in hot environments. 1

Common Pitfalls

• Failing to recognize that diuretic-induced alkalosis requires both chloride AND potassium repletion—giving potassium citrate or potassium bicarbonate will worsen the alkalosis rather than correct it. 3
• Overlooking Bartter or Gitelman syndrome in young patients with unexplained hypokalemic metabolic alkalosis and normal blood pressure, especially when there is no obvious gastrointestinal loss or diuretic exposure. 3
• Attempting to correct the elevated bicarbonate in compensated chronic respiratory acidosis, which is a protective mechanism that should be preserved. 3