Causes of Metabolic Alkalosis
Metabolic alkalosis results from either loss of fixed acid (hydrogen ions) or net accumulation of bicarbonate in the extracellular fluid, with the kidney's inability to excrete excess bicarbonate being essential for maintenance of the alkalosis. 1
Generation Mechanisms
The initial development of metabolic alkalosis requires one of the following:
Acid Loss Pathways
- Gastrointestinal losses: Vomiting or nasogastric suction removes hydrogen ions and chloride, generating alkalosis 1, 2
- Renal acid losses: Loop diuretics (furosemide, torsemide) and thiazide diuretics cause urinary hydrogen ion excretion 3, 2
Bicarbonate Gain
- Exogenous alkali administration: Oral or parenteral bicarbonate, or metabolism of lactate, acetate, or citrate to bicarbonate 1, 4
- Calcium-alkali syndrome: Excessive calcium supplement ingestion combined with absorbable alkali 5
Maintenance Factors
The kidney normally prevents metabolic alkalosis by excreting excess bicarbonate, so maintenance factors that impair this renal compensation are critical to understanding persistent alkalosis. 1
Key Maintenance Mechanisms
- Volume contraction (hypovolemia): Stimulates proximal tubule bicarbonate reabsorption and prevents bicarbonate excretion 1, 2
- Hypochloremia: Reduces the intraluminal chloride gradient necessary for bicarbonate excretion and triggers adaptive neurohormonal responses 3, 1
- Hypokalemia: Promotes hydrogen ion secretion and bicarbonate reabsorption in the collecting duct 1, 2
- Aldosterone excess: Increases distal sodium reabsorption and hydrogen ion secretion via epithelial sodium channels 3, 1
- Reduced glomerular filtration rate: Decreases filtered bicarbonate load, limiting excretion capacity 1, 2
Major Clinical Categories
Chloride-Depletion Alkalosis
- Vomiting or gastric drainage: The most common cause, resulting in hydrogen ion and chloride loss 2, 4
- Diuretic therapy: Loop and thiazide diuretics cause chloruretic effects with secondary hyperaldosteronism 3, 6
Mineralocorticoid Excess Syndromes
- Primary hyperaldosteronism: Autonomous aldosterone production 1, 6
- Cushing syndrome: Cortisol excess with mineralocorticoid activity 1, 4
- Adrenogenital syndrome: Enzyme defects leading to mineralocorticoid accumulation 4
Apparent Mineralocorticoid Excess
- Licorice ingestion: Glycyrrhizic acid inhibits 11β-hydroxysteroid dehydrogenase, allowing cortisol to activate mineralocorticoid receptors 1, 4
Genetic Disorders
- Bartter syndrome: Defective sodium-potassium-chloride cotransporter in the thick ascending limb 1, 4
- Gitelman syndrome: Defective sodium-chloride cotransporter in the distal convoluted tubule 1, 4
Clinical Context Considerations
In heart failure patients with diuretic resistance, hypochloremia and metabolic alkalosis both antagonize loop diuretic effects by reducing the intraluminal chloride gradient and triggering adaptive neurohormonal responses. 3 This creates a vicious cycle where the treatment (diuretics) perpetuates the alkalosis, which in turn reduces diuretic efficacy.
In hemodialysis patients, persistent metabolic alkalosis occurs commonly due to high alkali dialysate concentrations combined with decreased protein catabolic rate and increased dialysis dose, potentially causing detrimental cardiovascular effects including cardiac arrhythmias. 7