What are the causes of metabolic alkalosis?

Causes of Metabolic Alkalosis

Metabolic alkalosis results from either excessive loss of hydrogen ions (via gastrointestinal or renal routes), net gain of bicarbonate, or both, and requires maintenance factors that prevent the kidney from excreting the excess bicarbonate. 1, 2

Pathophysiological Framework

Metabolic alkalosis requires two components to persist: generation (initial creation of alkalosis) and maintenance (factors preventing renal bicarbonate excretion). 1, 2 Understanding this dual mechanism is critical because treating only the generation without addressing maintenance factors will fail.

Generation Mechanisms

Hydrogen Ion Loss:

• Gastrointestinal losses - Vomiting or nasogastric suction causes direct loss of gastric hydrochloric acid, the most common GI cause. 1, 2, 3
• Renal losses - Loop diuretics (furosemide) and thiazide diuretics cause urinary hydrogen ion wasting through enhanced distal sodium delivery and aldosterone-mediated proton secretion. 1, 2, 4

Bicarbonate Gain:

• Exogenous alkali administration - Oral or intravenous sodium bicarbonate, citrate (in blood transfusions), acetate, or lactate administration. 2, 3
• Excess calcium-alkali ingestion - Milk-alkali syndrome from calcium carbonate antacids. 2

Maintenance Factors (Why the Kidney Cannot Correct It)

The kidney normally prevents metabolic alkalosis by excreting excess bicarbonate, but these factors impair this protective mechanism:

• Volume contraction/hypovolemia - Stimulates proximal tubule bicarbonate reabsorption and prevents distal delivery needed for excretion. 1, 2, 3
• Chloride depletion (hypochloremia) - Chloride is required for bicarbonate excretion; without adequate chloride, bicarbonate reabsorption increases. 1, 2
• Hypokalemia - Potassium depletion enhances proximal bicarbonate reabsorption and stimulates distal hydrogen ion secretion. 1, 2, 3
• Decreased GFR/renal failure - Reduces filtered bicarbonate load, preventing excretion. 1, 2, 3
• Aldosterone excess - Directly stimulates distal hydrogen ion secretion and bicarbonate generation. 1, 2
• Elevated arterial PCO2 - Chronic hypercapnia promotes bicarbonate retention. 2

Clinical Classification by Urinary Chloride

Measuring urinary chloride concentration is the most practical diagnostic step after confirming metabolic alkalosis (pH >7.43, HCO3- >26 mmol/L). 1, 2

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

These conditions respond to saline and chloride repletion:

• Vomiting or nasogastric suction - The classic cause; gastric acid loss with volume and chloride depletion. 1, 2, 3
• Diuretic use (remote, after discontinuation) - Loop or thiazide diuretics cause chloride wasting; urine chloride is low once diuretics wear off. 2, 4
• Post-hypercapnic alkalosis - Chronic CO2 retention causes compensatory bicarbonate retention; rapid correction of hypercapnia leaves excess bicarbonate. 2
• Chloride-losing diarrhea - Rare congenital condition with intestinal chloride wasting. 2

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

These require specific treatment beyond saline:

With Hypertension (Mineralocorticoid Excess):

• Primary hyperaldosteronism - Adrenal adenoma or bilateral adrenal hyperplasia. 2, 3
• Renovascular hypertension - Secondary hyperaldosteronism from renal artery stenosis. 2
• Cushing syndrome - Cortisol excess with mineralocorticoid activity. 2, 3
• Exogenous mineralocorticoids - Fludrocortisone administration. 2

Without Hypertension:

• Active diuretic use - Ongoing loop or thiazide therapy maintains high urine chloride. 2, 4
• Bartter syndrome - Genetic defect mimicking loop diuretic effect; presents with normotension, hypokalemia, and metabolic alkalosis. 2, 3
• Gitelman syndrome - Genetic defect mimicking thiazide effect; similar presentation to Bartter but with hypocalciuria. 2, 3
• Severe hypokalemia (K+ <2.0 mEq/L) - Profound potassium depletion alone can maintain alkalosis. 2
• Magnesium depletion - Causes refractory hypokalemia and maintains alkalosis. 2

Apparent Mineralocorticoid Excess:

• Licorice ingestion - Glycyrrhizic acid inhibits 11β-hydroxysteroid dehydrogenase, allowing cortisol to activate mineralocorticoid receptors. 2, 4, 3
• Liddle syndrome - Genetic gain-of-function mutation in epithelial sodium channel. 2

Special Categories

Alkali Administration Syndromes:

• Milk-alkali syndrome - Excessive calcium carbonate intake (often from antacids) with hypercalcemia, renal insufficiency, and metabolic alkalosis. 2
• Massive blood transfusion - Citrate in stored blood is metabolized to bicarbonate. 2, 3
• Parenteral nutrition - Acetate in TPN solutions converts to bicarbonate. 2

Cystic Fibrosis:

• Excessive sweat chloride losses can cause metabolic alkalosis, particularly in hot weather or with fever. 2

Diagnostic Algorithm

1. Confirm metabolic alkalosis: Arterial pH >7.43 and serum HCO3- >26 mmol/L with compensatory PCO2 elevation. 1, 2, 5

2. Assess volume status: Check blood pressure (supine and standing), jugular venous pressure, skin turgor, and mucous membranes. 1, 5

3. Measure urinary chloride: This is the critical branching point. 1, 2

   • <20 mEq/L → Chloride-responsive (volume depleted)
   • >20 mEq/L → Chloride-resistant (proceed to step 4)

4. If chloride-resistant, check blood pressure and renin-aldosterone axis: 1, 2

   • Hypertensive → Measure plasma renin and aldosterone
     • Low renin, high aldosterone → Primary hyperaldosteronism
     • High renin, high aldosterone → Secondary hyperaldosteronism (renovascular disease)
     • Low renin, low aldosterone → Consider licorice, Liddle syndrome, or exogenous mineralocorticoids
   • Normotensive → Consider Bartter/Gitelman syndrome, active diuretic use, or severe hypomagnesemia

5. Check serum potassium and magnesium: Nearly all causes of metabolic alkalosis are accompanied by hypokalemia; check magnesium as hypomagnesemia causes refractory hypokalemia. 1, 2

Critical Clinical Pitfalls

• Do not assume all metabolic alkalosis is benign: Severe alkalosis (pH ≥7.55) in critically ill patients is associated with significantly increased mortality. 2

• Hypokalemia is almost universal: Failure to correct potassium will prevent resolution of alkalosis, as potassium depletion is both a cause and maintenance factor. 1, 2

• Vomiting-induced alkalosis requires potassium chloride, not just saline: While volume repletion with NaCl is important, potassium chloride infusion is essential to restore bicarbonate excretion. 1

• Urinary chloride can be misleading during active diuretic use: Urine chloride will be elevated (>20 mEq/L) while diuretics are active but drops below 20 mEq/L after discontinuation, despite the same underlying pathophysiology. 2

• Magnesium must be repleted before potassium: Hypomagnesemia causes renal potassium wasting; attempting to correct hypokalemia without addressing magnesium deficiency will fail. 2

• Post-hypercapnic alkalosis is often overlooked: Patients with chronic respiratory acidosis (COPD) who are mechanically ventilated and rapidly corrected will have persistent metabolic alkalosis from retained bicarbonate. 2