What are the causes of metabolic alkalosis?

Causes of Metabolic Alkalosis

Metabolic alkalosis results from either loss of hydrogen ions (via gastrointestinal or renal routes) or net gain of bicarbonate, with maintenance of the alkalosis requiring impaired renal bicarbonate excretion due to volume contraction, chloride depletion, hypokalemia, hyperaldosteronism, or reduced GFR. 1, 2

Generation Mechanisms

Metabolic alkalosis develops through two primary pathways that increase serum bicarbonate above 26 mmol/L and arterial pH above 7.43 1:

Hydrogen Ion Loss

Gastrointestinal losses:

• Vomiting or nasogastric suction causes direct loss of gastric hydrochloric acid, the most common gastrointestinal cause 1, 3, 2

Renal losses:

• Loop diuretics (furosemide, bumetanide) and thiazide diuretics increase urinary chloride, sodium, and water losses, leading to volume contraction and compensatory bicarbonate retention 4, 5, 2
• Mineralocorticoid excess states (primary hyperaldosteronism, Cushing syndrome, adrenogenital syndrome) enhance distal nephron hydrogen ion secretion 3, 2
• Bartter syndrome and Gitelman syndrome cause genetic defects in renal tubular chloride reabsorption, mimicking chronic diuretic use 3, 2

Bicarbonate Gain

• Exogenous alkali administration via oral or parenteral sodium bicarbonate, or metabolism of lactate, acetate, or citrate to bicarbonate 3, 6, 2
• Milk-alkali syndrome from excessive calcium carbonate ingestion 2
• Massive blood transfusions containing citrate, which is metabolized to bicarbonate 6

Maintenance Factors

The kidney normally prevents metabolic alkalosis by excreting excess bicarbonate, but several factors impair this protective mechanism 2:

• Volume contraction stimulates proximal tubule bicarbonate reabsorption and activates the renin-angiotensin-aldosterone system 1, 5, 2
• Chloride depletion directly impairs bicarbonate excretion, as chloride is required for bicarbonate secretion in the collecting duct 1, 3, 2
• Hypokalemia enhances proximal tubule bicarbonate reabsorption and increases distal hydrogen ion secretion 1, 3, 2
• Reduced GFR decreases filtered bicarbonate load, limiting renal bicarbonate excretion 3, 2
• Elevated aldosterone increases distal sodium reabsorption and hydrogen ion secretion 3, 2

Clinical Classification

Metabolic alkalosis can be categorized into four major groups based on underlying pathophysiology 6:

Chloride-Depletion Alkalosis (Saline-Responsive)

• Vomiting or nasogastric drainage 1, 2
• Diuretic therapy (urinary chloride >20 mmol/L during active diuresis, <20 mmol/L after discontinuation) 1, 2
• Post-hypercapnic alkalosis 2
• Congenital chloride diarrhea 2

Mineralocorticoid Excess Syndromes (Saline-Resistant)

• Primary hyperaldosteronism 3, 2
• Cushing syndrome 3, 2
• Renovascular hypertension 2
• Renin-secreting tumors 2

Apparent Mineralocorticoid Excess Syndromes

• Licorice ingestion (contains glycyrrhizic acid, which inhibits 11β-hydroxysteroid dehydrogenase) 3, 2
• Liddle syndrome (genetic gain-of-function mutation in epithelial sodium channel) 2
• 11β-hydroxysteroid dehydrogenase deficiency 2

Excess Alkali Administration

• Sodium bicarbonate therapy 6, 2
• Citrate from blood transfusions 6
• Acetate from parenteral nutrition 3

Special Clinical Context: Congestive Heart Failure

In heart failure patients, metabolic alkalosis is particularly common and multifactorial 5:

• Loop diuretic therapy causes chloride depletion, volume contraction, and activation of the renin-angiotensin system 5
• The disease state itself produces neurohormonal activation (renin-angiotensin system, sympathetic nervous system, endothelin) that amplifies alkalosis 5
• Contraction alkalosis develops as diuresis concentrates existing bicarbonate in a smaller extracellular fluid volume 4, 5

Diagnostic Approach

Measure urinary chloride concentration to distinguish saline-responsive from saline-resistant causes 1, 2:

• Urinary chloride <20 mmol/L suggests chloride depletion (vomiting, remote diuretic use) 1, 2
• Urinary chloride >20 mmol/L suggests mineralocorticoid excess or ongoing diuretic therapy 1, 2

Assess volume status, plasma renin, and aldosterone levels to identify specific causes within the saline-resistant category 1, 2.

Clinical Consequences

Severe metabolic alkalosis (arterial pH ≥7.55) is associated with significantly increased mortality in critically ill patients 2:

• Central nervous system effects including confusion and seizures 3
• Decreased myocardial contractility 7, 3
• Skeletal muscle weakness 3
• Hypoventilation as respiratory compensation, potentially causing hypoxemia 2

Common Pitfalls

• Failing to recognize that elevated CO2 on basic metabolic panel during diuresis represents contraction alkalosis, not respiratory acidosis 4
• Stopping diuretics abruptly in heart failure patients with alkalosis, when acetazolamide should be added instead to allow continued necessary decongestion 4
• Not repleting both chloride and potassium simultaneously in vomiting-induced alkalosis, as both are required to restore renal bicarbonate excretion 1
• Overlooking licorice ingestion or herbal supplements containing glycyrrhizic acid as a cause of apparent mineralocorticoid excess 3, 2