What are the causes, clinical features, and laboratory findings of metabolic alkalosis in patients with various underlying conditions, such as primary aldosteronism, bulimia nervosa, and heart failure, and how does it present in different scenarios?

Metabolic Alkalosis: Causes, Clinical Features, Laboratory Findings, and Clinical Vignettes

Definition and Pathophysiology

Metabolic alkalosis is characterized by elevated arterial pH (>7.43) and elevated plasma bicarbonate (>26 mEq/L), with compensatory increase in PaCO2 due to hypoventilation. 1, 2 The pathogenesis requires both generation (gain of bicarbonate or loss of hydrogen ions) and maintenance (impaired renal bicarbonate excretion) of the alkalosis. 1, 3

Major Causes of Metabolic Alkalosis

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

• Gastrointestinal losses: Vomiting and nasogastric suction cause loss of hydrochloric acid, leading to volume contraction, hypochloremia, and hypokalemia. 4, 1, 2
• Diuretic therapy: Loop and thiazide diuretics induce chloride and volume depletion with secondary hyperaldosteronism. 5, 6, 4
• Contraction alkalosis: Volume depletion concentrates existing bicarbonate in the extracellular fluid. 6
• Post-hypercapnic alkalosis: Rapid correction of chronic respiratory acidosis leaves elevated bicarbonate without compensatory hypercapnia. 1

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

• Primary hyperaldosteronism: Excess mineralocorticoid activity increases distal sodium reabsorption and hydrogen ion secretion. 4, 1, 3
• Bartter syndrome: Genetic salt-losing tubulopathy with impaired salt reabsorption in the thick ascending limb, causing polyuria, hypokalemia, hypochloremic metabolic alkalosis, and normotensive hyperreninemic hyperaldosteronism. 7, 5
• Gitelman syndrome: Similar to Bartter but typically presents later with hypocalciuria and hypomagnesemia. 5, 1
• Cushing syndrome and exogenous corticosteroids: Cortisol excess mimics mineralocorticoid effects. 4, 3
• Licorice ingestion: Inhibits 11β-hydroxysteroid dehydrogenase, causing apparent mineralocorticoid excess. 1, 3

Alkali Administration

• Milk-alkali syndrome: Excessive calcium and alkali intake (calcium carbonate antacids). 4, 1
• Massive blood transfusion: Citrate metabolism generates bicarbonate. 1
• Parenteral nutrition with acetate: Acetate is metabolized to bicarbonate. 3

Clinical Features

Cardiovascular Effects

• Arrhythmias: Hypokalemia and alkalemia increase risk of atrial and ventricular arrhythmias. 3
• Decreased myocardial contractility: Severe alkalosis (pH >7.55) impairs cardiac function. 1
• Coronary vasoconstriction: Alkalemia reduces coronary blood flow. 3

Neurological Effects

• Altered mental status: Confusion, lethargy, or delirium in severe cases. 3
• Seizures: Alkalemia lowers seizure threshold by decreasing ionized calcium. 3
• Paresthesias and tetany: Reduced ionized calcium from increased protein binding. 3

Respiratory Effects

• Compensatory hypoventilation: Increases PaCO2 by approximately 0.7 mmHg for each 1 mEq/L rise in bicarbonate. 1, 2
• Hypoxemia: Hypoventilation may cause oxygen desaturation, particularly in patients with underlying lung disease. 1

Metabolic Effects

• Hypokalemia: Nearly universal finding due to transcellular potassium shifts and increased renal potassium losses. 6, 1, 2
• Hypophosphatemia: Intracellular shift of phosphate. 3
• Paradoxical aciduria: Despite systemic alkalosis, urine pH may be <5.5 when severe volume depletion and hypokalemia drive distal hydrogen ion secretion. 6

Laboratory Findings

Arterial Blood Gas

• pH: >7.43 (severe alkalosis: pH >7.55 associated with significantly increased mortality). 1
• Bicarbonate: >26 mEq/L (often >35 mEq/L in severe cases). 1, 2
• PaCO2: Elevated as respiratory compensation (typically 40-55 mmHg). 1, 2

Serum Electrolytes

• Potassium: Typically <3.5 mEq/L, often <3.0 mEq/L in severe cases. 5, 6, 1
• Chloride: Decreased (often <95 mEq/L) in chloride-responsive alkalosis. 7, 6
• Sodium: Usually normal, but plasma Cl⁻/Na⁺ ratio may be decreased in Bartter syndrome. 7
• Magnesium: May be low, particularly in Gitelman syndrome and diuretic use. 5, 1

Urine Studies

• Urinary chloride: <20 mEq/L indicates chloride-responsive alkalosis; >20 mEq/L suggests chloride-resistant causes. 5, 4, 2
• Fractional excretion of chloride: >0.5% in Bartter syndrome despite volume depletion. 7, 6
• Urine pH: May be paradoxically acidic (<5.5) in volume-depleted states despite systemic alkalosis. 6
• Urine potassium: Elevated (>30 mEq/day) in renal potassium wasting disorders. 1

Additional Testing for Specific Causes

• Plasma renin and aldosterone: Elevated in both primary and secondary hyperaldosteronism; helps distinguish Bartter syndrome (high renin, high aldosterone) from primary hyperaldosteronism. 7, 2
• Renal ultrasound: Assess for nephrocalcinosis in Bartter syndrome types 1,2, and 5. 7, 5
• Genetic testing: Definitive diagnosis of Bartter or Gitelman syndrome. 7, 5

Clinical Vignettes

Vignette 1: Chloride-Responsive Alkalosis (Bulimia Nervosa)

Presentation: A 22-year-old woman presents with weakness and muscle cramps. She appears volume-depleted with orthostatic hypotension (BP 100/60 mmHg supine, 85/55 mmHg standing). 2

Laboratory findings:

• pH 7.52, PaCO2 48 mmHg, HCO3⁻ 38 mEq/L 1
• Serum K⁺ 2.8 mEq/L, Cl⁻ 88 mEq/L, Na⁺ 138 mEq/L 6, 2
• Urinary Cl⁻ 8 mEq/L (low, indicating chloride-responsive) 2
• Urine pH 5.0 (paradoxical aciduria) 6

Diagnosis: Self-induced vomiting causing gastric acid loss, volume depletion, and secondary hyperaldosteronism. 4, 2

Treatment: Volume repletion with normal saline and potassium chloride supplementation (20-60 mEq/day) to restore serum potassium to 4.5-5.0 mEq/L. 5, 2 Psychiatric evaluation for eating disorder. 2

Vignette 2: Chloride-Resistant Alkalosis (Primary Aldosteronism)

Presentation: A 48-year-old man with hypertension (BP 165/95 mmHg) presents with muscle weakness and polyuria. No orthostatic changes noted. 4, 3

Laboratory findings:

• pH 7.48, PaCO2 44 mmHg, HCO3⁻ 32 mEq/L 1
• Serum K⁺ 2.6 mEq/L, Cl⁻ 96 mEq/L, Na⁺ 144 mEq/L 1
• Urinary Cl⁻ 45 mEq/L (elevated, indicating chloride-resistant) 2
• Plasma aldosterone elevated, plasma renin suppressed 2

Diagnosis: Primary aldosteronism with hypertension, hypokalemia, and metabolic alkalosis. 4, 3

Treatment: Spironolactone 25-100 mg daily as aldosterone antagonist, potassium chloride supplementation, and evaluation for adrenal adenoma. 5 Avoid normal saline as it will not correct the alkalosis. 2

Vignette 3: Bartter Syndrome (Neonatal Presentation)

Presentation: A newborn delivered prematurely at 32 weeks after polyhydramnios. Infant has polyuria (>5 mL/kg/hr), failure to thrive, and dehydration despite adequate fluid intake. Blood pressure normal (65/40 mmHg). 7

Laboratory findings:

• pH 7.50, PaCO2 46 mmHg, HCO3⁻ 36 mEq/L 7
• Serum K⁺ 2.4 mEq/L, Cl⁻ 82 mEq/L, Na⁺ 136 mEq/L 7
• Plasma Cl⁻/Na⁺ ratio: 0.60 (decreased) 7
• Urinary Cl⁻ 65 mEq/L, fractional excretion of chloride 1.2% (>0.5%) 7, 6
• Plasma renin and aldosterone both markedly elevated 7
• Renal ultrasound shows bilateral nephrocalcinosis 7, 5
• Hypercalciuria present 7

Diagnosis: Bartter syndrome type 1 or 2 (antenatal variant) with salt-losing tubulopathy, normotensive hyperreninemic hyperaldosteronism. 7

Treatment: Sodium chloride supplementation 5-10 mmol/kg/day, potassium chloride supplementation, indomethacin 1-2 mg/kg/day to reduce prostaglandin-mediated salt wasting, and proton pump inhibitor for gastric protection. 5 Genetic testing for SLC12A1 (type 1) or KCNJ1 (type 2) mutations. 7

Vignette 4: Diuretic-Induced Alkalosis in Heart Failure

Presentation: A 72-year-old man with heart failure on furosemide 80 mg twice daily presents with weakness and confusion. Examination shows mild peripheral edema but no orthostatic hypotension. 5

Laboratory findings:

• pH 7.54, PaCO2 50 mmHg, HCO3⁻ 42 mEq/L 1
• Serum K⁺ 2.9 mEq/L, Cl⁻ 86 mEq/L, Na⁺ 140 mEq/L 6
• Urinary Cl⁻ 35 mEq/L (elevated due to ongoing diuretic effect) 5
• eGFR 45 mL/min/1.73m² 5

Diagnosis: Severe diuretic-induced metabolic alkalosis with hypokalemia in the setting of heart failure. 5, 4

Treatment: Add spironolactone 25 mg daily as aldosterone antagonist and potassium-sparing diuretic. 5 Potassium chloride supplementation 40-60 mEq/day. 5 Consider single dose of acetazolamide 500 mg IV to rapidly lower bicarbonate if adequate kidney function. 5 Reduce loop diuretic dose if volume status permits. 5 Critical pitfall: Avoid combining potassium-sparing diuretics with ACE inhibitors without close monitoring due to hyperkalemia risk. 5

Vignette 5: Gitelman Syndrome (Adolescent Presentation)

Presentation: A 16-year-old girl presents with recurrent muscle cramps, fatigue, and salt craving. Blood pressure 105/65 mmHg. No history of polyhydramnios or prematurity. 5, 1

Laboratory findings:

• pH 7.46, PaCO2 43 mmHg, HCO3⁻ 30 mEq/L 1
• Serum K⁺ 3.0 mEq/L, Mg²⁺ 1.2 mg/dL (low), Cl⁻ 92 mEq/L 5, 1
• Urinary Cl⁻ 40 mEq/L (elevated) 5
• Urinary calcium/creatinine ratio 0.08 (low, <0.2) 5
• Plasma renin and aldosterone elevated 1

Diagnosis: Gitelman syndrome with hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalciuria. 5, 1 Distinguished from Bartter syndrome by later presentation, hypocalciuria, and prominent hypomagnesemia. 5

Treatment: Sodium chloride supplementation 5-10 mmol/kg/day, potassium chloride supplementation, magnesium supplementation (magnesium oxide 400-800 mg daily), and potassium-sparing diuretics (amiloride 5-10 mg daily). 5 Avoid potassium citrate as it worsens metabolic alkalosis. 5

Diagnostic Algorithm

Step 1: Confirm metabolic alkalosis with arterial blood gas (pH >7.43, HCO3⁻ >26 mEq/L, elevated PaCO2). 1, 2

Step 2: Assess volume status clinically (orthostatic vital signs, skin turgor, mucous membranes). 2

Step 3: Measure urinary chloride to classify alkalosis type:

• Urinary Cl⁻ <20 mEq/L: Chloride-responsive (vomiting, remote diuretic use, contraction alkalosis). 4, 2
• Urinary Cl⁻ >20 mEq/L: Chloride-resistant (ongoing diuretic use, mineralocorticoid excess, Bartter/Gitelman syndrome). 5, 2

Step 4: If chloride-resistant, measure plasma renin and aldosterone:

• High renin, high aldosterone: Secondary hyperaldosteronism (Bartter/Gitelman syndrome, diuretics, renovascular disease). 7, 2
• Low renin, high aldosterone: Primary hyperaldosteronism. 2
• Low renin, low aldosterone: Apparent mineralocorticoid excess (licorice, Cushing syndrome). 4, 3

Step 5: If Bartter or Gitelman syndrome suspected, check:

• Fractional excretion of chloride (>0.5% in Bartter despite volume depletion). 7, 6
• Urinary calcium (high in Bartter, low in Gitelman). 7, 5
• Serum magnesium (low in Gitelman). 5, 1
• Renal ultrasound for nephrocalcinosis. 7, 5
• Genetic testing for definitive diagnosis. 7, 5

Treatment Principles

Chloride-Responsive Alkalosis

• Volume repletion with normal saline (0.9% NaCl) to restore chloride and allow renal bicarbonate excretion. 6, 2
• Potassium chloride supplementation 20-60 mEq/day to maintain serum potassium 4.5-5.0 mEq/L. 5, 2
• Discontinue offending agents (diuretics, nasogastric suction) when possible. 5

Chloride-Resistant Alkalosis

• Treat underlying cause: Surgical resection for aldosterone-producing adenoma, discontinue licorice, treat Cushing syndrome. 4, 3
• Potassium-sparing diuretics: Amiloride 2.5-10 mg daily or spironolactone 25-100 mg daily as first-line for mineralocorticoid excess. 5
• Potassium chloride supplementation (not potassium citrate, which worsens alkalosis). 5

Bartter/Gitelman Syndrome

• Sodium chloride supplementation 5-10 mmol/kg/day. 5
• Potassium chloride supplementation (avoid potassium citrate). 5
• NSAIDs (indomethacin 1-2 mg/kg/day) to reduce prostaglandin-mediated salt wasting in symptomatic Bartter syndrome. 5
• Proton pump inhibitor when using NSAIDs. 5
• Magnesium supplementation for Gitelman syndrome. 5

Severe Metabolic Alkalosis (pH >7.55)

• Acetazolamide 500 mg IV single dose in patients with heart failure and adequate kidney function (eGFR >30 mL/min/1.73m²) causes rapid bicarbonate reduction. 5
• Hemodialysis with low-bicarbonate/high-chloride dialysate for refractory cases with concurrent renal failure. 5
• Avoid sodium bicarbonate or alkalinization strategies as these worsen alkalosis. 5

Critical Pitfalls to Avoid

• Do not use potassium citrate or potassium bicarbonate for potassium repletion in metabolic alkalosis, as these worsen the alkalosis; use potassium chloride exclusively. 5
• Do not combine potassium-sparing diuretics with ACE inhibitors or ARBs without close monitoring due to severe hyperkalemia risk. 5
• Do not perform diuretic challenge tests in suspected Bartter syndrome, especially in infants, due to risk of severe volume depletion; genetic testing has replaced these obsolete tests. 7
• Do not assume normal blood pressure excludes Bartter or Gitelman syndrome; these are normotensive conditions despite hyperreninemic hyperaldosteronism. 7, 5
• Do not overlook Bartter syndrome in euvolemic patients with unexplained hypokalemic metabolic alkalosis, especially with history of polyhydramnios and prematurity. 5
• Do not use loop diuretics in metabolic alkalosis unless hypervolemia, hyperkalemia, or renal acidosis are present, as they perpetuate the alkalosis. 5
• Recognize paradoxical aciduria (urine pH <5.5 despite systemic alkalosis) as a sign of severe volume depletion and hypokalemia, not renal tubular acidosis. 6