Metabolic Alkalosis: Etiology, Genetic Syndromes, and Diagnostic Criteria

1. Generation Mechanisms

Loop diuretics (e.g., furosemide, torsemide, bumetanide) increase sodium excretion and promote hydrogen‑ion loss in the loop of Henle, predisposing to metabolic alkalosis. – American Society of Nephrology 1
Thiazide diuretics inhibit distal tubular Na⁺‑Cl⁻ cotransport, leading to enhanced potassium and acid secretion via ROMK2 channels, which can also precipitate metabolic alkalosis. – American Society of Nephrology 1
Hypochloremia and existing metabolic alkalosis blunt the natriuretic and diuretic efficacy of loop diuretics by lowering the intraluminal chloride gradient. – American Society of Nephrology 2

Bartter syndrome (types 1‑5) presents in pediatric patients with hypokalemia, metabolic alkalosis, hypercalciuria, hypovolemia, normal‑to‑low blood pressure, and secondary hyperreninemic aldosterone elevation. – Endocrine Society 3
Gitelman syndrome typically manifests in adult patients with milder hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalciuria, and similar volume‑depleted, low‑renin physiology. – Endocrine Society 3

Primary aldosteronism causes hypertension together with hypokalemia and metabolic alkalosis due to autonomous aldosterone secretion. – Endocrine Society 3
Cushing syndrome can produce hypertension, hypokalemia, and metabolic alkalosis when aldosterone co‑secretion occurs. – Endocrine Society 3
Liddle syndrome, an autosomal‑dominant activating mutation of epithelial sodium channels, leads to early‑onset hypertension, hypokalemia, metabolic alkalosis, and suppressed renin‑angiotensin‑aldosterone activity. – Endocrine Society 3
Apparent mineralocorticoid excess (genetic 11β‑HSD2 deficiency or chronic licorice ingestion) results in hypertension, hypokalemia, and metabolic alkalosis via unopposed mineralocorticoid receptor activation. – Endocrine Society 3
Congenital adrenal hyperplasia due to 11β‑hydroxylase or 17α‑hydroxylase deficiency generates excess 11‑deoxycorticosterone, a mineralocorticoid agonist, producing hypertension, hypokalemia, and metabolic alkalosis. – Endocrine Society 3

Cystic fibrosis (pseudo‑Bartter phenotype) causes excessive salt loss in sweat, leading to volume depletion and metabolic alkalosis. – Kidney International 4

Measurement of urinary chloride (fractional excretion or Na⁺/Cl⁻ ratio) is essential to differentiate renal from extrarenal salt losses in metabolic alkalosis. – Kidney International 4
In Bartter syndrome, urinary fractional chloride excretion is typically elevated (>0.5 %). – Kidney International 4
Severe hypokalemia is associated with a chloride‑resistant pattern of metabolic alkalosis (urinary chloride > 20 mEq/L). – Kidney International 5

Chloride‑responsive alkalosis – characterized by urinary chloride < 20 mEq/L and extracellular volume depletion; common causes include diuretic therapy after discontinuation. – American Journal of Kidney Diseases 2
Chloride‑resistant alkalosis – urinary chloride > 20 mEq/L; typical etiologies are primary aldosteronism, Cushing syndrome, ongoing diuretic use, Bartter/Gitelman syndromes, and severe hypokalemia. – Endocrine Society 3; American Journal of Kidney Diseases 2; Kidney International 5

Bartter syndrome presents with hypokalemia, hypochloremic metabolic alkalosis, hypercalciuria, polyuria, and a normotensive hyperreninemic hyperaldosteronism phenotype. 6
The disorder often manifests prenatally or in early childhood with polyhydramnios, premature delivery, failure to thrive, and growth retardation. 7
A urinary fractional chloride excretion greater than 0.5 % is typical and supports the diagnosis. 8

In cystic fibrosis, excessive sweat‑salt loss leads to volume depletion and metabolic alkalosis that mimics Bartter syndrome. 8

Determining urinary chloride (fractional excretion or Na⁺/Cl⁻ ratio) is essential for distinguishing renal from extrarenal salt‑loss causes of metabolic alkalosis. 8
In patients suspected of Bartter syndrome, a fractional chloride excretion > 0.5 % strongly supports the diagnosis. 8