Metabolic Alkalosis Due to ECF Volume Expansion

This category of metabolic alkalosis is also called chloride-resistant alkalosis or mineralocorticoid excess alkalosis. It is characterized by ECF volume expansion, hypertension, hypokalemia, and a urine chloride > 40 mEq/L (the hallmark that distinguishes it from chloride-responsive/volume-depleted alkalosis).

Pathophysiology

The core mechanism involves excess mineralocorticoid activity (primarily aldosterone), which acts on the collecting duct principal cells to:

Upregulate ENaC (epithelial Na+ channel) - increased Na+ reabsorption leads to ECF volume expansion and hypertension
Increase luminal electronegativity - the Na+ reabsorption without Cl- creates a transepithelial voltage gradient that drives:
- H+ secretion (via H+-ATPase in alpha-intercalated cells) → generates new HCO3- → metabolic alkalosis
- K+ secretion (via ROMK channels) → hypokalemia
Hypokalemia perpetuates alkalosis - K+ depletion causes intracellular acidosis, which further stimulates H+ secretion in both proximal and distal nephron, and activates H+/K+-ATPase in the collecting duct

The alkalosis is not progressive and is generally mild, partly due to "aldosterone escape": ECF volume expansion increases natriuretic peptides (e.g., ANP) and raises GFR, antagonizing the aldosterone-driven acid excretion to some degree.

Brenner and Rector's The Kidney, pp. 732-734
Harrison's Principles of Internal Medicine 22E, p. 418

Classification by Renin/Aldosterone Status

High Renin → Secondary Hyperaldosteronism

Renin is overproduced by the kidney, driving aldosterone excess. Total ECF may not be reduced despite "effective" volume issues:

Renovascular hypertension (renal artery stenosis) - reduced renal perfusion triggers renin release
Malignant / accelerated hypertension
Renin-secreting tumor (primary reninism) - rare
Estrogen use - increases renin substrate (angiotensinogen) → increased angiotensin II → secondary aldosteronism

Low Renin, High Aldosterone → Primary Hyperaldosteronism

Autonomous adrenal overproduction suppresses renin feedback:

Cause	Key Features
Primary aldosteronism (Conn's syndrome)	Adrenal adenoma (most common), bilateral hyperplasia, or rarely carcinoma; classic triad: hypertension + hypokalemia + metabolic alkalosis
Glucocorticoid-remediable hyperaldosteronism (GRA)	Autosomal dominant; chimeric gene fuses CYP11B1 promoter with CYP11B2 aldosterone synthase - ACTH drives excess aldosterone; corrected by glucocorticoids; associated with severe hypertension and stroke risk
Cushing's syndrome/disease	High glucocorticoids cause alkalosis via cross-reactivity at mineralocorticoid receptors + coexisting mineralocorticoid (deoxycorticosterone, corticosterone) hypersecretion
Adrenal enzyme defects (11β-hydroxylase, 17α-hydroxylase deficiency)	Accumulation of mineralocorticoid precursors (deoxycorticosterone)

Low Renin, Low Aldosterone (Pseudohyperaldosteronism)

ENaC is constitutively active despite low aldosterone:

Cause	Mechanism
Liddle's syndrome	Gain-of-function mutation in β or γ subunit of ENaC (disrupts PY motif binding to Nedd4 ubiquitin ligase → increased ENaC surface expression); autosomal dominant; severe childhood-onset hypertension, hypokalemia, metabolic alkalosis; does NOT respond to spironolactone (aldosterone receptor blocker); responds to amiloride/triamterene (direct ENaC blockers)
Apparent mineralocorticoid excess (AME)	Deficiency of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) → cortisol not inactivated to cortisone in kidney → cortisol occupies and activates mineralocorticoid receptors; same effect from licorice ingestion (glycyrrhizic acid inhibits 11β-HSD2)

Brenner and Rector's The Kidney, pp. 732-735
Harrison's Principles of Internal Medicine 22E, p. 418

Key Diagnostic Feature: Urine Chloride

Urine Cl-	Category	Interpretation
< 20 mEq/L	Chloride-responsive	Volume-depleted (vomiting, diuretics post-effect) - kidney is conserving Cl-
> 40 mEq/L	Chloride-resistant	Volume-expanded (mineralocorticoid excess) - kidney continues to waste Cl-

Associated Findings

Hypertension (from ECF volume expansion and Na+ retention)
Hypokalemia (from ongoing kaliuresis)
Polydipsia / polyuria (from persistent K+ depletion impairing urinary concentration)
Neuromuscular symptoms of alkalosis: paresthesias, muscular cramps, tetany, and in severe cases, seizures, mental confusion, obtundation, and worsening of arrhythmias

Treatment

Principle: Treat the underlying cause; do NOT give saline (unlike chloride-responsive alkalosis).

Cause	Treatment
Primary aldosteronism (adenoma)	Surgical adrenalectomy
Bilateral adrenal hyperplasia	Spironolactone / eplerenone (mineralocorticoid receptor antagonists)
Cushing's syndrome	Treat the source (pituitary, adrenal, ectopic ACTH)
GRA	Glucocorticoid administration (dexamethasone suppresses chimeric gene)
Liddle's syndrome	Amiloride or triamterene (NOT spironolactone)
AME / licorice	Stop licorice; spironolactone or amiloride
All cases with hypokalemia	Replenish K+ (essential, as K+ deficiency maintains alkalosis)

If saline cannot be given (e.g., heart failure) and alkalosis must be corrected, acetazolamide (125-250 mg IV) can accelerate renal HCO3- loss, though it also causes kaliuresis and requires monitoring.

Harrison's Principles of Internal Medicine 22E, p. 418
Costanzo Physiology 7th Edition

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