What are the causes of a non‑anion‑gap (hyperchloremic) metabolic acidosis?

Non-Anion Gap Metabolic Acidosis: Causes

Non-anion gap (hyperchloremic) metabolic acidosis results from either gastrointestinal bicarbonate loss, renal tubular acidosis, or iatrogenic chloride loading—with the specific cause determined by assessing volume status, serum potassium, and urinary ammonium excretion. 1, 2

Primary Mechanisms

The hyperchloremic pattern develops because bicarbonate loss triggers increased renal chloride reabsorption to maintain electroneutrality, which decreases the strong ion difference and lowers pH. 1 This creates a normal anion gap (10–12 mEq/L) despite significant acidemia. 3

Major Causes by Category

Gastrointestinal Bicarbonate Loss

• Diarrhea (acute watery diarrhea from any infectious, inflammatory, or medication-induced cause) produces direct bicarbonate loss in stool, leading to hyperchloremic acidosis. 3, 4
• High-output ileostomy or fistula causes massive bicarbonate losses, particularly when output exceeds 1–2 liters daily. 4
• Ureterosigmoidostomy results in colonic absorption of urinary chloride with bicarbonate secretion into the bowel lumen. 2

Renal Tubular Acidosis (RTA)

• Distal (Type 1) RTA occurs when the distal tubule cannot secrete hydrogen ions, resulting in inability to acidify urine below pH 5.5 despite systemic acidosis, often accompanied by hypokalemia. 5, 2
• Proximal (Type 2) RTA develops when the proximal tubule fails to reabsorb filtered bicarbonate, commonly presenting with Fanconi syndrome (concurrent phosphate, uric acid, glucose, and amino acid wasting). 6, 5
• Type 4 RTA (hyperkalemic RTA) results from aldosterone deficiency or resistance, characterized by hyperkalemia and inability to excrete acid due to impaired ammonium production. 2

Iatrogenic Causes

• Large-volume 0.9% saline administration produces dilutional hyperchloremic acidosis by increasing serum chloride, decreasing renal blood flow, and promoting sodium retention in a self-reinforcing cycle. 7, 3
• Recovery phase of diabetic ketoacidosis creates transient non-anion gap acidosis as chloride from IV fluids replaces ketoanions lost during osmotic diuresis; this is biochemically insignificant and requires no specific intervention. 1

Renal Insufficiency

• Early chronic kidney disease (stages 3–4) initially presents with normal anion gap acidosis due to impaired hydrogen ion excretion and reduced ammonia synthesis, though severe CKD (stage 5) eventually develops high anion gap acidosis. 6, 5

Medications and Toxins

• Carbonic anhydrase inhibitors (acetazolamide, topiramate) block proximal bicarbonate reabsorption, mimicking proximal RTA. 2
• Potassium-sparing diuretics (amiloride, triamterene) and calcineurin inhibitors (tacrolimus, cyclosporine) can produce Type 4 RTA. 2

Diagnostic Algorithm

Step 1: Confirm Non-Anion Gap Pattern

• Calculate anion gap: Na⁺ − (HCO₃⁻ + Cl⁻); normal is 10–12 mEq/L. 3
• Verify metabolic acidosis: pH <7.35, bicarbonate <22 mmol/L. 3

Step 2: Assess Serum Potassium

• Hypokalemia suggests gastrointestinal losses, distal RTA, or proximal RTA. 2
• Hyperkalemia indicates Type 4 RTA or early renal insufficiency. 2

Step 3: Evaluate Urinary Ammonium

• Urine anion gap (Na⁺ + K⁺ − Cl⁻): negative gap indicates appropriate renal ammonium excretion (extrarenal cause); positive gap suggests impaired renal acidification (RTA). 4, 2
• Urine osmolal gap provides direct assessment when urine anion gap is equivocal. 5, 2

Step 4: Check Urine pH

• Urine pH >5.5 during systemic acidosis confirms distal RTA. 5, 2
• Urine pH <5.5 suggests intact distal acidification (proximal RTA, gastrointestinal loss, or Type 4 RTA). 2

Common Clinical Pitfalls

• Overlooking mixed disorders: Patients may have combined high anion gap and normal anion gap acidosis (e.g., DKA with concurrent diarrhea or saline administration). 6, 8
• Misinterpreting saline-induced acidosis: The acidosis from 0.9% saline typically resolves spontaneously once administration stops and renal perfusion improves; bicarbonate therapy is unnecessary. 3
• Ignoring volume status: Distinguishing between diarrheal losses (volume depleted) versus RTA (typically euvolemic) guides initial fluid management. 4, 2
• Failing to measure urine studies: Serum electrolytes alone cannot differentiate renal from extrarenal causes; urinary ammonium assessment is essential. 4, 2