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Serum Anion Gap

Anion Gap Engine

Acid-Base Modeling Suite

Electrolyte Substrate

Sodium (Na⁺)

Chloride (Cl⁻)

Bicarb (HCO₃⁻)

Albumin (g/dL)

Anion Solver

Enter serum electrolytes to resolve anion deviation and delta-delta mixed disorders.

Guidelines & Evidence

Verified

Last Review: 2026

When to Use

What is the Serum Anion Gap?

The serum anion gap (AG) is a calculated value representing the difference between the concentration of measured cations (primarily sodium, Na⁺) and measured anions (chloride, Cl⁻, and bicarbonate, HCO₃⁻) in the blood. The "gap" represents the concentration of unmeasured anions in serum, which include albumin (the major contributor, accounting for ~75% of the normal gap), phosphate, sulfate, and organic acids (lactate, ketones, uremic anions, toxic alcohol metabolites). A normal anion gap is typically 8-12 mEq/L (assay-dependent). An elevated anion gap (>12 mEq/L) indicates the presence of unmeasured anions, most commonly organic acids (lactate, ketones, uremic anions, or toxins). A low anion gap (<8 mEq/L) is less common but may indicate hypoalbuminemia, hypercalcemia, hypermagnesemia, or paraproteinemia (multiple myeloma).

Primary Clinical Indications

Evaluation of metabolic acidosis – Differentiates high anion gap metabolic acidosis (HAGMA) from normal anion gap metabolic acidosis (NAGMA). HAGMA suggests accumulation of organic acids (lactate, ketones, uremic anions, toxins); NAGMA suggests bicarbonate loss (diarrhea, renal tubular acidosis) or dilutional acidosis.

Screening for toxic ingestions – Elevated anion gap in a patient with altered mental status or suspected overdose suggests toxic alcohols (methanol, ethylene glycol), salicylates, or iron toxicity.

Monitoring diabetic ketoacidosis (DKA) – Serial anion gap measurements track resolution of ketosis; the gap should close as ketones clear (despite persistent bicarbonate normalization lagging behind).

Detection of lactic acidosis – Elevated AG with elevated lactate confirms type A (tissue hypoxia, shock) or type B (medications, liver disease, malignancy) lactic acidosis.

Assessment of renal failure – Uremic acidosis (retention of phosphate, sulfate, organic acids) elevates the anion gap; degree of elevation correlates with azotemia (though not linearly).

Albumin correction in hypoalbuminemia – Hypoalbuminemia lowers the baseline anion gap, potentially masking a high AG metabolic acidosis. Corrected AG = measured AG + 2.5 × (4.0 - albumin in g/dL).

Evaluation of mixed acid-base disorders – Delta-delta ratio (ΔAG/ΔHCO₃) identifies concomitant metabolic alkalosis or normal AG acidosis in the presence of HAGMA.

Unexpected low anion gap workup – Low AG (<6 mEq/L) prompts evaluation for hypoalbuminemia, hypercalcemia (ionized calcium binds albumin, reducing gap), hypermagnesemia, lithium toxicity, bromide intoxication, or paraproteinemia (multiple myeloma, Waldenström macroglobulinemia).

Contraindications / Limitations

Not valid in severe hypertriglyceridemia – Extremely high triglycerides (>1000 mg/dL) cause pseudohyponatremia (if measured by indirect ISE), artificially lowering sodium and reducing the anion gap, potentially masking HAGMA.

Not valid in severe hyperproteinemia – Very high protein (multiple myeloma, IV immunoglobulin) can cause pseudohyponatremia, affecting AG.

Not diagnostic for specific toxins – Elevated AG indicates organic acidosis but does NOT identify which toxin; requires osmolal gap, serum toxic alcohol levels, salicylate level, or lactate.

Normal range varies by laboratory – Assay-dependent differences (flame photometry vs indirect ISE vs direct ISE) affect sodium and chloride values. Always use your lab's reference range (typically 6-12 mEq/L for modern ISE methods, 10-20 mEq/L for older flame photometry).

Not reliable in extreme pH (<7.0 or >7.7) – Severe acidemia or alkalemia alters protein binding and electrolyte distribution, making the AG less predictive.

Albumin correction required for accurate interpretation – Failure to correct for hypoalbuminemia is the most common clinical error, leading to missed HAGMA (e.g., a patient with cirrhosis has baseline AG 6 due to low albumin; if AG rises to 10, corrected AG = 14, indicating HAGMA).

Causes of Elevated and Low Anion Gap

Category	Anion Gap	Common Causes	Mechanism	Diagnostic Approach
High Anion Gap Metabolic Acidosis (HAGMA)	>12 mEq/L	Methanol, Uremia, DKA, Paraldehyde, Isoniazid/Iron, Lactic acidosis, Ethylene glycol, Salicylates (MUDPILES mnemonic)	Accumulation of unmeasured organic acids (lactate, ketones, formic acid, oxalic acid, glycolic acid, acetylsalicylate)	Check lactate, ketones (β-hydroxybutyrate), BUN/creatinine, toxic alcohol panel, salicylate level, iron level, osmolal gap
Normal Anion Gap Metabolic Acidosis (NAGMA)	8-12 mEq/L (normal)	Diarrhea (bicarbonate loss), Renal tubular acidosis (RTA types 1-4), Ureteral diversion, Pancreatic fistula, Dilutional acidosis, Hyperalimentation (TPN) without bicarbonate	Bicarbonate loss (GI or renal) or dilution, with intact anion gap	Check urine anion gap (UAG), urine pH, serum potassium (differentiates RTA types), stool studies for diarrhea
Low Anion Gap (<6 mEq/L)	<6 mEq/L	Hypoalbuminemia (most common), Hypercalcemia (ionized), Hypermagnesemia, Lithium toxicity, Bromide intoxication (pseudo-elevated chloride), Multiple myeloma (cationic paraproteins), Hyperviscosity	Reduced unmeasured anions (albumin) OR falsely elevated chloride (bromide interference) OR cationic paraproteins neutralising negative charge	Check albumin, total protein, calcium, magnesium, lithium level, serum protein electrophoresis (SPEP)

Related Scores in Practice

In clinical practice, this assessment is frequently evaluated alongside other validated measures. Depending on the patient's presentation and specific diagnostic requirements, you may also need to utilize the Delta-Delta Ratio, Osmolal Gap, Winter's Formula or the Bicarbonate Correction to formulate a comprehensive care plan.

Last Comprehensive Review: 2026

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