Anion Gap: Definition, Calculation, and Clinical Significance
The anion gap (AG) is a calculated value that represents the difference between measured cations and measured anions in the blood, serving as a crucial tool for diagnosing and categorizing metabolic acidosis. 1, 2
Definition and Calculation
The anion gap is calculated using the following formula:
AG = [Na⁺] - ([Cl⁻] + [HCO₃⁻])
Where:
- [Na⁺] = Serum sodium concentration
- [Cl⁻] = Serum chloride concentration
- [HCO₃⁻] = Serum bicarbonate concentration
Some laboratories may include potassium in the calculation: AG = [Na⁺ + K⁺] - ([Cl⁻] + [HCO₃⁻])
Normal Values
- Traditional normal range: 8-12 mEq/L (without potassium) 3
- With newer ion-selective electrode methods: 3-11 mEq/L 4
Clinical Significance
The anion gap divides metabolic acidosis into two main categories:
High Anion Gap Metabolic Acidosis (HAGMA):
- Indicates presence of unmeasured acids in the blood
- Common causes: lactic acidosis, ketoacidosis, toxic ingestions, renal failure
Normal Anion Gap (Hyperchloremic) Metabolic Acidosis:
- Bicarbonate loss is balanced by chloride retention
- Common causes: diarrhea, renal tubular acidosis, early renal failure
Clinical Applications
1. Diagnosis of Ethylene Glycol Poisoning
- An anion gap >27 mmol/L strongly indicates need for extracorporeal treatment in ethylene glycol poisoning 1
- An anion gap 23-27 mmol/L suggests consideration of extracorporeal treatment 1
2. Delta Gap Analysis
The delta gap helps identify mixed acid-base disorders:
Delta Gap = (Observed AG - Normal AG) - (Normal HCO₃⁻ - Observed HCO₃⁻) or Delta Gap = ΔAG - ΔHCO₃⁻
- Delta Gap ≈ 0: Simple anion gap metabolic acidosis
- Delta Gap > +6: Concurrent metabolic alkalosis
- Delta Gap < -6: Concurrent normal anion gap metabolic acidosis 5, 6
3. Relationship with Osmolal Gap
- Combined elevated anion gap and osmolal gap suggests toxic alcohol ingestion (methanol, ethylene glycol) 7
- The anion gap correlates linearly with glycolate concentration in ethylene glycol poisoning 1
Factors Affecting Anion Gap
Factors that can falsely lower AG:
- Hypoalbuminemia (each 1 g/dL decrease in albumin lowers AG by ~2.5 mEq/L)
- Hyperglobulinemia (especially IgG myeloma)
- Lithium or barium toxicity
- Laboratory error
Factors that can falsely elevate AG:
- Severe hyperglycemia
- Concomitant acute kidney injury
- Ketoacidosis
- Laboratory error
Clinical Pitfalls and Caveats
Measurement technique matters: Modern ion-selective electrode methods yield lower normal AG values than older methods. Using outdated reference ranges can lead to misinterpretation 4.
Albumin correction: In hypoalbuminemia, the AG should be corrected:
- Corrected AG = Observed AG + 2.5 × (normal albumin - measured albumin)
Pre-test probability: The anion gap is only useful for predicting glycolate concentrations if there is high pre-test probability of ethylene glycol exposure 1.
Rare extreme values: An anion gap exceeding 24 mmol/L strongly suggests metabolic acidosis, while values below 2 mmol/L are extremely rare 4.
Mixed disorders: The delta gap analysis helps identify concurrent acid-base disorders that might otherwise be missed 5, 6.
The anion gap calculation is a simple yet powerful tool that provides valuable diagnostic information when interpreted correctly in the appropriate clinical context.