What is an anion gap (AG)?

Anion Gap: Definition and Clinical Utility

The anion gap (AG) is a mathematical calculation that compares blood sodium concentration with the sum of chloride and bicarbonate concentrations, calculated using the formula [Na⁺] - ([Cl⁻] + [HCO₃⁻]), which helps differentiate types of metabolic acidosis and identify occult acid-base disorders. 1, 2

Definition and Normal Values

• The anion gap represents the difference between measured cations (primarily sodium) and measured anions (chloride and bicarbonate)
• It reflects the concentration of unmeasured anions minus unmeasured cations in the serum 2
• Normal range:
  • Traditional reference range: 8-16 mmol/L
  • Updated reference range with modern ion-selective electrode methods: 3-11 mmol/L 3
  • Most commonly used clinical reference range: 5-12 mmol/L 3

Clinical Significance

The anion gap serves several important clinical purposes:

1. Primary diagnostic utility: Categorizes metabolic acidosis into two types 4:

   • High anion gap metabolic acidosis (HAGMA)
   • Normal anion gap (hyperchloremic) metabolic acidosis

2. Identification of mixed acid-base disorders through delta gap calculations:

   • Delta gap = Δ AG - Δ HCO₃⁻ 5, 6
   • Delta ratio = Δ AG : Δ HCO₃⁻ 6
   • Interpretation:
     • Ratio ≈ 1:1: Simple high AG acidosis
     • Ratio < 1:1: Combined high and normal AG acidosis
     • Ratio > 2:1: Combined metabolic alkalosis and high AG acidosis 6

3. Detection of rare clinical disorders when AG is very small or negative 4

Factors Affecting Anion Gap

• Hypoalbuminemia: Decreases AG (albumin is a major unmeasured anion)
  • Correction: Add 2.5 mmol/L to AG for every 1 g/dL decrease in albumin below normal 4
• Severe hyperglycemia: May affect AG calculation 4
• Laboratory measurement techniques: Modern ion-selective electrode methods yield lower AG values than older methods 3

Clinical Applications

• High AG (>12 mmol/L): Suggests accumulation of unmeasured anions from:

  • Lactic acidosis
  • Ketoacidosis (diabetic, alcoholic, starvation)
  • Renal failure (retention of phosphates, sulfates)
  • Toxins (methanol, ethylene glycol, salicylates)
  • Severe hyperproteinemia 2

• Low AG (<5 mmol/L): May indicate:

  • Laboratory error
  • Hypoalbuminemia
  • Multiple myeloma (paraproteinemia)
  • Lithium toxicity
  • Bromide intoxication 3

Practical Considerations

• AG exceeding 24 mmol/L strongly suggests metabolic acidosis 3
• Negative AG values are extremely rare and warrant investigation 3
• When combined with osmolal gap calculations, AG can help identify toxic alcohol ingestions 2
• Urine anion gap can be calculated as (Na⁺ + K⁺) - Cl⁻ to assess renal ammonium excretion in normal AG metabolic acidosis 1

Common Pitfalls

• Using outdated reference ranges (8-16 mmol/L) with modern laboratory methods may lead to misinterpretation 3
• Failing to correct AG for hypoalbuminemia can mask a high AG acidosis 4
• Not considering mixed acid-base disorders when interpreting AG 5, 6
• Overlooking the possibility of laboratory measurement artifacts affecting electrolyte values 4