What is the anion gap (AG) in a blood test?

What is the Anion Gap in Blood Tests

The anion gap is a calculated value that represents the difference between measured cations (sodium and potassium) and measured anions (chloride and bicarbonate) in serum, serving as a critical tool to identify unmeasured anions and categorize metabolic acidosis into high anion gap versus normal anion gap (hyperchloremic) types. 1

Calculation Method

The anion gap is calculated using the formula: Na⁺ + K⁺ - Cl⁻ - HCO₃⁻ 2

• If potassium is not included in the calculation, add 4 mmol/L to the result 2
• If the calculation method is unclear, add 2 mmol/L 2
• The alternative simplified formula without potassium is: Na⁺ - (Cl⁻ + HCO₃⁻) 3

Normal Reference Range

The modern reference range for anion gap is 3-11 mmol/L or 5-12 mmol/L, which is significantly lower than the outdated range of 8-16 mmol/L that many clinicians still incorrectly use. 3

• This lower range reflects changes in laboratory techniques, specifically the adoption of ion-selective electrode methods for measuring electrolytes 3
• Using the outdated reference range of 8-16 mmol/L can lead to misinterpretation and missed diagnoses 3

Clinical Significance

The anion gap approximates the difference between unmeasured anions (UA) and unmeasured cations (UC) in serum, with the normal gap primarily representing negatively charged albumin. 1, 3

• The anion gap divides metabolic acidoses into two critical categories: high anion gap metabolic acidosis (HAGMA) and hyperchloremic (normal anion gap) metabolic acidosis 1
• This categorization immediately narrows the differential diagnosis and guides appropriate clinical decision-making 1

What the Anion Gap Detects

An elevated anion gap indicates the presence of unmeasured anions in the blood, typically non-chloride organic acids such as lactate, ketoacids, uremic acids, or toxic metabolites. 4

• In high anion gap acidosis, other acids replace bicarbonate rather than chloride, distinguishing it from hyperchloremic acidosis 4
• The anion gap provides vital diagnostic clues directing clinicians toward specific etiologies 1

Clinical Interpretation Thresholds

An anion gap exceeding 24 mmol/L strongly suggests the presence of metabolic acidosis and warrants immediate investigation. 3

• In ethylene glycol poisoning specifically, an anion gap >27 mmol/L indicates immediate hemodialysis (strong recommendation), while 23-27 mmol/L suggests considering hemodialysis (weak recommendation) 5
• Anion gaps >28 mmol/L define "late" toxic poisoning with significantly worse outcomes 2
• Values less than 2 mmol/L are rare and may indicate IgG multiple myeloma or laboratory error 3

Important Corrections and Adjustments

The anion gap must be corrected for hypoalbuminemia and severe hyperglycemia to avoid underestimating the severity of acidosis. 1

• Hypoalbuminemia lowers the measured anion gap because albumin contributes to unmeasured anions 5
• The anion gap may overestimate severity with concomitant acute kidney injury or ketoacidosis, or underestimate with hypoalbuminemia 5
• Certain medications and conditions can falsely alter the anion gap, including lithium, barium, and hyperphosphatemia 5

Delta Gap Analysis

Comparing the change in anion gap (Δ AG) with the change in bicarbonate (Δ HCO₃⁻) identifies coexisting acid-base disorders beyond simple high anion gap acidosis. 6, 4

• The delta ratio (Δ AG:Δ HCO₃⁻) is normally 1:1 in uncomplicated high anion gap acidosis 6, 4
• A ratio <1:1 indicates combined high and normal anion gap acidosis 6, 4
• A ratio >2:1 suggests combined metabolic alkalosis with high anion gap acidosis 6, 4

Common Pitfalls

Do not rely solely on anion gap without clinical context, as it has poor predictive value when used indiscriminately. 5

• Clinicians must recognize that many still use the outdated reference range of 8-16 mmol/L, leading to missed diagnoses 3
• Elevated glycolate concentration can falsely elevate plasma lactate on some analyzers 5
• Negative anion gap values are extremely rare and should prompt investigation for laboratory error or specific conditions like hyperglobulinemia 3

Quality Control Application

The anion gap serves as a quality control tool for laboratory electrolyte measurements. 3

• High incidence of anion gap >24 mmol/L or <2 mmol/L should trigger verification of electrolyte quality control and assessment for hypoalbuminemia or hyperglobulinemia 3
• Among hospitalized patients, approximately 59.5% have normal anion gap, 37.6% have increased anion gap, and 2.9% have decreased anion gap 3