How to Calculate the Anion Gap
The anion gap is calculated using the formula: Na⁺ − (Cl⁻ + HCO₃⁻), with normal values ranging from 8–12 mEq/L using older methodology or 3–11 mEq/L (more commonly 5–12 mEq/L) with modern ion-selective electrode techniques. 1, 2, 3
Standard Calculation Formula
Use the formula: [Na⁺] − ([Cl⁻] + [HCO₃⁻]) to calculate the anion gap from routine serum electrolyte measurements. 4, 1, 3
The calculation approximates the difference between unmeasured anions (UA) and unmeasured cations (UC) in serum, with the gap primarily representing negatively charged albumin under normal conditions. 2, 5
Alternative Formula Including Potassium
In ethylene glycol poisoning guidelines, the formula Na⁺ + K⁺ − Cl⁻ − HCO₃⁻ is used, which adds approximately 4 mEq/L to the standard calculation. 4
When potassium is included in the calculation, the normal range shifts upward accordingly (typically 12–16 mEq/L instead of 8–12 mEq/L). 4
Understanding Normal Values: Critical Update
Modern ion-selective electrode methodology has lowered the reference range from the traditional 8–16 mEq/L to 3–11 mEq/L (or 5–12 mEq/L in some laboratories), yet many clinicians and textbooks still reference the outdated higher values, leading to potential misinterpretation. 2, 6
The American College of Physicians recommends using 8–12 mEq/L as the normal range when applying the standard formula without potassium. 1
An anion gap >12 mEq/L signifies accumulation of unmeasured anions such as lactate, ketoacids, uremic toxins, or ingested toxins. 1
Clinical Interpretation Thresholds
An anion gap >27 mmol/L (using the K⁺-inclusive formula) indicates severe metabolic acidosis requiring emergent intervention such as hemodialysis in toxic ingestions. 4, 1
An anion gap of 23–27 mmol/L suggests the need for extracorporeal treatment in ethylene glycol poisoning. 4
An anion gap exceeding 24 mmol/L (standard formula) strongly suggests the presence of metabolic acidosis and warrants immediate investigation. 2
An anion gap <3 mEq/L should be considered abnormally low and may indicate hypoalbuminemia, hyperglobulinemia (such as IgG multiple myeloma), or laboratory error. 2, 6
Common Pitfalls to Avoid
Clinicians must know which reference range their laboratory uses (modern ion-selective electrode vs. older methodology) to avoid missing clinically significant elevations. 2, 6
Hypoalbuminemia artificially lowers the anion gap by approximately 2.5 mEq/L for every 1 g/dL decrease in albumin below 4 g/dL, potentially masking a high anion gap metabolic acidosis. 3, 7
Concomitant acute kidney injury or ketoacidosis can overestimate glycolate concentration in toxic ingestions when using the anion gap as a surrogate marker. 4, 1
Co-ingestions of lithium or barium can artificially lower the anion gap, creating diagnostic confusion. 4, 1
The anion gap only predicts the need for intervention when there is high pre-test probability of the suspected condition—indiscriminate use in patients without evidence of exposure (e.g., ethylene glycol) has poor predictive value. 4, 1
Quality Control Application
An unexpectedly high incidence of anion gaps >24 mEq/L or <2 mEq/L in a laboratory's patient population should trigger review of electrolyte quality control and assessment for systematic errors or patient population characteristics (hypoalbuminemia, hyperglobulinemia). 2
The anion gap serves as an internal quality control check for electrolyte measurements, as extreme values or negative anion gaps are physiologically implausible and suggest measurement artifacts. 2, 6