What is an Anion Gap?
The anion gap is a calculated value derived from routine serum electrolytes—specifically sodium minus the sum of chloride and bicarbonate (AG = Na⁺ − [Cl⁻ + HCO₃⁻])—that approximates the difference between unmeasured anions and unmeasured cations in serum. 1
Calculation Methods
The standard formula is: Anion Gap = Na⁺ − (Cl⁻ + HCO₃⁻), which is the most widely used method in clinical practice 1, 2
An alternative formula includes potassium: AG = Na⁺ + K⁺ − Cl⁻ − HCO₃⁻, which raises the calculated value by approximately 4 mEq/L compared to the standard formula 3, 1, 4
The potassium-inclusive formula is specifically endorsed in guidelines for evaluating toxic alcohol poisoning, particularly ethylene glycol exposure 4
Normal Reference Ranges
The normal range for the standard formula (without potassium) is 8–12 mEq/L, though modern ion-selective electrode methodology has lowered this to approximately 3–11 mEq/L or 5–12 mEq/L in some laboratories 4, 5
When potassium is included in the calculation, the normal range shifts upward to approximately 12–16 mEq/L 4
This discrepancy between older reference ranges (8–16 mEq/L) and newer ranges (3–11 mEq/L) reflects changes in laboratory measurement techniques, and clinicians must be aware which reference range their laboratory uses to avoid misinterpretation 5
Clinical Purpose and Utility
The anion gap provides the critical first step in the differential diagnosis of metabolic acidosis, immediately distinguishing between high anion gap and normal anion gap etiologies 4, 2
It approximates the concentration difference between unmeasured anions (such as albumin, phosphate, sulfate, and organic acids) and unmeasured cations (such as calcium, magnesium, and potassium when not included in the formula) 2, 5
Beyond acid-base evaluation, the anion gap serves as a quality control tool for electrolyte measurements and can detect paraproteins in conditions like multiple myeloma 5, 6
Clinical Interpretation Thresholds
High Anion Gap
An anion gap >12 mEq/L (using standard formula) typically indicates high anion gap metabolic acidosis, with common causes including diabetic ketoacidosis, lactic acidosis, uremic acidosis, and toxic ingestions 4, 2
In toxic alcohol poisoning, anion gaps typically measure around 32 mEq/L (interquartile range 25–39 mEq/L), with late-presentation ethylene glycol poisoning showing even higher values averaging 37 mEq/L 1
An anion gap >27 mEq/L in suspected toxic alcohol ingestion mandates emergent hemodialysis, while values between 23–27 mEq/L warrant strong consideration for hemodialysis 3, 1, 4
Mortality rises markedly when the anion gap exceeds 28 mEq/L in ethylene glycol poisoning (20.4% vs 3.6% in early poisoning), making this a critical prognostic threshold 3, 1
An anion gap exceeding 24 mEq/L is rare and strongly suggests the presence of metabolic acidosis requiring investigation 5
Low Anion Gap
An anion gap <3 mEq/L should be considered low using modern measurement techniques 7
Low anion gap can indicate hypoalbuminemia, cationic paraproteinemia (such as IgG multiple myeloma), halide poisoning, lithium intoxication, or liver cirrhosis with nephrotic syndrome 3, 5, 8, 7
A baseline low anion gap may mask the identification of high gap metabolic acidosis in certain patients, representing an important diagnostic pitfall 7
Important Limitations and Pitfalls
The anion gap alone has poor predictive value when applied without appropriate clinical context, particularly when pre-test probability of the suspected condition is low 3, 1, 4
The wide range of normal values (often 8–10 mEq/L) means that an increase in unmeasured anions can be present even when the calculated anion gap remains within the "normal" range 6
Concomitant acute kidney injury or ketoacidosis can overestimate the severity of acidosis, while hypoalbuminemia can underestimate it 3, 4
Certain medications and conditions can falsely alter the anion gap: lithium and barium co-ingestion can artificially lower it, while hyperphosphatemia can elevate it 3, 4
The type of retained anion affects the magnitude of anion gap increase relative to bicarbonate change, being greater with lactic acidosis compared to ketoacidosis 6
Elevated glycolate concentration in toxic ingestions can falsely elevate plasma lactate on some analyzers 3
Advanced Diagnostic Tools
Delta gap (Δ AG/Δ HCO₃⁻) ratio is typically 1:1 in uncomplicated high anion gap acidosis: a value below 1:1 suggests combined high and normal anion gap acidosis, while a value above 2:1 suggests combined metabolic alkalosis and high anion gap acidosis 2, 8
Urine anion gap (unmeasured anions minus unmeasured cations) provides an indirect estimate of urine NH₄⁺ excretion and is typically negative in patients with normal anion gap metabolic acidosis secondary to diarrhea 2, 8