What is the anion gap and how is it calculated?

Anion Gap Definition and Calculation

The anion gap is a calculated value that represents the difference between measured cations and measured anions in serum, serving as a critical tool for identifying unmeasured anions and diagnosing metabolic acidosis. 1

Standard Calculation Formula

The anion gap is calculated as: Na⁺ - (Cl⁻ + HCO₃⁻) 1, 2

• This formula reflects the difference between unmeasured anions (primarily albumin, phosphate, sulfate, and organic acids) and unmeasured cations (calcium, magnesium, potassium) 3, 4
• An alternative formula includes potassium: (Na⁺ + K⁺) - (Cl⁻ + HCO₃⁻), which raises the normal range by approximately 4 mEq/L 5, 1

Normal Reference Range

The modern reference range for anion gap is 5-12 mmol/L (or 3-11 mmol/L depending on laboratory methodology), significantly lower than the outdated range of 8-16 mmol/L still cited in older textbooks. 3

• This reduction reflects changes in electrolyte measurement techniques, particularly the widespread adoption of ion-selective electrode methodology 3
• Using outdated reference ranges leads to misinterpretation and missed diagnoses of subtle metabolic disturbances 3
• The normal gap is primarily attributable to negatively charged albumin, which is not measured in routine electrolyte panels 2

Physiologic Basis

The anion gap exists because of the principle of electroneutrality—total positive charges must equal total negative charges in plasma 4:

• Measured cations: Sodium (and potassium if included) 2
• Measured anions: Chloride and bicarbonate 2
• Unmeasured anions: Albumin (predominant), phosphate, sulfate, lactate, ketones, and other organic acids 3, 4
• Unmeasured cations: Calcium, magnesium, immunoglobulins 4

Clinical Significance

The anion gap serves three primary clinical functions: detecting laboratory errors in electrolyte measurement, identifying paraproteins, and most importantly, evaluating acid-base disorders. 6

In Metabolic Acidosis

• An elevated anion gap (>12 mmol/L) indicates accumulation of unmeasured anions, typically from organic acids such as lactate, ketones, or toxic metabolites 2, 7
• Normal anion gap metabolic acidosis (hyperchloremic acidosis) occurs when bicarbonate loss is replaced by chloride, maintaining a normal gap 2, 7

In Toxic Ingestions

• In ethylene glycol poisoning, the anion gap typically measures around 32 mEq/L (interquartile range 25-39 mEq/L), with late presentations showing even higher values averaging 37 mEq/L 1
• An anion gap >27 mmol/L with suspected toxic alcohol ingestion mandates emergent hemodialysis 5, 1

Important Caveats

The anion gap has significant limitations that must be recognized to avoid misdiagnosis:

• A wide normal range (8-10 mEq/L) means increased unmeasured anions can be present without exceeding the upper limit of normal 6
• Hypoalbuminemia lowers the anion gap (each 1 g/dL decrease in albumin reduces the gap by approximately 2.5 mEq/L), potentially masking an elevated gap acidosis 5
• Hyperglobulinemia (e.g., multiple myeloma) can cause falsely low or even negative anion gaps 3
• Concomitant acute kidney injury or ketoacidosis may overestimate glycolate concentration in toxic ingestions 5
• The anion gap alone has poor predictive value when applied without appropriate clinical context 1

Quality Control Application

Clinicians can use anion gap patterns as a quality control tool for laboratory electrolyte measurements:

• High incidence of anion gaps >24 mmol/L or <2 mmol/L should prompt verification of electrolyte assay quality control 3
• Anion gap values exceeding 24 mmol/L strongly suggest metabolic acidosis requiring investigation 3
• Negative anion gap values are extremely rare and should trigger laboratory investigation 3