What does the anion gap measure?

What the Anion Gap Measures

The anion gap measures the difference between unmeasured anions and unmeasured cations in plasma, calculated as sodium minus the sum of chloride and bicarbonate (AG = Na⁺ – [Cl⁻ + HCO₃⁻]), and serves as a critical tool to identify the presence of unmeasured acids in the blood. 1

Core Concept

The anion gap represents the charge difference that exists because we routinely measure only a few of the many ions present in plasma. 2 Specifically:

• The gap approximates unmeasured anions (primarily negatively charged albumin, phosphate, sulfate, and organic acids) minus unmeasured cations (primarily calcium, magnesium, and immunoglobulins). 3, 4
• In healthy individuals, the normal anion gap is primarily due to negatively charged albumin, which accounts for most of the unmeasured anions. 5

Calculation Methods

• The standard formula is AG = Na⁺ – (Cl⁻ + HCO₃⁻), with a normal range of 5-12 mEq/L using modern ion-selective electrode methods. 1, 3
• Including potassium in the calculation (AG = Na⁺ + K⁺ – Cl⁻ – HCO₃⁻) raises the expected normal range by approximately 4 mEq/L. 1

Important Update on Reference Ranges

• The reference range has been lowered from the historical 8-16 mEq/L to 3-11 mEq/L (or 5-12 mEq/L) due to changes in laboratory measurement techniques, though many clinicians and textbooks still incorrectly use the outdated range. 3
• Using the old reference values can lead to misinterpretation and missed diagnoses of acid-base disorders. 3

Clinical Utility: What It Tells You

Primary Diagnostic Function

• The anion gap divides metabolic acidoses into two categories: high anion gap metabolic acidosis (HAGMA) and normal anion gap (hyperchloremic) metabolic acidosis, thereby narrowing the differential diagnosis. 2, 6

High Anion Gap Metabolic Acidosis

• An elevated anion gap indicates the presence of unmeasured anions from non-chloride organic acids accumulating in the blood. 5, 4
• Common causes include lactic acidosis, ketoacidosis (diabetic, alcoholic, or starvation), uremic acidosis, and toxic ingestions (methanol, ethylene glycol, salicylates). 7, 3
• In toxic alcohol poisoning, the anion gap typically measures around 32 mEq/L (interquartile range 25–39 mEq/L). 1
• An anion gap exceeding 24 mEq/L strongly suggests the presence of metabolic acidosis and warrants immediate investigation. 3

Normal Anion Gap Metabolic Acidosis

• When metabolic acidosis exists without an elevated anion gap, chloride is elevated to replace the lost bicarbonate, indicating causes such as diarrhea, renal tubular acidosis, or early renal failure. 6

Low Anion Gap

• A decreased anion gap (mean 3 mEq/L, range 2-4 mEq/L) can indicate hypoalbuminemia, hyperglobulinemia (such as IgG multiple myeloma), or laboratory measurement artifacts. 3, 4
• Values less than 2 mEq/L are rare and should prompt investigation for these conditions or quality control issues with electrolyte measurements. 3

Advanced Diagnostic Applications

Delta Gap Analysis

• Comparing the change in anion gap (Δ AG) with the change in bicarbonate (Δ HCO₃⁻) identifies mixed acid-base disorders. 2, 6, 5
• The delta ratio (Δ AG:Δ HCO₃⁻) is normally 1:1 in uncomplicated high anion gap acidosis. 6, 5
• A ratio below 1:1 indicates a combined high and normal anion gap acidosis (bicarbonate falling more than expected). 6, 5
• A ratio above 2:1 suggests a combined metabolic alkalosis and high anion gap acidosis (bicarbonate not falling as much as expected). 6, 5

Osmolal Gap Correlation

• When used together with the osmolal gap, the anion gap helps identify toxic alcohol ingestions with acidic metabolites such as ethylene glycol and methanol. 2, 5

Albumin Correction

• The anion gap should be corrected for hypoalbuminemia, as low albumin reduces the measured anion gap and can mask the presence of unmeasured acids. 7, 2

Critical Clinical Thresholds

• An anion gap greater than 27 mEq/L in suspected toxic alcohol ingestion (especially ethylene glycol) mandates emergent hemodialysis. 1, 7
• When the anion gap lies between 23 and 27 mEq/L with suspected ethylene glycol exposure, strongly consider initiating hemodialysis. 1, 7
• Mortality rises markedly when the anion gap exceeds 28 mEq/L in ethylene glycol poisoning (20.4% mortality vs 3.6% in early poisoning). 1, 7

Important Caveats

• The anion gap alone has poor predictive value for clinical outcomes when applied without appropriate clinical context. 1, 7
• The anion gap may overestimate severity with concomitant acute kidney injury or ketoacidosis, or underestimate severity with hypoalbuminemia. 7, 8
• High incidence of anion gaps exceeding 24 mEq/L or below 2 mEq/L should prompt verification of laboratory quality control and assessment for hypoalbuminemia or hyperglobulinemia. 3