About the Anion Gap
The serum anion gap (AG) is the calculated difference between the major measured cations and anions in plasma. It estimates the concentration of unmeasured anions — organic acids, phosphates, sulfates, and proteins — that are not reported on a standard BMP. An elevated AG signals the presence of these unmeasured acid anions, narrowing the differential diagnosis of metabolic acidosis.
Anion Gap Formula
Normal range: 8–12 mEq/L (standard lab methods)
Corrected AG = AG + 2.5 × (4.0 − measured albumin)
Figge et al. 1992 correction for hypoalbuminemia
Delta-Delta (Δ/Δ) = (AG − 12) / (24 − HCO₃⁻)
Normalizes AG rise to HCO₃⁻ fall; identifies mixed disorders
High Anion Gap Metabolic Acidosis — MUDPILES
The mnemonic MUDPILES covers the most common causes of anion gap acidosis, from most to least frequent:
| Letter | Cause | Key Lab Findings | Next Step |
|---|---|---|---|
| M | Methanol (wood alcohol, windshield wiper fluid) | Serum osmol gap + metabolic acidosis; visual symptoms | Fomepizole; hemodialysis for severe |
| U | Uremia (renal failure / ESRD) | BUN/Cr elevated; often mixed HAGMA + non-AG | Nephrology consult; assess for dialysis |
| D | Diabetic Ketoacidosis (DKA) | Glucose elevated, ketones +, pH low, HCO₃⁻ low | Insulin, fluids, electrolyte replacement |
| P | Propylene Glycol (IV lorazepam, nitroglycerin) | High osmol gap; seen in ICU on continuous sedation | Stop or reduce offending infusion; hemodialysis |
| I | INH / Iron (isoniazid, iron tablets) | Seizures, refractory metabolic acidosis; ingestions | Pyridoxine (INH toxicity); deferoxamine (iron) |
| L | Lactic Acidosis (sepsis, shock, ischemia) | Lactate >2 mEq/L; lactate/pyruvate ratio >20:1 | Treat underlying cause; avoid vasopressor excess |
| E | Ethylene Glycol (antifreeze, coolant) | Calcium oxalate crystals in urine; osmol gap | Fomepizole; ethanol alternative; dialysis |
| S | Salicylates (aspirin, oil of wintergreen) | Mixed respiratory alkalosis + HAGMA; tinnitus | NaHCO₃ urine alkalinization; hemodialysis |
Delta-Delta Ratio — Identifying Mixed Disorders
The delta-delta ratio (ΔAG / ΔHCO₃⁻) is one of the most powerful tools in acid-base medicine. By comparing the magnitude of the AG rise to the magnitude of the HCO₃⁻ fall, it identifies concurrent disorders that would otherwise be invisible on a single BMP:
| Δ/Δ Ratio | Interpretation | Common Scenarios |
|---|---|---|
| < 1 | Concurrent non-anion gap metabolic acidosis | DKA + diarrhea, DKA + saline resuscitation, sepsis with concurrent RTA |
| 1–2 | Proportionate HAGMA (pure high AG acidosis) | Typical DKA, lactic acidosis, uremia — one process dominant |
| > 2 | Concurrent metabolic alkalosis (HCO₃⁻ higher than expected) | Vomiting, NG suction, diuretic use layered on HAGMA |
Albumin Correction — Figge Method
Albumin is the dominant unmeasured anion at ~2.5 mEq/g/dL. In hypoalbuminemic patients (common in cirrhosis, nephrotic syndrome, critical illness, burns), the baseline AG is lower, which can mask a mildly elevated true AG. The Figge correction adds back ~2.5 mEq/L for each 1 g/dL below the normal albumin of 4.0 g/dL:
Example: AG = 14, albumin = 2.0 → Corrected AG = 14 + 2.5 × 2.0 = 19 mEq/L (elevated)
Limitations
The anion gap assumes electroneutrality: total cations = total anions. This assumption breaks down in several situations: paraproteinemias (multiple myeloma, Waldenström's) add positively charged M proteins that artifactually widen the AG without metabolic acidosis; hypoalbuminemia reduces baseline AG (correct using Figge); hyperlipidemia can artifactually lower the measured Cl⁻ on some analyzers; laboratory methods differ in chloride measurement (ion-selective electrode vs colorimetric) and can shift the normal range. A normal AG in the setting of high clinical suspicion for acidosis should prompt direct measurement of lactate, ketones, and serum osmol.
References
Figge J, Jabor A, Kazda A, Fencl V. Anion gap and hypoalbuminemia. Crit Care Med. 1998;26(11):1807–1810.
Winter WE, Harris-Schmidt R, Fastenau T, et al. Acid-base and electrolyte disorders. In: Rifai N, ed. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed. Elsevier; 2018.
Berend K, de Vries APJ, Gans ROB. Approach to acid-base disorders in the ICU. N Engl J Med. 2014;371:1413–1424.