What is anion gap?
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Here is a thorough breakdown of the anion gap:
Anion Gap (AG)
Definition
The anion gap is a calculated value that reflects the difference between the major measured cation (sodium) and the major measured anions (chloride and bicarbonate) in serum. Because electrical neutrality must be maintained in any solution, the total cation charge must equal the total anion charge. The "gap" arises because we only measure a subset of ions - it represents the unmeasured anions in plasma.
Formula
AG = [Na+] - ([Cl-] + [HCO3-])
An extended version that includes potassium:
AG = ([Na+] + [K+]) - ([Cl-] + [HCO3-])
- National Kidney Foundation Primer on Kidney Diseases, p. 149
Normal Values
- Standard range: 8-12 mEq/L (most labs)
- Some sources cite 8-16 mEq/L; newer ion-activity measurement techniques may yield 5-11 mEq/L
- The normal AG is primarily made up of anionic albumin (~50% of the gap), plus phosphate, sulfate, urate, lactate, and pyruvate
What Makes Up the Anion Gap?
| Component | Contribution |
|---|---|
| Albumin | ~50% of normal AG |
| Phosphate | Minor |
| Sulfate | Minor |
| Lactate & organic acids | Minor |
Clinical Uses
The main use of the AG is to classify metabolic acidosis into two types:
1. High Anion Gap Metabolic Acidosis (HAGMA)
An organic anion (e.g., ketoacid, lactate) accumulates and replaces HCO3-. Since the replacing anion is unmeasured, the AG rises.
Causes - remembered by the mnemonic GOLDMARK:
-
G - Glycols (ethylene glycol, propylene glycol)
-
O - 5-Oxoproline (pyroglutamic acid)
-
L - Lactic acidosis
-
D - D-lactic acidosis
-
M - Methanol
-
A - Aspirin (salicylates)
-
R - Renal failure (chronic)
-
K - Ketoacidosis (diabetic, alcoholic, starvation)
-
Murray & Nadel's Textbook of Respiratory Medicine, p. 2390
2. Normal Anion Gap Metabolic Acidosis (NAGMA) - Hyperchloremic
HCO3- is lost but replaced by Cl- (a measured anion), so the AG does not change. Causes include diarrhea and renal tubular acidosis (RTA).
Corrected Anion Gap (for Hypoalbuminemia)
Since albumin contributes ~50% of the normal AG, low albumin falsely lowers the AG, potentially masking a high-AG process.
Corrected AG = AG + [0.25 × (40 - albumin in g/L)]
or equivalently: AG + [2.5 × (4 - albumin in g/dL)]
The AG falls approximately 2.5 mEq/L for every 1 g/dL drop in albumin below normal.
Delta Gap (Delta-Delta)
Once a high AG acidosis is confirmed, the delta gap helps detect mixed disorders:
Delta gap = Patient AG - 12 (normal AG)
Then: Delta gap + measured HCO3-
| Result | Interpretation |
|---|---|
| ~24 mEq/L | Pure AG acidosis |
| >24 mEq/L | Concurrent metabolic alkalosis |
| <24 mEq/L | Coexisting normal-AG (hyperchloremic) acidosis |
- Murray & Nadel's Textbook of Respiratory Medicine, p. 2392
Low Anion Gap
A decreased AG can occur due to:
- Hypoalbuminemia (most common cause)
- Excess unmeasured cations: hypercalcemia, hypermagnesemia, lithium toxicity
- Abnormal cationic proteins (e.g., multiple myeloma)
Urinary Anion Gap (UAG)
When the cause of a normal-AG acidosis is unclear, the UAG helps differentiate renal from GI causes:
UAG = [Na+]urine + [K+]urine - [Cl-]urine
- Negative UAG: GI bicarbonate loss (e.g., diarrhea) - kidneys are responding appropriately by excreting NH4+
- Positive UAG: Renal tubular acidosis - kidneys cannot excrete NH4+
In summary, the anion gap is a simple but powerful tool for quickly narrowing the differential in acid-base disorders, particularly metabolic acidosis.
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