What is a High Anion Gap?
A high anion gap is defined as a value >12 mEq/L when calculated using the formula [Na+] - ([Cl-] + [HCO3-]), and it indicates the accumulation of unmeasured anions in the blood, most commonly from organic acids. 1
Definition and Calculation
- The anion gap represents the difference between unmeasured cations and unmeasured anions in serum 2
- Calculate using the formula: Na+ - (Cl- + HCO3-) 3, 1
- An alternative formula includes potassium: Na+ + K+ - Cl- - HCO3- 3
- Normal anion gap range is 8-12 mEq/L; values >12 mEq/L are considered elevated 1
- Note that modern ion-selective electrode techniques have lowered reference ranges to 3-11 mmol/L in some laboratories, though clinical practice still commonly uses 8-16 mmol/L 2
Clinical Significance by Severity
Mild Elevation (13-20 mEq/L):
- Most common range for elevated anion gaps in hospitalized patients (mean 16 mmol/L, central 90% range 13-20 mmol/L) 2
- May indicate early metabolic acidosis or less severe causes 2
Moderate Elevation (20-27 mEq/L):
- Typically indicates significant organic acidosis requiring investigation 3
- In ethylene glycol poisoning, anion gaps of 23-27 mmol/L warrant consideration of hemodialysis 3, 4
Severe Elevation (>27 mEq/L):
- Anion gaps >27 mmol/L in suspected ethylene glycol poisoning require immediate hemodialysis 3, 4
- Values >24 mmol/L are rare and strongly suggest severe metabolic acidosis 2
Common Causes (MUDPILES Mnemonic)
The most common causes of high anion gap acidosis are renal failure, diabetic ketoacidosis, and lactic acidosis 5:
- Methanol/Toxic alcohols: Produces both anion gap and osmolar gap 1
- Uremia: Renal failure causes accumulation of organic acids with elevated BUN, creatinine, and hyperkalemia 1
- Diabetic ketoacidosis: Requires blood glucose >250 mg/dL, arterial pH <7.3, bicarbonate <15 mEq/L, and positive ketones 1
- Propylene glycol/Paraldehyde: Toxic ingestions 6
- Isoniazid/Iron: Drug-induced 7
- Lactic acidosis: Results from tissue hypoxia due to decreased oxygen delivery or impaired utilization 1
- Ethylene glycol: Glycolate metabolite causes severe acidosis 1
- Salicylates: Usually causes mild metabolic acidosis with respiratory alkalosis 6
Important Clinical Caveats
The anion gap can be misleading in several situations 3, 4:
- Overestimation of severity: Occurs with concomitant acute kidney injury or ketoacidosis 3, 4
- Underestimation of severity: Occurs with hypoalbuminemia, lithium ingestion, or barium exposure 3, 4
- False elevations: Glycolate can falsely elevate plasma lactate on some analyzers, confusing the clinical picture 3
- Poor predictive value: Don't rely solely on anion gap without clinical context 3, 4
Additional Diagnostic Considerations
- Always check arterial blood gases to determine if the elevated anion gap is associated with metabolic acidosis 3
- Serum osmolal gap should be calculated to detect low molecular weight toxins like methanol and ethylene glycol 1
- Blood lactate measurement is essential when lactic acidosis is suspected 1
- In NRTI-treated patients, monitor serum bicarbonate and electrolytes every 3 months for early detection of anion gap increases 8, 1