Causes of Low Anion Gap
A low anion gap (defined as <3 mEq/L with modern ion-selective electrode methodology) is most commonly caused by hypoalbuminemia, laboratory error, or increased unmeasured cations such as paraproteins from multiple myeloma, lithium, calcium, or magnesium. 1, 2
Understanding the Modern Definition
- The reference range for anion gap has shifted dramatically from 8-16 mEq/L to 3-11 mEq/L (or 5-12 mEq/L) due to widespread adoption of ion-selective electrode methodology over the past 25 years. 1, 2
- A value <3 mEq/L should now be considered low, and values <2 mEq/L are rare and warrant immediate investigation. 2
- Negative anion gaps (≤-1 mEq/L) are uncommon but clinically significant when they occur. 3, 4
Primary Causes of Low Anion Gap
Hypoalbuminemia (Most Common)
- Each 1 g/L decrease in serum albumin lowers the observed anion gap by 0.25 mEq/L (or 2.5 mEq/L per 1 g/dL decrease). 5
- Hypoalbuminemia is extremely common in critically ill patients, with 49% having albumin <20 g/L in one study. 5
- Critical pitfall: Hypoalbuminemia can mask a concurrent high anion gap metabolic acidosis by artificially lowering the calculated anion gap. 6, 5
- Correct for hypoalbuminemia using: Adjusted AG = Observed AG + 0.25 × ([normal albumin] - [observed albumin]) in g/L. 5
Increased Unmeasured Cations
- Multiple myeloma with IgG paraproteins is a classic cause, with documented cases showing anion gaps as low as 2 mEq/L. 2
- Lithium intoxication increases unmeasured cations. 6, 3
- Severe hypercalcemia or hypermagnesemia. 3
- Extreme hyperkalemia. 4
Laboratory Error and Interference
- Sporadic (nonreproducible) measurement errors must be ruled out first by repeating the test. 3
- Systematic (reproducible) laboratory errors affecting electrolyte measurement. 3
- Bromism (bromide interference with chloride measurement, falsely elevating chloride). 4
- Specimen contamination or analytical interference. 4
Clinical Conditions Associated with Low Anion Gap
- Liver cirrhosis (most common underlying condition in retrospective studies). 2
- Nephrotic syndrome. 2
- These conditions typically cause low anion gap through hypoalbuminemia. 2
Diagnostic Approach
Initial Steps
- Verify the result by repeating the measurement to exclude sporadic laboratory error. 3
- Calculate the anion gap using: Na⁺ + K⁺ - Cl⁻ - HCO₃⁻ (or Na⁺ - Cl⁻ - HCO₃⁻ if potassium not included). 6
- Check serum albumin immediately and calculate corrected anion gap. 5
If Hypoalbuminemia is Present
- Correct the anion gap using the formula above. 5
- If the corrected anion gap is elevated, investigate for concurrent high anion gap metabolic acidosis that was being masked. 5
- Identify the cause of hypoalbuminemia (malnutrition, liver disease, nephrotic syndrome, critical illness). 2
If Albumin is Normal
- Measure serum protein electrophoresis to evaluate for paraproteinemia/multiple myeloma. 2, 4
- Check lithium level if patient is on lithium therapy. 3
- Measure ionized calcium and magnesium. 3
- Review medications and consider bromide exposure. 4
- Investigate for systematic laboratory error if no clinical explanation found. 3
Clinical Significance
- Low anion gap incidence is approximately 2.9% in hospitalized patients, making it relatively uncommon but clinically important when present. 2
- The finding can be a critical clue to life-threatening conditions like multiple myeloma or lithium toxicity. 1
- Most dangerous scenario: Missing a concurrent high anion gap metabolic acidosis in a hypoalbuminemic patient because the baseline low anion gap masks the elevation. 6, 5