What does a low anion gap indicate?

Low Anion Gap: Clinical Significance and Diagnostic Approach

A low anion gap of 8 mEq/L indicates possible laboratory error, hypoalbuminemia, or the presence of unmeasured cations such as paraproteins, lithium, or calcium/magnesium abnormalities. 1, 2

Definition and Normal Range

• Modern ion-selective electrode methodology has lowered the normal anion gap range from the traditional 12 ± 4 mEq/L to approximately 6 ± 3 mEq/L 1
• An anion gap value of < 3 mEq/L is now considered truly low based on current clinical data 1, 2
• The reference range in healthy individuals using modern methods is approximately 5-12 mmol/L 2

Common Causes of Low Anion Gap

Laboratory Errors

• Sporadic (non-reproducible) measurement errors are the most common cause of a seemingly low anion gap 3, 4
• Repeatedly low values in the same patient are more likely to represent true clinical conditions 4

Decreased Unmeasured Anions

• Hypoalbuminemia - each 1 g/dL decrease in albumin can lower the anion gap by approximately 2.5 mEq/L 2, 5
• Common in liver cirrhosis and nephrotic syndrome 2

Increased Unmeasured Cations

• Paraproteinemia (especially IgG multiple myeloma) - positively charged paraproteins increase unmeasured cations 2, 5
• Lithium toxicity - therapeutic or toxic lithium levels contribute to unmeasured cations 3, 5
• Hypercalcemia or hypermagnesemia - elevated levels of these cations can lower the anion gap 1, 5
• Bromide intoxication - can cause falsely elevated chloride measurements on certain analyzers 5

Clinical Significance

• A low anion gap can be a valuable diagnostic clue for underlying conditions that might otherwise be missed 1
• May indicate the presence of occult neoplasms such as multiple myeloma 1, 2
• Can mask the identification of a high anion gap metabolic acidosis in certain patients 1
• Very low values (< 2 mmol/L) or negative values are rare and warrant thorough investigation 2, 3

Diagnostic Approach

1. Verify the result by repeating the electrolyte measurements to rule out laboratory error 4, 5
2. Check serum albumin levels - hypoalbuminemia is a common cause 2, 5
3. Evaluate for paraproteinemia with serum protein electrophoresis and immunofixation, especially if multiple myeloma is suspected 2, 5
4. Measure serum calcium and magnesium levels to identify electrolyte abnormalities 5
5. Review medication history for lithium use or exposure to bromide-containing medications 3, 5
6. Consider rare causes such as polymyxin B therapy or hyperviscosity syndromes if other causes are ruled out 5

Pitfalls to Avoid

• Don't dismiss a low anion gap as clinically insignificant - it may provide valuable diagnostic information 1, 5
• Be aware that hyponatremia can artificially lower the anion gap 4
• Remember that the anion gap calculation may vary depending on whether potassium is included in the formula 2
• Consider that a baseline low anion gap may mask a superimposed high anion gap metabolic acidosis 1