What does a low anion gap indicate?

What Does a Low Anion Gap Indicate?

A low anion gap (defined as <3 mmol/L using modern ion-selective electrode methodology) most commonly indicates severe hypoalbuminemia, but critically can also signal life-threatening conditions including lithium or barium intoxication, paraproteinemias like multiple myeloma, or laboratory error—and importantly, a baseline low anion gap can mask concurrent high anion gap metabolic acidosis. 1

Defining a Low Anion Gap

• Modern ion-selective electrode methodology has lowered the normal anion gap range from the historical 12 ± 4 mEq/L to 6 ± 3 mEq/L, making values <3 mEq/L the appropriate threshold for defining a low anion gap 2
• The reference range using current methodology is 3-11 mmol/L (or 5-12 mmol/L in some studies), so clinicians must abandon outdated reference ranges of 8-16 mmol/L to avoid misinterpretation 3
• Calculate the anion gap using: Na⁺ + K⁺ - Cl⁻ - HCO₃⁻ and always recalculate to confirm the value 1

Primary Causes of Low Anion Gap

Hypoalbuminemia (Most Common)

• Severe hypoalbuminemia significantly lowers the anion gap because albumin is a major unmeasured anion 1
• Common underlying conditions include liver cirrhosis and nephrotic syndrome 3
• When hypoalbuminemia is present, calculate a corrected anion gap to unmask potential concurrent metabolic acidosis 4

Life-Threatening Intoxications

• Lithium or barium intoxication increases unmeasured cations, thereby lowering the calculated anion gap 1
• These represent critical diagnoses that require immediate recognition and specific management 2

Paraproteinemias

• Multiple myeloma (particularly IgG type) can present with anion gaps as low as 2 mmol/L 3
• The low anion gap serves as a diagnostic clue for occult neoplasms that might otherwise be missed 2
• Paraproteins act as unmeasured cations, reducing the calculated anion gap 4

Laboratory Issues

• Specimen contamination or analytical interference can produce spuriously low values 4
• Extreme hyperkalemia may contribute to negative anion gap calculations 4
• Bromism (bromide intoxication) interferes with chloride measurement, falsely elevating chloride and lowering the anion gap 4

Critical Clinical Pitfall

The most dangerous aspect of a low baseline anion gap is that it can mask concurrent high anion gap metabolic acidosis 1. For example:

• A patient with severe hypoalbuminemia (baseline anion gap of 2 mmol/L) who develops lactic acidosis might have a "normal-appearing" anion gap of 10 mmol/L
• Always check arterial blood gas to assess actual acid-base status when encountering a low anion gap 1
• The presence of metabolic acidosis with a seemingly normal anion gap in a patient with hypoalbuminemia should prompt calculation of the corrected anion gap

Diagnostic Approach

When encountering a low anion gap:

1. Verify the calculation and rule out laboratory error by recalculating and potentially repeating the measurement 1, 5

2. Check serum albumin to identify hypoalbuminemia as the cause 1

3. Review medication history specifically for lithium, and consider barium exposure 1

4. Evaluate for paraproteinemia by checking serum protein electrophoresis if multiple myeloma is suspected 3

5. Assess acid-base status with arterial blood gas to ensure no masked metabolic acidosis 1

6. Consider bromide toxicity if there is a history of bromide-containing medication exposure 4

Incidence and Quality Control Implications

• In hospitalized patients, decreased anion gaps occur in only 2.9% of cases, with a mean of 3 mmol/L and central 90% range of 2-4 mmol/L 3
• Anion gap values <2 mmol/L or negative values are extremely rare and should trigger investigation for laboratory error, specimen interference, or the specific pathologic conditions mentioned above 3, 4
• High incidence of extremely low anion gaps (<2 mmol/L) in a clinical setting should prompt review of laboratory quality control and assessment for hypoalbuminemia or hyperglobulinemia in the patient population 3