What does a low anion gap in a blood test indicate?

What Does a Low Anion Gap Indicate?

A low anion gap (defined as <3 mEq/L with modern ion-selective electrode methodology) most commonly indicates severe hypoalbuminemia, but also serves as a critical diagnostic clue for lithium or barium intoxication, paraproteinemias (particularly IgG multiple myeloma), and can mask concurrent high anion gap metabolic acidosis. 1

Defining a Low Anion Gap with Modern Laboratory Methods

• The reference range for anion gap has shifted dramatically from the historical 8-16 mmol/L to 3-11 mmol/L (or 5-12 mmol/L) due to widespread adoption of ion-selective electrode methodology for electrolyte measurement 2
• A value <3 mEq/L should be considered definitively low based on current clinical data 3
• Negative anion gaps (≤-1) are rare but clinically significant when they occur 4

Primary Causes to Investigate

Hypoalbuminemia (Most Common)

• Albumin is a major unmeasured anion in serum; severe hypoalbuminemia significantly lowers the calculated anion gap 1
• Common underlying conditions include liver cirrhosis and nephrotic syndrome 2
• For every 1 g/dL decrease in albumin below normal, the anion gap decreases by approximately 2.5 mEq/L 1

Toxic Ingestions

• Lithium or barium intoxication increases unmeasured cations, thereby lowering the calculated anion gap 1
• These represent life-threatening conditions requiring immediate recognition 3

Paraproteinemias

• IgG multiple myeloma can present with anion gaps as low as 2 mmol/L 2
• The cationic paraproteins act as unmeasured cations, reducing the calculated gap 3
• This represents an occult neoplasm that may be diagnosed through recognition of the low anion gap 3

Laboratory Error

• Historically considered the most common cause when using older methodology 5
• With modern techniques, true low anion gaps are more clinically meaningful 2
• Specimen contamination or analytical interference should still be considered 4

Critical Clinical Pitfall

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

• A patient with baseline hypoalbuminemia (anion gap of 3 mEq/L) who develops diabetic ketoacidosis may have a "normal-appearing" anion gap of 12 mEq/L
• Always obtain arterial blood gas analysis to assess actual acid-base status when a low anion gap is identified 1
• The corrected anion gap should be calculated when hypoalbuminemia is present 4

Diagnostic Algorithm

1. Recalculate the anion gap using the formula: Na⁺ + K⁺ - Cl⁻ - HCO₃⁻ to confirm the value 1

2. Check serum albumin immediately - if <3.0 g/dL, this explains the low gap 1, 2

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

4. Order serum protein electrophoresis if paraproteinemia is suspected (particularly if anion gap ≤2 mEq/L) 2

5. Obtain arterial blood gas to rule out masked metabolic acidosis 1

6. Verify laboratory quality control if no clinical explanation is found, as analytical error remains possible 2, 5

Epidemiology and Clinical Context

• Low anion gaps occur in approximately 0.8-2.9% of hospitalized patients 2, 5
• The mean value for decreased anion gap is 3 mmol/L with a central 90% range of 2-4 mmol/L 2
• Values <2 mmol/L are rare and warrant aggressive investigation 2
• Hyponatremia can also contribute to a low anion gap, as there is a positive correlation between sodium concentration and anion gap 5