What are the causes of a low anion gap (less than 3-5 milliequivalents per liter)?

Causes of Low Anion Gap

A low anion gap (less than 3-5 mEq/L) is primarily caused by hypoalbuminemia, laboratory error, and increased unmeasured cations such as paraproteins from multiple myeloma, lithium, calcium, or magnesium. 1, 2

Definition and Normal Range

• The anion gap (AG) approximates the difference between unmeasured anions and unmeasured cations in serum 1
• The normal reference range has decreased from the traditional 8-16 mEq/L to 3-11 mEq/L due to changes in electrolyte measurement techniques using ion-selective electrodes 1, 2
• A value less than 3 mEq/L is now considered a low anion gap based on current clinical data 1
• Anion gap is calculated using the formula: Na⁺ + K⁺ - Cl⁻ - HCO₃⁻ 3

Common Causes of Low Anion Gap

Laboratory Errors (Most Common)

• Sporadic (non-reproducible) measurement errors 4
• Systematic (reproducible) laboratory errors 4
• In one large study, laboratory error was the most common cause of a low anion gap 5

Decreased Unmeasured Anions

• Hypoalbuminemia (most common physiologic cause) 2, 6, 5
  • Each 1 g/dL decrease in albumin can lower the anion gap by 2.5 mEq/L 2
  • Common in liver cirrhosis and nephrotic syndrome 2

Increased Unmeasured Cations

• Paraproteinemias (especially IgG multiple myeloma) 1, 2, 6
  • Can result in anion gaps as low as 2 mEq/L 2
• Lithium toxicity 4
• Hypercalcemia 4
• Hypermagnesemia 4
• Extreme hyperkalemia 6
• Bromism (bromide intoxication) 6

Other Causes

• Hyponatremia 5
• Specimen contamination or interference 6

Clinical Significance

• A low anion gap can be a useful diagnostic tool but is often clinically unrecognized 1
• May serve as a clinical clue for diagnosing life-threatening conditions or occult neoplasms like multiple myeloma 1
• A baseline low anion gap may mask the identification of a high gap metabolic acidosis in certain patients 1
• Anion gaps less than 2 mEq/L or negative anion gaps are rare and warrant thorough investigation 2, 6, 4

Pitfalls to Avoid

• Using outdated reference ranges (8-16 mEq/L) can lead to misinterpretation of anion gap values 2
• Failing to consider laboratory error as a common cause of low anion gap 5
• Not recognizing that a low anion gap may mask a concurrent high anion gap acidosis 1
• Overlooking the possibility of serious underlying conditions such as multiple myeloma 1, 2