Clinical Effects of Low Anion Gap
A low anion gap (defined as <3 mEq/L with modern ion-selective electrode methodology) is primarily a laboratory clue rather than a direct cause of clinical symptoms, but it serves as an important diagnostic marker for potentially life-threatening conditions including multiple myeloma, severe hypoalbuminemia, and bromide intoxication. 1
Direct Clinical Effects
Low anion gap itself does not cause direct physiologic symptoms or morbidity. The clinical manifestations observed in patients with low anion gap are attributable to the underlying conditions causing the abnormality, not the low anion gap value itself. 1, 2
Critical Diagnostic Implications
Masking of High Anion Gap Acidosis
- The most clinically significant effect of a baseline low anion gap is that it can mask the identification of a high anion gap metabolic acidosis in certain patients. 1
- A patient with baseline low anion gap (e.g., 2 mEq/L) who develops lactic acidosis or ketoacidosis may present with a "normal" calculated anion gap (e.g., 10 mEq/L), leading to delayed recognition and treatment of life-threatening metabolic acidosis. 1
Quality Control Indicator
- The American College of Physicians recommends verifying laboratory measurements first when encountering a low anion gap, checking for quality control issues with electrolyte measurement. 3
- Anion gap values less than 2 mEq/L are rare and should prompt investigation for laboratory error or specific pathologic conditions. 4, 5
Underlying Conditions Associated with Low Anion Gap
Most Common Causes
- Hypoalbuminemia (from liver cirrhosis, nephrotic syndrome, malnutrition, or severe illness) is the most frequent cause of low anion gap. 4, 5, 2
- Each 1 g/dL decrease in serum albumin lowers the anion gap by approximately 2.5 mEq/L. 2
- Nephrotic syndrome and liver cirrhosis are among the most common clinical conditions presenting with decreased anion gap. 4, 5
Life-Threatening Conditions
- Multiple myeloma with IgG paraproteinemia can present with anion gaps as low as 2 mEq/L and should be considered when encountering unexplained low anion gap. 4, 6
- The low anion gap in multiple myeloma results from the presence of unmeasured cationic immunoglobulin proteins. 6, 2
- Bromide intoxication produces a low or even negative anion gap and represents a potentially fatal condition requiring prompt recognition. 2
Other Associated Conditions
- Hypercalcemia and hypermagnesemia increase unmeasured cations, lowering the anion gap. 2
- Hyperviscosity syndromes and certain paraproteinemias can produce low anion gap values. 2
- Severe hemorrhage and intestinal obstruction have been associated with decreased anion gap. 5
Clinical Approach to Low Anion Gap
Initial Verification Steps
- Recalculate the anion gap using the formula: Na+ - (Cl- + HCO3-), or Na+ + K+ - Cl- - HCO3- if potassium is included. 3
- Verify quality control of electrolyte measurements, particularly if the anion gap is <2 mEq/L. 3, 4
- Check for hypoalbuminemia or hyperglobulinemia as potential causes. 4
Diagnostic Workup
- Measure serum albumin to assess for hypoalbuminemia as the cause. 5, 2
- Consider serum protein electrophoresis and immunofixation if multiple myeloma is suspected, particularly in patients with unexplained anemia, bone pain, renal dysfunction, or altered mental status. 6
- Evaluate for bromide exposure if history suggests possible intoxication. 2
- Assess for hypercalcemia, hypermagnesemia, or hyperviscosity syndromes based on clinical context. 2
Important Clinical Pitfalls
- Do not dismiss a low anion gap as clinically insignificant—it may be the only clue to occult neoplasms like multiple myeloma or life-threatening intoxications. 1, 6
- Remember that patients with chronic low anion gap may develop superimposed high anion gap metabolic acidosis that appears "normal" on routine calculation. 1
- A low anion gap of <3 mEq/L warrants investigation even in asymptomatic patients, as it may indicate underlying pathology requiring treatment. 1