What is the significance and management of a negative anion gap?

Negative Anion Gap: Significance and Management

A negative anion gap is a rare laboratory finding that requires investigation as it may indicate laboratory error, specimen contamination, or significant underlying pathology such as paraproteinemia, severe hypoalbuminemia, or lithium toxicity. While elevated anion gaps are well-studied, negative anion gaps deserve careful clinical attention as they can provide valuable diagnostic clues to serious conditions.

Definition and Normal Values

• The anion gap (AG) is calculated using the formula: Na⁺ + K⁺ - Cl⁻ - HCO₃⁻ 1
• Modern ion-selective electrode methodology has lowered the normal reference range from the traditional 8-16 mmol/L to approximately 3-11 mmol/L 2
• A value less than 3 mmol/L should be considered low, and negative values (below 0) are particularly rare 3

Causes of Negative Anion Gap

Laboratory Errors

• Sporadic (non-reproducible) measurement errors 4
• Systematic (reproducible) laboratory errors 4
• Specimen contamination or interference with electrolyte measurements 5

Pathophysiological Causes

• Hypoalbuminemia: Reduced unmeasured anions 5, 4

  • Each 1 g/dL decrease in albumin can lower the anion gap by 2.5 mEq/L

• Increased unmeasured cations:

  • Severe hyperkalemia (when potassium is not included in the AG calculation) 5
  • Hypercalcemia (especially in malignancy) 3
  • Hypermagnesemia 4
  • Lithium toxicity 3, 4
  • Bromism (rare) 5

• Paraproteinemias:

  • Multiple myeloma (particularly IgG myeloma) 5, 2
  • Other monoclonal gammopathies 3

Clinical Significance

• A negative anion gap can serve as an important diagnostic clue for:

  • Occult paraproteinemia, potentially leading to earlier diagnosis of multiple myeloma 3
  • Lithium toxicity in patients on lithium therapy 4
  • Severe hypoalbuminemia that may be overlooked 4

• A baseline low or negative anion gap may mask a superimposed high anion gap metabolic acidosis 3, 6

  • For example, a patient with multiple myeloma (causing negative AG) who develops diabetic ketoacidosis may present with a "normal" anion gap

Management Approach

1. Verify the result:

   • Repeat electrolyte measurements to rule out laboratory error 4
   • Check specimen quality (hemolysis, lipemia) 5

2. Investigate albumin levels:

   • Measure serum albumin and correct the anion gap 6
   • Corrected AG = Measured AG + 2.5 × (4 - measured albumin in g/dL) 6

3. Evaluate for paraproteinemia:

   • Consider serum protein electrophoresis and immunofixation if negative AG persists 5, 3
   • Two cases of IgG multiple myeloma with anion gap of 2 mmol/L have been documented 2

4. Check additional electrolytes:

   • Measure calcium, magnesium levels 4
   • Check lithium levels in patients on lithium therapy 3

5. Consider underlying mixed acid-base disorders:

   • A negative AG may mask a high anion gap metabolic acidosis 3
   • Calculate the osmolal gap if toxic alcohol ingestion is suspected 6

Clinical Pearls and Pitfalls

• The incidence of decreased anion gap among hospitalized patients is approximately 2.9%, making it an uncommon but significant finding 2
• Anion gap values less than 2 mmol/L are particularly rare and warrant thorough investigation 2
• Common causes of decreased (but not necessarily negative) anion gap include liver cirrhosis and nephrotic syndrome 2
• A negative anion gap should never be dismissed as a laboratory error without proper investigation, as it may be the first clue to a serious underlying condition 3, 4

Special Considerations

• The reference range for anion gap has decreased with modern laboratory methods, but many clinicians and textbooks still refer to older reference values (8-16 mmol/L), which may lead to misinterpretation 2
• In patients with a known cause of negative anion gap, serial measurements can be useful for monitoring disease progression 3