What is the anion gap?

What is the Anion Gap?

The anion gap is a calculated value derived from routine serum electrolytes—specifically sodium minus the sum of chloride and bicarbonate (Na⁺ - [Cl⁻ + HCO₃⁻])—that serves as the critical first step in diagnosing and categorizing metabolic acidosis. 1

Calculation Methods

The anion gap can be calculated using two formulas, depending on clinical context:

• Standard formula (most common): Na⁺ - (Cl⁻ + HCO₃⁻), with a normal range of 8-12 mEq/L 1, 2
• Potassium-inclusive formula: Na⁺ + K⁺ - Cl⁻ - HCO₃⁻, which raises the normal range to approximately 12-16 mEq/L 3, 1

The potassium-inclusive formula is specifically recommended by the American College of Critical Care when evaluating toxic alcohol ingestions, particularly ethylene glycol poisoning, as it provides more accurate thresholds for intervention decisions 1.

Clinical Purpose and Utility

The anion gap serves multiple diagnostic functions:

• Divides metabolic acidosis into two categories: high anion gap metabolic acidosis (HAGMA) versus normal anion gap (hyperchloremic) acidosis, immediately narrowing the differential diagnosis 2, 4
• Identifies life-threatening conditions requiring urgent intervention, including diabetic ketoacidosis, toxic alcohol ingestions, and lactic acidosis 1, 5
• Detects measurement errors in electrolyte panels and can identify paraproteins or occult neoplasms like multiple myeloma 6

Normal Values and Modern Considerations

Important caveat: The widespread adoption of ion-selective electrode methodology over the past 25 years has lowered the normal anion gap range from the traditional 12 ± 4 mEq/L to approximately 6 ± 3 mEq/L in many laboratories 6. This means:

• An anion gap value >12 mEq/L typically indicates pathology when using standard methodology 1
• Values <3 mEq/L should be considered abnormally low and warrant investigation 6
• Always compare your patient's value to your specific laboratory's reference range 7

What the Anion Gap Represents Physiologically

The anion gap reflects "unmeasured" anions in the blood—primarily albumin and phosphate under normal conditions 8, 2. When pathologic acids accumulate (lactate, ketones, toxic metabolites, uremic acids), these unmeasured anions increase, widening the gap 2, 4.

• The gap is not just a function of unmeasured anions alone—it is also influenced by plasma non-carbonate buffers (albumin and phosphate), plasma pH, and measurement methodology 8
• Albumin contributes significantly to the normal anion gap through its negative charge at physiologic pH 8

Critical Clinical Thresholds

When evaluating toxic ingestions, specific anion gap thresholds guide urgent interventions:

• Anion gap >27 mmol/L (using potassium-inclusive formula) in suspected ethylene glycol poisoning mandates immediate hemodialysis 3, 1, 5
• Anion gap 23-27 mmol/L suggests hemodialysis should be strongly considered 1, 5
• Anion gap >28 mmol/L is associated with approximately 20% mortality in toxic alcohol ingestions 3

Common Pitfalls and Limitations

Several factors can distort the anion gap's accuracy:

• Hypoalbuminemia causes the anion gap to underestimate the severity of acidosis, as each 1 g/dL decrease in albumin lowers the anion gap by approximately 2.5 mEq/L 5, 2
• Acute kidney injury or concurrent ketoacidosis can overestimate glycolate concentrations when the gap is used as a surrogate marker 3, 1
• Lithium or barium co-ingestion can artificially lower the anion gap 1, 5
• The type of retained anion matters: lactic acidosis typically produces a larger increase in anion gap relative to bicarbonate decrease compared to ketoacidosis 7
• Wide normal range (often 8-10 mEq/L) means significant anion accumulation can occur without the gap exceeding the "normal" upper limit 7

When to Calculate the Anion Gap

Calculate the anion gap immediately in these scenarios:

• Any patient with suspected or confirmed metabolic acidosis (low bicarbonate or low pH on blood gas) 1, 4
• Diabetic patients with any degree of metabolic derangement, even with "controlled" glucose, as SGLT2 inhibitors can cause euglycemic ketoacidosis 1
• Suspected toxic alcohol ingestion (methanol, ethylene glycol) 1, 5
• Unexplained altered mental status with metabolic derangement 5
• To identify electrolyte measurement errors or detect occult paraproteins 6, 2

The anion gap has poor predictive value when used indiscriminately in patients with low pre-test probability of the suspected condition 3, 1—clinical context is essential for proper interpretation.