What is the normal anion gap (AG)?

Normal Anion Gap Range

The normal anion gap range is 8-12 mEq/L when calculated as [Na+] - ([Cl-] + [HCO3-]) 1.

Understanding the Anion Gap

The anion gap (AG) is a calculated value that approximates the difference between unmeasured anions and unmeasured cations in serum. It's an essential tool in evaluating acid-base disorders, particularly metabolic acidosis.

Calculation Method

The standard formula for calculating anion gap is:

• AG = [Na+] - ([Cl-] + [HCO3-])

Some laboratories may include potassium in the calculation:

• AG = [Na+] + [K+] - ([Cl-] + [HCO3-])

Evolution of Normal Range Values

It's important to note that the reference range for anion gap has changed over time due to advances in laboratory measurement techniques:

• Historical reference range: 8-16 mEq/L 2
• Current reference range: 8-12 mEq/L 1 or 5-12 mmol/L 2

This shift occurred primarily due to the introduction of ion-selective electrode methodology for measuring serum electrolytes 3.

Clinical Significance

The anion gap has significant diagnostic utility:

• Normal AG (8-12 mEq/L): Seen in approximately 59.5% of hospitalized patients 2
• Elevated AG (>12 mEq/L): Seen in about 37.6% of hospitalized patients 2
  • Values exceeding 24 mmol/L are rare and strongly suggest metabolic acidosis 2
  • Common causes include hypertensive disease, chronic renal failure, malignant neoplasms, diabetes mellitus, and heart diseases 2
• Decreased AG (<8 mEq/L): Seen in approximately 2.9% of hospitalized patients 2
  • Values less than 2 mmol/L are rare 2
  • Common causes include liver cirrhosis and nephrotic syndrome 2

Important Considerations

• Albumin correction: Since albumin is a major contributor to the anion gap, hypoalbuminemia can lead to a falsely low anion gap. For every 1 g/dL decrease in albumin, the anion gap decreases by approximately 2.5 mEq/L.

• Quality control: Unusually high (>24 mmol/L) or low (<2 mmol/L) anion gap values should prompt verification of electrolyte measurements 2.

• Delta gap: When evaluating metabolic acidosis, comparing the change in anion gap to the change in bicarbonate (delta ratio) can help identify mixed acid-base disorders 4:

  • Delta ratio 1:1 suggests uncomplicated high AG acidosis
  • Delta ratio <1:1 suggests combined high and normal AG acidosis
  • Delta ratio >2:1 suggests combined metabolic alkalosis and high AG acidosis

• Recent research: A 2024 study found that using individual patient baseline values rather than population means for calculating delta AG/delta bicarbonate ratios may provide more accurate assessment of acid-base disorders 5.

Clinical Application

The anion gap is particularly valuable as an initial step in evaluating metabolic acidosis, helping differentiate between:

1. High anion gap metabolic acidosis: Due to accumulation of acids (e.g., lactic acidosis, diabetic ketoacidosis, toxic ingestions)
2. Normal anion gap metabolic acidosis: Due to bicarbonate loss or failure of renal acid excretion

Recognizing a low anion gap can also provide valuable clinical information and may be a clue for diagnosing conditions like multiple myeloma 3.