Anion Gap

What the anion gap is and what it is used for

The anion gap is the difference between sodium and the sum of chloride and bicarbonate in serum. Blood is electrically neutral, so this difference represents the anions that are not measured routinely, mainly albumin, plus phosphate, sulfate and organic anions.

According to the review by Kraut and Madias (2007), the anion gap is used to:

• detect and classify acid-base disorders, especially metabolic acidosis, which is divided into high anion gap and normal anion gap forms;
• support quality control in the clinical chemistry section, since very low values often indicate analytical error;
• raise suspicion of paraproteinemias, as in multiple myeloma, and of lithium, bromide or iodide intoxication.

The anion gap is often assessed together with the calculated serum osmolality, whose difference from the measured value (osmolal gap) helps investigate toxic alcohol poisoning.

How to calculate the anion gap: inputs and units

The calculator asks for three electrolytes, all in mEq/L, a choice about potassium and, optionally, albumin:

• Sodium (Na⁺), between 100 and 200. Example: 140.
• Chloride (Cl⁻), between 50 and 150. Example: 100.
• Bicarbonate (HCO₃⁻), between 1 and 60. Example: 24.
• Include potassium (K⁺) in the calculation? No (default) or Yes. With Yes, the Potassium field, between 1 and 10 mEq/L, becomes required.
• Albumin, optional, in g/dL, between 0.5 and 7. Example: 3.0.

Values outside these ranges produce a message saying which field to correct. The tool's step-by-step process:

1. Adds chloride and bicarbonate.
2. Subtracts that sum from sodium, or from the sum of sodium and potassium if potassium was included.
3. If albumin was entered, also calculates the corrected anion gap.

Results are shown with one decimal place, together with a note: the normal range is the laboratory's. For mEq/L and mmol/L, the numbers are the same for these monovalent ions. With the field examples (140, 100 and 24, without potassium and with albumin 3.0), the anion gap is 16.0 and the corrected value is 19.5 mEq/L.

Anion gap formula, with and without potassium

The tool uses the classic definition of the anion gap, described by Kraut and Madias, and a variant with potassium. The two expressions are:

AG = Na⁺ − (Cl⁻ + HCO₃⁻)
AG with potassium = (Na⁺ + K⁺) − (Cl⁻ + HCO₃⁻)

• Na⁺: serum sodium, in mEq/L.
• K⁺: serum potassium, in mEq/L, only in the potassium variant.
• Cl⁻: serum chloride, in mEq/L.
• HCO₃⁻: bicarbonate, usually serum total CO₂, in mEq/L.

Most laboratories use the version without potassium, because the potassium concentration is small and varies little relative to sodium. The potassium version gives values a few mEq/L higher and requires its own comparison range.

When albumin is entered, the tool also calculates the corrected anion gap with the Figge formula, detailed in the section on errors and albumin correction.

Worked anion gap examples

With sodium of 140, chloride of 104 and bicarbonate of 24 mEq/L, the anion gap is 12.0 mEq/L. The steps:

1. Chloride + bicarbonate: 104 + 24 = 128 mEq/L.
2. Anion gap: 140 − 128 = 12.0 mEq/L.
3. The tool shows 12.0 mEq/L, without classification, with the note to compare against the laboratory's reference.

Including potassium of 4.0 mEq/L, the calculation becomes 140 + 4.0 − 128 = 16.0 mEq/L: the potassium version gives higher values and needs its own reference.

In a third example, with sodium of 140, chloride of 100 and bicarbonate of 12 mEq/L, the anion gap is 140 − 112 = 28.0 mEq/L, well above the first example. A low bicarbonate with a high anion gap is the pattern of high anion gap metabolic acidosis, but the cause is only established with blood gases, lactate, ketones, kidney function and clinical history.

The examples are for teaching purposes and do not represent a real patient.

How to understand the anion gap result

The normal range of the anion gap is not universal. Kraut and Madias (2007) point out that it varies widely with the methods used to measure sodium, chloride and bicarbonate and between individuals; for that reason, each laboratory should define its own reference.

For that reason the tool does not classify the result as low, normal or high. Fixed ranges, such as 8 to 16 mEq/L, come from older methods and do not apply to every laboratory; compare the value with the reference on the report, which should take into account whether potassium was included.

According to the same review, the most common causes are:

• Low anion gap: laboratory error or low albumin; more rarely, paraproteinemia or lithium, bromide or iodide intoxication.
• High anion gap: most often, metabolic acidosis; also laboratory error, metabolic alkalosis, elevated phosphate or paraproteinemia.

The ratio between the change in anion gap and the change in bicarbonate (delta/delta) has been used to detect mixed disorders, but Kraut and Madias show that it varies too much to be used on its own. Clinical interpretation is the responsibility of the professional caring for the patient.

Common errors, albumin correction and checklist

The most common interpretation error is reading the anion gap without looking at albumin. Figge and colleagues (1998) showed, in critically ill patients, that each 1 g/L drop in albumin lowers the observed anion gap by 0.25 mEq/L, which can mask a high anion gap acidosis.

Corrected AG = observed AG + 2.5 × (normal albumin − observed albumin), with albumin in g/dL
With albumin in g/L, the factor is 0.25.

The tool adopts 4.4 g/dL as normal albumin. Many texts use 4.0 g/dL, and the Figge abstract refers only to normal albumin, so the laboratory's value may differ. Example: an anion gap of 12.0 mEq/L with albumin of 2.0 g/dL becomes 12.0 + 2.5 × (4.4 − 2.0) = 18.0 mEq/L.

• Are the three electrolytes from the same sample?
• Is the bicarbonate serum total CO₂, and not the value calculated from a blood gas drawn at another time?
• Was potassium included on purpose, and is the comparison reference the matching one?
• Is albumin in g/dL? If the report gives g/L, divide by 10.

Albumin is also the basis of albumin-corrected calcium.

Limitations and comparison with other acid-base calculations

The anion gap is inexpensive and useful, but it is an indirect index, subject to the combined errors of three measurements. Kraut and Madias note that a normal value does not rule out high anion gap acidosis when albumin is low, and that abnormal values may come from laboratory error.

In hyperglycemia, measured sodium falls by dilution, but the anion gap is calculated with measured sodium, not with glucose-corrected sodium. In the renal assessment of acidosis, the CKD-EPI equation estimates the glomerular filtration rate.

Frequently asked questions about the anion gap

References

1. Kraut JA, Madias NE. Serum anion gap: its uses and limitations in clinical medicine. Clin J Am Soc Nephrol. 2007;2(1):162-74. doi:10.2215/CJN.03020906. View
2. Figge J, Jabor A, Kazda A, Fencl V. Anion gap and hypoalbuminemia. Crit Care Med. 1998;26(11):1807-10. doi:10.1097/00003246-199811000-00019. View