Anion gap


The anion gap is a value calculated from the results of multiple individual medical lab tests. It may be reported with the results of an electrolyte panel, which is often performed as part of a comprehensive metabolic panel.
The anion gap is the difference between certain measured cations and the measured anions in serum, plasma, or urine. The magnitude of this difference in the serum is often calculated in medicine when attempting to identify the cause of metabolic acidosis, a lower than normal pH in the blood. If the gap is greater than normal, then high anion gap metabolic acidosis is diagnosed.
The term "anion gap" usually implies "serum anion gap", but the urine anion gap is also a clinically useful measure.

Calculation

The anion gap is a calculated measure. This means that it is not directly measured by a specific lab test; rather, it is computed with a formula that uses the results of several individual lab tests, each of which measures the concentration of a specific anion or cation.
The concentrations are expressed in units of milliequivalents/liter or in millimoles/litre.

With potassium

The anion gap is calculated by subtracting the serum concentrations of chloride and bicarbonate from the concentrations of sodium and potassium :

Without potassium (daily practice)

Because potassium concentrations are very low, they usually have little effect on the calculated gap. Therefore, omission of potassium has become widely accepted. This leaves the following equation:
Normal AG = 8-16 mEq/L
Expressed in words, the equation is:

Uses

Calculating the anion gap is clinically useful because it helps in the differential diagnosis of a number of disease states.
The total number of cations should be equal to the total number of anions, so that the overall electrical charge is neutral. However, routine tests do not measure all types of ions. The anion gap is representative of how many ions are not accounted for by the lab measurements used in the calculation. These "unmeasured" ions are mostly anions, which is why the value is called the "anion gap."
By definition, only the cations sodium and potassium and the anions chloride and bicarbonate are used to calculate the anion gap.
The cations calcium and magnesium are also commonly measured, but they aren't used to calculate the anion gap. Anions that are generally considered "unmeasured" include a few normally occurring serum proteins, and some pathological proteins.
Similarly, tests do often measure the anion phosphate specifically, but it isn't used to calculate that "gap," even if it is measured. Commonly 'unmeasured' anions include sulfates and a number of serum proteins.
In normal health there are more measurable cations than measurable anions in the serum; therefore, the anion gap is usually positive. Because we know that plasma is electro-neutral, we can conclude that the anion gap calculation represents the concentration of unmeasured anions. The anion gap varies in response to changes in the concentrations of the above-mentioned serum components that contribute to the acid-base balance.

Normal value ranges

Different labs use different formulae and procedures to calculate the anion gap, so the reference range from one lab isn't directly interchangeable with the range from another. The reference range provided by the particular lab that performed the testing should always be used to interpret the results. Also, some healthy people may have values outside of the "normal" range provided by any lab.
Modern analyzers use ion-selective electrodes which give a normal anion gap as <11 mEq/L. Therefore, according to the new classification system, a high anion gap is anything above 11 mEq/L and a normal anion gap is often defined as being within the prediction interval of 3–11 mEq/L, with an average estimated at 6 mEq/L.
In the past, methods for the measurement of the anion gap consisted of colorimetry for and as well as flame photometry for and . Thus normal reference values ranged from 8 to 16 mEq/L plasma when not including and from 10 to 20 mEq/L plasma when including . Some specific sources use 15 and 8–16 mEq/L.

Interpretation and causes

Anion gap can be classified as either high, normal or, in rare cases, low. Laboratory errors need to be ruled out whenever anion gap calculations lead to results that do not fit the clinical picture. Methods used to determine the concentrations of some of the ions used to calculate the anion gap may be susceptible to very specific errors. For example, if the blood sample is not processed immediately after it is collected, continued cellular metabolism by leukocytes may result in an increase in the HCO concentration, and result in a corresponding mild reduction in the anion gap. In many situations, alterations in renal function may modify the anion gap that may be expected to arise in a particular pathological condition.
A high anion gap indicates that, usually due to disease or intoxication, there are elevated concentrations of anions like lactate, beta-hydroxybutyrate, acetoacetate, PO, and SO in the blood. These anions are not part of the anion-gap calculation and there is a secondary loss of HCO without a concurrent increase in Cl−. Thus, the presence of a high anion gap should result in a search for conditions that lead to an excess of these anions.

High anion gap

The anion gap is affected by changes in unmeasured ions. In uncontrolled diabetes, there is an increase in ketoacids due to metabolism of ketones. Raised levels of acid bind to bicarbonate to form carbon dioxide through the Henderson-Hasselbalch equation resulting in metabolic acidosis. In these conditions, bicarbonate concentrations decrease by acting as a buffer against the increased presence of acids. The bicarbonate is consumed by the unmeasured cation resulting in a high anion gap.
Causes of high anion gap metabolic acidosis :
Note: a useful mnemonic to remember this is MUDPILES - Methanol, Uremia, Diabetic Ketoacidosis, Paraldehyde, Infection, Lactic Acidosis, Ethylene Glycol and Salicylates

Normal anion gap

In patients with a normal anion gap the drop in HCO is the primary pathology. Since there is only one other major buffering anion, it must be compensated for almost completely by an increase in Cl−. This is therefore also known as hyperchloremic acidosis.
The HCO lost is replaced by a chloride anion, and thus there is a normal anion gap.
Note: a useful mnemonic to remember this is FUSEDCARS - fistula, uretero-enterostomy, saline administration, endocrine, diarrhea, carbonic anhydrase inhibitors, ammonium chloride, renal tubular acidosis, spironolactone.

Low anion gap

A low anion gap is frequently caused by hypoalbuminemia. Albumin is a negatively charged protein and its loss from the serum results in the retention of other negatively charged ions such as chloride and bicarbonate. As bicarbonate and chloride anions are used to calculate the anion gap, there is a subsequent decrease in the gap.
The anion gap is sometimes reduced in multiple myeloma, where there is an increase in plasma IgG.

Correcting the anion gap for the albumin concentration

The calculated value of the anion gap should always be adjusted for variations in the serum albumin concentration. For example, in cases of hypoalbuminemia the calculated value of the anion gap should be increased by 2.3 to 2.5 mEq/L per each 1 g/dL decrease in serum albumin concentration. Common conditions that reduce serum albumin in the clinical setting are hemorrhage, nephrotic syndrome, intestinal obstruction and liver cirrhosis. Hypoalbuminemia is common in critically ill patients.
Hypoalbuminemia can mask a mild elevation of the anion gap, resulting in failure to detect an accumulation of unmeasured anions. Therefore, it is important to correct the calculated value of the anion gap for the concentration of albumin, particularly in critically ill patients. Corrections can be made for the albumin concentration using the Figge-Jabor-Kazda-Fencl equation to give an accurate anion gap calculation as exemplified below.

Sample calculations

Given the following data from a patient with severe hypoalbuminemia suffering from postoperative multiple organ failure, calculate the anion gap and the albumin-corrected anion gap.
Data:
Calculations:
In this example, the albumin-corrected anion gap reveals the presence of a significant quantity of unmeasured anions.