Anion gap

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Priyamvada Singh, M.D. [2]


The anion gap is a representative of the unmeasured anions in the plasma, and is made of negatively charged phosphates, sulfates, organic acids and plasma proteins (including albumin). Rather than measuring all these anions in a patient, an indirect way is to measure the difference of the dominant cation i.e. sodium to the dominant anion i.e. chloride and bicarbonate, with the understanding that the difference in anions is caused due to the unmeasured anions i.e. phosphate, sulfate, and albumin. Chloride and bicarbonate comprise 85% of the anions in the serum. The differential diagnosis of a patient with a metabolic acidosis is broad and can be narrowed and further evaluated by calculating the anion gap. Normal reference range AG is between 3 and 11 meq/L (average 6 meq/L).


The primary function of the anion gap measurement is to allow a clinician to narrow down the possible causes of a patient's metabolic acidosis. For example, if a patient presents with metabolic acidosis, but a normal anion gap, then conditions that cause a high anion gap can be ruled out as being the cause of the acidosis.


It is calculated by subtracting the serum concentrations of chloride and bicarbonate (anions) from the concentrations of sodium plus potassium (cations):

Serum AG = Measured cations - measured anions; Serum AG = Na - (Cl + HCO3)
Serum AG = Unmeasured anions - unmeasured cations
Anion Gap = ( [Na+]+[K+] ) - ( [Cl-]+[HCO3-] )

However, for daily practice, the potassium is frequently ignored, leaving the following equation:

Anion Gap = ( [Na+] ) - ( [Cl-]+[HCO3-] )


Anion gap can be classified as either high, normal or, in rare cases, low. A high anion gap indicates that there is loss of HCO3- without a subsequent increase in Cl-. Electroneutrality is maintained by the increased production of anions like ketones, lactate, PO4-, and SO4-; these anions are not part of the anion-gap calculation and therefore a high anion gap results. In patients with a normal anion gap the drop in HCO3- is compensated for by an increase in Cl- and hence is also known as hyperchloremic acidosis.

Complete Differential Diagnosis of the Causes of Anion gap

Low anion gap

A low anion gap is relatively rare but may occur from the presence of abnormal positively charged proteins, as in multiple myeloma, or in the setting of a low serum albumin level. The mnemonic for low anion gap is BAM

Normal anion gap (hyperchloremic acidosis)

Usually the HCO3- lost is replaced by a chloride anion, and thus there is a normal anion gap. In normal anion gap acidosis, the increased anion is chloride, which is measured, so the anion gap does not increase. Thus, normal anion gap acidosis is also known as hyperchloremic acidosis. Urine anion gap is useful in evaluating a patient with a normal anion gap.

The mnemonic for the most common causes of a normal-anion gap metabolic acidosis is "DURHAM."

  • M- Miscellaneous (chloridorrhea, amphotericin B, toluene - toluene causes high anion gap metabolic acidosis followed by normal anion gap metabolic acidosis.

High anion gap

The bicarbonate lost is replaced by an unmeasured anion and thus you will see a high anion gap. The mnemonic "MUDPILES" is used to remember the causes of a high anion gap.

M - methanol/Metformin
U - Uremia
D - Diabetic ketoacidosis
P - Paraldehyde/Propylene glycol
I - Infection/Ischemia/Isoniazid
L - Lactate
E - Ethylene glycol/Ethanol
S - Salicylates/Starvation

Some people, especially those not in the emergency room, find the mnemonic KIL-U easier to remember and also more useful clinically:

K - Ketones
I - Ingestion
L - lactic acid
U - uremia

All of the components of "mudpiles" are also covered with the "KIL-U" device, with the bonus that these are things that can kill you.

Ketones: more straightforward than remembering diabetic ketosis and starvation ketosis, etc.

Ingestion: methanol, metformin, paraldehyde, propylene glycol, isoniazid, ethylene glycol, ethanol, and salicilates are covered by ingestion. These can be thought of as a single group: "ingestions" during the initial consideration, especially when not triaging a patient in the emergency room.

Lactate: including that caused by infection and shock

Coexistent elevated anion gap and normal anion gap metabolic acidosis

  • An elevated anion gap can coexist with a normal anion gap metabolic acidosis.
  • In a single acid-base disorder of elevated anion gap metabolic acidosis, serum bicarbonate (HCO3) will decrease by the same amount that the anion gap increases.
  • However, a situation in which the anion gap increases less and serum bicarbonate decreases significantly indicates that there is another metabolic acidosis present, which is decreasing the the serum bicarbonate, but not affecting the anion gap i.e. normal anion gap metabolic acidosis is also present.
  • Thus, it is advised to compare the changes in the anion gap with the changes in the serum bicarbonate.
  • This is often referred as the delta-delta equation, or the corrected bicarbonate equation.
  • Delta-Delta equation: Change in anion gap = Change in bicarbonate


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