Anion Gap

The body strives to maintain electroneutrality at all times by keeping the concentrations of anions equivalent to cations in serum (or plasma). In a healthy individual, sodium and potassium (also called "measured" cations) account for about 95% of total cations, whereas chloride and bicarbonate (also called "measured" anions) account for about 85% of the total anions. gamblegram"Unmeasured" cations (UC+) and anions (UA-, see below) account for the differences. The concept of electroneutrality is illustrated by the following formulas and the image to the right:

Sum of cations = Sum of anions


(Na++ K+ + UC+) = (Cl- + HCO3- + UA-)

The anion gap reflects the difference in the serum (plasma) concentrations of the "measured" cations and "measured" anions and is calculated using the following formula:

Anion gap = (Na+ + K+) - (Cl- + HCO3-)

However, we need to incorporate "unmeasured" cations and "unmeasured" anions in the above equation, as follows:

Anion gap = (Na+ + K+ + UC+) = (Cl-+ HCO3- + UA-)

or (rearranging the above equation)

Anion gap = UA- - UC+ = (Na+ + K+) - (Cl- + HCO3-)


Anion gap = UA- - UC+

Thus, the anion gap is calculated using "measured" cations (sodium, potassium) and anions (choride and bicarbonate) in mEq/L, but actually is an indicator of the difference between "unmeasured" anions and cations. Since "unmeasured" anions are more important in terms of disease than "unmeasured" cations, the anion gap is really a marker of the amount of "unmeasured" anions in circulation.

  • "Unmeasured" cations (UC+): This includes proteins that are positively charged at physiologic pH (gamma globulins) and the free or ionized forms of calcium (Ca2+) and magnesium (Mg2+). The latter are not seen in high enough concentrations to make much impact on the anion gap.
  • "Unmeasured" anions (UA-): This includes protiens that are normally negatively charged at physiologic pH (particularly albumin) and organic acids that are produced during physiologic and pathologic processes, including lactate, phosphates, sulfates, and ketones. Some exogenous toxins and drugs, including methanol, salicylate and ethylene glycol (and its metabolites), are also "unmeasured" anions. Because "unmeasured" anions are found in higher concentrations than "unmeasured" cations, they have a far greater impact on the anion gap.

Note that the term "unmeasured" is really a misnomer, as many of these anions and cations are actually or can be measured, however they are not included in the anion gap equation (and are "unmeasured" for this purpose).

Changes in anion gap are used primarily to distinguish between causes of a metabolic acidosis, i.e. that due to titration of bicarbonate or loss of bicarbonate. With a metabolic acidosis due to titration, there is accumulation of an organic acid, whose proton (H+) is being bufferd by bicarbonate (HCO3-), leading to a decrease in bicarbonate and an increase in the anion of the acid. The anion of the acid is an "unmeasured" anion (UA-) and will thus increase the anion gap. This concept is illustrated in the image below. In contrast, with an acidosis due to bicarbonate loss, there is no accumulation of an organic acid and electroneutrality is maintained by chloride (which increases, offsetting the decrease in bicarbonate), thus the anion gap is usually normal in a bicarbonate loss acidosis.

titration acidosis
In a titration high anion gap metabolic acidosis, a strong organic acid accumulates and dissociates into a proton and the anion portion of the acid. The anionic part of the acid is an "unmeasured" anion so it increases the anion gap, whereas the proton is titrated by bicarbonate (with the resultant catbon dioxide being blown off by the lungs), causing a decreased bicarbonate.

The table below summarizes the changes seen in the anion gap in these two forms of metabolic acidosis.

The anion gap in metabolic acidosis
Mechanism of low bicarbonate Expected Anion Gap Chloride
Titration by excess organic acid Increased Normal
Loss of bicarbonate Normal High

General causes of an increased and decreased anion gap are given below.

Increased anion gap

  • Titration acidosis: This is the most common cause of an increased anion gap and is due to accumulation of an organic acid, such as lactate, ketones and uremic acids (sulfates and phosphates). Some toxins and drugs are also organic acids (methanol, salicylate, ethylene glycol) and toxicity with these compounds is characterized by a high anion gap (or titration) metabolic acidosis, a primary metabolic acid-base disturbance.
  • Alkalemia: Loss of protons from plasma proteins (particularly albumin) increases their negative charge. Alkalemia also stimulates lactic acid production, which will increase the anion gap. The increase in AG is usually mild.
  • Dehydration: This may incresae the anion gap through increasing albumin concentrations (which is an "unmeasured" anion).
  • Sodium-containing drugs: Sodium salts, penicilliin will increase the anion gap because their sodium content is measured as part of the sodium concentraton on a chemistry panel.
  • Decreased "unmeasured" cations: These have minimal affect on the anion gap because of their low concentrations.

Decreased anion gap

  • Acidemia: Protons released from acids are buffered by plasma proteins, which decreases their normal negative charge.
  • Decreased albumin: A very common cause of a lower than expected or decreased anion gap, which can be due to various reasons, including hemodilution. A decrease in albumin of 1 g/dL may decrease the anion gap by 2.4-3 mEq/L.
  • Assay artifacts: A falsely high chloride or bicarbonate measurement will decrease the anion gap. The anticonvulsant drugs, bromide or zonisamide, are measured as "chloride" by ion-selective electrodes and will falsely increase chloride concentrations and thus decrease the anion gap. Similarly, very high concentrations of pyruvate and lactate dehydrogenase (both of which can interfere with the enzymatic reaction used for bicarbonate measurement) secondary to severe muscle injury may falsely increase bicarbonate concentrations and decrease the anion gap, but this is very rare.
  • Administration of bicarbonate-rich fluids: Fluids containing high concentrations of bicarbonate will decrease the anion gap, by increasing bicarbonate values on the chemistry panel. This rarely happens with chloride-rich fluids since the chloride is administered with sodium (NaCl).
  • Increased "unmeasured" cations: Since ionized magnesium and calcium concentrations are low (compared to other charged compounds) and marked increases are not compatible with life, increases in these two "unmeasured" cations usually does not affect the anion gap. Marked increases in gamma globulins (e.g. with B cell or plasma cell neoplasia, such as multiple myeloma) could potentially decrease the anion gap.

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