Anion Gap
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.
"Unmeasured" cations (UC+) and anions (UA-, see below) account for the differences.
The anion gap refers to the concentration of unmeasured anions in blood. It represents anions
other than chloride and bicarbonate that are required to electrically balance cations, such as
sodium. Unmeasured anions include protein, phosphate, sulfate, and organic acids. The most
commonly used formula to measure the gap is:
Sodium - (chloride + bicarbonate) = anion gap
Another way to think of anion gap is:
sodium + unmeasured cations = chloride + bicarbonate + unmeasured anions
or sodium - (chloride + bicarbonate) = unmeasured anions - unmeasured cations
The anion gap is primarily used to classify metabolic acidosis, which is caused by the retention
of acid within the body. Hydrogen ion reacts with bicarbonate to form carbon dioxide, which is
eliminated by the lungs. As acidosis develops bicarbonate levels decrease and are replaced by
the anionic component of the acid.
In inorganic acidosis, the anion is chloride and the anion gap does not change.
In organic acidosis, the anion gap increases because bicarbonate decreases, chloride remains
constant, and the unmeasured anion (lactate, ketone, phosphate) increases.
Metabolic acidosis can be divided into two categories: normal anion gap and high anion gap.
High anion gap acidosis is caused by acid retention, while normal anion gap acidosis is usually
due to loss of bicarbonate.
High Anion Gap
Ketoacidosis (diabetes, starvation, ethanol)
Lactic acidosis (circulatory or respiratory failure, liver failure, tumors, oral hypoglycemics)
Renal failure (uremic acidosis)
Poisoning (salicylates, methanol, ethylene glycol)
Normal Anion Gap
Drugs (acetazolamide, carbonic anhydrase inhibitor)
GI loss of bicarbonate (diarrhea)
Ureteroenterostomy (loss of bicarbonate from chloride-bicarbonate exchange)
Renal tubular acidosis
Excess IV replacement with NaCl
Occasionally, the anion gap may be decreased. The principle causes are hypoalbuminemia,
monoclonal gammopathy, excess crystalloid infusion, and lithium intoxication. Albumin is an
unmeasured anion, whose concentration can be reduced by decreased synthesis or dilution with
IV fluids. A decrease in unmeasured anions decreases the anion gap. Monoclonal proteins,
especially IgG, represent unmeasured cations. An increase in unmeasured cations and a
decrease in measured cations narrow the anion gap.
Reference range is 3 -15 mEq/L.
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.
Na++K+ca+Mg+Protein=Cl+HCO3+protein+HPO4/HPO4+SO4
+OA
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
decrease 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.