Anion gap values, applications and diseases

Basil Manning

The anion gap or anion gap is known as the differentiation that exists between a positive charge (cation) and a negative charge (anion) measured in body fluids. The term anion gap is used in most cases for measurements or analysis of blood serum (blood plasma without fibrinogens). It is also possible to make measurements of these ions in the urine.

The differentiation between anions and cations occurs thanks to the concentrations of sodium, chlorine and bicarbonate (in the form of COtwo total or HCO3) that exist in body fluids (mainly blood plasma).

Graphical representation of the anion gap and its changes in high anion gap metabolic acidosis and normal anion gap metabolic acidosis. Taken and edited from Dr. Agnibho Mondal [CC BY-SA 4.0 (], from Wikimedia Commons.

It is used for clinical diagnoses, mainly for the diagnosis of altered mental states, metabolic acidosis, kidney failure, among other pathologies..

Article index

  • 1 Basic principle
  • 2 Values
    • 2.1 Low
    • 2.2 Normal 
    • 2.3 High
    • 2.4 Average
  • 3 Applications
    • 3.1 Low anion gap
    • 3.2 High anion gap
  • 4 Diseases
    • 4.1 Caused by a low anion gap
    • 4.2 Caused by a high anion gap
  • 5 References

Basic principle

The anion gap has as a basic principle that the plasma (mainly used) is electrically neutral. The desired result is to measure the acidity levels in the body fluid used (either plasma or urine)..

The principle of electrical neutrality of the fluid states that the resulting difference between the cations and the measured anions (measured cations - measured anions) is equal to the resulting difference between the cations and the unmeasured anions (unmeasured cations - unmeasured anions), and this in turn is equal to the junction gap or anion gap.

The most commonly used cation for measurements is sodium (Na+), while the anions used to be measured are chloride (Cl-) and bicarbonate (HCO3-).

Regarding the unmeasured anions, they are serum proteins (serum), phosphate (PO43-), sulfate (SO4two-) and organic anions.

And the unmeasured cations could be magnesium (Mg +) or calcium (Ca+). Being the formula to calculate the anion gap or anion gap: Anion gap = Na+-(Cl-+HCO3-).


The normal values ​​of the anion gap have historically been changing. This is due to the methods used to detect the ions. Previously, colorimeters or photometry were used to perform the measurements and this gave as normal values ​​concentrations of 8 to 16 millimoles / liter (mmol / L) and 10 to 20 mmol / L.

At present, specific ion electrodes are used. These are sensors that translate the activity of a particular ion dissolved in a solution into an electrical potential..

Said electric potential is measured by a pH meter to determine acidity, so the values ​​according to the current classification are:


An anion gap calculated as low is below 3 mmol / L.


Normal values ​​are those that are above 3 mmol / L, but below 11 mmol / L.


A high anion gap occurs when the calculated value is greater than 11 mmol / L.


Some authors agree that an estimated average value is 6 mmol / L.

The results obtained, however, may vary depending on the equipment used. Because of this, the medical community does not always agree with the use of a standard value for the interpretation of these calculations..

To solve this problem, each laboratory has, or should have, its own reference intervals..


The application of anion gap tests is practically clinical. It consists in the evaluation of acid-base alterations, particularly in the detection of metabolic disorders that lead to an increase in the acidity of the blood plasma..

These tests seek to determine values ​​from positively or negatively charged chemicals, and depending on the calculation of the anion gap, this will serve to establish corresponding medical diagnoses.

Low anion gap

An increase in the concentration of unmeasured cations, or a decrease in unmeasured anions, is considered a low anion gap..

There are several pathologies associated with a low anion gap value, but the physiological causes that lead to this value are very complex.

For example, people with IgG myeloma (a type of cancer caused by malignant plasma cells) produce large amounts of paraproteins..

The increase in the production of these molecules leads to low values ​​of the anion gap for these patients..

High anion gap

Hypothetically, a high anion gap could occur due to a reduction in unmeasured cations, or an increase in unmeasured anions..

However, clinical experience indicates that generally the increase in the anion gap is due to an increase in unmeasured anions. A clinical example of this is metabolic acidosis..


Caused by a low anion gap

The disease most commonly associated with a low anion gap is hypoalbuminemia. This disease is characterized by a low concentration of a blood protein called albumin..

Another disease related to a low anion gap is blood cancer Myeloma IgG. This type of cancer is caused by malignant plasma cells.

Histopathological image of blood cancer Multiple myeloma. Taken and edited from Machine-readable author not provided. KGH took over (based on copyright claims). [GFDL or CC-BY-SA-3.0 (], via Wikimedia Commons

Other pathologies associated with low anion gap values ​​are: hypercalcemia, hypermagnesemia (high levels of plasma calcium and magnesium, respectively), and lithium intoxication..

The latter can occur in psychiatric patients treated with drugs to stabilize the mood..

Caused by a high anion gap

High anion gaps are mainly indicative of a possible metabolic acidosis. Metabolic acidosis occurs when the body produces excess acid or when the excretory system (kidneys) does not remove acids efficiently..

Part of the pathologies associated with metabolic acidosis are: renal failure, lactic acidosis, pyroglutamic acidosis and intoxications by toluene, methanol and ethylene glycol.

Methanol, toluene, and ethylene glycol poisonings can occur from ingesting or inhaling chemicals with these components.

Such chemicals include paint thinners, hydraulic brake fluid, and antifreeze. Metabolic acidosis predisposes to cardiac dysfunction and bone demineralization, among others.

Elevated levels of albumin in plasma cause a condition called hyperalbuminemia. Hyperalbuminemia can be caused by a variety of causes, including AIDS, chronic inflammatory conditions, bone marrow disorders, and even dehydration..

Other less common diseases associated with high anion gaps include IgA myeloma blood cancer and metabolic alkalosis..


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