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Anion gap

The anion gap is used to aid in the differential diagnosis of metabolic acidosis.

Calculation

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

= ([Na⁺]+[K⁺] )  -  ([Cl^-]+[HCO₃^-] )

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

= ([Na⁺] ) - ([Cl^-]+[HCO₃^-] )

where the concentrations are expressed in units of milliequivalents/liter (mEq/L).

Uses

Anion gap is an 'artificial' and calculated measure that is representative of the unmeasured ions in plasma or serum (serum levels are used more often in clinical practice). The 'measured' cations are sodium (Na⁺), Potassium (K⁺), Calcium (Ca²⁺) and Magnesium (Mg²⁺). The 'unmeasured' cations include a few normally occurring serum proteins, and some pathological proteins (e.g., paraproteins found in multiple myeloma). Likewise, the 'measured' anions are chloride (Cl^-), bicarbonate (HCO₃^-) and phosphate (PO₃^-), with the 'unmeasured' anions being sulphates and a number of serum proteins (predominantly albumin). By convention (and for the sake of convenience) only Na⁺, Cl^- and HCO₃^- are used for calculation of the anion gap as noted above. In normal health there are more unmeasured anions (compared to unmeasured cations) in the serum, therefore the anion gap is usually positive. The anion gap varies in response to changes in the concentrations of the above mentioned serum components that contribute to the acid-base balance. Calculating the anion gap is helpful clinically, as it helps in the differential diagnosis of a number of disease states.

Normal value ranges

The average anion gap for healthy adults is 8-12 mEq/L. As typical in medicine, abnormal values are defined as 2 standard deviations over or under the average level, hence the upper limit of normal is 12 mEq/L. In the past, methods for the measurement of the anion gap consisted of colorimetry for [HCO₃^-] and [Cl^-] as well as flame photometry for [Na⁺] and [K⁺]. Thus normal reference values ranged from 8 to 16 mEq/L plasma when not including [K⁺] and from 10 to 20 mEq/L plasma when including [K⁺]. Some specific sources use 15 and 8-16 mEq/L. Modern analyzers make use of 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 between 3-11 mEq/L.

A reference range provided by the particular lab that performs the testing should be used to determine if the anion gap is outside of the normal gap. A certain proportion of normal individuals may have values outside of the 'normal' range provided by any lab.

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. Eg, if the blood sample is not processed immediately after it is collected, continued leukocyte cellular metabolism may result in an increase in the HCO₃^- concentration, and result in a corresponding mild reduction in the anion gap. In many situations, alterations in renal function (even if mild, e.g., as that caused by dehydration in a patient with diarrhea) may modify the anion gap that may be expected to arise in a particular pathological condition.

A high anion gap indicates that there is loss of HCO₃^- without a concurrent increase in Cl^-. Electroneutrality is maintained by the elevated levels of anions like lactate, beta-hydroxybutyrate and acetoacetate, PO₄^-, and SO₄^-. These anions are not part of the anion-gap calculation and therefore a high anion gap results. Thus, the presence of a high anion gap should result in a search for conditions that lead an excess of these substances.

High anion gap

In these conditions, bicarbonate concentrations decrease, in response to the need to buffer the increased presence of acids (as a result of the underlying condition). The bicarbonate is replaced by the unmeasured anion resulting in a high anion gap.

Lactic acidosis
Ketoacidosis

Toxins:

Ethanol
Ethylene glycol
Lactic acid
Methanol
Paraldehyde
Phenformin
Aspirin
Cyanide, coupled with elevated venous oxygenation
Iron
isoniazid

Note: a useful mnemonic to remember this is MUDPILES (methanol, uremia, DKA, paraldehyde, INH, lactic acidosis, ethylene glycol, salicylates)

Normal anion gap (hyperchloremic acidosis)

In patients with a normal anion gap the drop in HCO₃^- is compensated for almost completely by an increase in Cl^- and hence is also known as hyperchloremic acidosis. The HCO₃^- lost is replaced by a chloride anion, and thus there is a normal anion gap.

Gastrointestinal loss of HCO₃^- (i.e. diarrhea) (note: vomiting causes hypochloraemic alkalosis)
Renal loss of HCO₃^- (i.e. proximal renal tubular acidosis)
Renal dysfunction (i.e. renal failure, hypoaldosteronism, distal renal tubular acidosis)
Ingestions

Ammonium chloride and Acetazolamide.
Hyperalimentation fluids (i.e. total parenteral nutrition)

Some cases of ketoacidosis, particularly during rehydration with Na+ containing IV solutions.
Alcohol (such as ethanol) can cause a high anion gap acidosis in some patients, but a mixed picture in others due to concurrent metabolic alkalosis.

Note: a useful mnemonic to remember this is FUSEDCARS (fistula (pancreatic), uretogastric conduits, saline administration, endocrine (hyperparathyrdoism), diarrhea, carbonic anhydrase inhibitors (acetazolamide), ammonium chloride, renal tubular acidosis, spironolactone)

Low anion gap

Unlike a high anion gap, obtaining a low anion gap is relatively rare. One of the most common causes of a low anion gap is a low albumin level (which constitutes ~80% of the unmeasured anions). Correspondingly, an increase in the number of cations, either organic (eg, paraproteins as in multiple myeloma) or inorganic (bromide, lithium, Iodine or polymyxin B) can lead to low anion gap values. A decreased anion gap is also seen in multiple myeloma where the increased negatively-charged immunoglobulins interact with and bind cations in the blood