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The anion gap ^{[1] [2]} is the difference in the measured cations and the measured anions in serum, plasma, or urine. The magnitude of this difference (i.e. "gap") in the serum is often calculated in medicine when attempting to identify the cause of metabolic acidosis. If the gap is greater than normal, then high anion gap metabolic acidosis is diagnosed.

The term "anion gap" usually implies "serum anion gap", but the urine anion gap is also a clinically useful measure. ^{[3][4] [5] [6]}

  Calculation

The concentrations are expressed in units of milliequivalents/liter (mEq/L) or in millimoles/litre (mmol/L).

  With potassium

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

= ([Na⁺] + [K⁺]) − ([Cl⁻] + [HCO₃⁻])

  Without potassium (Daily practice)

However, omission of potassium has become widely accepted, as potassium concentrations, being very low, usually have little effect on the calculated gap. This leaves the following equation:

= [Na⁺] − ([Cl^-] + [HCO₃⁻])

  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).

Commonly measured cations include sodium (Na⁺), Potassium (K⁺), Calcium (Ca²⁺) and Magnesium (Mg²⁺). Cations that are generally considered 'unmeasured' include a few normally occurring serum proteins, and some pathological proteins (e.g., paraproteins found in multiple myeloma). Likewise, commonly 'measured' anions include chloride (Cl⁻), bicarbonate (HCO₃⁻) and phosphate (H₂PO₄⁻), while commonly 'unmeasured' anions include sulphates and a number of serum proteins.

By definition, only Na⁺, Cl⁻ and HCO₃⁻ (+/- K) are used when calculating the anion gap.

In normal health there are more measurable cations compared to measurable anions in the serum; therefore, the anion gap is usually positive. Because we know that plasma is electro-neutral we can conclude that the anion gap calculation represents the concentration of unmeasured anions. 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 clinically useful, as it helps in the differential diagnosis of a number of disease states.

  Normal value ranges

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 often defined as being within the prediction interval of 3–11 mEq/L,^[7] with an average estimated at 6 mEq/L.^[8]

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^[9] and 8–16 mEq/L.^[10][11]

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 range. 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. For example, 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 to an excess of these substances.

  High anion gap

The anion gap is affected by changes in unmeasured ions. A high anion gap indicates acidosis. e.g. In uncontrolled diabetes, there is an increase in ketoacids (i.e. an increase in unmeasured anions) and a resulting increase in the 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 consumed by the unmeasured anion (via its action as a buffer) resulting in a high anion gap.

• Lactic acidosis
• Ketoacidosis
  • Diabetic ketoacidosis
  • Alcohol abuse

• Toxins:
  • Ethylene glycol
  • Lactic acid
  • Uremia
  • Methanol
  • Propylene Glycol
  • Phenformin
  • Aspirin
  • Cyanide, coupled with elevated venous oxygenation
  • Iron
  • Isoniazid

• Renal failure, causes high anion gap acidosis by decreased acid excretion and decreased HCO₃⁻ reabsorption. Accumulation of sulfates, phosphates, urate, and hippurate accounts for the high anion gap.

Note: a useful mnemonic to remember this is MUDPILES (methanol, uremia, diabetic ketoacidosis, propylene glycol, isoniazid, lactic acidosis, ethylene glycol, salicylates). MUDPILERS is a variation with the addition of "R" for rhabdomyolysis. Another variation is MUDPALES which is the same as previous only with the "A" representing alcoholic ketoacidosis, a common emergency department presenting condition. A newer mnemonic CUTE DIMPLES includes "C" for Cyanide, "T" for Toluene, and a second "E" for ethanol (alcoholic ketoacidosis) (cyanide, uremia, toluene, ethanol, diabetic ketoacidosis, isoniazid, methanol, propylene glycol, lactic acidosis, ethylene glycol, salicylates). Historically, the "P" in MUDPILES was for paraldehyde. As paraldehyde is no longer used medically, the "P" in the MUDPILES mnemonic currently refers to propylene glycol, a substance common in race car radiator fluid and in pharmaceutical injections such as diazepam or lorazepam as a preservative. Accumulation of propylene glycol is converted into lactate and pyruvate, which causes lactic acidosis.

  Normal anion gap

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(RTA) also known as type 2 RTA)
• Renal dysfunction (i.e. distal renal tubular acidosis also known as type 1 RTA)
• Ingestions
  • Ammonium chloride and Acetazolamide, ifosfamide.
  • 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.
• Mineralocorticoid deficiency (Addison's disease)

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

  Low anion gap

A low anion gap is frequently caused by hypoalbuminemia. Albumin is a negatively charged protein and its loss from the serum results in the retention of other negatively charged ions such as chloride and bicarbonate. As bicarbonate and chloride anions are used to calculate the anion gap, there is a subsequent decrease in the gap.

In hypoalbuminaemia the anion gap is reduced from between 2.5 to 3 mmol/L per 1 g/dL decrease in serum albumin.^[12] Common conditions that reduce serum albumin in the clinical setting are hemorrhage, nephrotic syndrome, intestinal obstruction and liver cirrhosis.

The anion gap is sometimes reduced in multiple myeloma, where there is an increase in plasma IgG (paraproteinaemia).^[13]

Corrections can be made for hypoalbuminemia to give an accurate anion gap.^[14]

  References

  External links

• Clinical Physiology of Acid-Base and Electrolyte Disorders
• Intensive Care Medicine
• The ICU Book
• Calculator at mcw.edu
• Metabolic acidosis by Merck