The Anion Gap

The anion gap (AG) is the the serum sodium [Na+] concentration minus the sum of the serum chloride concentration and the serum bicarbonate concentration.

AG = Na+ – (Cl- + HCO3-).  The normal anion gap is 9 mEq/L + or – 3 mEq/l.

These lab values are found in the electrolyte panel which also includes a serum potassium [K+].

A metabolic acidosis is characterized by a below normal arterial pH (normal arterial pH is between 7.35 and 7.45) and a below normal serum bicarbonate (normal serum bicarbonate concentration is between 23 mEq/L to 28 mEq/L).

There are two groups of metabolic acidoses: the increased anion gap metabolic acidoses where the anion gap is greater than 12 mEq/L and the normal anion gap metabolic acidosis in which the anion gap is within the normal range (9 mEq/L + or – 3 mEq/L).

The causes of increased anion gap metabolic acidosis include lactic acidosis, ketoacidosis (diabetic ketoacidosis and alcoholic ketoacidosis), toxins* (eg, ethylene glycol, methyl alcohol, salicylate, paraldehyde, toulene, propylene glycol, pyroglutamic acidosis [acetaminophen use]).

*Suspect a toxin as the cause when the measured plasma osmolarity exceeds the calculated plasma osmolarity (Posm = 2Na+ + Glu/18 + BUN/2.8) by more than 10 to 15 mOsm/L.

A metabolic acidosis in which the AG is normal can be due to gastroinstinal  bicarbonate loss (for example, diarrhea) or renal tubular acidosis (both intrinsic and from non-renal causes).

The anion gap can be below normal (that is less than 9 mEq/L + or – 3 mEq/L) and is not uncommon.

The most common cause of a low serum AG is hypoalbuminemia. Albumin is a major contributor to the anion gap. For every decrease of 1 g/dl of serum albumin below the normal level of 4.5 g/dl, the anion gap will decrease by 2.3 to 2.5 mEq/L. So a decreased serum albumin could hide an anion gap metabolic acidosis. Therefore, when there is a low serum albumin, you need to correct for that when you calculate the anion gap.

Other causes of a decreased anion gap include elevations of positive ions such as magnesium and calcium.

But the most common cause of a decreased anion gap, after hypoalbuminemia, is an elevation in plasma proteins such as plasma cell disorders. So, if lab error and hypoalbuminemia are ruled out, it is important to search for elevated immunoglobulins.

Other causes of a decreased anion gap include lithium ingestion, bromism, or iodide intoxication.

Most acid-base disturbances involve only one of the four possible causes: respiratory acidosis, respiratory alkalosis, metabolic acidosis, or metabolic alkalosis. And these are relatively straightforward to diagnose.

It is more difficult to diagnose an acid-base disorder when a patient, often an ICU patient, has more than one of the four causes of acid-base disorders.

An example would be a patient with advanced renal failure and several days of vomitting. He has a metabolic acidosis and a metabolic alkalosis. In this case the bicarbonate and the pH might be normal or near normal.

But the patient’s anion gap would be abnormal and this would be the clue to consider a complex acid-base disorder.

So it is a good idea to calculate the anion gap whenever you have an electrolyte panel.

(1) Textbook of Critical Care 6th edition, 2011. JL Vincent et al, pp. 825-827.

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