Anion Gap

Overview

Calculating the anion gap (AG) can give you an insight into what kind of metabolic acidosis is at play in the body. It's a tool, not a precise calculation. We divide metabolic acidoses into those that increase AG and those in which AG is fairly normal.

Calculating the anion gap (AG)

There’s nothing really missing in anion gap. It is just a way of estimating how many of the anions in blood are the usual ones we measure (Cl^- and HCO₃^-), compared with the number of cations usually measured (Na⁺ and K⁺). Because the plasma levels of K⁺ are so low compared with Na⁺, many routinely leave K⁺ out of the equation. So:

This usually yields a positive number in the range 10-18 mM, since the normal ranges for each ion are:

Plasma ions are normally in good charge balance, so the fact that AG isn’t exactly zero simply reflects the magnitude of the total unmeasured ions such as Ca²⁺, Mg²⁺, SO₄^- and HPO₄^-. On the whole, there are more unmeasured anions than cations so the AG is usually slightly positive. AG is a tool, not a precise scientific calculation. While you might see minor alterations in AG in a variety of settings, its most useful application is in the differential diagnosis of metabolic acidosis, which fall into categories where AG is normal, or is larger than usual.

Metabolic acidosis

Metabolic acidosis describes any situation where the body retains excess acid which is unrelated to hypoventilation. Most acids consist of a proton or two and an anion. It is the nature of the anion that determines whether it will contribute to the anion gap: is it something that we usually measure (eg Cl^-)? If it isn’t then it will make the anion gap seem bigger, because we’re not looking for it. Such an acid will take up space that HCO₃^- and Cl^- don’t need to compensate for, and hence the AG will be larger than usual.

Normal AG metabolic acidosis

Let’s use an inappropriate infusion of HCl as an example of metabolic acidosis, as it’s nice and simple. HCl is a volatile acid: the H⁺ can be dealt with by combining it with HCO₃^- and converting it to water and CO₂. It’s an acid we can blow out of the body (thus, volatile). The Cl^- ion takes up the anion space that the lost HCO₃^- was taking. The overall effect is no change in anion gap (see Figure 1).

Figure 1: The normal measured anions are Cl^- and HCO₃^-. When challenged with an excess of a so-called volatile acid such as HCl (one that can be “blown off), the body loses some HCO₃^-, but gains some Cl^-. The balance has no effect on anion gap. By contrast, when the body ingests or accumulates a non-volatile acid (here generically labelled HA, but lactic acid is a good example), the donated proton takes away some HCO₃^-, but the anion (A^-) stays in the body. As such, the sum of HCO₃^- and Cl^- isn’t as large as it usually is, and the anion gap calculation returns a larger number. This is increased anion gap due to the metabolic acidosis. Whether anion gap is affected depends on the acid the body is producing/accumulating.

Diarrhoea is another example of metabolic acidosis with normal AG. In this condition, the body fails to reabsorb HCO₃^- in the colon, creating an excess of H⁺ relative to HCO₃^-. To restore the serum charge balance Cl^- increases, and for this reason such a disturbance is sometimes called hyperchloraemic acidosis. This increase means that there will be little or no change to the AG.

Metabolic acidosis with increased AG

By contrast, when a non-volatile acid such as lactic acid is produced or ingested, the H⁺ is dealt with in the same way (via HCO₃^-), but the anion accumulates. Because it isn’t Cl^- or HCO₃^-, it takes up space in the anion calculation and increases the gap. So, anion gap isn’t about something missing, it’s about something hiding in the anions we usually look at, making the numbers look wrong.

Causes of metabolic acidosis with normal anion gap: Simple loss of HCO₃^- or accumulation of H⁺
Renal tubular acidosis
Diarrhoea (HCO₃^- lost)
Some drugs (acetazolamide)
Addison’s disease

Causes of metabolic acidosis with increased anion gap: Increased production of non-volatile organic acid(s).
Lactate acidosis
Urate acidosis (renal failure)
Ketones (ketoacidosis – diabetes or starvation.)
Drugs/toxins (classically salicylate but others including ethanol and methanol)

AG can fool you

Serum albumin is a major unmeasured anion. In hypoalbuminaemia (blood loss, cirrhosis, intestinal obstruction, nephrotic syndrome) there will be a low AG potentially hiding a real metabolic problem that should cause an increased AG. Cl^- and HCO₃^- increase to compensate for the lack of anionic charge from the lost albumin.