the unknown anions, XA

The unknown anions are a diverse group of pathophysiologically significant substances.
They represent diverse substances, some being physiologically occurring metabolites like lactate (if not measured separately), citrate and acetate (related to the tricarboxylic acid cycle) or non-organic anions like sulfate, others of pathologic origin like ketoacids, toxic metabolites of poisons like glycole, others metabolic waste products normally taken away by the liver or kidneys.
Their value is calculated as the difference between the SID based on measuring the known strong ions ("apparent SID", SIDapp) and the SID based on measuring the known weak ions ("effective SID", SIDeff).
This is commoly called the "strong ion gap" (SIG, also known as XA or more correctly, but uncommonly, as "net unmeasured ions", NUI), and is very similar to the more familiar anion gap.

Several studies have tried to elucidate the nature of these ions - Forni et alii, for instance find:
"In five patients with lactic acidosis, a significant increase in isocitrate (0.71 ± 0.35 mEq l-1), α-ketoglutarate (0.55 ± 0.35 mEq l-1), malate (0.59 ± 0.27 mEq l-1), and D-lactate (0.40 ± 0.51 mEq l-1) was observed." (1)

There is, sadly enough, no common standard of how to calculate this SIG. Most authors agree that this is in principle to be done as mentioned: SIG = SIDapp - SIDeff, and there is but little variation in the formulae used to calculate SIDeff. SIDapp, though, is being calculated in many different ways. All include the values of Na+, K+ and Cl- and many that of lactate, but some do not include the bivalent cations, Ca2+ and Mg2+ at all, others only take their "ionised" values into account, some seem to use their molar values, others use their full molar concentrations doubling them to convert to mEq/l, Peter Lloyd even decided that their ionic strength was 3 Eq/mol.

Find a detailed discussion of this and the pertinent references on this page:
strong ion protein binding and its effect on SID

This leads, of course, to different reference ranges! Most authors prefer an approach like that of Kellum or Moviat (find more information via the link just given!) only using the "ionised" values for Mg and Ca, which leads to normal SIG values close to 0.
The formulae for calculating SIDeff, though, were derived by Figge et alii using the full concentration values for these ions! (2) For this reason we prefer this approach! (the formulae used on our website)
Our SIG normal range thus becomes 2 to 8 mEq/l.

(1 ) Lui G Forni, William McKinnon, Gwyn A Lord, David F Treacher, Jean-Marie R Peron and Philip J Hilton
Circulating anions usually associated with the Krebs cycle in patients with metabolic acidosis
Critical Care 2005, 9:R591-R595 (DOI 10.1186/cc3806)
This article is available online at: Critical Care

(2 ) Figge J, Rossing TH, Fencl V
The role of serum proteins in acid-base equilibria
J Lab Clin Med. 1991 Jun;117(6):453-67

consult the glossary for other aspects of acid-base equilibria and the rules and mathematics behind our website:     Glossary