The anion gap, advantages and disadvantages

A calculation of the anion gap is an essential part of practically every ABG interpretation question in the CICM fellowship exam. A profound understanding of the anion gap as a diagnostic tool is not an essential part of answering those questions. Only a crude workmanlike grasp is called for.

In brief:

• The anion gap is (Na⁺ + K⁺) - (Cl^- + HCO₃^-).
• The use of potassium in the calculation is thought to be optional, and though the college has occasionally used it in their model answers, the Chair of the Second Part Exam  had announced in July of 2019 that "anion gap calculations should be made without inclusion of potassium or correction to albumin" unless otherwise specified in the question stem.
• If you have used potassium, the "normal " gap you expect is 12, even though there is thought to be a range of normal values. 
• The "normal" expected value decreases by 1mEq/L for every 4g/L decrease in serum albumin

In a little more detail:

The anion gap is a mathematical test performed on laboratory electrolyte values to determine the cause of a metabolic acidosis. It is defined as the sum of serum anion concentrations subtracted from the serum cation concentrations. Specifically, by convention the cations are sodium and potassium, and the anions are bicarbonate and chloride. These measured anions account for only about 85% of the total anionic charge of the extracellular fluid. The gap affords us an estimate of the concentration of this unmeasured 15%, the "miscellaneous" anionic electrolytes which are present in the bloodstream. The "normal" expected value is around 12, though it is adjusted for the serum albumin, which - being a negatively charged protein - contributes to the anionic charge of the extracellular fluid.

What follows is a brief summary. A more detailed discussion of the merits and demerits of the anion gap is available elsewhere. Question 23 from the first paper of 2007 had asked for this sort of discussion as an answer, but the college has subsequently lost interest in such longform essays, because short ABG interpretation questions are substantially easier to mark. It is unlikely that the candidates will ever again be asked to hold forth extensively on this topic.

Advantages of the anion gap

• Easy to calculate: (Na+ + K+) - (Cl- + HCO3-)
• Offers a simple stratification of acid-base disorders into HAGMA and NAGMA

Limitations of the anion gap

• Subject to laboratory error in the measurement of any of the constituents
• Spurious sodium results can alter the anion gap (eg. in "pseudohyponatremia")
• Spurious chloride results can alter the anion gap (eg. bromide and iodide can be mistaken for chloride in the laboratory)
• Unmeasured or uncounted cation excess can alter the anion gap (eg. lithium, calcium, magnesium)
• Strongly cationic drugs can decrease the anion gap, or even make it negative (eg. polymyxin B)
• Modified by hypoalbuminaemia, and needs to be corrected (there is a 1mmol/L decrease in the "normal" anion gap for every 4g/L of albumin deficit below 40g/L)
• Modified by hyperprotinaemia, eg. in some sort of myeloma-like illness (an excess of charged proteins changes the anion gap; it is impossible to say in which direction, as the proteins may be anionic or cationic)

Causes of a high anion gap in the absence of acidosis

The anion gap represents several anionic species which could increase the numerical gap while not producing very much acidosis. Such situations would include:

• Gamma-globulinaemia
• High serum paraprotein in myeloma
• High serum phosphate or sulfate

Causes of a negative anion gap:

• Increase in unmeasured cations
  • Lithium
  • Polymyxin B
  • Magnesium
  • Calcium
• Interference with the measurement of chloride
  • Iodide
  • Bromide
  • Any damn halide, really
• Artifact of calculation
  • Extreme hyperlipidiaemia or hyperprotinaemia (by decreasing the reported sodium level, a "pseudohyponatremia")
  • Extreme hypoalbuminaemia (when one fails to correct the "normal" expected anion gap value, taking into account the low albumin)

Question 3.1 from the second paper of 2013 featured a negative anion gap (-2).

Adjustment of the anion gap due to changes in serum albumin

• The "normal" value for the anion gap is assumed to be 12.
• This normal value exists at a serum albumin of 40g/L.
• For every 4 g/L decrease in the albumin level, the "normal" anion gap decreases by 1.
• Thus, with an albumin value of 0, one has an "expected" anion gap of 2.