Tales of the Anion Gap, Part I

For a number of years, I have frequently asked physicians, nurses, and students the following questions dealing with the ionic composition of human serum:

1. What is the difference between the concentrations of anions and cations?

2. What is the normal anion gap in healthy human beings?

I have almost never received correct answers for either of these questions. The most common answer received for both questions is 12.

The correct answers are:

1. Zero

2. 6 mEq/L (or mmoles/L) with a standard deviation of about 1.5

As we will see, the correct answers are critically important in the understanding of fluid, electrolyte, and acid-base disturbances in clinical medicine.

Human serum (or plasma) contains approximately 154mEq/L of both cations and anions. To preserve electrical neutrality, the concentrations are necessarily equal.

Most commonly measured electrolytes are similarly expressed in traditional and scientific units. Important commonly reported electrolytes that may require conversion to scientific units include (I have listed normal values below):

1. Calcium 10mg/dl=5mEq/L

2. Magnesium 2mg/dl=1.67mEq/L

3. Phosphorus 3mg/dl=1.95 mEq/L

The normal concentrations of electrically charged particles in human serum may differ a bit amongst clinical laboratories and it is important for the clinician to become familiar with the pattern of his or her usual laboratory.

These normal concentrations include, approximately:

Cations (in mEq/L) Anions (in mEq/L)

Sodium 140 Chloride 108

Potassium 4 Total Co2 26

Calcium 5 Phosphorus 2

Magnesium 2 Other inorganic acids 1

Misc <3 Organic acids 5

Plasma Proteins 12

TOTAL 154 154

As will be seen from the table, plasma proteins play an important role in the electrical neutrality of human serum and therefore the anion gap. Serum globulins normally have minimal electrical charge and can be ignored in this discussion. Albumin, however, is a large protein with both positive and negative charges, related to the ionic activity of amino acid side chains, but in normal circumstances has a net negative charge. Because albumin is in high concentration in normal serum, it therefore accounts for a significant amount of unmeasured serum anions

.

Of the above noted electrically charged particles, only sodium, potassium, chloride, and total CO₂ are routinely measured. Since the "measured" cations almost always exceeds the 'measured' anions, there exists an "anion gap," which is usually calculated as:

Anion Gap equals: Sodium minus (Chloride plus Total CO₂)

In the United States, most practitioners calculate the anion gap without adding the potassium level into the equation. I prefer to calculate the anion gap without reference to the serum potassium, as significant changes in the serum potassium potentially affecting the anion gap calculation are unusual and would likely be indicative of a more severe disturbance in fluid, electrolyte, and acid-base homeostasis, rendering the effect on the anion gap less clinically important.

Although the anion gap is easy to calculate (as noted above), it is more clinically useful to think of the anion gap as the difference between anions not usually measured (about 20) and cations not usually measured (about 10, not including potassium); that is:

Anion Gap equals (unmeasured anions minus unmeasured cations)

Since the unmeasured cations are fairly constant in both health and disease, it is the unmeasured anions that are most important in clinical medicine. Indeed, many clinicians simply consider perturbations in the anion gap simply a question of the nature and amount of the unmeasured anions.

In past years, the "normal" anion gap has been calculated in the 11-15 range. With the use of modern ion-selective electrodes to measure sodium and chloride ions in serum, however, the normal anion gap has now been determined to be approximately 6 with a standard deviation of about 1.5. The decline in the calculated anion gap is mostly due to the 'rise' in the measured serum chloride from use of the ion-selective electrode. It is exceedingly important to understand the accuracy of the current measuement of the "normal" anion gap, since it implies that 95% of healthy individuals will have an anion gap between 3 and 9, whereas an anion gap of 12, felt normal by most clinicians would actually be four standard deviations above the mean and therefore would occur in less than 0.01% of the healthy population.

Another modern clarification in the interpretation of the anion gap, as inferred above, has involved the recognition of serum albumin to the calculation. It is now thought that each gm/dl decline of serum albumin concentration reduces the anion gap by about 2.5. Therefore, an otherwise normal individual with a serum albumin of 2.0 might have an anion gap of only 1, whereas an ICU patient with a significant metabolic acidosis and a serum albumin of 2.0, would have a 'normal' anion gap of 6, not an elevated level of 11, which would be associated with a normal albumin level, perhaps falsely reassuring the physician.

The anion gap is extremely useful in the detection and analysis of metabolic acidosis and also intoxicants and some hematologic conditions. These uses will be reviewed in the next entry.