The anion gap is a calculation that measures the balance of select negative and positive charges (anion and cations respectively) in plasma. Anion gap is critical for the assessment of acid -base disorders which is an umbrella diagnosis that has many causes including renal failure, toxicities, sepsis and diabetic ketoacidosis.
Though the name suggests there is a “gap” in the number cations and anions, this is not the case.
Ion Balance
Plasma has a balanced amount of cations and anions; it is electrically neutral. The overall charge is near zero.
The most abundant cations are sodium (Na+) and potassium (K+). The most abundant anions are chloride (Cl-) and bicarbonate (HCO3-). These are commonly referred to as electrolytes.
Notice that these concentrations in the image above are listed in descending order. The highest concentration of ions in the body is that of sodium, followed by chloride, bicarbonate and finally potassium.
The amount of sodium exceeds that of chloride and bicarbonate combined. These ions are considered the most critical ions for the maintenance of homeostasis. They are the select electrolytes used in the calculation of anion gap.
Anion Gap & Neutrality
Let’s clear up the confusing terminology. If plasma is electrically neutral how can a gap exist between the number of cations and anions?
The gap is calculated. It exists because we are only using the predominant electrolytes to calculate this value. In reality there is no gap. In addition to the ions used in the equation there are “other” anions and cations that ensure plasma remains electrically neutral.
The plasma anions not included in the equation have relatively insignificant quantities compared to chloride and bicarbonate. Phosphates, sulfates and proteins make small contributions to the negative charge of plasma. Albumin is the most abundant negatively charged protein in plasma.
Likewise, there are cations are that are not included in the equation. Magnesium and calcium are other cations in plasma that contribute to the total positive charge but are not included in the anion gap equation because of their relatively insignificant concentrations.
If we included ALL the cations and ALL the anions in the anion gap equation there would be no gap. Instead we consider only the most significant contributors to plasma electrolyte composition.
In reality, the true anion gap equation is:
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Anion Gap Equation
Anion gap is calculated as the difference between the concentrations of predominant cations and anions. You may see this equation with potassium included:
(Na+ + K+) – (Cl– + HCO3–)
K+ is often excluded because of its very low concentration relative to the other ions. In fact, the concentration of sodium exceeds all “other cations” to such a degree that “other cations” are rarely considered to contribute to the anion gap except in cases of toxicity where external positively charged particles are introduced into the body. An example being lithium (Li+) toxicity.
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Lexicomp and MDcalc provide calculators for anion gap.
Interpretation of Results
A normal anion gap is any value between 4-12mEq/ml. Because the amount of sodium exceeds the combined amount of bicarbonate and chloride, the value is positive.
If we think of this equation mathematically, it would suggests that the difference calculated tells us how much more cations there are than anions. Mathematically, it does. However we must interpret the calculated value together with the rule of plasma neutrality.
There can be no such thing as more positive charges. There must be something present in plasma, not accounted for by the equation, that is going to equal that excess positive charge. This is the “other anions” which makes up the anion gap. The most abundant “other anion” is albumin.
The anion gap represents the “other” anions, not accounted for by the equation, that maintains electrical neutrality of plasma
The calculated anion gap is not an indication of imbalance of charges but rather it gives a numerical value to the “other” anions that are maintaining the balance of opposing charges in plasma. Understanding this is crucial to understanding anion gap calculations.
Clinical Scenarios
Interpretation of anion gap cannot be considered in isolation. Pathologies can occur when the anion gap it too high, too low but also when it is within the normal range.
Because the anion gap represents “other anions” when they are low the anion gap will decrease. Since albumin is the most abundant “other anion” hypoalbuminemia is the most common cause of a low anion gap.
The effect of the predominant electrolytes on the anion gap is because of their ability to alter pH.
The main pH buffering system in the body centers around bicarbonate and therefore its concentration is most commonly affected by acid-base disorders. Chloride is the main contingency anion to counteract bicarbonate imbalances and maintain neutrality.
Cl– and HCO3– will always compensate for each other.
When the anion gap is normal there are 3 possible scenarios.
- Cations and anions are at normal concentrations: no pathology
- Bicarbonate is low and chloride is compensating with an increase in its concentration
- Bicarbonate is high and chloride is compensating with a decrease in its concentration
Ion-pH Connection
A normal anion gap is directly related to the maintenance of normal plasma pH. Chloride is a weak base. Bicarbonate is a weak base. As their concentrations decrease pH will decrease (more acidic).
Sodium and potassium are neither acidic nor basic. However they both regulate the transport of acidic hydrogen ions (H+) across the cell membrane.
Sodium achieves this via the Na+/H+ transporter located on cell membranes. As sodium moves in, H+ moves out (increased acidity).
Potassium achieves this via the K+/H+ transporter. As potassium moves in, hydrogen moves out (increased acidity).
This is why the anion gap is always so closely tied to acid-base disorders. Unfortunately, acid-base disorders dominate the discussion. The true mechanics of the anion gap, which is the foundation of acid-base disorders are seldom explained.
This unit explains the core of anion gap calculations. Can it get more complicated? Absolutely. But, if you can understand calculated anion gap as a combined mathematical and electrical neutrality concept, you can then apply it to more complicated scenarios.
My hope is that this unit helps with true understanding rather than simple memorization of an equation. If you’ve found this unit helpful, I would love to hear from you. Leave your comment or question below.
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The information on this website is intended to be used solely for educational and informational purposes. While the content may be about specific medical and health care issues, it is not a substitute for or replacement of personalized medical advice and is not intended to be used as the sole basis for making individualized medical or health-related decisions.
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