Overview of Plasma Anion Gap

Plasma anion gap is a measurement of the balance between positively charged ions called cations and negatively charged ions called anions, within the plasma. Its normal range is typically between 3 and 11 mEq/L, while anything below 3 mEq/L is considered abnormally low, and above 11 mEq/L is usually considered abnormally high.

Every single moment, trillions of cations and anions are floating around inside our blood vessels. For them to happily and stably coexist, the plasma has to be kept electrically neutral. That means that the sum of all positive charge from cations has to equal the sum of all negative charge from anions. The vast majority of cations are sodium Na+ ions, followed by potassium K+ ions, then calcium Ca2+ ions, then magnesium Mg2+ ions, and finally various positively charged proteins. The majority of anions are chloride Cl− ions, followed by bicarbonate HCO3− ions, then phosphate PO43- ions, then sulfate SO42- ions, and finally some organic acids and negatively charged plasma proteins, like albumin.

So, to prove that there’s electroneutrality, let’s say we try to measure the concentration of the cations and anions in our plasma. Unfortunately, not all of the ions are easy or convenient to measure. Specifically, among cations, usually just sodium Na+ is measured, which is typically around 137 mEq/L and among anions, chloride Cl− is measured, which is about 104 mEq/L, and bicarbonate HCO3− is measured, which is around 24 mEq/L. So just counting up these three ions, there’s a difference, or “gap” between the sodium Na+ concentration and the sum of bicarbonate HCO3− and chloride Cl− concentrations in the plasma, which is 137 minus 128 (104 plus 24) or 9 mEq/L. This is known as the anion gap, or in other words, how many more cations are there than anions. Now just a few moments ago, we said that cations equal anions, so why does this gap even exist? Well, it’s because sodium Na+ accounts for the vast majority of cations in the plasma, but by measuring only chloride Cl− and bicarbonate HCO3−, we are ignoring a bunch of anions, including the anion component of several organic acids and negatively charged plasma proteins, like albumin. In other words, this anion gap represents all these unmeasured, ignored negative charges out there, and normally, ranges between 3 and 11 mEq/L. If the anion gap is high, it’s usually because there’s an unusually high amount of these unmeasured anions.

Calculating the anion gap is a useful diagnostic tool, because it can help identify potential causes of metabolic acidosis. “Acidosis” refers to a process that lowers blood pH to less than 7.35 and “metabolic” refers to the fact that it’s caused by a decrease in the concentration of bicarbonate HCO3− ions. One way that the bicarbonate HCO3− ion concentration decreases is by binding of bicarbonate HCO3− ions and protons H+, which results in the formation of H2CO3 carbonic acid, which subsequently breaks down into carbon dioxide CO2 and water H2O. These protons come off of various organic acids. For example, in cases of heart failure, when not enough blood is pumped to the tissues, the cells won’t have much oxygen to break down glucose, so they will be forced to accumulate lactic acid molecules- each of which has a proton to donate. That’s known as lactic acidosis.

Another situation might be diabetic ketoacidosis which leads to the buildup of ketoacids, which are also molecules that carry along a proton. Another situation might be after accidental ingestion of ethylene glycol, which is a common antifreeze. This can cause oxalic acid to build up. A metabolite of methanol, a highly toxic alcohol, is formic acid. Paint or glue has a molecule called toluene, which leads to a buildup of hippuric acid. Organic acids, such as uric acid or sulfur- containing amino acids, might also build up in chronic renal failure, because the kidneys simply can’t get rid of them.

Alright, so say you have one of these organic acids, and then a sodium ion and a bicarbonate ion, so one positive and one negative ion, meaning we have electroneutrality. At a physiologic pH, these organic acids dissociate into protons H+ and corresponding organic acid anions. Protons H+ quickly grab bicarbonate HCO3− ions floating around. Since we still have one positive and one negative ion, there’s still electroneutrality, since we lost a bicarbonate ion but gained an organic acid anion. Since we lost a bicarbonate ion though, this decreases bicarbonate’s plasma concentration and shifts the pH towards the acidic range. If we remember our anion gap equation, we have sodium, the measured cation, minus chloride and bicarbonate, the measured anions. So in this example it’d be 1 - zero plus 1, which is 0. On the other side, we have 1 minus 0 plus 0, since the organic acid is unmeasured, and this equals 1, so we see that even though we’re still electrically neutral, our anion gap increases and will be high in the cases of increased organic acids!

But that’s not what happens in all cases of metabolic acidosis, for example with diarrhea, excessive bicarbonate gets lost in the stool, and in renal tubular acidosis, excessive bicarbonate is lost in the urine. In these cases, the kidneys start reabsorbing more chloride ions, which build up in the plasma and replace the bicarbonate ions. Since chloride ions are measured in the equation, the bicarbonate concentration goes down but the chloride concentration goes up, so the anion gap remains normal. That’s why a normal anion gap metabolic acidosis is sometimes called a hyperchloremic metabolic acidosis.

Much less commonly, a high anion gap may be unrelated to a metabolic acidosis, and instead might reflect a buildup of some of the unmeasured anions. Some examples are hyperphosphatemia, or increased plasma concentrations of phosphate PO42- ions, hyperalbuminemia, or increased plasma concentration of albumin, or IgA producing multiple myeloma, where IgA immunoglobulin, an anionic protein is produced. To keep the total charge in balance, when there are more unmeasured anions around, the bicarbonate HCO3−and chloride Cl- concentrations decrease. As a result, the anion gap [Na+] - ([Cl−] + [HCO3−]) goes up.

A small elevation in anion gap can also be seen in metabolic alkalosis. This is because a high, or alkaline pH, triggers albumin to release H+ protons. This results in an increase in the net negative charge on each albumin molecule. Once again, there are more unmeasured anions in the form of albumin around, and the bicarbonate HCO3−and chloride Cl- ion concentrations go down, making the anion gap increase.

In rare cases, the plasma anion gap can be lower than normal, which is typically defined by less than 3 mEq/L. This can be caused by a decrease in the concentration of unmeasured anions, for example, due to hypoalbuminemia, or decreased plasma concentration of albumin. To prevent the overall negative charge of the plasma from decreasing, the bicarbonate and chloride concentration will rise, which means the anion gap = [Na+] - ([Cl−] + [HCO3−]) will fall. Even more rarely, a low anion gap can result from an increase in unmeasured cations, such as in hyperkalemia, or increased concentration of K+ potassium, hypercalcemia or increased concentration of Ca2+, hypermagnesemia or increased concentration of Mg2+, or, for example in individuals with IgG producing multiple myeloma, producing IgG immunoglobulins. Interestingly, IgG is cationic whereas IgA is anionic. Positive charges in the plasma need to be maintained, so, essentially, sodium concentration will fall off and the anion gap = [Na+] - ([Cl−] + [HCO3−]) will get a lower value.

All right, as a quick recap, the plasma anion gap is the difference between the plasma concentration of Na+ sodium and the sum of plasma concentrations of (Cl− + HCO3−) and represents the unmeasured anions in the plasma. Its range of normal values is 3–11 mEq/L, while its elevation is almost always caused by an organic acid metabolic acidosis, such as lactic acidosis and diabetes ketoacidosis.