Introduction

Using the results of the comprehensive metabolic panel (CMP), the anion gap is the difference between measured cations (positively charged ions like Na+ and K+) and measured anions (negatively charged ions like Cl- and HCO3-). There are three types: serum, plasma, and urine anion gaps. The most common application of the anion gap is classifying cases of metabolic acidosis, states of lower than normal blood pH. Specifically, classifying into either those that do and those that do not have unmeasured anions in the plasma. The human body is electrically neutral; therefore, in reality, does not have a true anion gap. The calculation then finds utility in exposing variations in that balance. However, changes in albumin and bicarbonate concentrations warrant specific attention.[1][2]

Fundamentals

In essence, the anion gap is a mathematical calculation that provides practitioners with the foresight to plan for managing current problems associated with acid-base balance, fluids, and electrolytes.

For reference, a normal anion gap depends on the concentration of phosphate and albumin in the serum and ranges from 4 to 12 mmol/L. An increased or normal anion gap metabolic acidosis is typically due to excess acid and/or decreased base. A reduction in the anion gap is most commonly due to decreased albumin concentration as albumin is the primary unmeasured anion.

To best understand the concept of anion gap, let us revisit the law of electrochemical neutrality. This law states that for any given solution, the net charge after accounting for all cations (positive ions) and anions (negative ions) should arrive at zero. However, at face value, the subtraction between the measured cations and measured anions of the blood does not yield a zero; the 4 to 12 mmol/L range for “normal anion gap.” However, this does not reflect an integral problem in the mathematical derivations, but rather its paramount utility. The resulting positive number in a healthy, asymptomatic patient is a result of the formula accounting only for measured cations and anions, leaving uncalculated cations and uncalculated anions to reach the zero value.

As an example, an anion gap of 8 means after accounting for measured ions (Na+, Cl-, HCO3-, and depending on your institution, K+) we have a net positive charge of 8. However, this gets neutralized by unmeasured anions such as albumin, phosphorus, and miscellaneous proteins. Thus, one can see if the anion gap increased or decreased out of the 4 to 12 mmol/L range, one can expect tangible derangements in measured cations and anions vs. theoretical derangements in their uncalculated counterparts.

Calculation relies on measuring specific cations, Na+ and K+ and specific anions, Cl- and HCO3-. The equation is as follows: (Na+ + K+) – (Cl- + HCO3-) = Anion Gap.

The anion gap formula can be manipulated to expose the presence of unmeasured cations and anions as shown below.

([Na+] + [K+] + [UC]) = ([Cl-] + [HCO3-] + [UA])

Rearrangement shows:

([Na+] +[K+]) – ([Cl-] + [HCO3-]) = [UA] – [UC]

Anion Gap = UA – UC

From this manipulation, a health care practitioner or researcher can see that the 4 to 12 mmol/L range of the anion gap is precisely equal to the difference between the unmeasured anions and cations.[3][4]

Function

The anion gap is used to identify errors in the measurement of electrolytes (sodium, chloride, bicarbonate, and potassium most notably), detect paraproteins (IgG for example), and evaluate for suspected acid-base disorders – the latter being the most common and essential use.

Pathophysiology

General pathophysiology of anion gap revolves around derangements in concentrations of cations and anions. In terms of metabolic acidosis, no matter the cause, the inciting event involves a reduction in bicarbonate concentration. This reduction can be due to increased use as a buffer of abnormal acids, decreased production, or increased loss from the body. However, the law of electrochemical neutrality is never breached, so either chloride concentration increases in tandem, or, unmeasured anions increase. If it is chloride, one would have a normal anion gap metabolic acidosis because it is a measured anion.[3] However, if it is unmeasured anions, it would be reflected as an increased anion gap metabolic acidosis.

Two of the most common and notable causes of increased anion gap metabolic acidosis

High anion gap metabolic acidosis (HAGMA) conditions include diabetic ketoacidosis (DKA) and salicylate poisoning.[5] Descriptions of their pathophysiology are below.

In DKA, the patient presents with rapid onset of vomiting, abdominal pain, increased urination, confusion, and in some cases, fruity odor to the breath. At the cellular level, the foundational error is a lack of insulin in the body. Decreased insulin and increased glucagon cause the liver to release glucose via glycogenolysis and gluconeogenesis. Increased glucose in the blood results in osmotic diuresis, taking water and solutes (sodium and potassium) with it. Most relevant is the lack of insulin leading to lipolysis (release of free fatty acids from adipose tissue). The free fatty acids undergo beta-oxidation in the liver and ketone bodies, acetoacetate and B-hydroxybutyrate form. While they provide energy in the absence of glucose, they have lower pKa, causing blood to turn acidic ultimately resulting in the myriad of symptoms discussed at the beginning.[6][7]

In salicylate poisoning, classic symptoms include ear ringing, nausea, abdominal pain, and hyperventilation. Interestingly, in this case, we find a mixed disorder resulting through three phases:

1. Through direct respiratory center stimulation, hyperventilation causes respiratory alkalosis and compensation through alkaluria. This phase lasts about 12 hours.
2. After significant amounts of potassium lost, paradoxical aciduria results.
3. Eventually, dehydration, hypokalemia, and progressive metabolic acidosis results, which presents within 4 to 6 hours in an infant and typically greater than 24 hours for an adolescent or adult.[8][9][10]

Clinical Significance

While any deviation from normal, reduced or increased, is clinically relevant, the most clinically significant is an increased anion gap, particularly when associated with metabolic acidosis. In terms of DKA, this is the development of acetoacetate and B-hydroxybutyrate. In terms of Lactic Acidosis, it is the increased formation of and decreased metabolism of lactate.

Overall, the clinical significance has as its basis in detecting and aiding the body in handling, metabolizing or removing the inciting factor causing derangements in ion concentrations.

Pearls

Every 1 g/L decrease in albumin will decrease the anion gap by 0.25 mmol/L. A patient with hypoalbuminemia may present with a normal anion gap when in actuality, they have a high anion gap acidosis. Consider in ICU patients. Another ratio worth adding to your anion gap toolkit is every decrease in 10 g/L albumin = 2.3 mmol/L decrease in the anion gap.

Interestingly, paraproteins such as IgG also cause a reduction in anion gap due to their positive charge. Thus, patients with monoclonal proliferation such as those suffering from IgG myeloma have significant increases in cation or positive ion concentration resulting in decreased and rarely increased anion gaps. Likewise, a polyclonal proliferation of IgG would have the same effect, which can present in a patient with HIV.

Finally, patients prescribed lithium carbonate for bipolar disorder can have reduced anion gap. At therapeutic doses of 1.0 mmol/L, no change in the anion gap materializes. However, in lithium intoxication, a noticeable reduction is appreciated.

Other causes of reduced ion gap include hypoalbuminemia, hypertriglyceridemia, decreased unmeasured anions such as phosphorus, and increased unmeasured cations such as magnesium.

Mnemonic to remember increased anion gap metabolic acidosis("CATMUDPILES"):

1. Carbon monoxide/cyanide
2. Aminoglycosides
3. Theophylline
4. Methanol
5. Uremia
6. Diabetic ketoacidosis
7. Paracetamol/acetaminophen
8. Iron/isoniazid
9. Lactic acidosis
10. Ethanol/ethylene glycol
11. Salicylate/ASA

Mnemonic to remember normal anion gap metabolic acidosis ("USEDCARP")[11][12][13]:

1. Ureterostomy
2. Small bowel fistula
3. Extra chloride
4. Diarrhea
5. Carbonic anhydrase inhibitor
6. Adrenal insufficiency
7. Rental tubular acidosis
8. Pancreatic fistula