The anion gap is a calculated measurement derived from a basic blood test, such as a metabolic panel, used to assess the body’s acid-base balance and overall electrolyte status. This calculation helps medical professionals quickly determine if there is an imbalance in the electrically charged particles, or ions, within the blood plasma. Understanding this value is a crucial step in diagnosing the underlying causes of various metabolic disturbances.
The Principle of Electrical Neutrality in Blood
The foundation of the anion gap calculation rests on the law of electrical neutrality. This law dictates that the total concentration of positively charged ions (cations) must precisely equal the total concentration of negatively charged ions (anions) in the blood plasma. If every ion were measured, the net electrical charge of the blood would always be zero.
Standard laboratory tests only routinely measure the concentrations of the most abundant ions. The major measured cation is sodium (Na+), and the major measured anions are chloride (Cl-) and bicarbonate (HCO3-). The anion gap exists because the sum of the measured anions is consistently less than the concentration of the measured cation, sodium.
This difference is accounted for by the “unmeasured” ions, which are primarily anions like albumin, phosphate, and sulfate. In a healthy person, these unmeasured anions are consistently present at a predictable concentration, resulting in the normal, non-zero “gap.” The calculation serves as an indirect measure of the concentration of these unmeasured ions in the blood.
How to Calculate the Anion Gap
The anion gap is calculated using the concentrations of the three major measured electrolytes from a standard blood chemistry panel. The formula represents the difference between the most abundant cation and the two most abundant anions. The standard formula is: Anion Gap = [Na+] – ([Cl-] + [HCO3-]).
The concentrations for sodium, chloride, and bicarbonate are reported in millieiequivalents per liter (mEq/L) or millimoles per liter (mmol/L). Potassium (K+) is often excluded from the calculation in modern clinical practice because it is found in low concentration and varies less predictably than the other ions. The resulting numerical value represents the concentration of the unmeasured anions.
To illustrate the calculation, consider a typical healthy patient’s lab values. If the sodium concentration is 140 mEq/L, the chloride concentration is 104 mEq/L, and the bicarbonate concentration is 24 mEq/L. The calculation is 140 – (104 + 24), which simplifies to 140 – 128. This results in an anion gap of 12 mEq/L.
Clinical Meaning of the Results
The calculated anion gap falls within a predictable normal range, typically 8 to 12 mEq/L, though this range can vary slightly between laboratories. A result outside this range suggests an underlying physiological problem. A high anion gap is the most common and clinically significant finding, signifying an accumulation of unmeasured acids in the blood that are not accounted for in the standard calculation.
Conversely, a low anion gap is a much rarer finding, often associated with specific protein abnormalities or laboratory error. A decrease in the primary unmeasured anion, albumin, can cause the calculated gap to drop below the normal range, a condition known as hypoalbuminemia. Specific conditions, such as multiple myeloma where cationic proteins increase, can also lead to an abnormally low result.
It is important to consider the patient’s albumin level when interpreting the result, as albumin is the most significant contributor to the unmeasured anions. A low albumin level can mask a true high anion gap, potentially leading to a misdiagnosis. For every one gram per deciliter (g/dL) decrease in albumin, the normal anion gap decreases by approximately 2.5 mEq/L, requiring an adjustment for accurate interpretation.
Conditions Leading to an Abnormal Anion Gap
A high anion gap metabolic acidosis is the most common and concerning abnormality. It indicates the addition of a significant amount of acid to the body that consumes the bicarbonate buffer. When the body generates or ingests an acid, the hydrogen ions are buffered by bicarbonate, and the resulting unmeasured anion enters the bloodstream, causing the calculated gap to increase. The common causes of this condition are often categorized using the mnemonic MUDPILES.
The letters in MUDPILES stand for:
- Methanol
- Uremia
- Diabetic Ketoacidosis (DKA)
- Paraldehyde/Propylene glycol
- Infection/Iron/Isoniazid
- Lactic Acidosis
- Ethylene glycol
- Salicylates
Methanol and ethylene glycol are toxic alcohols whose metabolism produces potent organic acids, such as formic acid and glycolic acid, which are unmeasured anions that raise the gap. DKA, a complication of uncontrolled diabetes, causes the body to produce excessive ketoacids, which are also unmeasured anions.
Uremia, the accumulation of waste products due to severe kidney failure, leads to the retention of unmeasured organic acids and sulfates. Lactic acidosis is a common condition caused by shock or severe tissue oxygen deprivation, resulting in the overproduction of lactate, a strong unmeasured anion. Salicylate overdose, typically from aspirin, causes the accumulation of salicylate anions and interferes with cellular metabolism, contributing to a high gap.
A low anion gap is less frequent but can signal specific conditions, such as severe hypoalbuminemia from malnutrition or liver disease. Since albumin is a major unmeasured anion, its reduction causes the calculated gap to fall. The presence of abnormal, positively charged proteins, known as paraproteins, in conditions like multiple myeloma can also reduce the calculated gap by increasing the unmeasured cations.