The anion gap is a simple calculation used in blood tests that helps medical professionals understand the electrical balance within the body’s fluids. It represents the difference between the concentration of the main measured positive ions (cations) and the main measured negative ions (anions) in the blood serum. The result estimates the presence of other, unmeasured components in the blood. This calculation helps diagnose a specific type of metabolic acidosis, a condition where the body’s acid-base balance is disturbed. By flagging this imbalance, the anion gap guides the search for the underlying medical cause.
How the Anion Gap is Calculated
The anion gap relies on the biological principle of electroneutrality, meaning the total positive charges (cations) in the blood must equal the total negative charges (anions). Clinical labs focus on the most abundant measured electrolytes. The primary measured positive ion is sodium (\(\text{Na}^+\)), and the primary measured negative ions are chloride (\(\text{Cl}^-\)) and bicarbonate (\(\text{HCO}_3^-\)).
The mathematical formula is: \(\text{Anion Gap} = [\text{Sodium}] – ([\text{Chloride}] + [\text{Bicarbonate}])\). This resulting “gap” is not empty space. It represents the concentration of unmeasured ions, both cations and anions, that are present in the blood but are not included in the calculation.
The largest component of this unmeasured group is albumin, a protein that carries a negative charge and accounts for most of the normal gap. Other normal unmeasured ions include phosphates, sulfates, and organic acids. A typical normal reference range is between 8 and 12 milliequivalents per liter (\(\text{mEq/L}\)), though this can vary between laboratories.
Interpreting a High Anion Gap
A high anion gap, typically above \(12\ \text{mEq/L}\), signals an abnormal accumulation of unmeasured acids in the bloodstream. This finding is the hallmark of high anion gap metabolic acidosis (HAGMA). When a new acid enters the blood, it breaks down, releasing a hydrogen ion (\(\text{H}^+\)) and a corresponding unmeasured anion.
The body uses bicarbonate as a chemical buffer against this excess acid. Bicarbonate rapidly combines with the hydrogen ions to neutralize them, consuming and removing bicarbonate from the measured ions pool. Because the new, unmeasured anion replaces the lost, measured bicarbonate, the mathematical “gap” widens.
The blood’s electrical balance must always be maintained. When a new acid is added, its negative part (the unmeasured anion) increases the unmeasured anions column. Simultaneously, the measured bicarbonate decreases because it was consumed neutralizing the acid. The calculation then yields a larger result, reflecting this physiological shift.
Common Medical Conditions That Cause a High Anion Gap
A high anion gap indicates that metabolic acidosis is caused by conditions introducing large quantities of unmeasured acids into the body. Diabetic ketoacidosis (DKA) is a frequent cause, occurring when the body lacks sufficient insulin and begins breaking down fat for energy. This process creates a buildup of ketoacids—specifically acetoacetate and beta-hydroxybutyrate—which are the unmeasured anions that widen the gap.
Lactic acidosis is another common cause, resulting from the excessive production or inadequate clearance of lactic acid. This often happens in situations of severe tissue oxygen deprivation (hypoxia), such as shock, sepsis, or cardiopulmonary arrest, forcing cells to rely on anaerobic metabolism. Even intense physical exercise can temporarily cause a mild lactic acidosis.
Chronic kidney failure, known as uremia, also leads to a high anion gap. As the kidneys fail, they can no longer effectively excrete the normal daily production of acid and its corresponding anions, such as sulfates and phosphates. These waste products accumulate in the blood, acting as unmeasured anions that contribute to the widening gap.
Toxic ingestions represent an urgent category of high anion gap causes. Substances like methanol (windshield fluid) and ethylene glycol (antifreeze) are metabolized by the liver into highly toxic organic acids. Methanol forms formic acid, and ethylene glycol forms glycolic and oxalic acids, which rapidly consume bicarbonate and create a large anion gap. Salicylate (aspirin) overdose also causes a high anion gap by disrupting cellular metabolism.
What a Low Anion Gap Indicates
A low anion gap, defined as a value below \(8\ \text{mEq/L}\), is much less common than a high one and suggests a different set of issues. The most frequent reason for a low gap is a decrease in the concentration of the main unmeasured anion, albumin, a condition called hypoalbuminemia. Since albumin is negatively charged and contributes to the normal gap, its reduction directly lowers the calculated result.
Hypoalbuminemia can be caused by malnutrition, severe liver disease, or prolonged inflammation. A low anion gap may also occur due to an increase in unmeasured positive ions (cations), which decreases the difference between total measured cations and anions. This rare situation can be seen in blood cancers, such as multiple myeloma, where abnormal, positively charged proteins accumulate. Technical or measurement error should be considered when a low anion gap is reported.