The anion gap is a diagnostic calculation derived from the electrolyte panel of a standard blood test, used to assess a patient’s acid-base balance. The body must maintain electrical neutrality, meaning total positive charges (cations) must equal total negative charges (anions) in the blood plasma. This calculation determines if an abnormal accumulation of acids is present in the bloodstream, often indicating a serious underlying medical condition. It measures the difference between two groups of charged particles, making it a useful screening and diagnostic indicator.
Calculating the Gap and Normal Values
The anion gap is calculated by subtracting the concentration of the major measured anions from the concentration of the major measured cation. The standard formula is Sodium (Na+) minus the sum of Chloride (Cl-) and Bicarbonate (HCO3-). The result is expressed in milliequivalents per liter (mEq/L).
Sodium is the most abundant positively charged ion (cation) and is typically the sole cation used in the calculation. Chloride and bicarbonate are the two most abundant measured negative ions (anions). The normal range for the calculated anion gap is generally between 8 and 12 mEq/L, though this can vary slightly by laboratory. A result outside this window indicates an imbalance requiring further investigation.
The Role of Unmeasured Components
The body upholds electroneutrality, meaning the total positive and negative charges in the plasma are always equal. The calculated gap exists because the formula only accounts for the major measured ions. The positive result in a healthy person represents the difference between the unmeasured anions and the unmeasured cations in the plasma.
Unmeasured anions, present in higher concentrations than unmeasured cations, are the primary reason for the positive gap. These include proteins like albumin, phosphates, and sulfates. Albumin, a negatively charged protein, is the largest contributor to the normal anion gap, accounting for approximately 75% of the total unmeasured charge.
Unmeasured cations, present in lower concentrations, include ions like calcium (Ca2+) and magnesium (Mg2+). Because albumin is such a large component, fluctuations in its concentration can significantly alter the anion gap even if the acid-base status is normal.
Interpreting a High Anion Gap
An elevated anion gap (above 12 mEq/L) strongly suggests metabolic acidosis caused by an accumulation of unmeasured acids. When an abnormal acid enters the blood, the bicarbonate buffer system neutralizes the excess hydrogen ions. This process consumes the measured bicarbonate (HCO3-), which is replaced by the acid’s negatively charged anion.
Since the new acid anion is unmeasured in the formula, the loss of measured bicarbonate causes the calculated gap to widen. The most common causes of this accumulation are categorized by the type of unmeasured acid present:
- Lactic acidosis, often seen in severe tissue oxygen deprivation (shock or sepsis), causes the buildup of lactate.
- Ketoacidosis, associated with uncontrolled Type 1 diabetes (Diabetic Ketoacidosis), leads to the accumulation of unmeasured ketoacids.
- Kidney failure (uremia) impairs the kidneys’ ability to excrete metabolic wastes, resulting in the retention of unmeasured anions like sulfates and phosphates.
- Specific toxic ingestions, such as methanol, ethylene glycol, and salicylates, are metabolized into highly acidic, unmeasured end products.
Interpreting a Low Anion Gap
A low anion gap (less than 8 mEq/L) is much less common than a high gap and often less clinically significant. Laboratory error should be considered first. If confirmed, a low result indicates an imbalance caused by either a reduction in unmeasured anions or an increase in unmeasured cations.
The most frequent clinically relevant cause is hypoalbuminemia (low albumin concentration). Since albumin accounts for the majority of the normal negative charge, a significant decrease directly reduces the unmeasured anions, shrinking the calculated gap. Conditions like severe malnutrition, liver disease, or chronic inflammation can cause this reduction.
Less commonly, a low anion gap can be caused by an increase in unmeasured cations, which neutralizes unmeasured anions. This occurs in rare conditions such as multiple myeloma, where the body produces large amounts of abnormal, positively charged proteins (paraproteins). Certain intoxications, such as with lithium or bromide, can also cause a low result.