The serum anion gap (sAG) is one of the most widely used calculations in clinical medicine, particularly in the evaluation of metabolic acidosis. It provides insight into the presence of unmeasured ions in the bloodstream, which helps clinicians differentiate between various causes of acidosis. By subtracting the sum of chloride and bicarbonate (the main measured anions) from sodium (the primary measured cation), the serum anion gap highlights the contribution of unmeasured ions such as phosphate, sulfate, lactate, and plasma proteins.

A normal anion gap indicates balance between measured and unmeasured ions. In the setting of metabolic acidosis, if the anion gap remains normal, it suggests a hyperchloremic (non-gap) acidosis, most often caused by gastrointestinal bicarbonate loss (e.g., diarrhea) or renal tubular acidosis.

A high anion gap metabolic acidosis (HAGMA) suggests accumulation of unmeasured anions. Classic causes include lactic acidosis, ketoacidosis (diabetic, alcoholic, starvation), renal failure, and ingestion of toxins such as methanol, ethylene glycol, or salicylates. This makes the sAG a key early clue in toxicology and critical care.

A low anion gap is rare but may occur in hypoalbuminemia (the most common reason), paraproteinemias such as multiple myeloma (where positively charged proteins reduce the gap), or laboratory error. Because albumin contributes approximately 75% of the normal anion gap, correction for low albumin is essential: add about 2.5 mEq/L for every 1 g/dL decrease below 4.0 g/dL.