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Serum Anion Gap: Its Uses and Limitations in Clinical Medicine

Jeffrey A. Kraut^*, and Nicolaos E. Madias

^* Medical and Research Services VHAGLA Healthcare System, UCLA Membrane Biology Laboratory, and Division of Nephrology VHAGLA Healthcare System and David Geffen School of Medicine, Los Angeles, California; and Department of Medicine, Division of Nephrology, Caritas St. Elizabeth’s Medical Center, and Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts

Address correspondence to: Dr. Jeffrey A. Kraut, Division of Nephrology VHAGLA Healthcare System, 11301 Wilshire Boulevard, Los Angeles, CA 90073. Phone: 310-268-3703; E-mail: jkraut{at}ucla.edu

The serum anion gap, calculated from the electrolytes measured in the chemical laboratory, is defined as the sum of serum chloride and bicarbonate concentrations subtracted from the serum sodium concentration. This entity is used in the detection and analysis of acid-base disorders, assessment of quality control in the chemical laboratory, and detection of such disorders as multiple myeloma, bromide intoxication, and lithium intoxication. The normal value can vary widely, reflecting both differences in the methods that are used to measure its constituents and substantial interindividual variability. Low values most commonly indicate laboratory error or hypoalbuminemia but can denote the presence of a paraproteinemia or intoxication with lithium, bromide, or iodide. Elevated values most commonly indicate metabolic acidosis but can reflect laboratory error, metabolic alkalosis, hyperphosphatemia, or paraproteinemia. Metabolic acidosis can be divided into high anion and normal anion gap varieties, which can be present alone or concurrently. A presumed 1:1 stoichiometry between change in the serum anion gap (AG) and change in the serum bicarbonate concentration (HCO₃^–) has been used to uncover the concurrence of mixed metabolic acid-base disorders in patients with high anion gap acidosis. However, recent studies indicate variability in the AG/HCO₃^– in this disorder. This observation undercuts the ability to use this ratio alone to detect complex acid-base disorders, thus emphasizing the need to consider additional information to obtain the appropriate diagnosis. Despite these caveats, calculation of the serum anion gap remains an inexpensive and effective tool that aids detection of various acid-base disorders, hematologic malignancies, and intoxications.

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