Anion Gap (AG)

Definition

The AG is an arithmetic approximation of difference between routinely measured serum anions (23) and cations (11) = 12 mmol/L.
Unmeasured ions include proteins (mostly albumin) = 15 mmol/L, organic acids = 5 mmol/L, phosphates = 2 mmol/L, sulfates = 1 mmol/L; total = 23 mmol/L.
Unmeasured cations include calcium = 5 mmol/L, potassium = 4.5 mmol/L, magnesium = 1.5 mmol/L; total = 11 mmol/L.
Calculated as Na+ ¢ (Cl ¢ + HCO3 ¢ ); typical normal values = 8 " 16 mmol/L; if K+ is included, normal = 10 " 20 mmol/L; reference interval varies considerably depending on instrumentation and between individuals. Increased AG reflects amount of organic (e.g., lactic acid, ketoacids) and fixed acids present.
AG initially began as a measure of quality assurance.

Organic (e.g., lactic acidosis, ketoacidosis)
Inorganic (e.g., administration of phosphate, sulfate)
Protein (e.g., hyperalbuminemia, transient)
Exogenous (e.g., salicylate, formate, paraldehyde, nitrate, penicillin, carbenicillin)
Not completely identified (e.g., hyperosmolar hyperglycemic nonketotic coma, uremia, poisoning by ethylene glycol, methanol)
Artifactual
- Falsely increased serum sodium
- Falsely decreased serum chloride or bicarbonate
When AG >12 " 14 mmol/L, diabetic ketoacidosis is the most common cause, uremic acidosis is the second most common cause, and drug ingestion (e.g., salicylates, methyl alcohol, ethylene glycol, ethyl alcohol) is the third most common cause; lactic acidosis should always be considered when these three causes are ruled out. In small children, rule out inborn errors of metabolism.

Hypoalbuminemia (most common cause), hypocalcemia, hypomagnesemia.
Artifactual (laboratory error, most frequent cause).
"Hyperchloremia " in bromide intoxication (if chloride determination by colorimetric method).
False increase in serum chloride or HCO3 ¢ .
False decrease in serum sodium (e.g., hyperlipidemia, hyperviscosity)
- Increased unmeasured cations
- Hyperkalemia, hypercalcemia, hypermagnesemia
Increased proteins in multiple myeloma, paraproteinemias, polyclonal gammopathies (these abnormal proteins are positively charged and lower the AG).
Lithium and bromide overdose.
Simultaneous changes in ions may cancel each other out, leaving AG unchanged (e.g., increased Cl ¢ and decreased HCO3 ¢ ). The change in AG should equal change in HCO3 ¢ ; otherwise a mixed, rather than simple, acid " base disturbance is present.