Clinical Utility: calculation of the anion gap is useful to differentiate anion gap metabolic acidoses (AGMA) (see Metabolic Acidosis-Elevated Anion Gap, [[Metabolic Acidosis-Elevated Anion Gap]]) from non-anion gap metabolic acidoses (NAGMA) (see Metabolic Acidosis-Normal Anion Gap, [[Metabolic Acidosis-Normal Anion Gap]])
Anion gap reflects the difference between unmeasured anions (i.e. the anions in the blood that are not routinely measured) – unmeasured cations
Calculation of the Serum Anion Gap
Anion Gap Na – (Cl + HCO3)
Normal Anion Gap Values: laboratory-dependent (so the laboratory should publish their normal range)
Correction of the Serum Anion Gap
Correction of Anion Gap for Serum Albumin: since albumin represents the major unmeasured anion responsible for the anion gap (with a net negative charge at physiologic pH), the expected anion gap must be corrected for serum albumin
Anion Gap Decreases 2.3-2.5 mEq/L for Each 1 g/dL Decrease in the Serum Albumin: Corrected Anion Gap = (Measured Anion Gap) + [2.5 x (4.5 – Serum Albumin)]
Correction of Anion Gap for Hyperkalemia: since potassium is an unmeasured cation
For example, serum potassium of 6.0 mEq/L will decrease the anion gap by 2 mEq/L
Correction of Anion Gap for Hypercalcemia: since calcium is an unmeasured cation, hypercalcemia decreases the anion gap
Correction of Anion Gap for Hypermagnesemia: since magnesium is an unmeasured cation, hypermagnesemia decreases the anion gap
Comparison of the Delta Gap and Delta Bicarbonate
In an Isolated Anion Gap Metabolic Acidosis, the Delta Gap = Delta Bicarbonate: anion gap generally increases by the same amount that the serum bicarbonate decreases (however, there are exceptions, as noted below)
Delta Anion Gap/Delta Bicarbonate Ratio in Lactic Acidosis is Typically Around 1.6: although since hydrogen ion buffering in cells and bone may take several hours to equilibrate, the ratio may initially be 1.1 and increase over time
Mechanisms
Most of the lactate anions which enter the extracellular space remain in that space
Urinary lactate excretion is decreased due to associated renal hypoperfusion/dysfunction
Lactate does not usually enter the intracellular fluid space
Over 50% of hydrogen ions are buffered in the cells and bone (even more so when the acidosis is severe): when hydrogen ions are buffered in cells/bone, the serum bicarbonate does not decrease -> therefore, anion gap increases more than the serum bicarbonate decreases
Delta Anion Gap/Delta Bicarbonate Ratio in D-Lactic Acidosis is Typically Around 1 (or <1) (see Lactic Acidosis, [[Lactic Acidosis]])
Mechanisms
Proximal tubule sodium/L-lactate co-transporter is stereospecific and does not transport L-lactate -> therefore, filtered L-lactate is rapidly excreted in the urine
Renal function is typically maintained in most ketoacidoses (except in the case of patients with decreased renal function) with resulting renal loss of ketoacids (acetoacetate, β-hydroxybutyrate) as sodium/potassium salts -> this decreases the anion gap without impacting the serum bicarbonate
Delta Anion Gap/Delta Bicarbonate Ratio in Toluene Intoxication is Typically <1 (see Toluene, [[Toluene]])
Mechanisms
In setting of intact renal function, hippurate is efficiently excreted (decreasing the anion gap)
Delta Anion Gap/Delta Bicarbonate Ratio in Chronic Kidney Disease (CKD) is Variable Depending on Stage of Renal Disease (see Chronic Kidney Disease, [[Chronic Kidney Disease]])
Mechanisms
Early Kidney Disease: greater dysfunction in acid excretion than acid anion excretion -> typically have non-anion gap metabolic acidosis or anion gap metabolic acidosis with delta anion gap/delta bicarbonate ratio <1
Later Kidney Disease: typically have anion gap metabolic acidosis with delta anion gap/delta bicarbonate ratio >1
Etiology of Negative Serum Anion Gap
Drug/Toxin
Bromide Ingestion (Bromism) (see Bromide, [[Bromide]])
Mechanism: bromide interferes with chloride measurement (being interpreted as chloride ions, with each bromide ion being read as multiple chloride ions), causing “pseudohyperchloremia”
Diagnosis: anion gap may be decreased or negative
Salicylate Intoxication (see Salicylates, [[Salicylates]]): may falsely elevate serum chloride, due to high salicylate levels altering the permeability of ion-selective electrodes used in the chloride assay
Laboratory Artifactual Decrease in the Serum Anion Gap
Artifactual Increase in Chloride/Bicarbonate Concentration: results in artifactual decrease in the anion gap
Artifactual Decrease in Sodium Concentration: results in artifactual decrease in the anion gap
Other
Severe Hyperlipidemia (see Hyperlipidemia, [[Hyperlipidemia]])
Mechanism: falsely elevates the chloride concentration when using certain colorimetric assays, as excess lipid affects light scattering
Severe Hypernatremia (see Hypernatremia, [[Hypernatremia]])
Epidemiology: occurs with serum Na >170 mEq/L -> serum Na is typically underestimated
Etiology of Decreased Serum Anion Gap
Drug/Toxin
Bromide Ingestion (Bromism) (see Bromide, [[Bromide]])
Mechanism: bromide interferes with chloride measurement (being interpreted as chloride ions, with each bromide ion being read as multiple chloride ions), causing “pseudohyperchloremia”
Mechanism: due to an increase in the unmeasured cation, potassium
Hypermagnesemia (see Hypermagnesemia, [[Hypermagnesemia]]): due to an increase in the unmeasured cation, magnesium
Magnesium Sulfate Administration (see Magnesium Sulfate, [[Magnesium Sulfate]]): the increase in serum magnesium (cation) is accompanied by an increase in sulfate anion -> this will not change the anion gap
Magnesium Chloride Administration (see Magnesium Chloride, [[Magnesium Chloride]]): chloride concentration increases without a change in sodium or bicarbonate -> this will decrease the anion gap
Epidemiology: most common etiology of decreased anion gap
Mechanism: decreased concentration of the unmeasured anion, albumin
Clinical: anion gap decreases 2.3-2.5 mEq/L for each 1 g/dL decrease in the serum albumin -> corrected anion gap = (measured anion gap) + [2.5 x (4.5 – serum albumin)]
IgG Multiple Myeloma (see Multiple Myeloma, [[Multiple Myeloma]])
Mechanism: IgG proteins are unmeasured cations
Polyclonal IgG Gammopathy
Mechanism: IgG proteins are unmeasured cations
Severe (Hyperchloremic) Non-Anion Gap Metabolic Acidosis (NAGMA) (see Metabolic Acidosis-Normal Anion Gap, [[Metabolic Acidosis-Normal Anion Gap]])
Mechanism: protons bind to albumin as the pH decreases, reducing albumin’s net negative charge
Etiology of Increased Serum Anion Gap
Organic Metabolic Acidoses
General Comments: most common etiologies of an increased anion gap
Mechanism: increase in the unmeasured anion, phosphate
Metabolic Alkalosis (see Metabolic Alkalosis, [[Metabolic Alkalosis]]): results in a small increase in the anion gap
Mechanisms
Alkaline pH Results in Albumin Molecules Releasing Protons: results in increased net negative charge on each albumin molecule
Volume Contraction (Commonly Present in Most Metabolic Alkaloses) Increases the Absolute Albumin Concentration: increasing its negative charge contribution
Alkalemia Increases the Generation of and Accumulation of Organic Acids (Lactic Acid, etc): this decreases the increase in bicarbonate increase (decreasing the alkalemia) and increases the anion gap
IgA Multiple Myeloma (see Multiple Myeloma, [[Multiple Myeloma]])
