Serum Anion Gap

Utility of the Serum Anion Gap

  • 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
    • Delta Anion Gap/Delta Bicarbonate Ratio in Ketoacidosis is Typically Around 1.1 (see Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State, [[Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State]], Alcoholic Ketoacidosis, [[Alcoholic Ketoacidosis]], and Starvation Ketoacidosis, [[Starvation Ketoacidosis]])
      • Mechanisms
        • 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”
    • Diagnosis: anion gap may be decreased or negative
  • Lithium Intoxication (see Lithium, [[Lithium]])
    • Mechanism: lithium acts as an unmeasured cation

Laboratory Artifactual Decrease in the Serum Anion Gap

  • General Comments: most common etiology of decreased 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

  • Hypercalcemia (see Hypercalcemia, [[Hypercalcemia]])
    • Mechanism: due to an increase in the unmeasured cation, calcium
  • Hyperkalemia (see Hyperkalemia, [[Hyperkalemia]])
    • 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
  • Hypoalbuminemia (see Hypoalbuminemia, [[Hypoalbuminemia]])
    • 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

Laboratory Artifactual Increase in the Serum Anion Gap

  • Artifactual Decrease in Chloride/Bicarbonate Concentration: results in artifactual increase in the anion gap
  • Artifactual Increase in Sodium Concentration: results in artifactual increase in the anion gap

Other

  • Hyperabuminemia (see Hyperabuminemia, [[Hyperabuminemia]])
    • Mechanism: increase in the unmeasured anion, albumin
  • Hyperphosphatemia (see Hyperphosphatemia, [[Hyperphosphatemia]])
    • 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]])
    • Mechanism: IgA proteins are unmeasured anions

References

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