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Causes of a low or negative serum anion gap

Causes of a low or negative serum anion gap
Cause Comments
Laboratory error Spuriously low serum Na+ or spuriously elevated serum Cl or HCO3; laboratory error is the most common cause of low anion gap
Hypoalbuminemia Second most common cause of low serum anion gap (after laboratory error); albumin is anionic, and reduced levels decrease the concentration of unmeasured anions
Salicylate poisoning or use of thiosulfate Increased concentration of unmeasured anions
Monoclonal or polyclonal gammopathy Immunoglobulins are usually cationic, and elevated levels increase the concentration of unmeasured cations (especially IgG and IgM)
Hypercalcemia or hypermagnesemia Increased concentration of unmeasured cations
Severe hyperkalemia Increased concentration of unmeasured cations
Lithium intoxication Lithium is an unmeasured cation, and a low anion gap can occur with lithium >4 mEq/L
Polymyxin B Polymyxin B is polycationic at physiologic pH
Psuedohyponatremia Measurement of serum Na+ with indirect ion-selective electrode in the setting of marked hypertriglyceridemia, hypercholesterolemia, or hyperproteinemia
Pseudohyperchloremia Can occur in the setting of bromide or iodide intoxication
Pseudohyperbicarbonatemia Rare, but can be present if there are markedly elevated levels of lactate dehydrogenase
IgG: immunoglobulin G; IgM: immunoglobulin M.
Reference:
  1. Emmett M. Approach to the patient with a negative anion gap. Am J Kidney Dis 2016; 67:143.

Adapted from: Kraut JA, Madias NE. Serum anion gap: Its uses and limitations in clinical medicine. Clin J Am Soc Nephrol 2007; 2:162.

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