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Anion Gap (Elevated) Differential Diagnosis

Normal Anion Gap:  8 - 12 +/- 2

    Acetaminophen

    • Associations:  Acute ingestion +/- liver damage (rising AST/ALT) +/- metabolic acidosis
    • Pathophysiology:  Acetaminophen metabolite, oxoproline and pyroglutamic acid.
    Alcoholic Ketoacidosis (AKA)

    • Associations:  History of alcohol abuse + normal glucose + ketones in urine
    • Pathophysiology:  Multifactorial: Decreases in insulin, increases in glucagon, impaired NADH to NAD+ ratios from alcohol metabolism and volume depletion with vomiting.
    Diabetic Ketoacidosis (DKA)

    • Associations:  Glucose levels > 250 mg/dL +/- abdominal pain +/- nausea & vomiting + ketones in the urine + serum bicarbonate < 18
    • Pathophysiology:  Insufficient presence of insulin that results in the abnormal breakdown of fatty acids that generate ketoacids.
    Ethylene Glycol (Antifreeze; Toxic Alcohol)

    • Associations:  Ingestion of antifreeze + inebriation +/- metabolic acidosis +/- acute renal impairment
    • Pathophysiology:  Ethylene glycol gets metabolized to eventually for glycolic acid and oxalic acid.
    Iron

    • Associations:  Iron ingestion or hemochromatosis or repeated blood transfusions
    • Pathophysiology:  Results in liver damage.
    Isoniazid (INH)

    • Associations:  History of tuberculosis (latent or active)
    • Pathophysiology:  Due to functional deficiencies in pyridoxine (vitamin B6) that can serve as a co-factor in metabolic reactions. This leads to a metabolic acidosis.
    Lactic Acidosis (from Cyanide or Hydrogen Sulfide)

    • Associations:  Numerous medical conditions or drugs containing propylene glycol (lorazepam; phenytoin)
    • Pathophysiology: Lactic acid formation is a byproduct of another underlying problem that prevents its metabolism or prevent pyruvate from entering the Krebs cycle.
    Metformin or Phenformin

    • Associations:  Type 2 diabetes +/- impaired renal function
    • Pathophysiology:  Impairs lactate metabolism in the liver.
    Methanol
    • Associations:  Reports of ingestion +/- metabolic acidosis +/- changes in vision
    • Pathophysiology:  Methanol is metabolized to formic acid.
    Paraldehyde

    • Associations:  Reports of ingestion (though no longer used)
    • Pathophysiology:  Metabolized to acetaldehyde.
    Salicylates (Aspirin; Salicyclic Acid)

    • Associations:  Reports of ingestion/Suicide Attempt (or) elderly patient  on chronic aspirin +/- mixed acid/base disorder
    • Pathophysiology:  Initially stimulates the medullary center in the brain and causes increased respirations leading to respiratory alkalosis. Then shifts to a metabolic acidosis and uncoupling of cellular respiration.
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    Editors & Reviewers

    Editors:

    • Anthony J. Busti, MD, PharmD, FNLA, FAHA

    Last Reviewed:  August 2015