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For further information, see CMDT Part 21-16: Metabolic Acidosis

For further information, see CMDT Part 21-17: Increased Anion Gap Acidosis

Key Features

Essentials of Diagnosis

  • Hallmark of this disorder is that metabolic acidosis (thus low HCO3) is associated with normal serum Cl, so that the anion gap increases

  • Decreased HCO3 is also seen also in respiratory alkalosis, but pH distinguishes between the two disorders

General Considerations

  • A gap metabolic acidosis is secondary to the addition of acid—either exogenous or endogenous

  • The major causes are lactic acidosis, ketoacidosis, kidney failure, and ingestions

  • Calculation of the anion gap is useful in determining the cause of the metabolic acidosis

  • Normochloremic (increased anion gap) metabolic acidosis

    • Generally results from addition to the blood of organic acids such as lactate, acetoacetate, β-hydroxybutyrate, and exogenous toxins

    • Uremia produces an increased anion gap metabolic acidosis via unexcreted organic acids and anions


  • Type A lactic acidosis

    • Results from tissue hypoxia, usually from

      • Septic, cardiogenic, or hemorrhagic shock

      • Mesenteric ischemia

      • Respiratory failure

      • Carbon monoxide poisoning

    • These conditions increase peripheral lactic acid production and decrease hepatic metabolism of lactate as liver perfusion declines

  • Type B lactic acidosis

    • Secondary to impaired mitochondrial oxygen utilization

    • May be due to

      • Metabolic causes (eg, diabetes mellitus, liver disease, kidney disease, thiamine deficiency, D-lactic acidosis, leukemia, or lymphoma)

      • Toxins (eg, ethanol, methanol, ethylene glycol, cyanide, isoniazid, or metformin)

    • Propylene glycol can cause lactic acidosis from decreased liver metabolism; it is used as a vehicle for intravenous drugs, such as nitroglycerin, etomidate, and diazepam

  • D-Lactic acidosis

    • May develop in patients with short bowel syndrome due to carbohydrate malabsorption and subsequent fermentation by colonic bacteria

    • A specific D-lactic acid assay is required as the standard lactic acid assay only detects the L-isomer

  • Diabetic ketoacidosis

    • The anion gap is generally large, often > 20 mEq/L, though it can be variable

    • The elevated serum glucose leads to a marked osmotic diuresis with sizeable losses of sodium, water, and potassium

    • Correction of ketoacidosis can be assessed by measurement of serum β-hydroxybutyrate, pH, or by normalization of the anion gap

  • Fasting ketoacidosis

    • Hepatic generation of ketones may occur as a normal response to fasting from relative hypoinsulinemia

    • Mild ketosis often occurs after 12–14 hours of fasting, peaking after 20–30 hours

  • Alcoholic ketoacidosis

    • May develop in chronically malnourished patients who consume large quantities of alcohol

    • Alcohol metabolism decreases gluconeogenesis, resulting in hepatic production of β-hydroxybutyrate and, to a lesser degree, acetoacetate

  • Toxins

    • Multiple toxins and drugs increase the anion gap by increasing endogenous acid production

    • Common examples include

      • Methanol (metabolized to formic acid)

      • Ethylene glycol (glycolic and oxalic acid)

      • Salicylates (salicylic acid and lactic acid)

    • Long-term acetaminophen use, even at therapeutic doses, can result in an elevated anion gap acidosis from accumulation of 5-oxoproline

  • Uremic acidosis (usually at glomerular filtration rate < 15–30 ...

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