Acidosis, Metabolic, Increased Anion Gap

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

Etiology

• 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 ...