What are the causes of an elevated anion gap?

Causes of Elevated Anion Gap

The most common causes of elevated anion gap metabolic acidosis can be categorized into four main groups: lactic acidosis, ketoacidosis, toxin/drug ingestions, and uremia. 1, 2

Definition and Calculation

• Anion gap is calculated using the formula: Na⁺ + K⁺ - Cl⁻ - HCO₃⁻ 1
• An elevated anion gap indicates the presence of unmeasured anions in the blood 2

Major Categories of Elevated Anion Gap

1. Lactic Acidosis

• Results from tissue hypoperfusion or impaired oxygen utilization leading to anaerobic metabolism 3
• Common causes include:
  • Shock (cardiogenic, septic, hypovolemic) 4
  • Severe tissue hypoxia 2
  • Seizures 3
  • Certain medications (metformin, nucleoside reverse transcriptase inhibitors) 5
• Associated with high mortality, especially when due to decreased oxygen delivery 3

2. Ketoacidosis

• Results from increased production of ketone bodies (acetoacetate and β-hydroxybutyrate) 4
• Three main types:
  • Diabetic ketoacidosis (DKA) - most common, occurs in uncontrolled diabetes 1, 2
  • Alcoholic ketoacidosis - occurs after cessation of alcohol consumption following chronic intake 1
  • Starvation ketoacidosis - less severe, occurs during prolonged fasting 1
• Distinguished by clinical history and plasma glucose levels (elevated in DKA, normal or low in alcoholic and starvation ketoacidosis) 1

3. Toxin and Drug Ingestions

• Toxic alcohols:
  • Methanol - metabolized to formic acid 3, 6
  • Ethylene glycol - metabolized to glycolic and oxalic acids 2, 6
  • Diethylene glycol 6
  • Propylene glycol (from certain IV medications) 4, 6
• Salicylates (aspirin overdose) - typically presents with mixed respiratory alkalosis and metabolic acidosis 3, 5
• Less common:
  • Pyroglutamic acid (5-oxoproline) - associated with chronic acetaminophen use and malnutrition 7
  • Isoniazid 7
  • Paraldehyde 7
  • Iron overdose 7

4. Uremia (Renal Failure)

• Results from decreased renal excretion of acid and retention of unmeasured anions 3, 4
• Usually causes a mild anion gap elevation 3
• Associated with decreased ammonia secretion by the kidneys 3

Less Common Causes

• Inborn errors of metabolism 7
• D-lactic acidosis (from bacterial overgrowth in short bowel syndrome) 4
• Cyanide poisoning (causes severe lactic acidosis) 5
• Carbon monoxide poisoning 5

Clinical Pearls and Pitfalls

• The mnemonic "MUDPILES" can help remember common causes: Methanol, Uremia, Diabetic ketoacidosis, Paraldehyde/Pyroglutamic acid, Isoniazid/Iron/Inborn errors, Lactic acidosis, Ethylene glycol, Salicylates 7
• Not all elevated anion gaps indicate acidosis - interpretation requires clinical context 2
• The anion gap may overestimate acidosis severity in cases with concomitant acute kidney injury or ketoacidosis 1, 2
• The anion gap may underestimate acidosis severity in hypoalbuminemia (each 1 g/dL decrease in albumin decreases the anion gap by approximately 2.5 mEq/L) 1, 2
• Toxic alcohol ingestions often present with both elevated anion gap and elevated osmolal gap 6
• An elevated glycolate concentration can falsely elevate plasma lactate on some analyzers 1
• Certain medications and conditions can falsely alter the anion gap (e.g., lithium, barium, hyperphosphatemia) 1