What are the causes of a high calculated anion gap (>20 mmol/L)?

Causes of High Anion Gap (>20 mmol/L)

A calculated anion gap >20 mmol/L most commonly indicates severe metabolic acidosis from conditions such as ethylene glycol poisoning, diabetic ketoacidosis, lactic acidosis, toxic alcohol ingestion, or severe uremia. 1

Common Causes of Elevated Anion Gap >20 mmol/L

Toxin/Drug-Related Causes

• Ethylene glycol poisoning

  • Particularly concerning when anion gap >28 mmol/L (associated with late poisoning) 2
  • Often presents with altered mental status, seizures, and acute kidney injury
  • Mortality increases substantially once plasma glycolate concentration exceeds 12 mmol/L

• Methanol poisoning

  • Associated with severe acidosis and elevated osmolar gap
  • Treatment includes alcohol infusion and dialysis to remove toxins 1

• Salicylate toxicity

  • Usually presents with mild metabolic acidosis and respiratory alkalosis 1

Metabolic Causes

• Diabetic ketoacidosis (DKA)

  • Characterized by ketoacid production
  • Treatment includes IV insulin infusion, electrolyte replacement, and close glucose monitoring 3

• Alcoholic ketoacidosis

  • Related to alcohol consumption and starvation
  • Treatment focuses on turning off ketogenesis and repairing fluid/electrolyte abnormalities 1

• Lactic acidosis

  • Due to decreased oxygen delivery or defective oxygen utilization
  • Associated with high mortality
  • Treatment focuses on improving tissue perfusion and oxygenation 1

Renal Causes

• Severe uremia/chronic renal failure
  • One of the most common causes of increased anion gap 4
  • Due to retention of unmeasured anions
  • Usually presents with elevated BUN and creatinine 3

Clinical Significance and Evaluation

Diagnostic Approach

1. Calculate the anion gap precisely:

   • AG = [Na+] - ([Cl-] + [HCO3-])
   • Modern reference range: 5-12 mmol/L (using ion-selective electrode methods) 4
   • Anion gap >24 mmol/L is rare and strongly suggests metabolic acidosis 4

2. Assess the delta ratio:

   • Δ AG/Δ HCO3- ratio helps identify mixed acid-base disorders
   • Ratio of 1: simple anion gap acidosis
   • Ratio <1: superimposed non-gap acidosis
   • Ratio >1: superimposed metabolic alkalosis 5

3. Calculate osmolar gap if toxic alcohol ingestion is suspected:

   • Helps narrow diagnosis to include toxic alcohols like ethylene glycol and methanol 5

Initial Laboratory Workup

• Arterial blood gases
• Serum electrolytes with calculated anion gap
• Serum ketones
• Lactate
• Glucose
• Renal function tests
• Toxicology screen if indicated 3

Management Considerations

General Approach

• Identify and treat the underlying cause
• Fluid resuscitation with isotonic saline (0.9% NaCl) at 15-20 ml/kg/hr unless contraindicated 3
• Consider sodium bicarbonate therapy when serum bicarbonate falls below 22 mmol/L 3

Specific Treatments

• For ethylene glycol poisoning:

  • Fomepizole or ethanol to block metabolism
  • Consider extracorporeal treatment (ECTR) with anion gap of 23-27 mmol/L 3
  • Hemodialysis is the most common ECTR (86.5% of cases) 2

• For DKA:

  • IV insulin infusion (0.1 units/kg/hr)
  • Electrolyte replacement (particularly potassium)
  • Close monitoring of glucose levels 3

• For lactic acidosis:

  • Focus on improving tissue perfusion and oxygenation
  • Treat the underlying cause
  • Consider vasopressors if needed for hemodynamic support 3

Special Considerations

• Hypoalbuminemia can mask an elevated anion gap - correction is needed for accurate assessment 6, 7
• Severe hyperglycemia may affect anion gap calculations and should be considered 7
• Patients with heart failure: Administer bicarbonate more slowly to avoid volume overload 3
• Elderly patients: Require closer monitoring due to increased vulnerability to dehydration and acidosis complications 3

Monitoring

• Monitor arterial blood gases after 30-60 minutes of treatment
• Monitor electrolytes, especially potassium (risk of hypokalemia)
• Watch for signs of volume overload and pulmonary edema
• Be alert for cerebral edema with too-rapid correction of acidosis 3

Remember that an anion gap exceeding 20 mmol/L almost always signifies a significant metabolic acidosis that requires prompt identification and treatment to prevent adverse outcomes.