What are the rare causes of high anion gap metabolic acidosis?

Rare Causes of High Anion Gap Metabolic Acidosis

Rare causes of high anion gap metabolic acidosis include 5-oxoproline accumulation, toxic alcohol ingestion (methanol and ethylene glycol), D-lactic acidosis, and certain inborn errors of metabolism. While common causes like diabetic ketoacidosis and lactic acidosis are well-recognized, these uncommon etiologies require specific diagnostic consideration and targeted management.

Toxic Alcohol Ingestions

Ethylene Glycol Poisoning

• Found in antifreeze, de-icing solutions
• Metabolized to glycolic and oxalic acids causing severe metabolic acidosis
• Clinical features:
  • Initial inebriation followed by cardiopulmonary symptoms
  • Calcium oxalate crystals in urine
  • Renal failure
  • Severe anion gap acidosis (>27 mmol/L strongly indicates need for treatment) 1
  • Elevated osmolar gap (>10) 1

Methanol Poisoning

• Found in windshield washer fluid, industrial solvents
• Metabolized to formic acid causing metabolic acidosis and visual disturbances
• Clinical features:
  • Visual disturbances (may progress to blindness)
  • Severe metabolic acidosis
  • Elevated osmolar gap
  • CNS depression

Management of Toxic Alcohol Ingestions

• Administer fomepizole to block alcohol dehydrogenase 2
• Consider hemodialysis for:
  • Significant metabolic acidosis
  • Renal failure
  • Ethylene glycol/methanol levels ≥50 mg/dL 2
• Fomepizole dosing: 15 mg/kg loading dose, then 10 mg/kg every 12 hours for 4 doses, then 15 mg/kg every 12 hours 2
• Adjust dosing during hemodialysis (every 4 hours) 2

5-Oxoproline (Pyroglutamic Acid) Accumulation

• Associated with chronic acetaminophen use 3, 4
• Risk factors:
  • Malnutrition
  • Female gender
  • Liver disease
  • Sepsis
  • Renal failure
  • Pregnancy 3
• Mechanism: Disruption of the γ-glutamyl cycle leading to 5-oxoproline accumulation 4
• Diagnosis: Urinary organic acid screen showing elevated 5-oxoproline levels 4
• Management:
  • Discontinue acetaminophen
  • Supportive care
  • Consider N-acetylcysteine in severe cases

D-Lactic Acidosis

• Occurs in patients with short bowel syndrome or after jejunoileal bypass
• Caused by bacterial fermentation of unabsorbed carbohydrates
• Clinical features:
  • Neurological symptoms (confusion, ataxia, slurred speech)
  • Metabolic acidosis
  • Normal L-lactate levels
• Diagnosis: Specific assay for D-lactate
• Management:
  • Carbohydrate restriction
  • Antibiotics to reduce bacterial overgrowth
  • Correction of acidosis

Diagnostic Approach to Unexplained High Anion Gap Metabolic Acidosis

1. Calculate anion gap: Na⁺ + K⁺ - Cl⁻ - HCO₃⁻ 1
2. Assess osmolal gap (measured - calculated osmolality)
   • Elevated osmolal gap (>10) suggests toxic alcohol ingestion 1, 5
3. Consider rare causes when common etiologies excluded:
   • Check medication history for acetaminophen use (5-oxoproline)
   • Evaluate for short bowel syndrome (D-lactic acidosis)
   • Screen for toxic alcohols if clinically suspected
4. Specific testing:
   • Urinary organic acid screen for 5-oxoproline
   • Serum methanol and ethylene glycol levels
   • D-lactate levels if suspected

Monitoring and Management

• Monitor serum electrolytes, anion gap, lactate levels, and renal function 6
• Correct underlying cause
• Consider hemodialysis for severe acidosis unresponsive to conventional therapy
• For toxic alcohol ingestion:
  • Begin fomepizole immediately upon suspicion based on history, anion gap, osmolar gap, or documented levels >20 mg/dL 2
  • Continue treatment until levels are undetectable or <20 mg/dL and patient is asymptomatic with normal pH 2

Pitfalls to Avoid

• Failing to consider rare causes when common etiologies are excluded
• Delaying treatment for toxic alcohol ingestion while awaiting confirmatory testing
• Missing the association between chronic acetaminophen use and 5-oxoproline accumulation
• Overlooking the need for hemodialysis in severe cases of toxic alcohol ingestion with anion gap >27 mmol/L 1
• Relying solely on lactate levels to explain high anion gap, as rare causes may have normal or only slightly elevated lactate

By maintaining awareness of these uncommon causes of high anion gap metabolic acidosis, clinicians can ensure appropriate diagnosis and timely management of these potentially life-threatening conditions.