High Anion Gap Metabolic Acidosis

Causes and Diagnostic Evaluation

Methanol can produce both an anion gap and osmolar gap due to being a low-molecular weight organic compound 1
Renal failure leads to accumulation of organic acids and impaired acid excretion, typically presenting with elevated BUN, creatinine, and hyperkalemia 2
Diabetic ketoacidosis results from insulin deficiency with elevated counterregulatory hormones, and diagnostic criteria include blood glucose >250 mg/dL, arterial pH <7.3, bicarbonate <15 mEq/L, and positive ketones 1
Lactic acidosis results from tissue hypoxia due to decreased oxygen delivery or impaired oxygen utilization, and can occur in healthy individuals during peak exercise when oxygen delivery is insufficient to meet demand 2
Blood lactate measurement is essential for diagnosis of lactic acidosis 1
The American Diabetes Association recommends calculating anion gap: [Na+] - ([Cl-] + [HCO3-]), with a normal anion gap being 8-12 mEq/L; high anion gap is >12 mEq/L 1
The American Diabetes Association suggests calculating serum osmolal gap to detect presence of low molecular weight toxins like methanol and ethylene glycol 3

Treatment of diabetic ketoacidosis requires fluid resuscitation, insulin therapy, and electrolyte management 4
Serum salicylate levels should be monitored during treatment of salicylate poisoning 3

Laboratory analysis of organic acids can help identify specific causes of high anion gap metabolic acidosis, particularly in cases of inborn errors of metabolism, as recommended by the American College of Medical Genetics and Genomics 5, 6, 7

NRTI antiretroviral medications can cause severe lactic acidosis with hepatic steatosis, though this is rare (estimated incidence 1.3 cases/1000 person-years), it carries high mortality 8
Lactic acidosis results from tissue hypoxia due to decreased oxygen delivery or impaired oxygen utilization, and can occur from shock states, severe hypoxemia, carbon monoxide poisoning, or mitochondrial dysfunction 8

Ethylene glycol poisoning causes anion gap acidosis through its metabolite glycolate; an anion gap >27 mmol/L is a strong indication for extracorporeal treatment, while 23-27 mmol/L suggests consideration of treatment 9
The anion gap may overestimate glycolate concentration in ethylene glycol poisoning when concomitant acute kidney injury or ketoacidosis is present, and may underestimate toxicity in cases of hypoalbuminemia or co-ingestions of lithium or barium 9
An elevated anion gap alone without evidence of specific exposure should not drive treatment decisions, as multiple factors can contribute, and glycolate can falsely elevate plasma lactate concentration on some analyzers, potentially confusing the clinical picture 9

Monitor serum bicarbonate and electrolytes every 3 months in patients on NRTIs to detect early anion gap increases 8