When is a high anion‑gap metabolic acidosis present?

High Anion Gap Metabolic Acidosis: Definition and Diagnostic Criteria

High anion gap metabolic acidosis is present when the calculated anion gap exceeds 12 mEq/L, accompanied by decreased pH, decreased bicarbonate or base excess. 1

Calculation and Normal Values

• Calculate the anion gap using the formula: [Na+] - ([Cl-] + [HCO3-]) 1
• Normal anion gap range is 8-12 mEq/L 1, 2
• High anion gap is defined as >12 mEq/L 1
• The gap primarily reflects unmeasured anions (mainly negatively charged albumin) minus unmeasured cations 2

Common Clinical Causes

The most frequent etiologies include:

Renal Failure

• Accumulation of organic acids and impaired acid excretion 1
• Typically presents with elevated BUN, creatinine, and hyperkalemia 1

Diabetic Ketoacidosis

• Results from insulin deficiency with elevated counterregulatory hormones 1
• Diagnostic criteria: 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 1
• Can occur from shock states, severe hypoxemia, carbon monoxide poisoning, or mitochondrial dysfunction 1
• Blood lactate measurement is essential for diagnosis 1
• Can occur even in healthy individuals during peak exercise when oxygen delivery is insufficient 1

Toxic Ingestions

Methanol and Ethylene Glycol:

• Produce both an anion gap and osmolar gap due to being low-molecular weight organic compounds 1
• Calculate serum osmolal gap to detect presence of these toxins 1
• Ethylene glycol poisoning causes acidosis through its metabolite glycolate; anion gap >27 mmol/L is a strong indication for extracorporeal treatment 1

Salicylate Poisoning:

• High anion gap metabolic acidosis is a hallmark of acute salicylate poisoning 3
• Acidemia with pH ≤7.20 in the setting of salicylate poisoning warrants consideration of extracorporeal treatment 3
• Serum salicylate levels should be monitored during treatment 1

Less Common Causes

• 5-oxoproline (pyroglutamic) acidosis: Associated with chronic acetaminophen use in susceptible individuals 1
• NRTI antiretroviral medications: Can cause severe lactic acidosis with hepatic steatosis (rare, estimated 1.3 cases/1000 person-years) 1
• Severe hyperphosphatemia can cause hyperphosphatemic acidosis 4

Critical Diagnostic Pitfalls

Albumin Correction:

• The anion gap must be corrected for serum albumin level, as hypoalbuminemia can mask an elevated anion gap 5
• The anion gap may underestimate toxicity in cases of hypoalbuminemia 1

Delta-Delta Analysis:

• Compare Δ anion gap/ΔHCO3- to identify mixed acid-base disorders 2
• Ratio of 1 suggests simple anion gap acidosis 2
• Ratio <1 indicates superimposed non-gap acidosis 2
• Ratio >1 indicates superimposed metabolic alkalosis 2

Osmolar Gap Considerations:

• The anion gap may overestimate glycolate concentration in ethylene glycol poisoning when concomitant acute kidney injury or ketoacidosis is present 1
• An elevated anion gap alone without evidence of specific exposure should not drive treatment decisions 1
• Glycolate can falsely elevate plasma lactate concentration on some analyzers, potentially confusing the clinical picture 1

Essential Diagnostic Workup

When high anion gap metabolic acidosis is identified:

• Obtain plasma glucose, serum and urine ketones 6
• Measure blood urea nitrogen, creatinine, and complete metabolic panel 6
• Obtain arterial blood gas (or venous pH) 6
• Calculate serum osmolality and osmolar gap 6
• Measure lactate level 6
• Obtain toxicology screen including methanol, ethylene glycol, and salicylate levels 6
• Consider urinalysis looking for calcium oxalate crystals (ethylene glycol) 6
• Laboratory analysis of organic acids can help identify specific causes, particularly in cases of inborn errors of metabolism 1