What are the causes of an elevated anion gap?

Causes of Elevated Anion Gap

Primary Etiologies

The most common causes of elevated anion gap metabolic acidosis can be systematically categorized using the GOLD MARK mnemonic: Glycols (ethylene and propylene), Oxoproline, L-lactate, D-lactate, Methanol, Aspirin, Renal failure, and Ketoacidosis 1, 2.

Ketoacidosis

• Diabetic ketoacidosis (DKA) is characterized by glucose ≥250 mg/dL, ketones in blood/urine, and typically presents with an anion gap around 22 mmol/L or higher 3, 4.
• Alcoholic ketoacidosis presents with mildly elevated or hypoglycemic plasma glucose concentrations, distinguishing it from DKA 1.
• Starvation ketosis similarly presents with normal to low glucose levels and must be differentiated from DKA by clinical history 1.

Lactic Acidosis

• Type A lactic acidosis results from decreased oxygen delivery or tissue hypoxia (shock, sepsis, severe hypoxemia) and carries high mortality 2.
• Type B lactic acidosis occurs from defective oxygen utilization or mitochondrial dysfunction 2.
• Metformin-associated lactic acidosis is characterized by blood lactate >5 mmol/L, anion gap acidosis without ketones, increased lactate:pyruvate ratio, and metformin levels generally >5 mcg/mL 5.

Toxic Ingestions

• Ethylene glycol poisoning produces glycolic and oxalic acids, causing severe metabolic acidosis with anion gaps frequently >28 mmol/L, calcium oxalate crystals in urine, and elevated osmolar gap 6, 7, 8.
• Methanol poisoning generates formic acid, leading to metabolic acidosis, visual disturbances, and elevated osmolar gap 7, 8, 2.
• Salicylate toxicity typically causes mild metabolic acidosis combined with respiratory alkalosis 2, 9.

Renal Failure

• Uremic acidosis develops from decreased ammonia secretion and retention of unmeasured anions (phosphate, sulfate, organic acids), typically causing mild anion gap elevation 2, 10.
• Severe hyperphosphatemia can independently cause hyperphosphatemic acidosis 10.

Less Common Causes

• Pyroglutamic acidosis (5-oxoproline) occurs with chronic acetaminophen use in the setting of malnutrition, causing profound anion gap elevation 11, 12.
• D-lactic acidosis from short bowel syndrome or bacterial overgrowth 1.
• Propylene glycol toxicity from high-dose intravenous medications 1.

Critical Diagnostic Considerations

Laboratory Assessment

• Calculate anion gap using: Na+ + K+ - Cl- - HCO3- (normal range 8-16 mmol/L with potassium included) 1, 4.
• Obtain arterial blood gases to assess pH and severity of acidosis 1, 4.
• Check serum osmolality and calculate osmolar gap when toxic alcohol ingestion suspected 7, 8.
• Measure blood glucose, serum ketones, lactate, renal function, and salicylate levels 1.

Important Pitfalls

• The anion gap may overestimate acidosis severity in patients with concurrent acute kidney injury or ketoacidosis 1, 4.
• The anion gap may underestimate acidosis severity in hypoalbuminemia (each 1 g/dL decrease in albumin lowers anion gap by ~2.5 mmol/L) 6, 1.
• Elevated glycolate can falsely elevate plasma lactate on some analyzers in ethylene glycol poisoning 1.
• Benzoic acid (from sodium benzoate supplements) can cause anion gap acidosis and interfere with salicylate assays 12.
• Certain medications (lithium, barium) and hyperphosphatemia can falsely alter the anion gap 1.

Clinical Context is Essential

• An anion gap <20 mEq/L rarely has a defined etiology and poor predictive value without clinical correlation 1, 2.
• Anion gaps >20 mEq/L almost always signify identifiable acidosis requiring investigation 2.
• For ethylene glycol poisoning specifically, anion gaps >27 mmol/L indicate severe toxicity with 20.4% mortality, while anion gaps <28 mmol/L have much lower mortality 6.