What are the causes of an elevated anion gap?

Causes of Elevated Anion Gap

An elevated anion gap results from accumulation of unmeasured anions in the blood, most commonly from diabetic ketoacidosis, lactic acidosis, toxic alcohol ingestion (methanol/ethylene glycol), and uremic acidosis. 1

Primary Etiologies

The major causes can be systematically categorized:

Ketoacidosis

• Diabetic ketoacidosis (DKA) is the most common cause, typically presenting with glucose ≥250 mg/dL, pH <7.3, and bicarbonate <15 mEq/L 1, 2
• Euglycemic DKA from SGLT2 inhibitors can occur with normal or near-normal glucose levels, making this diagnosis easily missed 3
• Alcoholic ketoacidosis presents with ketoacidosis but glucose <250 mg/dL, often with hypoglycemia 1
• Starvation ketosis shows mild ketoacidosis with mildly elevated or normal glucose 1

Lactic Acidosis

• Results from tissue hypoxia, shock, sepsis, or defective oxygen utilization 1, 4
• Associated with high mortality when caused by decreased oxygen delivery 5
• Can be medication-induced (e.g., biguanides, NRTI antiretrovirals) 1, 6

Toxic Ingestions

• Ethylene glycol produces glycolate and oxalate accumulation, causing anion gaps often >28 mmol/L with ~20% mortality 1
• Methanol generates formate as a toxic metabolite 6, 5
• Salicylates typically cause mild metabolic acidosis with concurrent respiratory alkalosis 5
• These toxic alcohols also produce elevated osmolar gaps, helping narrow the differential 7

Uremic Acidosis

• Chronic renal failure causes retention of unmeasured anions (phosphate, sulfate, organic anions) 1, 4
• Usually produces mild acidosis with decreased ammonia secretion 5

Less Common Causes

• Hyperphosphatemic acidosis from severe phosphorus elevation 4
• Drug-induced: Carbon monoxide, cyanide, polyhydric sugars 6

Calculation and Interpretation

The anion gap is calculated as: Na+ - (Cl- + HCO3-) with normal values 8-12 mEq/L 3

Critical thresholds for intervention:

• Anion gap >27 mmol/L (using K+-inclusive formula) indicates severe toxicity requiring emergent hemodialysis in ethylene glycol poisoning 1, 3
• Anion gap 23-27 mmol/L suggests hemodialysis should be considered 1, 3
• Anion gap >28 mmol/L is associated with significantly elevated mortality (20.4%) 1

Important Caveats

The anion gap has significant limitations:

• Wide normal range (8-10 mEq/L) means mild elevations can be missed 8
• Hypoalbuminemia artificially lowers the anion gap, potentially masking acidosis 1
• Acute kidney injury or concurrent ketoacidosis can overestimate glycolate concentration in toxic ingestions 1, 3
• Lithium or barium co-ingestion falsely lowers the anion gap 1, 3
• The magnitude of anion gap elevation varies by retained anion type—greater with lactate than ketoacids 8

The delta-delta calculation (Δ anion gap/Δ HCO3-) identifies mixed disorders:

• Ratio of 1 suggests simple anion gap acidosis 7
• Ratio <1 indicates superimposed non-gap acidosis 7
• Ratio >1 suggests concurrent metabolic alkalosis 7