What causes 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 lactic acid, ketoacids (diabetic, alcoholic, or starvation), toxic alcohol metabolites (methanol, ethylene glycol), salicylates, or uremic toxins in renal failure. 1, 2, 3

Primary Causes by Category

Lactic Acidosis

• Tissue hypoxia from shock, sepsis, or impaired oxygen delivery causes lactate accumulation and is associated with high mortality 2, 3
• Defective oxygen utilization at the cellular level can produce lactic acidosis even without obvious hypoperfusion 3
• Drug-induced lactic acidosis occurs with biguanides (metformin), particularly in patients with renal impairment 2
• NRTI-associated lactic acidosis in HIV patients on antiretroviral therapy presents with prodromal symptoms including unexplained abdominal distention, nausea, vomiting, and generalized weakness 1

Ketoacidosis

• Diabetic ketoacidosis produces acetoacetate and beta-hydroxybutyrate accumulation, typically with glucose >250 mg/dL, pH <7.3, and bicarbonate <15 mEq/L 1, 4, 2
• Alcoholic ketoacidosis presents with ketoacidosis but glucose <250 mg/dL, often with hypoglycemia 1
• Starvation ketosis causes mild ketoacid accumulation with mildly elevated or normal glucose 1

Toxic Ingestions

• Ethylene glycol poisoning produces glycolate and oxalate accumulation, with anion gaps frequently >28 mmol/L associated with 20.4% mortality 5, 1
• Methanol poisoning generates formate, causing severe acidosis with elevated osmolar gap 2, 3
• Salicylate toxicity produces salicylate anions and often concurrent lactic acidosis, typically with mild metabolic acidosis and respiratory alkalosis 4, 3

Uremia

• Chronic renal failure causes retention of unmeasured organic anions (sulfates, phosphates, hippurates) and decreased ammonia secretion, producing mild acidosis 2, 3
• The anion gap in uremia is typically modest compared to other causes 3

Other Causes

• Cyanide and carbon monoxide poisoning impair cellular oxygen utilization, leading to lactic acidosis 2
• 5-oxoproline acidosis (pyroglutamic acidosis) is an uncommon cause that requires systematic diagnostic approach when common etiologies are excluded 6
• Polyhydric sugars can induce anion gap acidosis through various mechanisms 2

Important Clinical Considerations

Magnitude and Interpretation

• Anion gaps >27-28 mmol/L indicate severe toxicity in ethylene glycol poisoning and warrant immediate hemodialysis 5, 1, 4
• Anion gaps <20 mEq/L rarely have a defined etiology, while significant elevations almost always signify identifiable acidosis 3
• The type of retained anion affects the magnitude of anion gap increase relative to bicarbonate change—greater with lactic acidosis compared to ketoacidosis 7

Critical Pitfalls

• Hypoalbuminemia causes the traditional anion gap calculation to underestimate the severity of acidosis, requiring correction for albumin level 8, 6
• Concurrent AKI or ketoacidosis may cause the anion gap to overestimate acidosis severity 1, 4
• Wide normal range (8-10 mEq/L) means anion accumulation can be present without exceeding the upper limit of normal 7
• Certain medications (lithium, barium) and conditions (hyperphosphatemia) can falsely alter the anion gap 1
• Elevated glycolate can falsely elevate plasma lactate on some analyzers in ethylene glycol poisoning 1

Diagnostic Approach

• Calculate anion gap using: Na+ + K+ - Cl- - HCO3- 1, 4
• Obtain arterial blood gases to confirm metabolic acidosis and assess pH 1, 9
• Measure serum lactate (>5 mmol/dL abnormal, >10 mmol/dL life-threatening) using proper technique with prechilled fluoride-oxalate tubes 1
• Check serum and urine ketones to identify ketoacidosis 1, 9
• Calculate osmolal gap if toxic ingestion suspected 1, 9
• Perform urinalysis for calcium oxalate crystals in suspected ethylene glycol poisoning 1, 9