What are the common causes of an elevated anion gap metabolic acidosis?

Common Causes of Elevated Anion Gap Metabolic Acidosis

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

Primary Causes

Ketoacidosis

• Diabetic ketoacidosis (DKA) results from insulin deficiency with elevated counterregulatory hormones, presenting with blood glucose >250 mg/dL, arterial pH <7.3, bicarbonate <15 mEq/L, and positive ketones 1
• Alcoholic ketoacidosis presents with ketoacidosis but typically has glucose <250 mg/dL, often with hypoglycemia 2
• Starvation ketosis can also produce elevated anion gap, distinguished by clinical history and mildly elevated or normal plasma glucose 2

Lactic Acidosis

• L-lactate acidosis results from tissue hypoxia due to decreased oxygen delivery (shock states, severe hypoxemia, carbon monoxide poisoning) or impaired oxygen utilization (mitochondrial dysfunction) 1
• Can occur in healthy individuals during peak exercise when oxygen delivery is insufficient to meet demand 1
• D-lactate acidosis may occur in patients with prior gastric bypass surgery or short bowel syndrome 3
• NRTI antiretroviral medications can cause severe lactic acidosis with hepatic steatosis, though rare (estimated incidence 1.3 cases/1000 person-years), with high mortality 1

Toxic Ingestions

• Ethylene glycol poisoning causes anion gap acidosis through its metabolite glycolate; anion gap >27 mmol/L indicates severe poisoning requiring immediate hemodialysis 4, 2
• Methanol produces both an anion gap and osmolar gap due to being a low-molecular weight organic compound, with toxic metabolite formate accumulation 1, 5
• Salicylate poisoning causes accumulation of salicylate anions and stimulates lactic acid production 5

Renal Failure

• Uremic acidosis leads to accumulation of organic acids (sulfate, phosphate, hippurate) and impaired acid excretion, typically presenting with elevated BUN, creatinine, and hyperkalemia 1
• Renal failure is a common thread in almost all cases of profoundly elevated anion gap values 6

Less Common Causes

• 5-oxoproline (pyroglutamic acid) accumulation from chronic high-dose paracetamol use, particularly in patients with female gender, sepsis, impaired renal function, or uncontrolled type 2 diabetes mellitus 3
• Hyperphosphatemic acidosis from severe increases in phosphorus concentration, often seen with rhabdomyolysis or exogenous phosphate intoxication 7, 6
• Cyanide and carbon monoxide poisoning cause cellular hypoxia and subsequent lactic acidosis 5
• Biguanides (metformin) can induce lactic acidosis, particularly in patients with renal insufficiency 5

Diagnostic Approach

Calculate the Anion Gap

• Use the formula: Na+ + K+ - Cl- - HCO3- with normal range 8-12 mEq/L; high anion gap is >12 mEq/L 2, 1
• The anion gap represents the difference between unmeasured cations and unmeasured anions; it increases secondary to accumulation of anions other than bicarbonate and chloride 7

Initial Laboratory Workup

• Obtain plasma glucose, serum ketones, urine ketones, blood urea nitrogen/creatinine, electrolytes, arterial blood gases, complete blood count, and urinalysis immediately 2
• Measure blood lactate levels (requires prechilled fluoride-oxalate tubes, immediate transport on ice, processing within 4 hours, collection without tourniquet) 2
• Calculate serum osmolal gap to detect presence of low molecular weight toxins like methanol and ethylene glycol 1
• Check for calcium oxalate crystals in urinalysis if ethylene glycol poisoning is suspected 2

Special Considerations

• The anion gap may overestimate severity with concomitant acute kidney injury or ketoacidosis, or underestimate severity with hypoalbuminemia, co-ingestions of lithium or barium 8, 1
• Elevated glycolate concentration can falsely elevate plasma lactate concentration on some analyzers, potentially confusing the clinical picture 4, 1
• Consider laboratory analysis of organic acids to identify specific causes, particularly in cases of inborn errors of metabolism 1

Common Pitfalls

• Multifactorial pathogenesis is common in cases of profoundly elevated anion gap, usually including renal insufficiency associated with organic metabolic acidosis 6
• Do not rely solely on anion gap without clinical context, as it has poor predictive value if used indiscriminately 2, 8
• Consider paracetamol-induced 5-oxoproline intoxication even when other more obvious causes like lactate, ketones, or renal failure are identified 3
• Be aware that benzoic acid (from dietary supplements) can cause anion gap metabolic acidosis and interfere with salicylate assays 9