What are the causes of anion gap metabolic acidosis?

Causes of Anion Gap Metabolic Acidosis

The primary causes of anion gap metabolic acidosis include diabetic ketoacidosis, lactic acidosis, toxic alcohol ingestion (methanol and ethylene glycol), salicylate poisoning, and chronic renal failure. 1, 2

Calculation and Definition

• The anion gap is calculated as: (Na+) - (Cl- + HCO3-), with normal values being 8-12 mEq/L and high anion gap defined as >12 mEq/L 2
• An anion gap >10-12 mEq/L is considered abnormal and warrants investigation 1
• The anion gap represents the difference between unmeasured cations and unmeasured anions, increasing when anions other than bicarbonate and chloride accumulate 3

Major Causes by Category

Ketoacidosis

• Diabetic ketoacidosis results from insulin deficiency with elevated counterregulatory hormones, with diagnostic criteria including blood glucose >250 mg/dL, arterial pH <7.3, bicarbonate <15 mEq/L, and positive ketones 2
• Alcoholic ketoacidosis occurs from alcohol consumption and starvation, producing ketoacid accumulation 4

Lactic Acidosis

• Lactic acidosis results from tissue hypoxia due to decreased oxygen delivery or impaired oxygen utilization 2
• This can occur from shock states, severe hypoxemia, carbon monoxide poisoning, or mitochondrial dysfunction 5, 6
• Blood lactate measurement is essential for diagnosis 2
• NRTI antiretroviral medications can cause severe lactic acidosis with hepatic steatosis, though this is rare (estimated incidence 1.3 cases/1000 person-years), it carries high mortality 5

Toxic Ingestions

• Methanol produces both an anion gap and osmolar gap due to being a low-molecular weight organic compound, with toxic metabolite formate causing the acidosis 2, 4
• Ethylene glycol poisoning causes anion gap acidosis through its metabolite glycolate; an anion gap >27 mmol/L is a strong indication for extracorporeal treatment, while 23-27 mmol/L suggests consideration of treatment 5
• Salicylates typically cause mild metabolic acidosis often accompanied by respiratory alkalosis 4
• Calculate the serum osmolal gap to detect presence of low molecular weight toxins like methanol and ethylene glycol 2

Renal Failure

• Chronic renal failure leads to accumulation of organic acids and impaired acid excretion, typically presenting with elevated BUN, creatinine, and hyperkalemia 2
• Uremia causes mild acidosis from decreased ammonia secretion and retention of unmeasured anions 4

Drug-Induced Causes

• Biguanides (metformin) can cause lactic acidosis 6
• Cyanide and carbon monoxide poisoning produce lactic acidosis from impaired oxygen utilization 6
• Polyhydric sugars can accumulate and cause anion gap acidosis 6

Clinical Pitfalls

• The anion gap may overestimate glycolate concentration in ethylene glycol poisoning when concomitant acute kidney injury or ketoacidosis is present 5
• The anion gap may underestimate toxicity in cases of hypoalbuminemia or co-ingestions of lithium or barium 5
• Hypoalbuminemia makes traditional anion gap calculations inaccurate, as albumin is a major unmeasured anion 7
• An elevated anion gap alone without evidence of specific exposure should not drive treatment decisions, as multiple factors can contribute 5
• Glycolate can falsely elevate plasma lactate concentration on some analyzers, potentially confusing the clinical picture 5

Diagnostic Approach

• When anion gap is significantly elevated (>20 mEq/L), a defined etiology can almost always be identified 4
• Laboratory analysis of organic acids can help identify specific causes, particularly in cases of inborn errors of metabolism 2
• In toxic alcohol ingestion, calculate the osmolal gap as an additional diagnostic tool 2
• Monitor serum bicarbonate and electrolytes every 3 months in patients on NRTIs to detect early anion gap increases 5