What are the common causes of a high anion‑gap metabolic acidosis in adults?

Common Causes of High Anion Gap Metabolic Acidosis

The most common causes of high anion gap metabolic acidosis in adults are lactic acidosis, diabetic ketoacidosis, renal failure, and toxic ingestions (methanol, ethylene glycol, salicylates). 1

Diagnostic Framework

Calculate the anion gap using the formula: [Na⁺] - ([Cl⁻] + [HCO₃⁻]), with a normal range of 8-12 mEq/L; values >12 mEq/L indicate high anion gap acidosis. 1

The elevated anion gap reflects accumulation of unmeasured anions—organic acids like lactate or ketoacids, uremic toxins, or ingested toxins. 1, 2

Primary Causes by Category

Lactic Acidosis

• Lactic acidosis results from tissue hypoxia due to decreased oxygen delivery or impaired oxygen utilization, occurring in shock states, severe hypoxemia, carbon monoxide poisoning, or mitochondrial dysfunction. 1
• Blood lactate measurement is essential for diagnosis. 1
• NRTI antiretroviral medications can cause severe lactic acidosis with hepatic steatosis (incidence 1.3 cases/1000 person-years), carrying high mortality. 1
• Monitor serum bicarbonate and electrolytes every 3 months in patients on NRTIs to detect early anion gap increases. 1

Diabetic 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. 1
• Treatment requires fluid resuscitation (isotonic saline 15-20 mL/kg/h initially), insulin therapy (0.1 units/kg/h), and electrolyte management. 1
• Bicarbonate therapy is not indicated unless pH falls below 6.9-7.0. 1

Renal Failure

• Renal failure leads to accumulation of organic acids and impaired acid excretion, typically presenting with elevated BUN, creatinine, and hyperkalemia. 1
• This is one of the three most common causes alongside lactic acidosis and diabetic ketoacidosis. 2

Toxic Ingestions

Methanol:

• Produces both an anion gap and osmolar gap due to being a low-molecular weight organic compound. 1
• Calculate serum osmolal gap to detect presence of low molecular weight toxins like methanol and ethylene glycol. 1

Ethylene Glycol:

• Causes anion gap acidosis through its metabolite glycolate. 1
• An anion gap >27 mmol/L is a strong indication for extracorporeal treatment, while 23-27 mmol/L suggests consideration of treatment. 1
• The anion gap may overestimate glycolate concentration when concomitant acute kidney injury or ketoacidosis is present, and may underestimate toxicity in hypoalbuminemia. 1

Salicylates:

• Acute salicylate poisoning characteristically produces high anion gap metabolic acidosis from salicylate metabolites. 1
• When pH ≤7.20 develops, extracorporeal removal (hemodialysis) should be considered. 1
• Serum salicylate levels should be monitored during treatment. 1

Less Common Causes

5-Oxoproline (Pyroglutamic Acid):

• A rare but important cause of profound high anion gap metabolic acidosis, particularly in malnourished patients with chronic acetaminophen use. 3, 4
• Suspect when the cause remains poorly defined, the anion gap cannot be explained by measured organic acids, and there is concomitant acetaminophen use. 4
• Requires urinary organic acid screening for diagnosis. 1, 4

Hyperphosphatemic Acidosis:

• Severe increases in phosphorus concentration can cause high anion gap acidosis. 2

Drug-Induced:

• Biguanides, alcohols, polyhydric sugars, cyanide, and carbon monoxide can induce anion gap acidosis through accumulation of organic anions like lactate or toxic anions. 5

Critical Diagnostic Pitfalls

• An elevated anion gap alone without evidence of specific exposure should not drive treatment decisions, as multiple factors can contribute. 1
• Glycolate can falsely elevate plasma lactate concentration on some analyzers, potentially confusing the clinical picture. 1
• The traditional "MUDPILES" mnemonic (methanol, uremia, diabetic ketoacidosis, paraldehyde, isoniazid/iron/inborn errors, lactic acid, ethylene glycol, salicylates) is usually sufficient but does not address all etiologies including organic acids like 5-oxoproline. 3
• Laboratory analysis of organic acids can help identify specific causes, particularly in cases of inborn errors of metabolism. 1