What are the causes of high anion gap metabolic acidosis in children?

Causes of High Anion Gap Metabolic Acidosis in Children

The most common causes of HAGMA in children are lactic acidosis (from hypoxia, sepsis, or hypovolemia), diabetic ketoacidosis, inborn errors of metabolism (organic acidemias and urea cycle disorders), and toxic ingestions (methanol, ethylene glycol, salicylates). 1, 2

Primary Etiologic Categories

Lactic Acidosis

• Tissue hypoperfusion from hypoxia, sepsis, gastroenteritis, and hypovolemia represents the most frequent cause of HAGMA in pediatric patients, particularly in infants and young children. 2
• Lactic acidosis from decreased oxygen delivery or defective oxygen utilization carries high mortality and requires immediate restoration of tissue perfusion rather than bicarbonate therapy. 3

Ketoacidosis

• Diabetic ketoacidosis presents with glucose >250 mg/dL, pH <7.3, bicarbonate <15 mEq/L, and anion gap >10-12 mEq/L, with severity directly correlating to the degree of anion gap elevation. 4
• Starvation ketosis produces milder acidosis with bicarbonate typically not falling below 18 mEq/L, distinguishing it from DKA. 4

Inborn Errors of Metabolism

• Organic acidemias (methylmalonic acidemia, propionic acidemia, isovaleric acidemia, multiple carboxylase deficiency) occur in approximately 1 in 21,000 births and cause mild to moderate hyperammonemia with HAGMA through competitive inhibition of N-acetylglutamate synthase. 1
• Mitochondrial respiratory chain defects can present with severe HAGMA and elevated anion gap, often proving fatal despite aggressive intervention. 2
• These metabolic disorders typically present in neonates within the first few days of life after feeding begins, when maternal placental transport is no longer available for waste elimination. 1

Toxic Ingestions

• Methanol and ethylene glycol poisoning produce severe acidosis with elevated osmolar gaps; ethylene glycol toxicity with anion gap >27 mEq/L indicates severe poisoning requiring immediate intervention. 4, 3
• Salicylate toxicity typically presents with mild metabolic acidosis accompanied by respiratory alkalosis, distinguishing it from other toxic ingestions. 3
• Treatment for methanol and ethylene glycol requires alcohol infusion to block formation of toxic metabolites plus dialysis for toxin removal. 3

Renal Failure

• Uremia causes mild HAGMA secondary to decreased ammonia secretion and retention of unmeasured anions (phosphate, sulfate, organic acids). 3
• Severe hyperphosphatemia can independently cause hyperphosphatemic acidosis. 5

Drug-Induced Causes

• Topiramate causes metabolic acidosis at doses as low as 50 mg/day in adults, with 67% of pediatric patients (<16 years) experiencing persistent bicarbonate decreases at approximately 6 mg/kg/day. 6
• Moderately severe metabolic acidosis has been reported in children as young as 5 months, especially at doses above 5 mg/kg/day, with average bicarbonate decreases of 4 mEq/L and rare severe decrements below 10 mEq/L. 6
• 5-oxoproline (pyroglutamic acid) accumulation from chronic acetaminophen use in susceptible individuals disrupts the gamma-glutamyl cycle, causing recurrent HAGMA that may be missed on standard toxicology screens. 7

Diagnostic Approach

Calculate the Anion Gap

• Anion gap = Na⁺ − (HCO₃⁻ + Cl⁻), with normal values 10-12 mEq/L; values >12 mEq/L signify accumulation of unmeasured anions such as lactate, ketoacids, uremic toxins, or ingested toxins. 8
• An anion gap <20 mEq/L rarely has a defined etiology, but significant elevations almost always indicate an identifiable acidosis. 3

Essential Laboratory Evaluation

• Obtain arterial blood gas for pH and PaCO₂ determination, serum electrolytes (Na, K, Cl, bicarbonate), plasma glucose, urea, creatinine, and serum/urine ketones. 4
• Measure lactate levels, toxicology screen including acetaminophen, methanol, ethylene glycol, and salicylates, and calculate effective serum osmolality: 2[Na (mEq/L)] + glucose (mg/dL)/18. 4, 3
• For unexplained HAGMA with negative standard workup, obtain urinary organic acid screen to detect inborn errors of metabolism or 5-oxoproline accumulation, particularly if there is concomitant acetaminophen use. 2, 7

Urine Studies

• Determine urine pH and anion gap to distinguish proximal from distal renal tubular acidosis when metabolic acidosis persists without clear etiology. 2

Critical Clinical Pitfalls

• Never assume lactic acidosis is the sole cause without excluding toxic ingestions and inborn errors of metabolism, especially in neonates and infants with unexplained severe acidosis. 1, 2
• Bicarbonate therapy is contraindicated in most HAGMA cases except when pH falls below 6.9-7.0 in DKA or below 7.1 in other severe acidoses, as bicarbonate generates CO₂ and may worsen outcomes. 8, 3
• In DKA, stopping insulin once glucose normalizes before acidosis resolves causes rebound hyperglycemia and ketoacidosis; continue insulin at 0.05-0.1 U/kg/h with dextrose-containing fluids until bicarbonate ≥18 mEq/L and pH >7.3. 4
• Suspect 5-oxoproline acidosis when HAGMA remains poorly defined, the anion gap cannot be explained by measured organic acids, and acetaminophen use is present, as standard toxicology screens are negative. 7
• Monitor for topiramate-induced acidosis in all pediatric patients receiving this medication, with baseline and periodic bicarbonate measurements; consider dose reduction or discontinuation if persistent acidosis develops, or add alkali therapy if continuing the drug. 6