What are the causes of toxin-related metabolic acidosis?

Causes of Toxin-Related Metabolic Acidosis

Toxin-related metabolic acidosis is primarily caused by toxic alcohols (methanol, ethylene glycol), salicylates, and metformin, which produce high anion gap acidosis through accumulation of toxic metabolites that induce severe acidemia, organ failure, and death if untreated. 1, 2, 3

Primary Toxic Causes by Mechanism

Toxic Alcohols

• Ethylene glycol poisoning causes metabolic acidosis through its toxic metabolites—glycolic acid (which contributes to acidemia) and calcium oxalate crystals (which cause acute kidney injury and neurological complications)—with acidosis typically appearing 3-6 hours post-ingestion after a latent period. 4
• Methanol poisoning produces formic acid as its toxic metabolite, inducing severe metabolic acidosis, visual disturbances, blindness, seizures, stupor, coma, and death. 2, 3
• Both toxic alcohols are metabolized by alcohol dehydrogenase, and their concentrations diminish as they convert to toxic metabolites, making diagnosis challenging and requiring frequent monitoring of both toxin levels and acid-base balance. 2, 3

Salicylate Toxicity

• Salicylate poisoning typically presents with mild metabolic acidosis combined with respiratory alkalosis, caused by uncoupling of oxidative phosphorylation. 5, 6
• The metabolic acidosis from salicylates is usually mild but can be accompanied by elevated anion gap. 6

Metformin-Associated Lactic Acidosis

• Metformin causes lactic acidosis with an incidence of 2-9 per 100,000 patients/year, with risk dramatically increasing in renal impairment (eGFR <30 mL/min/1.73 m²). 7
• Risk factors include elderly patients (>65 years), renal dysfunction, liver disease, sepsis/shock, and acute decompensation of chronic conditions. 7

Secondary Mechanisms of Toxin-Induced Acidosis

Lactic Acidosis from Medications

• Nucleoside reverse transcriptase inhibitors (NRTIs), particularly stavudine and didanosine, cause mitochondrial toxicity by inhibiting DNA polymerase γ, with an incidence of 1.3 cases per 1,000 person-years of NRTI exposure. 7
• Risk factors for NRTI-induced lactic acidosis include obesity, female sex, prolonged use (>6 months), and pregnancy. 7

Pyroglutamic Acidosis

• Impaired ammonia production by the proximal tubule plays a major role in the development of metabolic acidosis in pyroglutamic acidosis. 5
• This can occur with chronic acetaminophen use, particularly in malnourished patients. 4

Diagnostic Approach Algorithm

Step 1: Calculate Anion Gap

• High anion gap (>16 mEq/L) indicates presence of unmeasured organic anions and narrows differential to specific toxins. 1, 6
• Anion gap = Na - (Cl + HCO3). 1

Step 2: Calculate Osmolal Gap

• Osmolal gap is elevated (>30 mOsm/L) in methanol, ethylene glycol, and propylene glycol ingestions, providing crucial diagnostic information. 1, 5
• A modest increase in osmolal gap (<30 mOsm/L) suggests lower toxin levels and may require adjusted treatment dosing. 5

Step 3: Identify Specific Clinical Clues

• Visual disturbances or blindness → suspect methanol poisoning. 2, 3
• Oxalate crystals in urine → suspect ethylene glycol poisoning. 2, 3
• Severe leukocytosis → highly sensitive indicator of ethylene glycol poisoning. 5
• Respiratory alkalosis with mild metabolic acidosis → suspect salicylate toxicity. 6
• Renal impairment with lactic acidosis → suspect metformin accumulation. 7

Step 4: Measure Specific Toxin Levels

• Obtain serum ethylene glycol or methanol concentrations when suspected based on history, anion gap metabolic acidosis, increased osmolar gap, or clinical signs. 2, 3
• Measure serum lactate in all cases of suspected lactic acidosis, with levels >2 mmol/L considered elevated, >5 mmol/L abnormal, and >10 mmol/L life-threatening. 7

Critical Management Principles

Immediate Treatment for Toxic Alcohols

• Begin fomepizole treatment immediately upon suspicion of ethylene glycol or methanol ingestion, even before confirmatory levels return, based on patient history and/or anion gap metabolic acidosis, increased osmolar gap, visual disturbances, or oxalate crystals in urine. 2, 3
• Loading dose: 15 mg/kg IV, followed by 10 mg/kg every 12 hours for 4 doses, then 15 mg/kg every 12 hours thereafter. 2, 3
• Hemodialysis should be considered in addition to fomepizole when ethylene glycol or methanol concentrations ≥50 mg/dL, significant or worsening metabolic acidosis, or renal failure is present. 2, 3

When to Discontinue Treatment

• Discontinue fomepizole when ethylene glycol or methanol concentrations are undetectable or reduced below 20 mg/dL AND the patient is asymptomatic with normal pH. 2, 3

Metformin-Associated Lactic Acidosis

• Discontinue metformin immediately in patients with sepsis, acute kidney injury, or hemodynamic instability. 7
• Hemodialysis is the definitive treatment for metformin-associated lactic acidosis and often reverses symptoms. 7

Common Pitfalls to Avoid

• Do not wait for confirmatory toxin levels before initiating fomepizole treatment in suspected toxic alcohol ingestion—treatment should begin immediately based on clinical suspicion. 2, 3
• Do not rely on a single ethylene glycol or methanol level—concentrations diminish as they are metabolized to toxic metabolites, so both toxin levels and acid-base balance must be frequently monitored. 2, 3
• Do not ignore modest osmolal gap elevations (<30 mOsm/L)—these still indicate toxic alcohol ingestion but may require adjusted ethanol dosing if used. 5
• Do not overlook urine osmolal gap in suspected ethylene glycol poisoning—it can be diagnostically useful, though not for methanol poisoning. 5
• Do not continue metformin in patients with acute illness, sepsis, or renal impairment—the risk of lactic acidosis increases dramatically. 7