Residency · Residency · Emergency Medicine

Toxic Alcohol Ingestion: Methanol, Ethylene Glycol, and Isopropanol

General Principles

Overview

The toxic alcohols are methanol, ethylene glycol (EG), and isopropanol. Methanol and ethylene glycol are dangerous not because of the parent compounds themselves but because of their toxic metabolites. Isopropanol, by contrast, is toxic from the parent compound and is generally less dangerous than the other two. All three produce an osmolar gap early in the course of poisoning. Methanol and ethylene glycol additionally produce an anion gap metabolic acidosis later, as they are metabolized into toxic acids. The key enzyme in all three pathways is alcohol dehydrogenase (ADH), which converts each parent compound to its respective metabolite.

Sources

Methanol is found in windshield washer fluid, fuel additives, solvents, moonshine, and hand sanitizer substitutes. Ethylene glycol is the main component of antifreeze, which has a sweet taste that makes it attractive to children and pets. Isopropanol is found in rubbing alcohol, hand sanitizers, and cleaning products.

Osmolar and Anion Gaps

Serum Osmolality and Osmolar Gap

The osmolar gap is calculated by subtracting the calculated osmolality from the measured osmolality. The calculated osmolality is determined by the formula: 2(Na) + glucose/18 + BUN/2.8 + ethanol/4.6. The normal osmolar gap ranges from -10 to +10 mOsm/kg, though there is wide variability between individuals. An elevated osmolar gap suggests the presence of an unmeasured osmotically active substance, which may include a toxic alcohol, propylene glycol, mannitol, or contrast dye. Critically, a normal osmolar gap does not exclude toxic alcohol ingestion.

The Gap-Gap Concept

The relationship between the osmolar gap and the anion gap changes over time as the parent compound is metabolized. Early in the course, when the parent compound is still present, the osmolar gap is elevated while the anion gap remains normal. Late in the course, after the parent compound has been metabolized to its acidic metabolite, the osmolar gap normalizes while the anion gap rises. At a mid-point, both gaps may be elevated simultaneously. A normal osmolar gap with a normal anion gap does not exclude toxic alcohol ingestion, because the patient may be between stages or may have ingested a small amount. An elevated anion gap with a normal osmolar gap suggests a late presentation in which the parent compound has already been fully metabolized.

Methanol

Metabolism

Methanol is metabolized by alcohol dehydrogenase to formaldehyde, which is then converted by aldehyde dehydrogenase to formic acid. Formic acid is the toxic metabolite, causing retinal and optic nerve damage as well as metabolic acidosis. Folate serves as a cofactor for the final step of metabolizing formic acid to carbon dioxide and water.

Clinical Presentation

Early in the course (0 to 12 hours), the presentation resembles ethanol intoxication with inebriation, nausea, and headache. Late in the course (12 to 24 or more hours), as formic acid accumulates, visual disturbances develop, including blurred vision, "snowfield" vision, central scotoma, and decreased visual acuity progressing to blindness from retinal toxicity. Severe anion gap metabolic acidosis develops along with CNS effects (headache, confusion, seizures, coma), GI symptoms (abdominal pain, pancreatitis), and basal ganglia necrosis with characteristic putaminal hemorrhage visible on CT or MRI. Co-ingestion with ethanol delays methanol metabolism and may delay the clinical presentation.

Diagnosis

The diagnosis rests on finding an elevated osmolar gap early or an anion gap metabolic acidosis late, or both. Serum methanol levels can be obtained but are often not readily available at most hospitals. Serum formic acid levels require specialized laboratories. Surrogate markers of significant toxicity include severe acidosis with pH below 7.0, elevated lactate, and visual symptoms.

Treatment

Fomepizole (4-methylpyrazole) is a competitive ADH inhibitor that prevents the formation of toxic metabolites and is the first-line treatment. The loading dose is 15 mg/kg IV, followed by maintenance at 10 mg/kg every 12 hours for four doses, then 15 mg/kg every 12 hours (the dose increase accounts for auto-induction of its own metabolism). Fomepizole is very expensive, costing $5,000 to $10,000 or more per course, so some resource-limited settings still use ethanol as an alternative ADH inhibitor. Ethanol is given as a 10 percent IV solution with a loading dose of 7.6 mL/kg, then 1 to 2 mL/kg per hour, targeting a serum ethanol level of 100 to 150 mg/dL. Its disadvantages include CNS depression, hypoglycemia, the need for ICU-level monitoring, and difficulty titrating.

Folic acid or folinic acid (leucovorin) at 50 mg IV every six hours enhances the metabolism of formic acid to carbon dioxide and water. Sodium bicarbonate should be used aggressively to correct acidosis. Hemodialysis removes both methanol and formic acid and is indicated per EXTRIP guidelines when the methanol level exceeds 50 mg/dL (in conjunction with fomepizole), when severe metabolic acidosis is present with pH below 7.15, when visual impairment has developed, when renal failure is present, or when the patient deteriorates despite treatment.

Ethylene Glycol

Metabolism

Ethylene glycol is metabolized by alcohol dehydrogenase to glycoaldehyde, which is further converted to glycolic acid, then glyoxylic acid, and finally oxalic acid. Glycolic acid is the primary cause of the metabolic acidosis. Oxalic acid combines with calcium to form calcium oxalate crystals, which deposit in the renal tubules and cause acute kidney injury.

Clinical Presentation

Stage I (0 to 12 hours) produces CNS depression resembling intoxication, along with nausea and vomiting. Stage II (12 to 24 hours) involves cardiopulmonary toxicity with tachycardia, hypertension, pulmonary edema, and heart failure. Stage III (24 to 72 hours) is characterized by renal toxicity with flank pain, oliguria, acute kidney injury, and hematuria. Hypocalcemia develops as calcium binds to oxalate, and this can produce QTc prolongation, tetany, and seizures.

Diagnosis

Early diagnosis relies on an elevated osmolar gap, while late diagnosis shows an anion gap metabolic acidosis from glycolic acid. Calcium oxalate crystals may be seen on urinalysis, appearing as monohydrate (needle-shaped) or dihydrate (envelope-shaped) forms, though they are present in only about 50 percent of cases. Hypocalcemia and elevated creatinine support the diagnosis. Wood's lamp fluorescence of urine is unreliable because the sodium fluorescein additive in antifreeze is inconsistent and has poor sensitivity. Serum ethylene glycol levels can be obtained if available.

Treatment

Fomepizole is first-line with the same dosing as for methanol. Ethanol is the alternative ADH inhibitor with the same protocol. Pyridoxine (vitamin B6) at 100 mg IV every six hours serves as a cofactor for an alternative metabolism pathway converting glyoxylic acid to glycine. Thiamine (vitamin B1) at 100 mg IV every six hours is a cofactor for a separate alternative pathway. Sodium bicarbonate is used for acidosis. Calcium gluconate or calcium chloride is given for symptomatic hypocalcemia, though repletion should be cautious because it may worsen calcium oxalate deposition. Hemodialysis indications per EXTRIP guidelines include ethylene glycol level above 50 mg/dL, severe metabolic acidosis with pH below 7.15, acute kidney injury, and clinical deterioration despite treatment.

Isopropanol

Metabolism

Isopropanol is metabolized by alcohol dehydrogenase to acetone. Acetone is not a strong acid, which is the key distinction: isopropanol does not produce an anion gap metabolic acidosis. The hallmark laboratory pattern is an osmolar gap without an anion gap metabolic acidosis, combined with ketosis without acidosis.

Clinical Presentation

Isopropanol is the most potent CNS depressant among the toxic alcohols, two to three times more than ethanol. It causes GI symptoms including nausea, vomiting, abdominal pain, and hemorrhagic gastritis. Ketosis without acidosis develops because acetone is a ketone body detected on urine ketone testing. The breath has a fruity odor from acetone. Hypotension occurs in severe cases. Notably, there are no visual symptoms (no retinal toxicity) and no renal failure (no calcium oxalate formation).

Diagnosis

The diagnosis is supported by an elevated osmolar gap, elevated serum ketones or acetonemia, and the absence of an anion gap metabolic acidosis, which is the key distinguishing feature from methanol and ethylene glycol poisoning. Serum isopropanol levels can be obtained if available.

Treatment

Treatment is primarily supportive, as isopropanol toxicity is generally less severe than methanol or ethylene glycol. Fomepizole is not routinely indicated because acetone is actually less toxic than the parent compound. IV fluids are given for hypotension. Charcoal does not bind alcohols effectively. Hemodialysis is rarely needed but should be considered for refractory hypotension, coma, or levels exceeding 400 mg/dL.

Comparison Summary

<image>A metabolic pathway diagram showing the metabolism of all three toxic alcohols side by side. Left pathway: Methanol → (ADH) → Formaldehyde → (ALDH) → Formic acid, with formic acid leading to retinal toxicity and metabolic acidosis. Folic acid cofactor shown enhancing the final step of formic acid to CO2 and H2O. Center pathway: Ethylene glycol → (ADH) → Glycoaldehyde → Glycolic acid → Glyoxylic acid → Oxalic acid, with glycolic acid causing acidosis and oxalic acid combining with calcium to form calcium oxalate crystals causing renal injury. Pyridoxine and thiamine shown as cofactors for alternative pathways. Right pathway: Isopropanol → (ADH) → Acetone (not further metabolized to acid), with acetone causing CNS depression and ketosis without acidosis. All three pathways show the ADH step blocked by fomepizole or ethanol.</image>

<image>A two-panel diagram illustrating the osmolar gap and anion gap relationship over time in methanol and ethylene glycol poisoning. Panel 1 (Early presentation): Large osmolar gap (parent compound present) with normal anion gap — parent alcohol is measured as unmeasured osmoles but has not yet been metabolized to acid. Panel 2 (Late presentation): Normal osmolar gap (parent compound metabolized) with large anion gap metabolic acidosis — toxic acid metabolites now present. A middle zone shows both gaps elevated simultaneously. A warning box states: "A normal osmolar gap does NOT exclude toxic alcohol ingestion — the patient may be in the late phase when the parent compound is fully metabolized."</image>

<image>A urinalysis microscopy image showing calcium oxalate crystals in a patient with ethylene glycol poisoning. The image shows two types: monohydrate crystals (needle-shaped or dumbbell-shaped, labeled) and dihydrate crystals (envelope-shaped or octahedral, labeled). A note states that crystals are present in only approximately 50% of EG poisoning cases and their absence does not exclude the diagnosis.</image>

Clinical Pearls

A normal osmolar gap does not exclude toxic alcohol ingestion, because the patient may be in the late phase when the parent compound has been fully metabolized to toxic acids. The organ-specific patterns are key to differentiation: methanol damages the eyes (visual loss, putaminal necrosis), ethylene glycol damages the kidneys (calcium oxalate crystals, acute kidney injury), and isopropanol causes CNS depression with ketosis but without acidosis. Fomepizole blocks ADH and prevents the formation of toxic metabolites, making it first-line for methanol and ethylene glycol, though its high cost means ethanol remains the alternative where fomepizole is unavailable. Adjunct vitamins should always be given: folic acid for methanol, and pyridoxine plus thiamine for ethylene glycol, as these cofactors enhance alternative elimination pathways. If a patient presents with an osmolar gap, ketones, and no acidosis, isopropanol should be the leading diagnosis. Wood's lamp fluorescence of urine is unreliable for detecting ethylene glycol and should not be used to rule out ingestion. Hemodialysis removes both the parent alcohol and its toxic metabolites and is indicated for severe acidosis, high levels, end-organ damage, and deterioration despite antidotal therapy. Co-ingestion of ethanol delays metabolism of methanol and ethylene glycol, so patients may present late with a delayed toxicity course.

References

• Kraut JA, Kurtz I. Toxic alcohol ingestions: clinical features, diagnosis, and management. Clin J Am Soc Nephrol. 2008;3:208-225.
• Brent J, et al. Fomepizole for the treatment of ethylene glycol poisoning. NEJM. 1999;340:832-838.
• Brent J, et al. Fomepizole for the treatment of methanol poisoning. NEJM. 2001;344:424-429.
• Roberts DM, et al. EXTRIP workgroup recommendations for treatment of methanol poisoning. Crit Care Med. 2015;43:461-472.
• Barceloux DG, et al. American Academy of Clinical Toxicology practice guidelines on the treatment of ethylene glycol poisoning. J Toxicol Clin Toxicol. 1999;37:537-560.

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