Methanol poisoning: formate and fomepizole
Methanol (an alcohol) is poorly toxic itself; alcohol dehydrogenase (the liver enzyme that breaks down alcohols) converts it to formate (formic acid), and fomepizole (the preferred treatment) blocks that enzyme.
Remember
Methanol is poorly toxic by itself and becomes dangerous once alcohol dehydrogenase converts it to formate, so fomepizole slows that conversion rather than neutralising formate already made.
Memory aid
fomepizole blocks the gate (alcohol dehydrogenase) so the Trojan horse never opens
Methanol is the Trojan horse, poorly toxic on arrival and harmful once the liver enzyme (the gate, alcohol dehydrogenase) opens it up into formate; fomepizole blocks that gate, so the horse never opens.
Methanol is poorly toxic by itself. The damage comes from what the liver does to it. Alcohol dehydrogenase (the liver enzyme that breaks down alcohols) turns methanol into formate (formic acid).
Formate builds up and causes a severe high anion gap metabolic acidosis: the blood becomes acidic because an acid that the laboratory does not routinely measure has built up. That acid widens the anion gap (the calculated difference between the main positive and negative ions in the blood). Formate also blocks cytochrome oxidase, an enzyme in the mitochondria (the cell's energy-producing structures) that cells need in order to use oxygen. The brain and the optic pathway (the nerves that carry vision) are the most sensitive tissues, so blurred vision and even blindness can occur.
A raised osmolar gap (the difference between the measured and calculated concentration of dissolved particles) shows that an extra osmotically active substance, one that adds dissolved particles, is present. With a high anion gap acidosis, it suggests methanol or ethylene glycol (antifreeze).
This pathway also explains the treatment. Fomepizole is a competitive inhibitor of alcohol dehydrogenase. It competes with methanol for the enzyme's binding site (the active site, the part of the enzyme that grips the alcohol), so the conversion slows and less formate is produced. Ethanol (the alcohol in drinks) is an alternative that competes for the same enzyme. Fomepizole acts at the first step, so it limits further acidosis and organ damage but cannot undo acid already made. Folinic acid (a form of folate that helps the body break down formate) is added alongside, sodium bicarbonate buffers the acid, and haemodialysis (which removes both methanol and the toxic products made from it) is used in severe poisoning.
Key facts
- Toxic compound
- formate (formic acid), made from methanol by alcohol dehydrogenase, because methanol is poorly toxic by itself.
- Laboratory picture
- a high anion gap metabolic acidosis with a raised osmolar gap suggests methanol or ethylene glycol (antifreeze) poisoning.
- Most sensitive tissues
- the brain and the optic pathway, so blurred vision and even blindness can occur.
- Preferred treatment
- fomepizole, a competitive inhibitor of alcohol dehydrogenase, so the conversion slows and less formate is produced.
- Alternative
- ethanol competes for the same enzyme.
- Limit of fomepizole
- it limits further acidosis and organ damage but does not remove formate that has already formed, so haemodialysis may still be needed.
- Ethylene glycol
- shows the same pattern, but its toxic acids are glycolate and oxalate (a later product that forms crystals that injure the kidneys), not formate.
Exam traps
- Fomepizole does not work by neutralising formate in the bloodstream. It works earlier in the pathway, by stopping formate from being made, so it does not neutralise formate already made.
- Folinic acid helps dispose of formate, but it does not inhibit alcohol dehydrogenase, so it does not stop formate being produced.
- Activated charcoal binds many poisons in the gut, but it does not bind alcohols such as methanol and ethylene glycol, and the problem is the toxic metabolism of the alcohol already absorbed, so it is not the way to limit toxicity.
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