This article is part of a series on USMLE Step 1 Study.
A 43-year-old man is brought to the emergency department by his wife. He has headaches, severe abdominal pain with vomiting, and weakness. His vision is also blurry, and he is afraid he is going to lose his vision. His wife is unsure of the duration of his symptoms as she went to bed eight hours ago while he went to work in the garage. When she woke up, she found him lying on the garage floor with an empty bottle of windshield wiper fluid next to him. Which of the following is the most appropriate treatment?
The answer is A. This patient is suffering from acute methanol toxicity. Methanol is the main ingredient of windshield washing fluid, which might be ingested in a suicide attempt. Vision loss and retinal involvement are typical signs of methanol toxicity.
Primary treatment of methanol toxicity
The treatment for methanol consumption is ethanol! The key here is that methanol and ethanol are both metabolized by the same set of enzymes.
Formic acid is incredibly toxic to the body, especially to the retina. So, the goal of treatment of methanol toxicity is to avoid accumulation of formic acid. This can be achieved by ethanol therapy. Ethanol competes with methanol for the active site of the alcohol dehydrogenase enzyme. So, ADH might have converted 10 molecules of methanol –> formaldehyde per second before treatment. If 9 parts of ethanol are added for each 1 part of methanol, ADH will then convert only 1 molecule methanol –> formaldehyde per second. So, accumulation of formic acid will slow tenfold.
I would imagine that, in addition to ethanol competing with methanol for activity at alcohol dehydrogenase, acetaldehyde would also compete with formaldehyde for activity at aldehyde dehydrogenase. I haven’t heard much about this latter mechanism, though. The reason might be that the action of aldehyde dehydrogenase is extremely fast, and so, even with addition of ethanol, conversion of formaldehyde to formic acid still occurs very quickly. In other words, alcohol dehydrogenase mediates the rate-limiting step, and so this is the step we care about.
Another treatment of methanol toxicity is fomepizole. Fomepizole is actually preferred to ethanol. The effect of fomepizole is essentially the same as that of ethanol. Fomepizole, like ethanol, competes with methanol for the binding site of alcohol dehydrogenase. The difference is that fomepizole itself is not metabolized by alcohol dehydrogenase, in contrast with alcohol. Thus the effects of fomepizole might be longer lived.
Fomepizole might also be preferred because it’s inert. One reason methanol toxicity is dangerous is because methanol, like ethanol, is a CNS depressant. Ethanol would prevent the metabolic effects of methanol toxicity, but it could exacerbate the neurological effects. Fomepizole would not cause neurological effects.
CNS depression is one mechanism of methanol toxicity. Methanol’s most dangerous effects, though, are metabolic.
Mechanisms of toxicity: retinal damage
Also mentioned previously is the fact that formic acid is toxic to the retina. Why is this the case? Well, formic acid is an inhibitor of mitochondrial cytochrome c oxidase. Cytochrome C Oxidase, also known as oxidative phosphorylation’s complex IV, is the same protein complex that is targeted by cyanide and carbon monoxide.
Why does formic acid inhibit complex IV, while similar substances, like acetic acid, the analogous metabolite of ethanol, does not? I don’t have a clear answer for this. But one thing I have noticed is that inhibitors of complex IV tend to be very small molecules. That CO inhibits complex IV should be no surprise. CO’s primary, and most well-known, mechanism of toxicity is competitive binding of hemoglobin’s oxygen binding site. So, we know that CO achieves toxicity because of the fact that it resembles oxygen. Well, oxygen is also a substrate to complex IV: recall that complex IV orchestrates the final reaction of OxPhos, which is 1/2O2 + 2H+ –> H2O. Well, if CO looks similar enough to oxygen to bind hemoglobin, it should also look similar enough to oxygen to bind complex IV. I presume that CN- and HCOOH are also small enough to resemble O2, but CH3COOH is not. This is a somewhat unscientific and conjectural explanation, and I ask the audience to step in here.
Why does complex IV inhibition manifest as retinal toxicity? Well, first note that our patient also experienced headaches, weakness and GI distress. So, methanol causes systemic damage. Still, though, methanol poisoning and blindness are always spoken of together. And, blindness isn’t particularly associated with cyanide or carbon monoxide poisoning. So, I’m not sure why the retina would be the first to fall. Also deferring to the audience here.
Mechanisms of toxicity: metabolic acidosis
Formic acid is, well, an acid, so accumulation of this metabolite causes anion-gap metabolic acidosis. This acidosis itself is a primary reason for toxicity. Acidosis inhibits metabolic pathways that deal with a pH gradient, such as OxPhos. Also, severe acidosis can also cause cardiac arrhythmias. The reason for this is that acidosis directly depolarizes the cardiac membrane, causing a predisposition to early afterdepolarization and torsades de pointes.
So, buildup of formic acid is dangerous simply because it’s an acid.
This raises a similar question to that which I brought up earlier, though: why wouldn’t ethanol ingestion, then, cause the same metabolic acidosis?
The answer is simply that the body can do something with ethanol. Acetic acid, the principal metabolite of ethanol, is seamlessly metabolized via the citric acid cycle. This produces NADH, which produces ATP via OxPhos (this is why alcohol contains so many calories!). So, acetic acid doesn’t stick around long enough to cause metabolic acidosis.
Formic acid, on the other hand, has nowhere to go. The body doesn’t deal as much with formic acid on a regular basis. So, it accumulates for long enough to cause metabolic acidosis, as well as the retinal toxicity described earlier.
This discussion, though, raises the possibility of two secondary treatments for methanol toxicity.
Secondary treatments for methanol toxicity
We mentioned that methanol toxicity causes anion-gap metabolic acidosis. So, given this, it only makes sense that we should treat methanol toxicity with sodium bicarbonate, which would raise blood pH.
Another treatment for methanol toxicity, which might be more advanced than what we’d expect on USMLE, but is still very interesting, is folic acid. We mentioned that the body doesn’t encounter much formic acid. However, formate does appear in folate metabolism! Recall that formate converts tetrahydrofolate –>10-Formyl-tetrahydrofolate.
At rest, though, this reaction proceeds pretty slowly, because folate is limiting. However, as a treatment for methanol toxicity, we can give folic acid, which is metabolized to tetrahydrofolate. Tetrahydrofolate is a reactant in the equation formate + TH4 –> 10-F-TH4, and addition of a reactant causes the reaction to proceed faster, causing formate to be eliminated faster. Formate’s one-carbon unit will then go on to produce 5-Methyl-TH4; it will be transferred to B12, and then to homocysteine –> S-Adenyl Methionine; and then it will go on to synthesize specialized products like catecholamines and melatonin.
I thought it was interesting that formate, this dreadful toxin, appears in an obscure corner of a process as benign as folate metabolism.