There was a man who presented to the emergency room at least 2 days after he drank a home
made snowglobe.
The medical team wasnt told that he drank that snowglobe.
So they didn’t know that he drank the ethylene glycol, which is same toxic alcohol that’s
found in anti freeze.
They did know that he was suffering from ethanol withdrawal.
He came in with an elevated anion gap, metabolic acidosis, along with renal failure, altered
mental status, that progressed to cranial and peripheral neuropathy after the acidosis
corrected.
By the time he came in, his acidosis wasn’t too bad, and he had no osmolal gap.
Cases like this, highlight why ethylene glycol can be hard to diagnose, especially if it’s
a late presentation, because the findings aren’t sensitive or specific to that poisoning.
And if it’s a late presentation, then there’s a likelihood that things are already too late,
for that patient.
So first off, what is ethylene glycol?
Well, it’s an alcohol, but really it’s a di-ol so it has 2 alcohol groups.
It really doesnt look too different from ethanol on paper, but having that extra alcohol group
makes all the difference.
Ethylene glycol by itself, if it’s never metabolized in the body, actually doesn’t
cause harm in humans.
It can cause some mild sedation, but overall, it’s pretty water soluble as is, so the
body can excrete it as is.
The problem is without treatment, the body is gonna do something to it, so that makes
it a TOXIC alcohol.
This is the same as what happens with Methanol, which is found in poorly distilled moonshine.
To get moonshine, you have to distill a wash, which means heating it up.
Heating it up causes the lighter components to vaporize, so you catch those vapors and
condense them back down to a liquid.
Methanol is the lightest alcohol possible, so it’s what gets vaporized first, and when
the person making the moonshine doesn’t throw that head of the distillate away, then
they’re gonna have methanol in their drink.
And methanol is water soluble in itself, so the body can rid of it as is too.
But that’s not what happens.
Methanol is broken down to chemicals that cause blindness.
So why are these TOXIC alcohols?
Well, lets take a look.
How are alcohols broken down?
In the liver we have alcohol dehydrogenase.
That Ase suffix means enzyme.
So in this case, we’re looking at an oxidation of the alcohol functional group to a carbonyl.
Keep in mind primary, secondary and tertiary alcohols make a difference.
Ethanol becomes ethanal, an aldehyde that’s sometimes called acetaldehyde, acetyl aldehyde.
Isopropyl alcohol, which is rubbing alcohol, becomes acetone, which is nail polish remover.
And that’s the final form in the body because this kind of ketone isn’t reactive in the
body like an aldehyde is.
So what happens with the aldehyde?
Well it gets broken down again by aldehyde dehydrogenase.
Ase as in enzyme.
Aldehyde oxidized to carboxylic acid.
Ethanol becomes ethanoic acid, which is vinegar.
Methanol becomes methanoic acid, which is toxic.
And in ethylene glycol’s case glycoaldehyde becomes glycolic acid.
But that second alcohol also needs metabolism.
So glyoxylic acid, then oxalic acid, bringing us back to the patient who drank a snowglobe.
The patient was going through alcohol withdrawal.
While obtaining the history, his son had mentioned that his dad could hear voices and see little
elves dancing around a few nights before.
This likely alcoholic hallucinosis is not the same as the delirium from severe withdrawal.
But important details were 1) that he was in withdrawal, 2) he may have recently binged
on alcohol and 3) he was malnourished because of his chronic alcoholism.
All of these can cause acidosis, which was clear at his admission.
A withdrawal post binge means there could be a sudden, temporary stop on ethanoic acid
production, also known as acetic acid.
Now, that acetic acid can be utilized for energy or it can be converted to acetyl CoA,
which can be used to make fats with the end goal of energy.
It’s not a great source of energy alone explaining why alcoholics become malnourished,
but when ethanol levels in the blood start to fall, then levels stress increase.
Increased stress means increased cortisol, it means increased norepinephrine levels,
promoting lipolysis.
The patient’s in starvation, so insulin becomes low.
This activates lipase, an enzyme that breaks down fats.
Long chain fatty acids go to the mitochondria in the liver, where even more acetyl CoA is
generated.
So much so, that the Krebs cycle becomes overloaded, and ketoacids are made.
The problem with all of this was that the patient’s blood didn’t test positive for
ketones.
That’s not definitive, but whatever the case was, he did have high anion gap metabolic
acidosis.
In the body, the definition of acid is a little bit different than what you learn in chemistry
class.
In high school chemistry, you learn that an acid is a chemical that donates hydrogen ion.
You learn that strong acids completely dissociate, so they give off all their H+, and weak acids
like acetic acid do not completely dissociate.
No one ever forgets their high school chemistry titration experiments.
But thinking about how it happens in the body is a little bit different.
You see, the human body has a good buffer system to maintain pH.
What’s pH?
It’s the negative log of the hydrogen concentration in solution.
Human blood is kept around 7.4.
Any lower, there’s acid.
Any higher, there’s base.
And human pH is maintained in part by breathing.
Fun fact, when people lose a lot of fat from diet and exercise, a lot of that “fat”
is actually breathed out over time.
Because what are fats?
They’re long chains of carbon.
What’s the simplest carbon form from our body?
Carbon dioxide.
So, human body is made of on average 60% water.
Life on earth is carbon-based and needs water and oxygen to survive.
So what happens when carbon dioxide is dissolved in water?
Well some of it forms in to carbonic acid.
But remember, if it’s in water, this is a solution, and carbonic acid isn’t a strong
acid so it doesn’t completely dissociate.
So we have an equilibrium of positive hydrogen ion and negative bicarbonate, which is part
of baking soda.
The more carbon dioxide you have in your body, the more acid you have.
The less carbon dioxide, the more base.
So if you increase your breathing rate, you’re accelerating carbon dioxide removal.
Less carbon dioxide is more base because the equilibrium shifts to help produce more carbon
dioxide to keep up, and that shift consumes acid.
If you stop breathing, then carbon dioxide builds up.
More CO2 means more acid.
But what happens when we go outside this system and have metabolic acidosis?
Meaning the body is either making acids or can’t get rid of them?
Well, This is where things can get confusing.
Body water needs to be electrically neutral, so positive and negative charges need to be
equal.
But… how do you measure pH?
By the hydrogen ion concentration.
Hydrogen is positive, so it has to contribute to the overall positive charges, right?
Well, if you do the math, you’ll find that the hydrogen concentration by that equation
is several million times less than the sodium concentration.
Sodium is the predominant cation, so if H+ is why we’re calling it acidosis, but it’s
also millions of times less than sodium, and also bicarbonate, then why do we call it acidosis?
Well, lets pick the easiest and most abundant ions in serum.
Sodium is overwhelmingly abundant as extracellular fluid, so it’s the main positive charge.
Potassium is around too as a distant second, but it’s more than 20 times less than sodium.
Chloride is the predominant negative charge.
And bicarb isn’t measured directly, the value comes from carbon dioxide.
So if blood is supposed to be electrically neutral, then subtracting the easily measured,
predominant anions from the easily measured predominant cations should be close to zero.
Or if it’s not, then we can collect an average of what that difference is in healthy people.
And that difference is not zero, bringing us to the idea of an anion gap.
The blood has lots of negative charges that aren’t necessarily easy to measure.
Proteins like albumin are negatively charged at physiologic pH.
Other organic anions like lactate can have levels fluctuate in the body at various times
so there’s always an equilibrium to maintain, but there’s also the requirement that positive
and negative must be equal.
So, if we know that there’s going to be a gap no matter what, that there’s always
going to be more negative anions that aren’t accounted for in the body, and that the equation
holds true, then what happens if we rearrange the equation to center on bicarbonate?
That would mean that changes in anions impact changes on bicarbonate.
And what happens when bicarbonate levels change?
Well, that impacts carbon dioxide.
What happens when carbon dioxide levels change?
Acid levels change.
So lets go back to the name, metabolic acidosis.
Metabolic meaning that the body is producing something, causing a large influx of acid.
And that name could be misleading, because by producing anion through metabolism, that
increases the anion gap.
If the gap is larger, then the difference between Sodium and Chloride plus the gap,
which equals bicarbonate, decreases.
Bicarbonate is a base.
What happens when there’s less base?
The blood becomes acidic, due to an increase in anion produced by metabolism.
This equation tells us a lot about acid base disorders.
What happens when there is hypochloremia.
That is low chloride presence in blood?
This can happen from repeat vomiting as a gastrointestinal loss.
Well if chloride decreases, then the total anion goes down.
That means bicarbonate increases, so alkalosis.
What happens when someone takes a diuretic?
That would cause anion excretion, so a decrease in anions.
That would cause bicarbonate to go up, meaning alkalosis.
How about a woman who is having a heart attack.
She goes into cardiac arrest, so her heart stops.
She’s resuscitated but doesnt produce any urine after coming back.
Because of tissue hypo perfusion, the medical team finds elevated lactate, which is an organic
anion.
Additional anion, decreases bicarbonate, causing acidosis.
Remember, doctors didn’t know about this patient’s snow globe at first.
His high anion gap metabolic acidosis was attributed to kidney failure rather than toxic
alcohol ingestion at first because, well there was no osmolal gap.
And a CT scan looked like he could have had a kidney infection, all of which could be
consistent with high anion gap metabolic acidosis, except, after a few days, antibiotics weren’t
working. Because he didn't have an infection.
And after a few days, it may have been to late.
Alcohols dissolved in body water exert a different pressure than water alone, contributing to
something called the osmolal gap, which could be helpful in diagnosing ethylene glycol ingestion
at first, but remember, as the toxic alcohol gets metabolized, less of it is present as
it’s consumed.
That osmolal gap disappears, it becomes harder to diagnose ethylene glycol ingestion, which
leaves the patient with kidney injury.
It takes time to biopsy the kidney and for those samples to return.
It takes time to analyze the urine for presence of crystals.
So because of these, sometimes the poisoning is found too late.
But thinking about the high anion gap, which anion exactly was being produced by ethylene
glycol?
We know alcohol is oxidized to aldehyde, then to carboxylic acid, and again because it’s
a diol, producing oxalate.
Oxalate has a negative two charge.
Meaning to the anion gap equation, it does significantly contribute to the gap term in
context of charge.
So that’s why there’s a profound anion gap metabolic acidosis usually found with
ethylene glycol ingestion.
Not just oxalate, but the other organic acids that are metabolites too.
But from a chemistry standpoint, it can be reactive with things floating around in the
blood.
But what “things” exactly?
Well sodium is positive and it can interact with it.
But the result isn’t anything spectacular.
Potassium is the next most abundant cation and that doesn’t do anything either.
Which brings us to calcium.
Calcium has a tendency to form solids.
I mean, it’s in our bones.
Calcium has a plus two charge, so it binds one to one with oxalate.
Calcium oxalate falls out of solution and becomes a solid crystal.
And as these crystals form, they collect in the kidneys.
The innate immune system reacts.
White blood cells can phagocytose some of the crystals, but then those white blood cells
die in a way that triggers more inflammation, called necroptosis.
More immune cells enter the kidneys, causing damage because signals are sent that something’s
there that shouldn’t be.
These crystals continue to cause damage to the lining of the kidney.
Damage that may not be reversible if not caught early.
So, the part of all this that might disturb people is that over days after ingesting ethylene
glycol, the metabolic acidosis could resolve itself.
This is what happened to the patient who drank a snow globe, as the high anion gap metabolic
acidosis did resolve.
The oxalate is consumed by reacting to calcium and would then no longer be part of the anion
gap equation, because it’s not an anion anymore.
It’s an ionic solid.
No more osmolal gap either since it’s all gone.
And the acid part of it wouldn’t be detectable after days, if someone happens to survive
the original injury.
And this patient happened to survive that initial injury.
But things aren’t done here.
On day 6 of his hospital admission, neurology consult found part of his face drooping.
He had sluggish responses to light and myoclonic jerks of his limbs.
He also had lower distal limb weakness, slow tongue movement and diminished reflexes, all
while complaining of distal neuropathic pains.
It was here that the patient mentioned the home made snow globe that he drank, and let
the medical team know that this was a case of ethylene glycol ingestion.
Oxalate consumes calcium.
Although, hypocalcemia is not a good marker for ethylene glycol ingestion.
It’s not specific and it’s not sensitive to it.
Hypocalcemia could cause twitching.
In some cases, neuropathy from ethylene glycol has been documented several days after ingestion,
but the reasons for it happening are unclear.
The muscle weaknesses could be due to calcium, but there isnt good data out there on why
this happens.
So what would be the treatment for this, had it been diagnosed quickly?
Well, if the breakdown products are what cause the problem, then a solution would be to stop
the breakdown from happening.
Starting from the top, alcohol dehydrogenase can be competitively inhibited.
Ethanol has higher affinity for the active site in the enzyme than ethylene glycol.
Because the body can renally excrete ethylene glycol as is, preoccupying the ADH enzyme
for as long as possible can prevent conversion of the parent toxic alcohol to the toxic metabolites.
There’s also fomepizole, which inhibits ADH.
It has a low rate of toxicity, and for some hospitals where it can be easily available,
it’s good if doctors have a low threshold to use it whenever toxic alcohol ingestion
is suspected.
And really, some cases of the ingestion can be very obvious.
High anion gap metabolic acidosis can be caused by several things that are enshrined in a
few mnemonics that are taught in schools.
It’s not rare and students often see it on rotations.
There was the old MUDPILES which was Methanol, Uremia, Diabetic Ketoacidosis, Paracetamol
Propylene glycol, Infection iron isoniazid, Lactic acidosis, Ethylene glycol, and Salicylate.
But there’s a newer one GOLDMARK, Glycol, oxoproline, L-lactate, D-lactate (from short
bowel syndrome), methanol, aspirin, renal failure, and ketoacidosis.
Acute oxalate nephropathy can also happen from eating too many peanuts, which is a source
of oxalate by itself.
In this case, it’s not broken down by the liver, it’s just something floating around
in large amounts.
The nephropathy can also come from too much vitamin C, and it can also come from starfruit
and iced-tea.
Ethylene glycol toxicity is not fun.
It’s also not easy to diagnose.
Collecting a history on patients in this setting is notoriously difficult, and waiting for
acute nephropathy to happen is impending disaster, because that renal damage is not reversible.
In many cases, these are patients who are alcoholics, who may be going through alcohol
withdrawal.
The treatment happens to be more of that alcohol that caused their withdrawal in the first
place, and that’s if the hospital doesn’t have the medicine fomepizole.
And many hospitals don’t have fomepizole available.
The high anion gap metabolic acidosis, while confusing to understand, centers upon both
the acid base equilibrium equation, the notion that positive and negative charges in the
body water must be equal, and that changes in those charges will triggers shifts in the
amount of acid and base present in the body.
The formation and deposition of calcium oxalate crystals in the kidney tissue induces an inflammatory
response, along with the crystals destroying tissue, which results in permanent kidney
damage, from a parent alcohol that by itself, ironically, is not toxic.
Thanks so much for watching.
Take care of yourself.
And be well.