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Thursday, January 29, 2015



A Student Ate 5-Day-Old Pasta For Lunch.
This Is How His Liver Shutdown.
AJ is a 20 year old man, presenting to the emergency room with abdominal pain, nausea,
and diffuse bleeding.
Paramedics were scrambling because he kept vomiting in the ambulance until he fell unconscious.
AJ was a struggling college student.
Like most other people born in his time, he was looking forward to crushing student loan
debt that would wipe away his entire adult life.
The most affordable food for him was cheap pasta, cooked with premade sauce.
AJ would make all his food for the week on Sunday.
He’d refrigerate it into containers.
This way, he could ration it by day, but sometimes, he’d accidentally leave his food out overnight,
and then eat it following morning.
His friends loved to joke that one day, AJ would die of food poisoning.
Except this time, it wasn’t really a joke.
Earlier in the week, AJ accidentally left his pasta out for 2 days.
He typically would have thrown that away, but his roommate didn’t know.
He thought it may have just been out for a few hours so he put it back into the fridge.
As AJ reheated the now 5 day old pasta that was left out for 2 days, he thought it smelled
kind of strange.
But, he used a different brand of sauce this time, so he didn’t think much of it.
Immediately after finishing the entire plate of pasta, AJ’s stomach started to hurt.
He was bloating.
He could feel gas build up in his stomach and the flatulence was so embarrassing, he
had to go outside to air out his pants.
A stinging pierced through his cheeks and he could feel his eyes push out of his skull
as he suddenly vomited in a way like never before.
That pasta must have been no good, he thought.
It’s probably just a little food poisoning, he thought.
Back in his dorm room now, AJ in a world of hurt, joked to his roommate Bradley that more
than just pasta had exited his body from both ends.
Hoping that he’d feel better, he went to bed, but before that, he made sure to drink
an entire bottle of stomach medicine in hopes that it would do something for the nausea,
vomiting and diarrhea.
But it wasn’t enough.
3 am.
AJ, laying in a pool of cold sweat, runs to the bathroom to huddle over the sink for a
couple more hours.
As his roommate goes into the bathroom, he sees AJ passed out on the floor, his skin
and the whites of his eyes a sickly greenish yellow.
AJ gets up and weakly stumbles around before falling down again.
Bradley calls for 911 and AJ is brought to the emergency room where we are now.
Given this history of present illness, it’s clear that AJ is suffering from some kind
of food poisoning that is causing liver failure.
But to the medical team, that's not immediately obvious.
AJ is an otherwise healthy 20 year old man, who wasn’t taking any medicines.
Given that he’s coming from a college dorm, and he was vomiting and became unconscious,
then that sounds like it could be an alcohol poisoning case.
The yellowing of his skin and eyes is called jaundice and it comes from a chemical called
bilirubin something that makes poop brown and is produced from breaking down red blood
cells in the liver.
And if bilirubin is floating around in the blood making the skin yellow, then it means
the liver is probably damaged, which brings us back to the suspicion of alcohol poisoning
as that can damage the liver.
Similarly, another cause of liver damage and unconsciousness in a healthy, college-aged
person could be a drug overdose, of which even the roommate may not be aware.
Except, a blood test finds no evidence of alcohol or drug use.
Instead, it’s found that AJ has hypoglycemia.
Hypo meaning low.
Glyce from Ancient Greek (γλυκυς) glykys meaning sweet referring to sugar.
and Emia meaning presence in blood.
Low Sugar Presence in Blood.
AJ ate his last meal of spoiled pasta about 16 hours ago.
Blood sugar levels spike after eating, and level off 4 hours after, wherein the human
body continuously works to maintain normoglycemia, but for AJ, that mechanism isn’t functioning,
meaning something that’s supposed to be releasing that sugar, isn’t releasing it.
Hypoglycemia by itself, is a relatively nonspecific problem.
It means you could have several different problems that could be causing it.
But given that the liver is the most immediate source of stored sugar, then this developing
developing hypoglycemia could give us a biochemical basis for explaining his fulminant liver failure.
You see, the liver is a highly metabolic organ.
You can’t live for very long without one.
Everything that enters your mouth, ends up in the liver, as it breaks down chemicals
and red blood cells, secretes bile for digestion, makes blood clotting factors that stop you
from bleeding, and processes proteins, among other functions, and it maintains blood sugar
levels, bringing us back to metabolism.
Sugar, or glucose is the cell’s primary source of energy, and the liver, to perform
all these functions, commands a high demand of cellular energy.
Given that glucose is no longer being released from the liver into the blood stream, then
it indicates that there is likely a metabolic problem developing inside AJ’s liver.
And because fatty acids are oxidized into glucose, which then results in ATP production,
then it means there is likely fatty deposits growing inside, stopping all essential liver
functions.
We can assume here that AJ’s food poisoning from rotten pasta is likely from some kind
of bacterial, maybe fungal source, but something’s wrong.
Typically food poisoning just causes stomach inflammation, nausea, vomiting and diarrhea.
It doesn’t typically cause acute liver failure, and even worse, we can’t find out which
bacteria is causing the problem because culturing it would take days.
Days that AJ doesn’t have, because his liver is quickly shutting down.
His response to broad spectrum antibiotics is limited.
Additional blood tests find multiple liver enzymes, floating around in his blood at a
level 500 times the upper limit of normal, meaning parts of his liver have started to
die and are circulating now all throughout his body.
His kidneys are starting to fail because analysis of his urine finds blood in it.
In liver failure, especially with the presence of bacteria, the body signals to the immune
system that something’s wrong.
White blood cells and inflammatory markers rush to the site, and vasodilate the splanchnic
arteries.
From Ancient Greek splankhnikos meaning entrails.
Because about 30% of systemic blood is in the splanchnic circulation, this volume expansion
decreases the effective blood volume.
The heart detects this and secretes hormones to tell the body to hold on to water and sodium,
and to constrict all other blood vessels, including the ones going into the kidneys,
preventing blood flow in and causing acute renal injury in conjunction to fulminant hepatic
failure.
If there is no available liver for transplantation within the next day, AJ has minimal odds of
survival.
The idea of liver failure arising from toxic compounds ingested orally was not understood
until recent times.
In 1778, the ackee tree was transported to Jamaica from Western Africa by the British.
In 1875, unripened ackee fruit was consumed by people, followed by a record of vomiting,
hypoglycemia, hyperammonemia, elevated liver enzymes in blood, and fat buildup in the liver.
This was named Jamaican Vomiting Sickness.
It was found 100 years later in 1976 that hypoglycin A is the chemical that inhibits
liver mitochondrial activity, leading to fatty acid build up, hypoglycemia, hyperammonemia,
resulting in liver failure.
A famous description of aspirin overdose in children in the 1960s was published and named
Reye’s syndrome.
It was noted that children who received aspirin for fever reduction from the flu had a syndrome
of hypoglycemia, hyperammonemia, elevated liver enzymes and metabolic acidosis, symptoms
that looked very similar to those who suffered from Jamaican Vomiting Sickness.
We know today that excess aspirin uncouples the electron transport chain in mitochondria
during ATP synthesis, leading to fat buildup and liver failure.
Today, any aspirin prescribed for a child is considered a mistake and at medication
dispensing will almost always be substituted for a different drug.
For AJ, no liver was available in time for transplant and autopsy opened the opportunity
for further investigation.
Liver histologies revealed diffuse microvesicular steatosis, that is small vesicles of fat that
had accumulated inside his liver.
The cellular necrosis, that is, dead cells suggested that mitochondrial toxins were at
play meaning that bacteria may not have been the only problem with his spoiled pasta.
Post-mortem laboratory experiments and bacterial cultures were developed.
Samples of AJ’s vomit were collected while he was admitted, in addition to bile and the
pasta he ate.
The bacteria Bacillus Cereus was identified as the causative agent.
It’s well known as a foodborne pathogen that causes gastritis.
By itself, the food poisoning that results from it is usually self-limiting, meaning one can
recover from it through intrinsic bodily function.
But for AJ, a second agent was found.
Additional lab methods were used to detect, extract, isolate and purify the toxin from
Bacillus Cereus cultures, revealing the protein known as cereulide, which points us to the
final answer of AJ’s case.
Certain strains of Bacillus Cereus produce cereulide in its microenvironment.
This protein is an ionophore, meaning it has an affinity for 1 specific electronically
charged ion, namely, potassium.
For the bacteria, excess potassium is beneficial in its survival locally, but in humans this
is highly toxic.
Cereulide easily diffuses through cell membranes.
Inside, they embed onto the surface (inner membrane) of the mitochondria.
Human intracellular fluid is potassium rich, meaning it gives this toxin sufficient resources
to perform its ionophoresis, incessantly pumping potassium into the mitochondria.
This eventually overloads the ability of mitochondria to perform oxidation required to produce ATP
and energy, therefore preventing the use of glucose and fats.
The gradual swelling of the mitochondria causes it to burst, killing the cell, and on a macroscopic
scale, allows fat to pool into the liver, and causing the entire organ to fail, leading
to regional inflammation, splanchnic vasodilation, leading to the heart to release hormones for
the body to hold on to water, and to constrict the blood vessels of the kidneys, causing
kidney failure, and releasing ammonia and glutamate, that leads to swelling of the brain,
ending in death.
All because AJ unknowingly ate pasta that was left out unrefrigerated for 2 days.
The final link in this case comes not from the pasta.
but that stomach medicine AJ drank after initially vomiting
Bismuth subsalicylate is a salicylate, or more colloquially known as aspirin.
Aspirin overdoses, just like in Reye's Syndrome also result in liver failure because aspirin uncouples the electron
transport chain in mitochondria, preventing conversion of glucose into ATP, causing backing
up of glucose and pooling of fats in tissue.
So adding this medicine overdose to cereulide poisoning resulted in a dual blockade of ATP
synthesis, and leading to acute liver failure.
It’s important to note that this is NOT a typical food poisoning case.
Many people eat pasta, or any other kind of noodle that is left over for a day or two and are fine.
But tragic cases such as this one have been reported in literature, and the fulminant
hepatic failure is sudden, with patient expiration happening within hours after presenting to
the emergency room.
Some particularly tragic published cases are from families who go out on a picnic with
their children, only to have multiple small kids under 10 years old suffer from sudden
liver failure due to spoiled pasta.
And the end of those stories, are the same as in AJ's case.
Be careful of food left out for more than a few hours.
If food smells funny, it’s always better to be safe than sorry, and for cases like
cereulide poisoning, sometimes there isn’t much time left after initially eating the
spoiled food, just like for AJ.
This case was presented at a grand rounds in Illinois.
It’s based off some famous toxicology cases that all unfortunately had the same ending,
this one modified to teach residents and fellows about acute cirrhosis from microvesicular steatosis
hepatorenal syndrome, and the pathogenesis of cerebral edema in this particular
cereulide poisoning setting.
Thank you so much to all my toxicology colleagues in helping me structure this video to be palatable
for a general audience, and thank you for watching.
Take care of yourself.
And be well.




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