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Acetaminophen Toxicity and Liver Zone Physiology [#DaVinciCases GI 5 – Physiology Case 3]

Posted on November 29, 2022 By
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This case covers the metabolic pathways involved in acetaminophen toxicity and the physiology of liver zones. #DaVinciCases​ is a video series covering clinical cases that are frequently tested on school exams and the USMLE. Download the PDF notes for this case at

What’s up everybody and welcome to this week’s edition of davinci cases all right so the way this works is we’ve got a clinical case followed by a board style question so we’re going to go through the question stem point out the relevant clinical findings take a look at the question and the answer choices and then kind of divert for a minute and go through the

Relevant concepts to answering the question then we’ll come back and apply those concepts that we went over to answering the question so for this case we’ve got a 37 year old woman presents the emergency room after taking an entire bottle of acetaminophen which acetaminophen is tylenol so an entire bottle of acetaminophen tablets in an apparent suicide attempt she

Denied ingesting any other drugs or alcohol so this is important and you’ll see why when we get into the discussion aspect of this but other drugs and alcohol can have an impact on how acetaminophen is metabolized which can contribute to its level of toxicity as we’ll talk about her only symptoms are abdominal pain and nausea and then her vital signs are temperature

Of 37 degrees celsius so she’s a-febrile heart rate is a little high at 102. blood pressure is 116 over 70. maybe a tad below normal but nothing too concerning respirations are 16 per minute which is kind of on the lower end of normal but still okay and then o2sat is 98 percent so hemodynamically stable respiratory status-wise she’s stable anytime anyone comes in

You know this time we know what the drug is but when someone comes in with a drug overdose you definitely want to be paying attention to the respiratory status especially if they overdosed on opioids which can depress respiratory function so you definitely want to be paying attention to that as well labs are notable for an aspartate amino transferase or ast 634

Which is as you can see much higher than the upper limit of normal of 32 and then alanine amino transferase or alt of 423 which is much higher than the upper limit of normal for alt which is 25 so her liver enzymes are extremely elevated this is what’s called a transaminitis so the question is which of the following zones in the image to the right would be most

Affected in this patient so we have a histology image here and there’s three zones one outlined in yellow one out he outlined here in green and one outlined here in bluish or purplish and it’s abc and it’s asking which of these zones would be most affected so this is a slide of the liver and this slide is generously provided by dr lisa lee from the university

Of colorado school of medicine dr lee is a collaborator of da vinci academy we produced the histology course with her she’s the histology course director at the school of medicine at colorado definitely check out our histology videos and histology course many of them are on youtube and then we have practice questions and lab videos on our website so make sure

You check out our histology offering as well from davinci academy anyways this is a liver slide these are the liver parenchyma and we’ll get more into what the slide shows in a minute here but just kind of to summarize the key findings again here so this is a young woman presenting with acetaminophen toxicity she’s experiencing abdominal pain and nausea which are

Typical symptoms of acetaminophen toxicity again it’s affecting the liver so when or liver inflammation can manifest as you know abdominal pain nausea her vital signs are stable her labs are notable for transaminitis notably an elevated astn alt most likely reflecting an acute liver injury so which zone of the liver parenchyma is most affected by metabolic toxins

That’s essentially what this question is asking you and so if you remember there’s a zone one there’s a zone two and there’s a zone three we’ll go over this in a minute here so it’s asking you which of these is most affected by metabolic toxins which is what acetaminophen would be and we’ll talk about how you characterize the metabolic toxin in a minute here so

The answer is zone three answer choice a here all right guys we’re going to take a quick break from the case right now to let you know that davinci cases are brought to you by da vinci academy which provides online video courses for the medical basic sciences these courses are taught using a variety of teaching methods including bullet point outlines diagrams

Radiology images and chalk talks to explain the fundamental concepts we then teach the application of those concepts to numerous clinical pearls that are frequently tested on medical school exams and the usmle our video courses are available on our website dviacademy.com as monthly subscriptions starting at 9.99 per month each video course has a corresponding

Outline format textbook as well you can find the link to our website in the description below also be sure to use the discount code dc20 to receive 20 percent off any of our video courses now back to the case to understand this first we have to talk about how acetaminophen is metabolized now acetaminophen is one of the most commonly used drugs in the world it’s

For headaches fever joint pain those types of things and so you know obviously taking it isn’t toxic but it’s when you take way too much of it that’s when you get to toxic levels so acetaminophen has been mostly metabolized in the liver there’s a little bit of it that’s processed and released in the kidney which is maybe about five percent but 95 of it happens in

The liver so there’s a process called glucoronidation which gives you acetaminophen gluconeride and that gets you know obviously excreted then you have sulfation which gives you acetaminophen sulfate and this is probably 90 95 percent of how acetaminophen is metabolized even in the liver and so the majority of it goes through that probably five to ten percent

Of it though goes through the cytochrome p450 pathway which is another enzyme for metabolizing toxins drugs you name it all types of things in the liver when it goes through the cytochrome p450 pathway though it produces a molecule called napqi and this stands for n-acetyl para benzoquinonamine for short we’ll call it napqi and so napqi is actually toxic to the

Hepatocytes so you don’t want to have too much of it because then that can cause toxicity so what happens is you have glutathione which is commonly used to essentially clean up cells and so it helps process and clean up napqi so it doesn’t damage the liver and breaks it down into cysteine and mercaptopuric acid and those get excreted and those are of much less

Toxicity and so that’s kind of the liver’s way of dealing with the small amount of napqi that is produced via the cytochrome p450 pathway now what happens is is if you have used up glutathione or depleted it then what happens is you have a buildup of napqi and that is very toxic and can cause significant cell damage there’s some worsening factors here so if you

Have dramatically high levels of acetaminophen then you’re going to obviously over saturate these other pathways and you’re going to actually have to force more that comes through the cytochrome p450 pathway these are essentially going to max out you’re going to max out sulfation and force it through the cytochrome cytochrome p450 pathway so you’re going to have

A significantly high level of napqi and then you’re going to deplete glutathione even further and force it more towards this pathway the other things that can result this is that these glucronidation and sulfation pathways can be saturated by malnourishment they don’t mention that for this patient but that’s just something to be aware of so that can force more

Acetaminophen to go through the cytochrome p450 pathway the other thing is that alcohol actually increases cytochrome p450 activity so ingesting alcohol large amounts of alcohol can increase napqi and then alcohol breakdown so the metabolic process of breaking down alcohol in the liver actually depletes glutathione so for our patient she’s ingested a large amount

Of acetaminophen you’ve maxed out these normal pathways for breakdown of acetaminophen and then created a large amount of napqi and then as a result of just an overwhelming amount of acetaminophen you’ve depleted all your glutathione and then it’s resulted in significant amounts of napqi which leads to cell damage and so then that would that’s what leads to your

Elevated ast and alt and so that’s how you get your transaminitis and more importantly this is really toxic to the liver and so you need it needs to be treated so to understand which zone of the liver gets most affected by metabolic toxins or acetaminophen toxicity we have to understand what a liver asanas is it’s a functional unit of the liver parenchyma and now

The liver can be divided in a number of different functional units but for the purpose of this we’ll just focus on the asanas it’s a triangular shaped with one central vein forming the apex of the triangle so you can see here you have a central vein which is shown here in this histology section and so this forms the apex of the triangle and so again you have zone

One two and three and if you see it’s kind of how in close approximation they are into this central vein so zone one then zone two zone three and you move closer and closer to that central vein now the central vein forms the apex now this is a theoretical sense of organize this or look at this and so you have zone one at the base of the triangle and then you move

Closer zone two and zone three is here the apex or the top portion of the triangle and then the portal triad forms the base of the triangle which would be down here and the portal triad remember contains a branch of the portal vein a branch of the hepatic artery and then a bile ductule the vial ductile is what carries bile remember bile is produced in the liver

And then it’s carried through these ductules into the biliary tree or the bile ducts and then down into you know where it’s released into in small intestines to help digest lipids and fatty acids and so these three zones are actually divided based on the direction of blood flow and blood o2 content you’ll see why that’s important in a second now what’s important

To know is that if we blow this section up here for histology so we’ve taken this section here and made it more magnified you can see each of these this is an h e stain you know hematoxylin and eosin so remember the hepatocytes you know full of proteins they’re going to stain more eosinophilic or this pinkish color here and then these round purple colored circles

Or dots are the nuclei of the hepatocytes and you can kind of see where they form these almost like these channels in between you have these rows of hepatocytes and we’ll show you a diagram here in a second illustrate this but you can appreciate this where it’s these rows of hepatocytes and then you have these channels in between or called sinusoids so the apical

Surface faces the bile cannuliculi which drain into the bile ductule and then the basolateral surface faces the sinusoids so for this diagram here we illustrate how the portal triad plays a role in this so you have the portal triad which would be here at the base of this triangle of the liver asanas kind of at the base of this zone one here remember the portal

Triad you have a branch of the portal vein which the portal vein is actually the main blood supply to the liver it’s formed by the splenic vein and the superior mesenteric vein which both terrain the gi tract and so remember after we absorb a number of nutrients and other things that we ingest through the intestinal tract it actually has to get first processed by

The liver and so that’s why so the portal veins actually the majority of the blood supply the hepatic artery is kind of the back up it provides some of it but only if like the portal vein went down let’s say if you had a thrombosis of the portal vein then the hepatic artery could take over and provide the majority of the blood supply so what’s important though

Is the way they flow and so again we’re just indicating here that you have a dual blood supply to the liver the the portal vein will flow towards the central vein the hepatic artery will also flow towards the central vein and then remember the central vein they all kind of come together and drain into these hepatic veins which then drain as the ivc and send the

Blood back to the heart now remember bile is produced by hepatocytes within the liver parenchyma and so it’s important to remember here is that bile is actually going to flow in the opposite direction of blood in this case in these liver asanas and so it’s going to flow towards this bile ductule make its way there then all of those will drain into the bile ducts

And then make their way into the common bile duct which then goes into the intestines so on the diagram here you have portal venous blood which by this blue arrow as you can see is heading towards the central vein then you have the hepatic arterial blood as well and then you can see we have the green arrow going in the opposite direction and that represents bile

Flow from bile production to the bile ductule so the reason we care about all of this is that if you remember the flow of blood it starts in zone one so this is where you’re going to get the first hit of blood both from the portal vein and from the hepatic artery so this is going to receive the most oxygenated blood remember you haven’t made your way all the way

To this final draining vein so this is the first kind of zone of parenchyma or zone of cells they get first pick essentially of oxygen so they’re going to get the highest amount for zone one by receiving the most oxygenated blood it’s the least susceptible to ischemia so if you have some kind of ischemic event patients in shock you know losing blood something like

That where there’s you know decrease of blood to the liver itself it the least susceptible is going to be zone one now on the flip side because it receives blood first it’s going to be most affected by ingested toxins such as cocaine and then it’s also affected first by viral hepatitis so viral hepatitis traveling through the blood it’s gonna first hit this is the

First zone to be hit because of that it’s the first hit by viral hepatitis now zone two isn’t that interesting it’s kind of it’s called the intermediate zone it’s between zone one and zone three a little tidbit it’s affected by yellow fever that’s an infectious disease pearl that you should remember sometimes it’s asked on your could be asked on your board exam

So just keep that in mind but other than that the intermediate zone there’s not much else to it zone three by the time again by the time you got into zone three that you’re receiving the least oxygenated blood because you’ve given up a lot of oxygen to zone one and zone two so for that reason it’s the first affected by ischemia so if you have ischemia again zone

Three is going to be the first one where you’re going to have you know potentially cell death and cell necrosis it also contains the highest concentration of cytochrome p450 remember that enzyme we’re talking about that is involved in you know drug metabolism acetaminophen metabolism the at the highest concentration is here in zone three for that reason it’s the

Most sensitive to metabolic toxins so when toxins are getting broken down it’s predominantly in zone three by the cytochrome p450 pathway is it is a major player in the breakdown of toxins so then it’s going to get affected same thing with alcohol remember alcohol is also involved in the cytochrome p450 metabolism this is going to be the most affected by alcohol

So remember anything that’s like metabolized in the liver whether it’s alcohol drugs any of those types of things that are metabolized in the liver it’s going to be this zone three and a big part of that is because it contains the highest concentration of cytochrome p450 the other thing is it receives the lowest amount of oxygen so it’s also affected by first by

Ischemia so zone three can really get hit for a lot of different reasons zone one the big one is that it’s ingested toxins so these are toxins when we say ingest i mean they haven’t been metabolized so they’re just coming to us fresh in the blood they haven’t been metabolized so if we come back to the question here you know unfortunately there’s a young woman with

Acetaminophen toxicity we’re asking which zone in the image to the right is most effective in this patient if we look at this again you have zone three zone two zone one central vein here’s your if you imagine your triangle like this zone three is the answer it’s the zone that receives the least auctionated blood it’s the first zone affected by ischemia for that

Reason it’s also the most susceptible to metabolic toxins such as acetaminophen because of that high concentration of cytochrome p450 zone two the biggest thing to remember there is it’s just affected by yellow fever and then zone one it was it’s the first one to receive perfusion so it’s going to receive the most oxygenated blood it’s also the most effective by

Ingested toxins because it’s the first one to receive blood also for that reason it’s the first zone affected by viral hepatitis so again this is a patient with acetaminophen toxicity and the zone of the liver that will be most affected is zone three all right that’s all i have for you this time be sure to check out all the davinci cases videos available on our

Youtube channel and our website dvi dviacademy.com the pdf notes for every davinci cases is also available on our website also be sure to check out our podcast the davinci hour where we interview attendings and residents across medicine to learn more about their experiences their specialties and to get their insights on navigating a career in medicine you can find

The davinci r podcast on our website or any platform or podcasts are found lastly you can find all of our video courses and corresponding outline of books on our website don’t forget to use the discount code dc20 for 20 percent on

Transcribed from video
Acetaminophen Toxicity and Liver Zone Physiology [#DaVinciCases GI 5 – Physiology Case 3] By DaVinci Academy

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