DIP Episode 190 - Updated USMLE Step 1 GI Review Series 4

Good morning my name is divine I'm a resident this is episode 190 of the Divine intervention podcasts in this podcast I'm going to be contained the updated gastroenterology review for the US Emily step one I'll be talking about the liver today so let's jump right into it and I'm only able to finish all of the liver today from a new super long podcast so I'll just you know kind of talk about some major things especially like mechanisms and then we'll develop those points for the in future podcast so the thing is I mean why is the liver important well the thing is the liver is important because it helps us a lot with metabolism most of the biochemical pathways you learn in like biochemistry the all many of them emanating the liver things like the urea cycle for example although one good thing about the liver right with all that said is that the liver is actually very good at regenerating right so say for example if you like basically liver almost has like you know like pretty good reserve I mean like if you think about it if you actually cut off up to like 60% of a person's liver yeah you know they won't feel good for a while but actually within like a four to six week period most of that liver master was taken away will eventually be restored right so the thing is the liver actually has a pretty good reserve it's usually pretty good with regenerating so what are some key things that can I guess ultimately cause liver injury well the thing is there's actually like three big things that can cause liver injury right like well I guess like maybe we can call it like three patterns of liver injury right one is where a person has like a cute liver failure right and again we'll talk about causes of all these things the liver is kind of like a nebulostopic for step one so you know we can't talk about these things but you know we can just have like this massive like a cute liver

failure usually it's from like you know like like a drug or if a person has like a viral kind of hepatitis where basically they go from all they were doing fine and then you're beginning to have like signs and symptoms of like hepatic cancer fallopathy within like a two to three week period right typically that's you if you look on histology typically for these people they'll have like massive neckerses of hepatocytes remember hepatocytes at the unitary cells that make up the liver so that's one pattern of liver injury another pattern which is probably the most common right is you know a person just having like chronic liver disease let's say from alcoholism or from Wilson's disease or from alpha one antitripsine deficiency right and typically these people right like the classic finding on histology will be these people having like the bridging fibrosis and the regenerating modules I'll talk about those things in a second and then in some people they may actually have so I guess maybe the third pattern is a person may actually have like liver injury but you look on histology you don't really see many signs of neckerses typically these kinds of things happen where like you know the hepatocytes actually work but they have some problem with like the metabolic function right like a classic example is a person that has like a rice syndrome right like rice syndrome typically it arises because the mitochondria in those hepatocytes have been injured or if you see a person that has something known as like acute fatty liver pregnancy that typically arises because something has happened with with bedoxidation right in the liver hepatocytes right so those the examples of like oh you know this person's liver looks pretty good almost think of it as like a minimal change disease pattern in the liver and the thing is really the liver again like I said it has a lot of reserves you ha

ve to lose like almost like 80 to 90 percent of your liver function for you to begin to have like signs and symptoms of liver failure now what are some clinical features what are some things they may give you in a question stamp that tells you that okay you know this person has liver failure well the thing is the person will have John this right so they'll have like sclerolicturus you have yellowing of the skin right you have low levels of albumin right because remember your liver is the primary producer of albumin and if you have low levels of albumin the oncotic pressure your bloodstream will go down right so those people will get like a peripheral edema and then because the urea cycle is undertaken primarily in the liver right these people can have like very high levels of ammonia so they have a hyper ammonia remember uremia develops from kidney disease hyper ammonia develops from liver disease right so uremia does not develop from from liver disease right because you're not making the urea in the first place right and then these people may have like primary thema right I'll talk about some outro mechanisms behind like the visual dilation because you probably hear this term oh these people have like visual dilation when they have liver disease I'll talk about the mechanisms behind that and then right like the spider and jomas on the skin those are just again like it's like you have like this central arterial and then you have like these dilated arterial that are kind of proceeding from it almost like a star right that's what you classically find in liver disease and then the problem with liver disease is when you liver does not work you begin to have troubles metabolizing estrogen and if you have trouble metabolizing estrogen right you can begin to have things like hypogonadism right in a guy right and you may also see like gynecomastia right because again remember

a gynecomastia I mean estrogen drives the growth of breast tissue another thing that can also happen liver disease people can have like a coagulopathy right so what do I mean by a coagulopathy I just mean that people that have liver disease they are very high risk of bleeding and you may see okay divine why is that the case will think about it most of your clotting factors come from the liver right so the thing is if a person does not have good liver function you're not making those clotting factors right and that can increase the risk of like really nasty bleeds right especially if they already have poor hypertension right they can have these nasty GI bleeds they can have like a very sealed bleed and stuff like that right and the thing is when a person has liver dysfunction because they don't make including factors they have like a high risk of GI bleeds but the thing is in addition to that when you bleed from a gastrointestinal perspective that actually places like a big metabolic load on your liver right because you have to like make the urea cycle happen so that you can break down that blood well I mean the proteins in the blood or guess what in the blood that you have reabsorbed because you've had the GI bleed or guess what if your liver doesn't work it's like you're even worse than the problem even more so it's almost like almost like a self-fulfilling prophecy kind of thing now let's talk about this joint dish of the thing and then I think I'll maybe see some things about bilirubin because ultimately bilirubin comes from I mean joint dish comes from a person retaining bilirubin right that's the ultimate cause of of joint dish and the thing is in fact I think maybe one thing that may be hopefully years to try to differentiate between bilirubin and bi okay the thing is bilirubin is a substance that we ultimately make from the breakdown and metabolism of him okay

now biol is the thing that actually helps you excrete bilirubin okay so bilirubin you get it from the breakdown of him but biol is the thing that helps you excrete that bilirubin and that's one function of biol right but besides that biol also helps us get rid of like too much cholesterol in the body right it's an excretory mechanism and then biol also helps us with like emulsifying the fat that we consume right so that it can be absorbed within the lumen of the GI tract right but the thing is if whatever reason a person is beginning to retain bilirubin right especially if like your total bilirubin in the serum is more than like two milligrams per desglator that will certainly increase the presence risk of of John this so how do we make bilirubin in the first place while bilirubin again starts from again you'll bring down red blood cells right these are like your mononucleoreticulin dofilium reticulo and dothelium system macrophages they bring down red blood cells right as they bring down red blood cells they ultimately foreign him well the thing is that him there is an enzyme known as hemoxygenase that converts that into something called bilirubin and then that bilirubin can then be reduced right it can undergo reduction reaction to bilirubin and the enzyme that does that right must be an enzyme that reduces bilirubin like bilirubin reductase and then the thing is when bilirubin reductase acts on bilirubin you form bilirubin you form indirect bilirubin the thing is indirect bilirubin is not water soluble right so the thing that happens that it gets conjugated with albumin like in the serum and then it travels to the liver right the thing is when it travels to the liver remember the liver the hepatocytes has like two faces one face face one side faces the sinusoid the other side faces the bowel can't look you like okay so the thing is the side of the hepatocytes the

fizzy sinusoid basically thing that happens is that the albumin that's conjugated to the indirect bilirubin you know it kind of passes through the sinusoid gets into the side of soil of the hepatocytes and then through some transport mechanisms it gets delivered to the endoplasmic reticulum the thing is at the endoplasmic at the level of the endoplasmic reticulum we have an enzyme known as UDPGT so UDP glucoronacyl transfer is that would add like glucoronic acid groups to the indirect bilirubin and then that will convert it to something called direct bilirubin or conjugated bilirubin okay so direct bilirubin conjugated bilirubin mean the same thing okay and the thing is conjugated bilirubin is water soluble now that you've made that water soluble conjugated bilirubin it then gets excreted into the bowel now the thing is that conjugated bilirubin you know gets excreted into the bowel that goes through the biliratory mix it's with the dot the thing is in the dot especially in the colon we have like a lot of bacteria that actually express something known as a bit of glucoronides that bit of glucoronides right cleaves those glucoronic acid groups from the conjugated bilirubin right and that ultimately you know the some other things happen and you degrade that conjugated bilirubin to something called a eurobilinogen right now the thing is the eurobilinogen right and you know some breakdown products of it like stucco bilin those are the things that ultimately cause the color of your stool that is why for person has like liver disease or like pancreatic cancer that's obstructing conjugated bilirubin from getting to the GI tract those people have ecolics tools right because the stool color just basically does not does not happen now the thing is it's not all these eurobilinogen that ultimately you know gets to cause your stool color or whatever some of it is actually reabsorb

ed like 20% of it is reabsorbed yeah for the most part reabsorbed like in the terminal helium right and also some parts of the color you know they get back to the liver and then you dump them in bulk again and then you increase the you then do the process all over again and then the thing is some of this eurobilinogen right it ultimately gets broken down to like eurobilin and that eurobilin is responsible for the color of a person's ear so again this pathway I just described is a very very high your pathway to make sure that you know and understand and the thing is you may say okay so divine how does this all play into John as well the thing is for the most part I think of humans I mean for is not even for the most part pretty much most humans are operating equilibrium right like the thing is the amount of bilirubin you make typically equals the amount of bilirubin that your liver takes like your hepatocytes take up and then they conjugate and then they excrete so there's a nice balance there between how much bilirubin you're making and how much bilirubin you excrete the thing is a person will develop John this when this equilibrium is thrown out of whack right so that's like the primary thing if you can sort of think of things in that fashion you'll be very easy to keep the different causes of John this straight right and let me take a quick sidebar here with kids right so remember that kids when they are born like they have very reduced activity of UDPGT right and even like the biliary system for like helping with like exfilling bilirubin and all that stuff it's actually not fully developed until at least it hits about two weeks of age right so the thing is pretty much every newborn for the most part gets some kind of unconjugated or you can see indirect hyperbiblinemia right so that's why you probably hear this term like oh physiologic John this of the newborn alth

ough some things can happen right in certain people where they can have like I mean like you probably heard this you've probably seen this on exam so this is the way we'll classically present where the subscriber person that you know gets surgery or gets sick and then they have like this mild indirect type of bilirubinemia if you see that you want to think about something called Gilbert syndrome okay Gilbert syndrome the thing is it's an indirect hyperbiblinemia that arises in people because these people have you know just decreased activities of UDPGT there is in they have those decreased activities it is they have like a mutation in the gene that quotes for UDPGT so that mutation causes decreased production of UDPGT so when these people on the go like severe metabolic stress they get an indirect hyperbiblinemia from that the thing is for the most part you don't treat Gilbert syndrome there's nothing you need to do it's basically there's no more B2 or mortality with Gilbert syndrome now one way thing we also find again again they typically make this a pediatric disorder on mbim exams is something called like the Bing Johnson syndrome right so the Bing Johnson syndrome right it's inherited in a Rosomar recessive fashion right and basically the mutation is in a protein known as MRP2 okay it's a protein known as MRP2 the thing with MRP2 is that it's a transporter that helps with getting things from the hepatocytes right because remember I said something I said the hepatocytes right they have a sinusoidal surface that faces those are fenestrated as sinusoidal acupelaries that brings stuff into the hepatocytes and then after they do their processing function they don't think through the bowel like the side that faces the bowel bowel calendulae the thing is they are transporters on that side that get things like across those bowel can elicula into like your biliary treat t

he thing is people that have the Bing Johnson syndrome they have mutations in those transporters so those transporters don't work again it's Rosomar recessive inheritance then you will not be able to get conjugated bilirubin out right so those people tend to have like a conjugated hyperbiblinia right and the thing is so people may say okay divine I hear that people that have the Bing Johnson syndrome have a dark liver well why does that happen the thing is that transport mechanism is not just for conjugated bilirubin that transport mechanism is also for like like polymers of epinephrine right so the thing is those polymers of epinephrine if they're not able to get out of their hepatocytes right they cannot stick around and that's what actually causes the dark pigmentation of the liver and obviously already for a person has like an obstructive cause of liver disease like you'll typically have like innovations in direct bilirubin again like do Bing Johnson syndrome right versus a person that has like problems with UDPGT or a person having like a ton of himolises where you are over producing a ton of bilirubin where they will have more of like an elevation in indirect bilirubin right so key quick things to mention here for person has himolises like severe hemolises or person has problems with UDPGT for example like in Gilbert syndrome or like Kregler in a heart syndrome that I'll talk about later and those people have an indirect type of bilirubinia for person has like an obstructive cause of liver disease like you know colidocolithiasis or ascending colonitis or do Bing Johnson syndrome or Router syndrome Router syndrome is basically the same thing as the Bing Johnson syndrome with the exception that in Router syndrome the liver is not black those people have a conjugated hyperbular bignia and the thing is if wherever is in again there's like that obstruction or you kno

w bowel is kind of flowing slowly through the biliric trick those people have like a colistatic pattern of liver disease right so again like I said they'll have a conjugated hyperbular bignia but in addition to that they will actually have an elevation in our alkaline phosphatisein alphosphate right alphosphate is classically elevated in people that have a colistatic liver disease colistatic liver disease so again if you notice I'm spending time kind of trying to explain these different mechanisms these are things you just want to make sure you understand because once I start getting all like many of these diseases I've talked about I'm gonna mention them again but I'll talk about them like this like this greatly but I'm just using them as examples of the principles I'm trying to buttress and the thing is I guess let's maybe talk about some mechanisms behind cirrhosis right so if you remember earlier in this podcast I said that people that have cirrhosis is basically called word for for end-stage liver disease right and the thing is there is a classic histological pattern that your friends at the NBME expect you to memorize I'll see that again there is a classic histological pattern your friends at the NBME expect you to memorize so what's this histologic pattern the thing is you need to remember regenerating modules and region fibrosis those are both words that you need to commit to memory I'll see that again regenerating modules and region fibrosis so basically when a person has an end-stage liver disease right you know as the hepatocytes die the body will try to regenerate like the liver will try to regenerate them because remember the liver has regenerative function as I mentioned earlier right but the thing is for some reasons that I will explain in a couple of a couple of seconds those people have fibrosis between different regions of the liver right and that fi

brosis just makes communication between different regions of the liver like difficult and ultimately those people will develop a poor hypertension and they will develop some sequelaide of poor hypertension that again I'll talk about in a couple of minutes right so the thing is how does the liver die basically how do people go from my liver was working well to not my liver how do people go from their liver liver working well to liver dead well the thing that happens is that normally if you're kind of following it as a time sequence the normal thing that happens in in in you know in a normal liver is that so remember I said I keep you know that I keep referring to this because this just tends to pop up a couple of times here and then on the US emilys and people typically get this wrong hepatocytes think of it as a send think of this as a sandwich right so we have the hepatocytes in the middle it's like the feeling of the sandwich and then on either side of the either side not either sides either side of the sandwich we have the sinusoidal capillaries on one side that have been shredded endothelium knowing that we have been shredded endothelium is very high to know for the US emilys and then on the other side we have like the bowel can eliculi surface okay so the thing is between the hepatocytes and those sinusoidal capillaries right that have like finished shredded endothelial cells the thing is there is a space between those two things that space is known as the space of this I'll say that again the space between the sinusoidal capillaries and the hepatocytes is known as the space of this di double S okay is known as the space of this and for the most part that space of this you know it just has like type 4 collagen pretty much you know type 4 collagen remember that's very helpful for like basement membranes I mean it's not truly a basement membrane but type 4 collagen

kind of adds out in that space of this and you know kind of keeps things nice and smooth well the thing is when people have cirrhosis that type 4 collagen gets replaced by type 1 and type 3 collagen okay so it means you okay divine why does this replacement happen because if you actually think about it right 5 broses typically is accompanied by the position of type 1 and type 3 collagen so you may see divine how do we go from type 4 collagen to type 1 and type 3 collagen well the thing is in addition to the so if again if you're looking at the normal hepatocytes in addition to the type 4 collagen that you find in that space of this one of the thing you find is you find some cells known as stale cells okay and that's some people call them peri sinusoidal stale cells right so they are stale cells that hang out close to the sinusoid the thing is these stale cells for the most part all they do is the store vitamin A right all they do is the store vitamin A again this is why if you consume a ton of liver you can actually get vitamin A toxicity from that so like liver from an animal you consume a ton of it you get vitamin A toxicity believe it or not that is a very high-heeled question that pops up on the US Emily step one and the US Emily step 2 CK exam you may say oh divine that's really low yield just wait until you take those exams and then come back and come back and talk to me so basically right so these stale cells the normal job is just of vitamin A that's pretty much all they do right but the thing is if a person undergoes like liver injury let's say like you know a hepatocyte cell dies or because of some inflammation you stimulate your cuffer cells the thing is those hepatocytes and those cuffer cells they begin to release things like like you know like IL1 TNF alpha all that stuff and those things stimulate those stale cells and then they differentiate into a ki

nd of cell known as a myocybroblast right and then those myocybroblasts begin to lead down type 1 and type 3 collagen as they lead on that type 1 and type 3 collagen you ultimately have you ultimately have like fibrosis right and that's the mechanism behind the bridging fibrosis that accompanies in stage liver disease aka cirrhosis right so that's a very very important thing to remember again you activate those cuffer cells you have a hepatocyte injury release all these substances that then convert those stale cells to myocybroblasts right and the thing that happens is as you begin to lead on all that collagen right then that blocks like those fenestrations in the sinusoid and if you block those fenestrations in the sinusides right then obviously the pressure in those sinusoidal couplers would increase right that's ultimately what will cause for all hypertension right so you have that bridging fibrosis and then you also have those regenerative nodules because as the hepatocytes die the body is like oh let me try to regenerate these hepatocytes let me try to regenerate them but it doesn't end up working as well as you'd expect right so that's ultimately the path of physiology behind the cirrhosis and cirrhosis in this country right if you think if you see cirrhosis on the USML exams you want to think about like two big causes right want to think about the hepatitis viruses especially like eb and ebc right and then you also want to think about like alcoholism right so like alcoholic stato hepatitis or like non-alcoholic stato hepatitis those are all causes of nstage liver disease or cirrhosis on mbim exams so again remember type 4 collagen gets converted to type 1 and type 3 collagen by action of these steli cells that normally stop vitamin A that are ultimately converted to myofibroblasts okay then ultimately converted to myofibroblasts now that I've talked about the m

echanism right behind cirrhosis right so let's talk about some sequelae of cirrhosis well once equally that's probably you know the most common that you will see is portal hypertension right is portal hypertension right and I've already kind of explained one mechanism behind the portal hypertension right I said that for the most part the thing that happens is that you know with all these fibrosis that you lay down because normally these sinusoid remember the liver has a sinusoidal capillary system actually did a ton of research on that one of my publications is on on those sinusoidal capillaries but basically when a person has those sinusoidal you know capillaries they have spaces they have fenestricions between them that allow space for communication with the hepatocytes well if you lay down all that type 1 type 3 collagen you know you put down all these fibrosis well it kind of becomes hard for blood to leave those sinusoidal capillaries and interact with the hepatic pyreancome right so that fibrosis is one of the causes of portal hypertension right because that fibrosis again it compresses the sinusoid it compresses the central veins and then those people get into trouble now the thing is as the pressures in those portal veins increase right ultimately you begin to form some weird and asthmosis right so why does this make sense well think about it right let's say you are in a battle right you know you are dealing with like a lot of problems you're like man I'm getting swapped right like oh like I can handle all this pressure that's getting at me right you typically try to ask people for help right so the thing is if a person sinusoid I encourage with blood very high pressures the body is like okay you know what let's try to relieve this pressure in some way shape of form so the thing that happens is that your body then begins to form an asthmosis between the portal

system and the arterial system because remember right the hepatic artery actually also brings blood to the liver right so it begins to form an asthmosis between like hepatic artery branches and the portal veins okay you begin to form those anastomosis begin to form those anastomosis but the thing is remember that arteries operate under a completely different set of games compared to veins right remember arteries an arterial system is a high pressure system a venous system is a low pressure system so the thing is as those veins begin to body up with those arteries the thing is they then begin to get exposed right so they actually get more than the ads they ask for right they ultimately begin to get exposed to those high pressures in the arterial system again now ultimately contributes to portal hypertension now another thing that can also cause a portal hypertension is that is this whole concept of splanchonic visodilation right so you may see divine I've heard this term countless times I have no clue what this means like oh splanchonic visodilation splanchonic visodilation because many times you'll hear that if a person has portal hypertension well we can try to profile out so treat it with like a spurnolactone or like proprenolone because those things apparently cause splanchonic viso constriction right so let's talk about what what splanchonic visodilation means in the first place and why splanchonic visodilation causes portal hypertension well the thing is I think maybe the first thing to mention is what is the splanchonic circulation what is the splanchonic circulation the thing is the splanchonic circulation refers to the circulation of your GI tract e.k.e the cilia cardory and its branches the supermissenteric artery and its branches and the infirmissenteric artery and its branches I'll see that again splanchonic circulation refers to the cilia cardory and its

branches the supermissenteric artery and its branches and infirmissenteric artery and its branches okay now the thing is when people have portal hypertension right I mean typically it means the liver doesn't work very well right one thing that your liver actually helps with because some people may wonder divine why do we have immune system cells within the sinusoid of the liver well here's the thing there is an actual reason behind that I mean like your body doesn't just put things in place for the fun of it believe it or not right so the thing is those copper cells which I again also did research on as a med student the copper cells now we find in the sinusoid of the liver okay those copper cells actually help with clearing bacterial DNA right definitely help with clearing bacterial DNA so the thing is if a person has liver dysfunction right and those copper cells you know they are kind of walled off from the blood that's coming in through the portal system because remember right your portal system ultimately gets blood from the GI tract and remember that your GI mucus right is ex is has a direct communication with the outside world right so you know it gets exposed to a lot of bacteria and all that stuff so the thing is those copper cells that line the hepatic sinusoid help with clearing that bacterial DNA well the thing is if a person has liver feel like like cirrhosis right they won't be able to clear those bacteria DNA and the thing that happens is that when you have all that bacterial DNA and you have all these weird shunts that I talked about that begin to form between the portal system and the hepatic arteries some of that bacterial DNA kind of makes its way into the arterial system and when that happens you begin to make a ton of nitric oxide the thing is the production of nitric oxide is and is the body's response right is the body's response to exposure to

bacterial DNA so if your body sees a ton of bacterial DNA it begins to make a ton of nitric oxide well we know that nitric oxide is a viso diluter right so ultimately that will cause dilution of the splanchonic system right like your cilia cardinans branches your superior mesenteric cardinans branches your inferior mesenteric cardinans branches right and that will begin to put more blood into like again those are like the hepatic artery and all that stuff you know that feeds the liver right and again because you have shunts that develop between the hepatic artery and the portal veins right that will again be further even like like make those portal pressures go people more right so the person will have portal hypertension so that is actually the mechanism big that is actually like the mechanism behind splanchonic viso dilution leading to portal hypertension okay so again it's just one of those things where you hear the buzzword I just decided especially for the because I know that many people that listen to those podcasts they don't just want to you know memorize stuff they actually want to understand what's going on right so I figured it probably makes sense to you know spend the two or three minutes to try to explain those things to people so that's those are different mechanisms behind portal hypertension well if a person has portal hypertension can he cause any bad things well he certainly can right one thing that portal hypertension can cause right is he can cause pneumagaly right because remember the splitting vein joins up with the infamous enteric vein to form the portal vein right so if you have portal hypertension you have like build up of pressures in the splitting vein so those people can have splinomagaly because the splitting vein drains the split right and then people that also have portal hypertension ready can have things like kaput medusa we're like

the period of belly coveings get diluted right they can have hemorrhoids right around the region of the around the region of the rectum right they can have a subgeal varicis that can present with like you know like high volume life threatening hematemesis right and then they can also have acitis right they can also have acitis and I mean what is acitis basically acitis is just where you have a ton of excess fluid kind of collecting in the period to new cavity ready let me say what the vine what is acitis bad well acitis is bad because when you can cause abdominal distension right I mean like I've seen people where like as an intern I probably trained like not me training right cause of the intervention or radiology obviously but they ended up training about 10 liters of fluid from these people's beds right so acitis like I mean think about the 10 liters of fluid is like 10 kilograms of body weight right that's probably almost like I don't like 20 pounds that's a ton of weight right that is just confined to a presence bin right so acitis is bad for that reason and then and the way thing that can happen is that acitis can get infected right and then the person can develop spontaneous bacteria to 90 self talk about that in a later podcast right and the thing is that acytic fluid can also sip through the diaphragm because remember the diaphragm many people think oh the diaphragm is just no the diaphragm also contains like lymphatic vessels right so the thing is some of that acytic fluid can actually leak into those lymphatic vessels and then leak into the into the like the plural cavity and the person can have like a plural of fusion that's classically known as basically it's like a hydro thorax okay they can have a hydro thorax and it's very high you to know that if a person has a plural of fusion in the setting of portal hypertension and acitis it usually is on the righ

t side on the usml exams not on the left it can be on the left but that will be very non-classic on a usml exam classically will be on the right okay that's a very high-yield tidbit of not tidbit very high-yield like weird factory that you want to commit to memory and later I will talk about this thing called like the because the thing is acitis right it's almost like an ultra-fuel trait of blood right so it's going to contain some things you'd ordinary flood ordinary finding blood like albuming right so the thing is there's this measure known as the serum acitis abumine gradient right the thing is the serum acitis abumine gradient basically means the difference between the albuming that you find in the serum right and the albuming that you're finding the acitis you take the difference between those two and that's your sag your SAAG gradient the thing is if your SAAG gradient is greater than 1.1 it means that the person likely has portal hypertension as the cause of the acitis but if the sag gradient is less than 1.1 they need to mean that the person may have like a malignancy that is the cause of the acitis right because remember like cancers like ovarian cancer love to cause acitis love to cause acitis and again like I said right this portal hypertension where you can cause acitis so we've talked about the mechanisms again I want to kind try to keep back because I feel like it's kind of hard to describe the liver in an organized fashion that's why if you notice I keep back tracking also we've talked about this so we've talked about this so we've talked about this just to kind of keep both of us on the same page right so and also to help my brain keep things out organized as I give this podcast so we've talked about the mechanisms that give rights to portal hypertension we've talked about acitis that can be a sequel I of portal hypertension right another thing that c

an happen with portal hypertension or if I've kind of talked about this in a in a pasta like anatomy podcast is people that have portal hypertension or to relieve those pressures they can begin to form shunts between the portal venous system and the caveo venous system right so what I mean by the caveo venous system basically veins that ultimately lead to the inferior venocative right so they can have things like they can have like hemorrhoids right they can have as of a joe varicies right they can have um kaput medusa right where you have um like you know the period on melico veins are being dilated right and the thing is you know all those things are a bad but the one that's real bad is the so-for-joe varicies as a joe varicies can kill right and I mean like it's probably one of the most common causes of death in people that have instig liver disease right because if a person has bleeding varicies they can have like a very life threatening bleed lose a ton of blood right I mean you see divine if a people lose a ton of blood why do they die because think about your area like yeah this person loses a ton of blood let's give them what they've lost I give them like fluid back give them blood back and they'll be fine well the thing is is not like when people because typically right a bleeding varicies you know kind of shows up acutely right like the person just is like sitting at home and then they vomit and then boom they keep having like these balls of just vomiting like a crap ton of blood the thing is it's not like the moment the person starts vomiting right blood it's not like oh you can start ivy fluids instantaneously I mean obviously if you're in the hospital and start bleeding like that wake you know it will take a few minutes to establish ivy access and start like a large volume transfusion of protocol the thing is in those three minutes or so where they're ble

eding where that blood is not being replaced right the thing that can happen is they're kind of coupled I mean they're pre-load basically goes down significantly right so they're kind of coupled goes down I've got kind of coupled goes down they're not able to profuse important organs like the brain right remember the brain if the brain loses oxygen for even just a few seconds it can cause like profound injury right so the thing that ultimately happens is that those people can get like an oxy brain injury they become brain dead and then they die right or other organs in their body can take a hit like the kidneys can take a hit and then they develop develop like a end stage a kidney disease like you know like acuteroenophilia that then becomes chronic and then they become like dialysis dependent then they get into all this trouble and right typically those people right again as they have like all these bleeds many a lot of that blood gets reabsorbed in the GI tract and then the liver has to deal with it a liver that's already dead right so they have like really profound hypermonemia because the urethyclydose in work and then they get a paricancer fallopathy right so these are all the things that ultimately cause death in people that have a solidio viruses I mean I have certainly seen people maybe maybe not necessarily people that have a solidio viruses but people that have like large scale GI bleeds die because of that right so those are kind of like the mechanisms behind like you may be like oh why do people you know die so much when they have like big GI bleeds well those are some of the reasons I mean there's any number of reasons why they would die but those are some of the more common reasons at least that I've observed clinically why those people ultimately die and again if a person has you know like poor hypertension right obviously those people have like a splee

n omega and the thing is the spleen can sequester like a ton of bleaklets right almost like 30% of your bleaklet poor so thrombocytopenia can actually be a sequelite of a person having an nstageletary disease and I want to keep this podcast short so I'll probably try to think within the next like six minutes oh they're about here right now some quick things I guess I want to talk about these I'll see maybe these two conditions I'm about to talk about people don't really understand the mechanisms behind them but I'll try to give you like some decent explanation what these things certainly show up on the USML exams and the things you want to make sure you can recognize okay so the first thing I think I want to talk about is something called hepato renov syndrome okay hepato renov syndrome basically the way that I'll present on an exam will be a person that has kidney like renov failure right but if you look at the kidney parent and everything looks just fine right and that renov failure arises in the setting of that renov failure arises in the setting of liver failure right and the thing is the mechanism behind hepato renov syndrome to be honest people don't really understand it but the thing is people think that when you have like a lot of splenching visual dilation by those mechanisms that I described remember the splenching circulation is just limited to your celiac artery and its branches SMN is branches I mean his branches the thing is if all that blood is going to your GI system right you will ultimately have like constriction of the other vessels because it's like at least this is the way I think about it you have this flenching visual dilation right so this blood is going into like three vessels and its branches well all that blood that's going into those three vessels and their branches and not necessarily going to other vessels in the body see for example like

the renov arteries right or just other vessels in general right so if the other vessels in your body general and I'll get in that blood they'll be like okay how can I try to combat these low blood pressures well one thing that can happen is that you can try to constrict your vessels right you constrict your vessels not your splenching vessels right because those ones have an upper-end response because of that bacterial DNA I talked about earlier right so if you constrict your vessels well I mean your brain will be well supplied which is good I mean you need your brain to live right but the thing is if you constrict vessels in the body then you may not be profusing the kidneys well right so you can almost get like a pre-renew kind of reno failure from that right so that's that's at least my understanding from reasoning through the so maybe for me suffice it to say like wishy washi explanations have seen in the literature like just from kind of going through those different things and kind of like trying to just think for myself and put things together I have come up with this teleologic explanation for why um hepato reno syndrome develops and I think there is I'm fairly certain there is some truth to what I'm explaining right but again like it's just not very clear quite until someone does a some more research on this stuff right and the classic way this again will present is it will be a present that has liver failure right and then you'll notice that this person's urine output is dropping the abu and the creatinine is going up right but notice from this explanation I gave that's this is actually part of the reason I gave this explanation right I said that hepato reno syndrome is almost like a pre-renew aka kind of deal right guess what if people that have pre-renewed aka what is typically true of the urine concentration it's usually pretty pretty high right because

the body is trying to retain a ton of fluid right that is actually the same thing that happens in hepato reno syndrome right because your friends at the end of the end we may try to trick you that oh if a person has a hepato reno syndrome their kidneys does not work so the the ability to concentrate urine is not there that is not true when people have a hepato reno syndrome the concentrating ability of their kidneys is completely intact right so these people typically have like very hyper or smaller urine and the thing is their urine sodium is usually pretty long right so the thing is if you're looking at the urine labs for a person that has a pato reno syndrome think of pre-renew aka labs this is a florida hyal thing to understand for your exams and at least I feel like with the things I kind of described like the mechanisms I described for a pato reno syndrome they should make perfect sense to you and the thing is really hepato reno syndrome is bad right I mean you can analyze these people all you want do all the things you want to do it's not going to do squat for these people the only thing that cares hepato reno syndrome is if their liver recovers or they get a liver transplant I mean this is like a classic indication for referral to a liver transplant center now to all the disorders that you miss your exams and again I know I promised to keep this under for five minutes apologize I'm sorry I won't be able to fulfill that I will try to keep this I will try to go for not much longer though right so one thing that can happen in again as a weird sequel of photo hypertension is something known as podo pomenary hypertension okay I'll say that again podo pomenary hypertension okay basically this is something that people don't really understand right but again I'm kind of going with that mantra of if a person has a splantly visual dilation right and you drop blood press

ures in other parts of the body those are the parts of the body say okay let's try to retain our pressures by constructing our vessels right well that vessel construction can cause some problems right so photo pomenary hypertension is basically like a kind of pulmonary arterial not venous pulmonary arterial hypertension that develops in a person that has in stage liver disease that has pulmonary hypertension I mean that has portal hypertension right so people think that again people have like you know like they just have like pulmonary visual constriction they have like all these vascular remodeling right and then ultimately these people have you know signs and symptoms of pulmonary hypertension like like right heart failure so if you get a question about a person that has like cirrhosis that's complicated by portal hypertension and then detail you that oh you know this person for the last couple of days or weeks has been having like dyspion exertion and the person has like finger club in which essentially tells you that the person has hypoxia right and you have like shortness of breath like a rapid heart rate so like they feel like your heart is recent like repetitions think about portal pulmonary hypertension under those circumstances now last next thing I want to talk about is hepato pulmonary syndrome right so kind of like hepato renal syndrome there's also such a thin ass hepato pulmonary syndrome right the thing is hepato pulmonary syndrome the thing you just want to be able to recognize is if they give you a question about a person that has again liver disease and when they lie back they find it easier to breathe but when they sit up they become short of breath think about hepato pulmonary syndrome okay that phenomenon I just described is something called platypnea so P L A T Y P N E A platypnea orthodioxia OR T H O D E O X I A so platypnea orthodioxia syndrome

okay it's kind of a weird thing and the thing is it's something that classically on mbim exams is associated with hepato pulmonary syndrome but it can also arise in people that have any kind of rights to left shunt so like a p F O or like a pen and doctor satiriosis so like a very bad H O C E P T O D effect but on mbim exams I want you to keep hepato pulmonary syndrome in mind as the primary cause of platypnea orthodioxia syndrome it's like very very rare people don't really understand why this is like like wider raises but again if you read the literature one thing that people think propose as a mechanism is that people that have a portal hypertension for whatever reason they begin to develop some weird EV mouth formations right so basically an EV mouth formation is a fistula between the pulmonary artery and pulmonary vein well think about it if you go from pulmonary artery stretch if blood flows from pulmonary artery straight to pulmonary vein right we essentially bypassing the pulmonary capillaries so gas exchange does not happen so those people become hypoxic right those people become hypoxic right so that's sort of kind of the pathophysiology where and I mean for whatever reason when people have this this EVM's form when they lie back you know the oxygenation status kind of improves when they sit up the oxygenation status just goes in the toilet and then they become like markedly short on breath and if you see that think about that platypnea orthodioxia syndrome and again the classic cause on the USMLA exams is is a um hepato pulmonary syndrome okay is a photopulmonary syndrome so please do not confuse hepato pulmonary syndrome okay which is typified by again that platypnea orthodioxia phenomenon or with um photopulmonary hypertension which is a pulmonary arterial hypertension that arises in people that have in state liver disease and again really hepato pulmona

ry syndrome just like hepato renal syndrome the only treatment is uh um and also even photopulmonary hypertension the only treatment for the most part is liver transplant and it also actually doesn't work well for for many people that actually get the transplant okay now um just I guess maybe a few quick special topics that I want to talk about because again I also don't want to make 50 different podcasts just for GI right so these are just quick topics that I can mention and they won't take too much time right so uh don't forget um or maybe let me let me do it this way let me talk about the different zones of the liver okay let me talk about the different zones of the liver right so the thing is we have different liver zones okay we have different liver zones um there is zone one there is zone two and there is zone three right but the thing is to understand those different zones you need to understand this whole concept of a hepatic lobule right the thing is the hepatic lobule is kind of shaped like a hexagon right and the thing is in the center of that lobule we have something called a centroid vein we should make sense because it's in the center right so it should make sense that it's called centroid right the thing is the centroid vein ultimately dumped into the hepatic vein okay now so the centroid vein is in the center of this hepatic lobule and again the hepatic lobule is shaped like a hexagon and then on each almost like each side like at each quadrant like oh like off to the side at the periphery of this hepatic lobule we have the we have the portal tract right so where does the portal tract contain the portal tract contains the portal vein contains the hepatic artery and country contains the bowel duct okay so hepatic artery portal vein bowel duct okay and I will talk about these zones in the next podcast but I kind of want to introduce that concept now so t

hat that's one lesson for me to talk about in the next podcast so the thing is this lobule we divide this lobule into zones based on distance from blood supply right so I said that the portal tract the portal triad is on the periphery right so there's the part of the lobule that is close to that portal tract is called zone 1 right so thanks you may see if your friends at the US Emily you don't want to mess with your head they'll call it like the periportal zone okay the periportal zone is zone 1 it's the one that's closest right I mean like just think of it as your number one the number one is closest to all the action right closest to the blood supply and then zone 3 is the zone that is farthest from the blood from the source of blood that's basically the zone that's around the central vein okay so that's sometimes they call it like the central lobular zone okay so periportal zone is zone 1 it's close to the portal triads that you find on the periphery of the hepatic lobule and then the central lobular zone is zone 3 you'll find it close to the central vein right because the central vein is the most distal from the blood supply to the liver and then in between those two you have zone 2 sometimes that's called like the mid zone you're very likely not see mid zone only you examine it just call it zone 2 okay the thing is you don't need to know these different things because there are different pathologies that arise there are different pathologies that arise along these regions of the along these different zones of the liver if you may right so that's one key thing you want to make sure you understand and remember now the thing is let me maybe take a quick sidebar and talk about like I said I mean of in toxicity right so if you take a ton of acetylamino fin right you'll usually be a person that's trying to commit suicide on an enemy mix yeah and then they start develop

ing like liver failure like a cute liver failure that actually need like transplant in fact believe it or not acetylamino fin is actually the most common cause of acute liver failure in the US that makes people ultimately need a transplant I'll say that again acetylamino fin is the most common cause of acute liver failure in the US that necessitates a liver transplant right and I mean so the thing is what causes the liver failure in a person that has that has a as the aminofin toxicity well the thing is that I said a aminofin the problem is it is actually metabolized by the side of chrome p450 system okay it is metabolized by the side of chrome p450 system so the thing is the side of chrome p450 system we have very large amounts of side of chrome p450 system enzymes in the zone three hepatocytes I mean we have them also in zone so don't believe anyone that tells you that oh we don't have a side of chrome p450 system in zone two zone one that that's a lie okay that's a lie right so the thing is the key thing you want to remember is that the side of chrome p450 system that we find in the hepatocytes in zone three of the hepatic lobule those are the things that take first crack at trying to metabolize acetylamino fin the thing is as those side of chrome p450 system enzymes metabolize acetylamino fin they make a metabolite known as NEPQI the thing is NEPQI causes like a very powerful oxidative stress on the liver and that can cause hepatocytes injury right that can cause hepatocytes injury that's actually why if a person has acetylamino fin toxicity we try to give like NACIDO system because NACIDO system will regenerate that growth the thion system right and by by protein that growth the thion system are along that can help you deal with like reactive oxygen species so if a person has again visa just one of those weird things you can see on the exam out of the blue and yo

u're like oh crap it's not in any resource well you heard heard it from me here when a person has a seduminofin toxicity the first part of the liver to be destroyed is the sentry lobular zone zone three okay the thing is if you kill off many of the zone three hepatocytes right then you go to your next line of defense zone two hepatocytes those die off and then after that the zone one hepatocytes ultimately die and then the person gets like like complete liver failure on that circumstances so again don't forget NACIDO system is the primary treatment of choice for for acetylamino fin toxicity so I think I'm gonna go ahead and you know pause here I feel like I've kind of talked about a lot today but again please I'm begging you try to understand these mechanisms because as I've said in like multiple podcasts like especially in recent times the USMLE not just step one but also step two CK they are beginning to like they are still testing the same classic pathologies so it's not like the the outline for the USMLE has changed drastically no it hasn't changed but the thing is the USMLE is beginning to move away from testing associations associated with classic pathologies to now testing mechanisms associated with classic pathologies so the thing is you need to kind of like really dig down and understand things to be able to do and on these exams I mean and again you don't need to believe me just look on Reddit look on SDN I mean I post pretty heavily on Reddit just check you don't need to believe me like don't believe because again don't believe everything I say right just hear other people out and ask them like yeah like this exam was it just primarily associations it suggested you see that yeah you still have those questions but those questions are becoming rare as the day goes by right so you need to be prepared to actually understand mechanisms because the thing is these

mechanisms help you kind of understand oh this is why this association exists because the thing is the NBM instead of asking you like oh a person has so so so and so condition which what what is the most likely finding on blah blah blah they won't ask that they'll ask they was the most likely on the line mechanism behind this right so if you don't have an understanding then you'll never be able to get those questions right and the thing is when the NBM test these weird pathologies in obscure ways having an understanding of the path of physiology helps you actually recognize what the NBM is trying to test because the thing is if you have understanding you can see through a difficult question like exams are typically not difficult for people that have what let me say less difficult for people that have very good understanding so as I do at the end of every podcast I don't for one or one or one to learn for many exams so step one step two CK step two CS step three pre-clinical med school exams third year shelf exams if you're a medicine resident you need to learn for like the intrading exam the ibi-m board exam or your college students and you need to learn for like you know genkame okame physics biochem histology physiology of a tutoring for all those things and I do like one or one tutoring that's probably what I do it like like 99% of the people I work with these days but also do a large group like teaching right and I can do like booster courses I call them booster courses where it's like 10 hours for step two CK step three 20 hours for step one or like more comprehensive courses that are more along the lines of like a hundred to a hundred and 10 hours for any of the US Emily exams so if you know if you're interested in any of those things you know either fill out the form on the website send me an email or you can directly send me an email at divine intervention po

dcasts with an S at the end at gmail.com and if you also need like advice in or like coaching for like if let's see your medicine or plant a residency so like an air application or a cholesterol and a plant to med school so like an Amcass application I do offer like you know like coaching with like rec letters personal statements editing applications mock interviews um and then um I mean I I mean I've worked with tons of people and most of people have worked with they've actually much like their first choices and again I also have admissions committee experience I mean I was on the admissions committee of a top two med school in this country for a year right so again I've reviewed tons of very high quality applications so I wish you all the best I do hope you gain something from this podcast have a wonderful Saturday God bless you I'll see you next time thank you

1) Acute failure/Necrosis; 2) Chronic disease/Bridging fibrosis; 3) Metabolic dysfunction/Minimal change pattern.

UDP glucuronosyl transferase (UDPGT).

Regenerating nodules surrounded by bridging fibrosis.

Stellate cells (or hepatic stellate cells).

Splanchnic vasodilation $\rightarrow$ Increased bacterial DNA exposure $\rightarrow$ Nitric Oxide production $\rightarrow$ Vasodilation of splanchnic vessels.

Calculating the Serum-Ascites Albumin Gradient (SAAG). SAAG > 1.1 suggests portal cause; < 1.1 suggests malignancy.

Type I and Type III collagen.

Hepatitis viruses (especially EBV, HEB, etc.) and Alcoholism.

Platypnea Orthodoxia syndrome (shortness of breath when sitting up).

Direct hyperbilirubinemia.

Accumulation of copper/metals due to impaired excretion via transporters like MRP2.

Hypovolemic shock leading to cerebral hypoperfusion and oxygen deprivation (cerebral injury).

Type I and Type III collagen.

Hepatitis viruses (especially EBV, HEB, etc.) and Alcoholism.

Platypnea Orthodoxia syndrome (shortness of breath when sitting up).

Direct hyperbilirubinemia.

Accumulation of copper/metals due to impaired excretion via transporters like MRP2.

Hypovolemic shock leading to cerebral hypoperfusion and oxygen deprivation (cerebral injury).