in this video we're going to be talking about bilirubin and congenital hyperbilirubinemia so in today's video we're going to be talking about bilirubin and as sort of an overview of what we're going to be going through this is what this video is going to touch on so we'll start by talking about bilirubin physiology and then we'll talk about what is the difference exactly between unconjugated and conjugated bilirubin and we'll conclude the video by talking about the different types of diseases that i'm sure you've seen in your textbooks and in your question banks that come up when you have congenital hyperbilirubinemia and those diseases are gilbert syndrome krigler najar syndrome type 1 and type 2 dubin johnson syndrome and rotor syndrome but it's probably asking too much of you to simply memorize different diseases if you don't understand how bilirubin works physiologically so where i want to start in today's video is let's break down how bilirubin works and what it does and how it moves from one area of the body to the other because once you understand that physiology understanding the diseases that occur congenitally when those different aspects of normal physiology don't work becomes very simple so let's just start by talking about bilirubin so we're going to start with a blood vessel and in the blood vessel you have heme everybody should be familiar with what heme is before starting this lecture and through two different enzymes heme will ultimately be converted to bilirubin and when heme gets converted to bilirubin we're talking about unconjugated bilirubin if you wanna we're gonna talk about unconjugated versus conjugated in just a bit but to start conjugation is a step where there is a chemical alteration of bilirubin where a little molecule gets stuck onto bilirubin and that occurs downstream so at this point we're just talking merely about unconjugated bilirubin so heme will go to bilirubin through two enzymes the first enzyme is heme oxygenase and then the second enzyme is biliveran reductase so technically although it's not pictured on this slide there is an intermediate product between the first and second arrow and that's billy verdin so heme gets converted to biliverdin by heme oxygenase and then billy verdin gets converted to bilirubin through biliverdin reductase now everything that i've just mentioned i want you to imagine as happening in the reticuloendothelial system so everything in that gray box including the enzymes that we just mentioned that's all occurring in the reticulo endothelial system so now we've got bilirubin and at this point it's still unconjugated okay it has not undergone an alteration which will occur downstream of this in the liver by attaching a molecule to it now the bilirubin is going to flow through the body attached to albumin and this is really important because if you get a question that puts a patient in some disease state where they have decreased levels of albumin that can it you know indirectly affect the the availability of circulating unconjugated bilirubin but at this point again bilirubin is just circulating bound to albumin and ultimately that bilirubin which is still unconjugated at this point will make its way into the liver now let me be clear everything that we've talked about so far which i'm going to show you now by highlighting all the different bilirubin in blue this is all unconjugated bilirubin because again just to really harp on this because it's so important the bilirubin has not yet been modified in the liver and it's that chemical modification that's going to occur shortly that's ultimately going to conjugate it so at this point we're talking merely about unconjugated bilirubin so now the bilirubin has arrived in the liver and now we can finally get to that step where the bilirubin will become conjugated when you conjugate bilirubin what you're doing is you're converting unconjugated bilirubin into bilirubin with glucoronic acid attached to it and the enzyme that does bilirubin conjugation is udp glucoronal transferase okay so that is a very important enzyme to memorize because it conjugates unconjugated bilirubin now once bilirubin is conjugated again all it the only difference is that it has glucuronic acid attached to it and it's that chemical attachment that allows conjugated bilirubin to then move further through this cycle so once conjugated bilirubin is conjugated and that is to say that it has glucuronic acid now it can be secreted into the biliary system and once that bilirubin gets secreted into the biliary system it will go through the biliary system and of course spill into the intestine okay so now bilirubin which is conjugated and it has its glucuronic acid attached to it has made its way to the intestine where certain modifications are going to occur squarely in the intestine so the first one is that bilirubin will be converted to urobilinogen and it's actually the bacteria in the gi tract that makes that conversion possible now urobalinogen takes one of three different steps okay and i've shown the three different steps by having three different colored arrows here the purple arrow the yellowish arrow and the brown arrow the first option shown in purple is that that urobalinogen can simply be reabsorbed and then you can go through this cycle and just keep cycling bilirubin the other option shown in yellow is that that urobalinogen can make its way to the kidney and ultimately be converted into urobilin and it's urobilin that is a yellow pigmented chemical which gives urine its yellow color the other option is that urobalinogen can go contin can continue through the colon and ultimately be converted to stercobilin and sterocobilin is also a pigmented bilirubin derivative that is brown and that's what gives poop the brown color so it's really interesting that when you look at somebody's urine or you look at somebody's poop the reason that urine is yellow and the reason that poop is brown is because of the bilirubin derivative urobilinogen getting converted into either urobiline or stercobilin and in both of those cases they are pigmented chemicals so interestingly it's bilirubin that gives your poo and your pee its color so this is everything we've talked about and just to simplify this i'm going to now make everything black so you can see this overview and i want to really delineate what the difference is between the unconjugated and conjugated bilirubin so your unconjugated steps are shown in blue and your conjugated steps are shown in red so this is what happens with with bilirubin and if you understand this pathway and you're understanding how bilirubin comes from heme flows through the blood goes to the liver gets conjugated and then enters the biliary and ultimately the intestinal system you should be unable to understand where congenital hyperbilirubinemia is coming from so that's bilirubin and that's unconjugated versus conjugated now let's transition and talk about the high yield diseases that you'll get tested on on test day this whole group of diseases is referred to as congenital hyperbilirubinemia which basically means that from the time that you're born there's something wrong in the in the physiology that we just talked about that causes you to have too much bilirubin in your system congenital hyperbilirubinemias are classically uh described as either being unconjugated or conjugated which which is to say that if you have an unconjugated congenital hyperbilirubinemia it's a disease where there's too much unconjugated bilirubin and likewise if you have a conjugated congenital hyperbilirubinemia you you have a disease where there's too much conjugated bilirubin so let's first talk about the unconjugated side and before we even talk about the diseases recall from the previous discussion that we just had about the physiology that this is where the unconjugated steps of bilirubin come from so in order for there to be an unconjugated congenital hyperbilirubinemia which is to say that there's a disease somewhere in this pathway causing too much unconjugated bilirubin the problems occur at the areas where you see the two red stars so either the problem is initially with the heme accumulation or the problem is with the enzyme udp glucoronal transferase now let's briefly talk about heme first because this is the probably the lowest yield part of today's lecture if you have a disease where you undergo way too much hemolysis you're going to have the generation of a lot of heme because that's a breakdown product from the red blood cell and if there's all this heme coming into the system and all of that heme is going to be converted into bilirubin well then of course you're going to have too much unconjugated bilirubin because you're converting heme which is just accumulating in these massive quantities because your red blood cells are being hemolyzed and then you've got all that unconjugated bilirubin that the body just doesn't know what to do with it so that can cause an elevation in unconjugated hyper excuse me unconjugated bilirubin the other problem is with the enzyme udp glucoronal transferase because if you either have a deficiency of or a complete knockout of that enzyme as you can see on this slide you're not going to be able to convert the unconjugated bilirubin in the liver to the conjugated form because the enzyme that's responsible for that reaction is is not working properly and that is the highest yield part of the unconjugated hyperbilirubinemias so let's talk about the three diseases that are that are unconjugated so you've got gilbert syndrome and krigler najar syndrome type 1 and krigler najar syndrome type 2. let's just go through them one at a time so we'll start with gilbert syndrome so the problem here is that you have a knockout of the gene that is ugt1a1 and that gene is responsible for basically coding for that enzyme and if you have a problem with the gene that codes for the enzyme then you have decreased or dysfunctional levels of udp glucoronal transferase which means you have increased levels of unconjugated sometimes referred to as indirect bilirubin so remember here's the slide that we've seen already so if you take out the gene that codes for the enzyme udp glucoronal transferase then that enzyme is gone which means you have increased levels of the unconjugated bilirubin because it cannot be conjugated into the form of bilirubin that gets the glucuronic acid attached to it so that's the problem with gilbert syndrome now how do you remember this right that's quite a bit of information well what i say is ugt which reminds me of a few things one ugt for unconjugated gilbert okay so the u the g and the t reminds me that gilbert syndrome is an unconjugated elevation of bilirubin ugt also is directly taken from the name of the gene knockout and ugt reminds me of udp glucoronal transference so gilbert is ugt and there's only one of these diseases with the g in the name and that's gilbert so pretty easy to remember that's gilbert syndrome the other two unconjugated congenital hyperbilirubinemias are the two different types of krigler najar syndrome and i think for the sake of studying it's probably best if we just include this discussion on the same slide so that you can see the differences between type one and type two so for type one krig luna jar the problem is that you have a complete dysfunction of udp glucoronal transfer so a knockout basically the enzyme just simply isn't there so you're going to have very elevated levels of indirect or unconjugated bilirubin the problem with type 2 krigler najar is that you don't fully knock out the enzyme but you have a deficiency of the enzyme okay so the enzyme activity is decreased but it's still there a little bit and because of that you're going to get an increase in your unconjugated or indirect bilirubin but it's not going to be as high of a level that you see in type 1 critical in a jar where you simply have no enzyme whatsoever okay so let's go back to this slide remember if you knock out that enzyme udp glucoronal transferase then you have increasing levels of unconjugated bilirubin if you only have a little deficiency of that enzyme you're still going to get an elevation of unconjugated bilirubin but it's not going to be as much so that's type 1 versus type 2. now something that's really important to understand is that because you have massively increased levels of indirect bilirubin in type 1 these patients are prone to getting kernicterus whereas patients who have type 2 kriglanjar are not going to get kernicterus and if you've never heard about kernicterus before basically it's when all of this bilirubin accumulates in the bloodstream and that goes up to the brain and becomes neurotoxic so you might see something like this a cat scan of the brain which shows a bilirubin encephalopathy with neurotoxic lesions in the basal ganglia so bilirubin is neurotoxic if it goes up to the brain it's going to cause lots of issues and it can be fatal very quickly so these patients who have kriglin najar syndrome type 1 are not going to do well the other thing that you need to know is that type 1 krigler najar syndrome will not respond to phenobarbital but type 2 kriegler najar syndrome will basically phenobarbital is a barbiturate medication that can be given to decrease levels of unconjugated bilirubin but only patients with type 2 qriglina jar syndrome will have any response to that so on test day if you're taking your test and you see a question and they give you a patient who was treated with phenobarbital and that bilirubin level came down that tells you immediately that they must they can't have type one quick little jar syndrome because those patients simply don't respond my mnemonic for remembering that patients with type 2 krigler najar syndrome respond to phenobarbital is i say phenobarbitu so instead of phenobarbital i say phenobarbi2 which reminds me that phenobarb patients with type 2 respond to it so those are your krigler najar syndrome so at this point in the lecture we've talked about bilirubin physiology and how bilirubin works in the body normally we've talked about the difference between unconjugated bilirubin without the glucuronic acid and conjugated bilirubin with the glucuronic acid what those differences are and we just had a discussion about the three different types of unconjugated hyperbilirubinemias now let's wrap up by switching gears and talking about the other side of this chart the conjugated congenital hyperbilirubinemias so remember that what we talked about the difference between unconjugated and conjugated this is the slide that we were we were on and the problem in conjugated hyperbilirubinemias is where the pink star is located so it's a problem with getting the conjugated bilirubin basically out of the liver and into the biliary system because as you might imagine if you have difficulty moving that conjugated bilirubin around you're going to have increased levels of it the two diseases where that happens are dubin johnson syndrome and rotor syndrome so these are the two that you need to know on the conjugated side let's start by talking about dubin johnson syndrome so the the pathophysiology here is that the mrp2 protein is dysfunctional and the mrp the mrp2 protein is basically responsible for the hepatic excretion of conjugated bilirubin so if that protein is missing or is not working then you're not going to be able to get conjugated bilirubin out of the liver and when that happens as you see on this slide where the pink star is located if that bilirubin with the glucuronic acid attached to it can't leave the liver then you have increased levels of conjugated bilirubin as you see on this slide so you knock out the ability to shuttle that conjugated bilirubin out of the liver and you get increased levels of the conjugated bilirubin that has the glucuronic acid attached to it now interestingly in dubin johnson syndrome one of the very high yield features is that patients will have a black liver they will have a black liver and that's due to the accumulation of a pigment in the liver due to the inability to get that conjugated bilirubin out of the liver so if you see this picture on your exam they're talking about dubin johnson syndrome the other really high yield bit of information that you need to know is that in these patients with dubin johnson syndrome oral contraception is actually contraindicated the reason for that is that the mrp2 protein which is obviously dysfunctional in dubin johnson syndrome well that protein is also involved in the metabolism of estrogen and progesterone so if you give somebody oral contraception and they can't metabolize properly the estrogen or the progesterone in the oral contraception they can become toxic quite quickly so that's very high yield do not give these patients oral contraception because oral contraception also relies on the mrp2 protein so that's dubin johnson syndrome and rotor syndrome is pretty similar rotor syndrome the problem is that you have two different polypeptides that are defective you have the oatp1b1 and oatp1b3 they're both defective those are similarly responsible for the uptake and excretion of conjugated bilirubin from the liver so just like doom and johnson syndrome if you have a problem getting that conjugated bilirubin out of the liver because you can't excrete it you're going to have an elevation in the conjugated bilirubin because since it can't get out it's just sitting around really the way to differentiate rotor syndrome from dubin johnson syndrome at least clinically is that there's no black liver in rotor syndrome but in dubin johnson syndrome you do see that black liver so for some reason test writers love to go after this they'll give you all the lab printouts that will suggest to you that conjugated bilirubin is elevated and in your head you're now generating a differential this is either dubin johnson syndrome or rotor syndrome and if they don't tell you anything about the pathophysiology which is to say they don't tell you if it's oatp1 or mrp2 whatever the only difference is that one has a black liver grossly when you look at the liver and one doesn't so test writers will go after that just like in dubin johnson syndrome in rotor syndrome oral contraception is contraindicated okay because oatp1b1 and oatp1b3 are also involved in the metabolism of estrogen and progesterone so how do you remember this well i say rote rotor syndrome and i replace the o with oat roacher syndrome and that reminds me of oat for oat p1b1 and oatp1b3 that's roacher syndrome so again very high yield dubin johnson and rotor syndrome both cause increased levels of conjugated bilirubin but only dubin johnson syndrome has the black liver test writers go after this all the freaking time you have to memorize this now i know what you're thinking dirty if i have to memorize this if this is as high yield as you claim it to be what's your mnemonic well when i think of dubin johnson i think of dwayne johnson dwayne johnson arguably the greatest wrestler of all time dwayne the rock johnson is part black and that reminds me that in dubin johnson or in dwayne johnson you get a black liver finally the rock has come back to dirty medicine that's it guys i hope that you enjoyed this video i hope that now you have a better understanding of how bilirubin works what the difference is between conjugated and unconjugated and what those diseases actually mean i think that i did a good job of breaking this down but if you have any further questions do not hesitate to put a comment on this video and support the channel love you good luck