Hello and welcome to part one of chapter 14 on the liver. This first part of the recording is probably going to be the longest of three parts that we will get to. In this one we're going to cover the normal anatomy and physiology of the liver and then we'll talk about all the things that go wrong. In in the other sections I mean. All right, so I'm going to super simplify the liver. I'm going to use some analogies. And and let me just say I know several of you have told me how much you appreciate the analogies and I really appreciate hearing that. They help me in understanding and they help me in remembering and organizing information. I will never test you on an analogy. There's they're not perfect. They're just a tool to help us understand things better. So I'm going to talk about the liver and and different characteristics of what the liver does, but there's a lot of overlap. And so please if if you find overlap do not sweat it for a second thinking I don't know which is it filter or is it kitchen? It doesn't matter. There's there's a lot of overlap in these functions. So let's talk about the liver. It is not a super sexy organ. So it is not the leading man kind of organ, but it's a really exceptional character actor if you know what that is. It's the you know the one who gets the small part and in community theater it's sometimes the same person you know changing costumes and doing all these different jobs. Like they're the bailiff in this scene, but then they're a prisoner in a different scene and um and I I feel like that's what the liver is doing. Oh my gosh, it's this big brown lump, right? And it's just not super enticing, but as we learn more and more about what the liver does it's really extraordinary how many different roles it plays. And so as a way of trying to organize our thoughts I very roughly broke the activities of the liver into three main categories. Filter. That is blood's going to go through the filter through the filter blood's going to go through the liver and some stuff is going to be taken out. Kitchen. This is a very broad category and by kitchen I mean some materials are going to come in. There's some chemical reactions that are going to happen and then something different will be at the end. Some things will be ready to use and other things will be now ready to get rid of you know. And then finally storage unit. There are some items that reside in the liver for longer or shorter periods of time and we'll talk about those different things. All right, to understand the filter and where some of the materials are coming from that are going through this organ we have to understand the blood supply and it it confuses everybody and it's usually explained badly. So I'm going to try to explain it in a different way from how I usually see it explained and I'm going to show you a diagram that you've seen before when we were in the circulation chapter. And we used this diagram to talk about the pulmonary circulation versus the systemic circulation. Remember it's the patient's right side of the heart that the the blood's going to be right back. It goes just out to the lungs and then comes back and then the blood that goes to the systemic circulation that has left the thorax that's coming out of the left side of the heart. Okay. Um What all of this has in common is that the blood leaves out of an artery. It goes through a capillary bed and then returns to the heart in a vein. And that's true in the pulmonary circuit and it's true in the systemic circuit. Blood leaves through an artery goes through some capillary bed somewhere and then gets recollected into a vein and back to the heart. And that is true in the liver and it's true in the kidneys. So there's artery supply and there's vein recollection. This is the part that's weird. People always focus on the liver being weird. The liver is actually pretty normal. What's weird is what the GI tract does. It gets its blood supply. You know it has arteries supplied from the heart. The blood goes through the capillary veins around um the the GI tract you know around the base of the esophagus, the stomach, the small intestine, large intestine and instead of just being recollected and going straight back to the heart, that is the blood that gets into this other vein that then dumps into the liver. That's why the liver has the two blood supplies. It has the the artery blood supply from the heart, but then it also has this big amount of blood coming from the GI tract. And that explains two things. One it explains you know this double blood supply, but the other thing it explains is how it can act as such an effective filter. And remember last week when we talked about the GI tract we said this is the receiving department. This is how you like pull things into the body. Well before that's going to be allowed into regular circulation we want to check that out as best we can before allowing it to go back to the heart and then circulate around the rest of the body and that's where the filter part comes in. Where the liver gets to take a you know first crack at everything that's coming in through the GI tract. Very very nice. Okay, now on the next slide you're going to see the same diagram over on the right and then there's a whole lot of stuff over on the left. And we'll walk through it slowly. I lied. All right, so here is the same diagram. Some basic anatomy. The liver is in the upper right quadrant of the abdomen. If it helps you at all. I tell my you know general anatomy students you know the the liver is a big structure. I think it looks roughly like a lower case R which as a student helped me to remember that's on the right side of mostly on the right side of the abdomen. It's divided into these great big lobes. But again you know just I don't know. It's just not a very elegant looking organ and then the lobes are further divided into lobules and we'll go over these in a little bit more detail so you can understand how the blood flows and how it's um how the filtering happens. So here's the blood supply issue. The oxygenated blood like for all of the organs of the body oxygenated blood is coming from an artery coming from the heart. Um But in addition to that oxygenated blood the liver is also getting a bunch of blood, but this is the blood that's like could you check this for me before it goes to the rest of circulation. I'm never going to test you on exactly how much, but some of you will be wondering this and so about a quarter of all the blood that comes through the liver about a quarter of it is coming straight from the heart. And that three quarters of what's coming through is that you know screen this blood before it gets to go out the rest of the body. That blood that's coming through the so-called portal vein system, that is the name of this vessel that is recollecting all of the blood from the GI tract and bringing it to the liver. It's called portal vein. I think of it as portage. If you have a boat in a river and you have to go to a different river you have to pick up the boat and walk with it to the other river to continue your travels or from one lake to another. I don't know. Just it helps me to to think about okay this is that kind of blood. It went through this capillary bed. Now it has to get recollected and then shut you know shuttled somewhere else and then it can go through another capillary bed. So that blood the portal blood it's going to have a lot of nutrients from the gut the small intestine was doing all that absorption and it's also recollecting blood from the pancreas. And remember the pancreas is going to be releasing insulin glucagon at different times and so one of the first organs to get that signal is the liver. That's what I mean by hormones from the pancreas. So these two sources of blood they mix they're not kept separate in the in the liver and they they pass by the liver cells the hepatocytes, and some immune cells. Because remember, we are checking everything that just came in through the receiving department, um that has its own immune cells, but there's some more immune cells in the liver also checking um for anything that needs to be attacked. And then, uh I'll I'll show you the central vein shortly. All right, so let's march through the filter kitchen and um storage unit, and then we'll go into the this the different um reactions under each one in more in more detail, but this is just a a quick first pass through the information. All right, so filter, uh we already mentioned the uh blood gets um Try that again. The liver gets blood directly from the GI tract, from the receiving department, and so it neutralizes toxins like alcohol and medications. We don't think of them as toxins, we think of them as medications that are useful, but our body perceives them as uh foreign things that need to be metabolized and gotten rid of. Um and then it Remember the the the immune cells, the macrophages and dendritic cells. These are um part of the innate immunity, and they're screening um for bacteria or um toxins that might be coming through the body. So, that's filter. Then let's do kitchen. There's a lot here. Uh So, kitchen, remember this means uh reactions, chemical reactions that that are going to be being done. We're cooking, we're changing things. Remember the three um macromolecules we deal with the most are carbohydrates, proteins, and lipids, and there's stuff happening with each of those categories. The carbohydrate processing I'm going to save for a little bit later. Um what I'm talking about is the glucose that comes in and gets made into put together into glycogen, but we'll we'll we'll cover that shortly. Um then there's protein synthesis and a lot of it. Remember we've been talking throughout the semester about um we just say it as an aside, oh and it's made in the liver. Um this is those proteins that we've been talking about. Um albumin is the one that the liver makes the most. Um so, it's a a protein that is in the blood. It's the most common protein in the blood. Uh but on top of that, there are all the things that we've talked about before, the clotting factors, um all of the Roman numeral ones, um they're all made by the liver. Uh the complement proteins, part of the immune defenses, innate defenses, that's all made by the liver. Uh alpha-1 antitrypsin, we mentioned this when we were talking about um emphysema and how this is the uh the protein that's supposed to act against the enzymes that are breaking down the elastase. That's that protein, and there are others and we'll we'll talk about the others as well. I just wanted to give you a a smattering of proteins that that we've mentioned before. Okay, so that's carbs, proteins, and now lipids. Uh yeah, the liver can make cholesterol. Cholesterol, you'll recall, is that four-ring structure. Um it's a lipid, meaning it doesn't dissolve well in water, um but it's the basis for making uh the steroid hormones, for making vitamin D, um and there was something else I wanted to mention about this. Oh, um some people who have elevated cholesterol levels can try desperately to limit the cholesterol that they take in in their diet, and they still have high cholesterol numbers, and and it's because we we make the cholesterol. Our livers make the cholesterol for us. And so, we're finding that a lot of people's cholesterol numbers are related to uh what their livers are doing. And then also, uh the liver's the one that makes triglycerides. When we have extra food, we have extra fuel, um the the liver detects, and we can talk about the mechanism by which it detects if there's excess fuel, there's excess energy, and it says, I'm going to store some of this for later. Um so, it makes triglycerides. Those are the three fatty acid chains that get stored up it gets stored away in adipose tissue. Thanks, liver. Uh cuz yeah, we'll use that later. All right, so those are the processing of the of those three macromolecules. Now, let's talk about uh some waste molecules. Um and you could put this in with the filter category. Um So, we take things uh from the blood. The liver takes things from the blood, like for example, bilirubin. And I'm going to remind you where bilirubin came from, and I'll remind you on another slide, too. It's from the red blood cells uh that are getting recycled, specifically the heme group after the iron's taken out. We've got to we've got to get rid of that heme group. Um and uh that's where the bilirubin comes from. Um and the liver takes care of that for us. Uh the other thing that it deals with for us is ammonia, uh and that came from the breakdown of the amino acids. Those were Amino acids are the subunits of proteins. If we're not using the proteins to be proteins, if we're using them for fuel, we take that amino group off, and that's got to go somewhere. And if we don't do anything else with it, it becomes ammonia. But the liver is looking out for us, and so it combines a couple of ammonias together and some other things to make something called urea, and we can pee that out. And um the liver also um processes medications, drugs. Aha. Then there's some stuff that leaves the liver and um and leaves circulation, isn't uh Yeah, there's some stuff that leaves the liver. Let's put it that way. Um and that stuff that leaves the liver is known as bile. Bile is a mixture of recycling, things that are useful, um they're going to be used, and then they're going to get sent back to the liver, and some trash that just needs to go out. And so, unlike where most communities have the separate bins for the trash and the recycling, the liver just puts it all in one bin, puts it out, and then says to the uh intestines, "Figure out some of that is trash and some of that we're going to need back, but take what you need, and then, you know, get rid of the rest in the stool." And what I'm talking about for recycling are the bile salts. These are the things that are needed for breaking up the fats in the digestive system. Um and so, they're necessary for fat digestion and absorption. Those things get used and recycled. They go back to the liver, and they can go back to the liver in the course of the same meal. They can go through this trip a few times. Um but then there's also some waste that's being released from the liver, and that's going to get eliminated just in the stool. It doesn't get reabsorbed and sent back to the liver. It's just out in the poop. And uh so, we did um filter, kitchen, storage unit. Uh we're we're going to do uh short-term storage and long-term storage. Short-term storage, I'm talking about a few hours. And this is where we do the carbohydrate processing. So, when we get monosaccharides from the digestive system, from the GI tract, you know, it takes the starches and breaks them up into the individual glucoses and absorbs those, and then that gets to the liver, and the liver um is going to store some of that stuff, cuz we can't use up all of the glucose all at once. I mean, some of our muscle cells and and neurons and whatever are going to, you know, take some of the glucose out of circulation, but there's too much glucose in circulation, and we know glucose is damaging to the capillaries if it's left uh in the bloodstream for too long. And so, the liver puts it together and stores it as this molecule called glycogen. And then a few hours later, uh we haven't eaten, but we need some uh an increase in our blood glucose, and so, the liver rebreaks down that that glycogen and releases it back into the bloodstream. And we'll we'll go about that we'll we'll go through that in more detail later. And that happens in the course of a several hours. Longer term, we're talking about weeks and months. Um things can get uh taken out of circulation and put in the liver, and it can just stay there until it's needed. Um examples of this, uh minerals, iron and copper, uh vitamins, we've talked about these two in particular, B9, that's folate, and B12, and also B6 are stored in the liver. And there are others. Okay, some things that can go wrong, and again, this is very high overview. Uh the liver can have infections, um uh specifically viral infections, we call them viral hepatitis, and we'll talk about the three kinds uh that are the most common. Um the liver's also susceptible to damage from alcohol. Uh it's kind of famous for that. As well as other intake. Um there's a condition called non-alcoholic fatty liver disease that is largely a a disease of lifestyle that is uh person's intake. Um we'll talk a little bit about that. Uh but both of these can lead all the way to cirrhosis, as can uh some of the hepatitis infections. Drug toxicity drug toxicity, most famously acetaminophen, but other drugs can also create a problem for the liver. And then uh some of these problems can progress all the way to hepatocellular cancer. Okay, that's the great big overview. Now let's get into a little bit more anatomy. Uh we're looking at a smaller scale. We're looking at lobules. They're mostly made of these general function uh cells of the liver called hepatocytes. The lobules are are roughly organized like this. Um there are some blood vessels around the outside of the lobule. And so it uh the blood comes in from the outside and then flows in towards the center. Um and what we're talking about here are the branches from the hepatic artery that's shown here in red uh because oxygenated blood and um portal vein. This is the stuff that's coming from the GI tract. And both of these blood supplies get mixed in the sinusoids. Sinusoids is a fancy name for uh really leaky capillaries uh that are in the liver. And they're really leaky cuz they have holes in the cells called fenestrations. Doesn't matter. They're windows in the in the cells. Um and stuff uh passes through easily. Remember we're talking about proteins and and taking proteins out of circulation and putting things into circulation. You need big holes for that. Cuz little holes like the ones in uh the renal capillaries, there's they're so small they're not supposed to let the proteins through. The liver's all about processing proteins. So it needs bigger holes um to get that stuff in and out. And so that blood is passing through and it passes right by the hepatocytes and then gets recollected through the central vein. Now bile is being made um by these hepatocytes. Uh they're taking some stuff from the blood, doing some kitchen reactions, and then putting some stuff into the bile. And so although the blood's flowing towards the center, the bile's actually flow flowing in the opposite direction. It's being made um in by the hepatocytes and then it's being put into a duct that flows towards the outside. That's not super important except um if you're an anatomy fan, these the way these uh tubes run, three tubes tend to run together. A branch of the hepatic artery, a branch of the um portal vein, and one of these bile ductules run together and they're referred to as the portal triad. Okay. Point is, blood supply passing by the cells, going into the center, bile being made and flowing out to the outside. And then this is going to get recollected and passed along from the liver to the small intestine. All right, a little bit more histology close-up. Um the hepatocytes, these regular cells I love how they're shown like little brown bricks. I mean, they're just like not sexy. But oh my goodness, when you get to know them, fabulous. Um yeah, so they uh highly permeable capillaries, um plates of hepatocytes, and oh then there's um lots of these uh immune cells, macrophages and dendritic cells. Uh portal vein, uh the arteriole on the outside, and where is it? The bile duct. The triad. Here the blood's flowing this way towards the central vein and bile's flowing the other way. All right, this is not super important for you to know, um but I wanted to make this point. And that is hepatocytes are not magic. They're cells like every other cell. They've got organelles like every other cell. And so they do a lot of different reactions and kitchen work. Um But they do it the way other cells do it, you know, for so for example, there there's a abundant rough ER, the rough endoplasmic reticulum, you'll remember. Uh the rough part is because of the ribosomes stuck on the outside. Ribosomes are all about translation, all about making proteins. So lots and lots of rough ER in a cell that's going to make lots and lots of protein. Albumin, complement proteins, all those different proteins get made in a cell and then that gets shipped out through exocytosis, which you remember learning about earlier this semester. There's also lots of smooth ER. That's where a lot of the lipid metabolism reactions happen. And then um there are it's referred to as granules. Um they're I don't know. Storage pockets um inside the cells for the glycogen and the lipids that get made and then have to sit around for a while, either for a few hours or for months or years. In in the case of the fat. All right, back to gross anatomy. Um the bile duct is what we're going to look at. So the liver, this big This is where I was saying it looks roughly like the lowercase R so you can remember it's on the right side, mostly on the right side. It does go all the way over to the left side. Um Let's see. So the duct the bile's being made throughout the liver and it's getting recollected. Uh we're getting collected into this bile duct. And here where it can uh empty into the small intestine, this is the duodenum. Duodenum, some people say. Um If we're not actively eating, there's a a little sphincter there that that stays mostly closed. And so this bile build builds up here and can back into this gallbladder. Um and so between meals, we build up some bile and we save it for later until somebody, you know, until we eat something, especially something that has some fat in it, then that bile gets pumped out um so that those bile salts can help emulsify, can help break up those fat glob globules. Um this common bile duct um joins with a duct from the pancreas that's shown here a little bit better. Bile duct is here and then the pancreas is also making its digestive enzymes, the proteases, the lipases, and the amylases. Um and those digestive enzymes come together into the duodenum along with the bile salts. Uh the sphincter of Oddi. Somebody's name. Um I have a preferred name for it, um the hepato uh pancreatic duct. It's just uh uh sorry. The the hepatopancreatic sphincter. Um It it just is more descriptive of what it is. Oddi was the guy who first described it. All right, so let's talk about some kitchen functions. The liver, along with the pancreas, uh plays a really important role in maintaining normal blood glucose levels. This diagram is not from our textbook, um but I think it it nicely illustrates this point. Normal blood glucose levels are between 70 and 110 mg of glucose per deciliter. Um You probably all already know that. Um As blood glucose levels rise, such as after we eat, um they don't have to even come out of this range. They just have to be on the trajectory upward, the pancreas is going to secrete some insulin. And that insulin is a signal to cells that have receptors for insulin. Those cells are going to bring the glucose from the blood into the those cells. And that means um cells of the body, the muscle cells, the neurons, they're going to bring glucose in. But so are lots and lots of cells in the liver are going to bring lots of glucose in. The cells um around the rest of the body are going to be using the glucose. The liver is going to be storing some glucose for us. But if it stored it just as glucose, um that would draw so much water into the cells that it would be non-functional. Um and so the glucoses are bound together to form glycogen, that branching carbohydrate. And between those two things, um you know, taking the glucose into the cells as individual glucoses and taking it in and forming it into glycogen, the blood glucose levels drop and come back down to into the normal range. A few hours later, we haven't eaten again, um but our blood glucose is is coming down. Now, um the the pancreas again is going to secrete a hormone, but instead of insulin, it's going to secrete something called glucagon. Glucagon, like insulin, it got into the bloodstream and all the cells get exposed to it, but only the cells that have receptors for it are going to respond. And those cells are in the liver. The liver's job at that point is now to break down that glycogen that it just made a few hours ago, break it up, and release those individual glucoses back into circulation. So, that brings the blood glucose back into the normal range. And we can continue doing the work that we need to do with our sodium-potassium pumps and and, you know, doing the make we made ATP, so we can continue functioning. It's fantastic. Um so, when we get to the endocrine chapter, we'll talk some more about why does the liver have to spend so much time doing that? Um but that's a huge part of what the liver does every day is help us maintain normal blood glucose levels. Okay, this is the the the um slide that's so busy. Okay, so here's the the diagram I just showed you, um and we're going to walk through this part slowly. So, there's some kitchen elements to this and there's some storage elements to this, but it's basically the processing of the carbohydrates. So, after we eat, uh the liver receives the the sugars that the the small intestine um uh took up. Uh mostly what we're talking about is glucose, and as I said, pancreas releases insulin, the glucose gets stored temporarily as glycogen. If there is a lot of glycogen, um that's when the liver says, "Oh, you're not going to need this in the next few hours cuz I know about how much you exercise, so I'm going to save this, you know, for next month in case we go through some kind of difficult period where we don't get to eat. So, I'm just going to put this together as a triglyceride, and then we can put that in the adipose tissue and put that right on your thighs for you, and you can use that later." Great. Okay. Um but if the glucose is um just, you know, the normal amount of glucose that we usually use and um the liver knows approximately how much we're going to need um for the amount of work that we usually do, um then it just stores it as glycogen. Okay, and then the between meals, um and the blood glucose comes down, the pancreas releases the glucagon, and that's the signal to the liver to break down that glycogen and release the glucose back into circulation. If um the glucose stores are low, if the glycogen stores are low, um the liver can also do this other trick. Uh it can produce glucose from other molecules. And this is called gluconeogenesis. Um this is not desperation measures. This is uh for example, I mean, it can be, but it can also be uh somebody just doesn't eat a lot of carbohydrates and they take more more of their calories in in the form of protein and and lipids and fats, um they can do this gluconeogenesis, and that's how they can keep their blood glucose in the normal range even though they're not eating a lot of carbohydrates. Okay, and it's just a normal liver function. All right, we're going to continue with kitchen uh work. Uh we already did carbs, now we're going to go to proteins, and you can guess that we're going to do lipids after this. So, uh proteins. The liver's making lots and lots of proteins. I've mentioned this before, the uh plasma protein albumin, um the clotting factors, that's what I mean by coagulation proteins, the complement proteins, part of uh immunity, and carrier proteins like uh transferrin, if we need to take uh iron from liver and take it out to the bone marrow for making hemoglobin. Oops. Those are the kind of carrier proteins I'm talking about. Also things like uh angiotensinogen. Um remember angiotensinogen is what we need to have already in circulation for the renin-angiotensin-aldosterone system to work. Renin cleaves the angiotensinogen to make angiotensin 1. Um I'm not going to those, uh acute phase proteins. Oh, inflammatory responses. So, um like C-reactive protein, for example. All of this stuff is being made by the liver. And then uh we've got regarding protein, urea is not a protein, but it's a waste that we make um because we've been processing amino acids. Amino acids are the things that make up proteins. Um and so, it's those amine groups. When they get taken off, you got to do something with them. You got to get rid of them somehow. And so, instead of letting them become just ammonia, which is really toxic to our to our tissues, um the liver will put two ammonias and some other atoms together and make something called urea. And that's how we can get rid of those amine groups. And it the urea largely gets that back into circulation and then gets uh eliminated by the kidneys. And then finally, we did carbs, did proteins, now we're going to do lipids. Um and we'll do we'll talk about triglycerides. I I've mentioned this when we were talking about glucose. Um triglycerides can be produced when we have excess glucose. We have more intake than we're anticipating to have output, um our liver will make these fat molecules for us, and then some of it can be stored in the liver itself. Um and some of it can get shipped out to adipose tissue. The liver, as I mentioned, can also make cholesterol. And it can also uh create the kind of shipping vessels for moving some cholesterols around, um high-density lipoproteins and low-density lipoproteins. Related to livers, bile salts are not uh What did I just say? Related to lipids, um bile salts are amphipathic. That means that they have the nonpolar side on one side and the polar side on the other. Um these are the molecules that are necessary for breaking up the fat globules in the small intestine. Um These are So, they they they get into the bile. That bile gets into the digestive system, and then they get used for breaking up fats, but then they get uh taken up again in the ileum, in the late part of the small intestine, and then gets recycled back to the liver, and the bile salts can actually do that trip a couple of times, a couple of three times in the in the time it takes to to eat a meal. So, yeah, very efficient recycling system. All right, the summary of all of this. Um the nutrients come in through the small intestine, and they get broken These are the carbs, um the proteins, and lipids. So, monosaccharides are the individual units of the sugars, amino acids individual units that make up the proteins and lipids. They use the different colors, um so this is all color-coded. Um let's see. The Then there's one place where things are not passing through the blood, and that's the bile that's made by the liver. That's going to get passed into the small intestine along the that bile duct, but everything else gets passed between the liver and the blood. Just lovely. All right, some more kitchen stuff. We're going to talk nitty-gritty about bilirubin. I'm going to remind you of uh red blood cell recycling that we looked at before when we were in the chapter on blood. Um we talked about how we recycle parts. We The usable parts of the red blood cell get recycled, and then what I'm talking about mostly is hemoglobin. The Here we go. Um we break up the hemoglobin, the globin part, that's the amino acids, those get recycled. The heme part is the problem. We take the iron out of it cuz we we want that iron. Um but then the part of the heme group that doesn't have the iron becomes the so-called unconjugated bilirubin. And I showed you these pictures in the other chapter. We talked about how if the unconjugated bilirubin gets uh put down in the dermis, excuse me, it's put down in the skin, um we have this jaundice appearance, kind of yellowing of the skin. If it gets put down in the sclera, then it's even more obvious. Um that's referred to as icterus. This I'm not going to test you on. I just wanted uh for those of you who are very detail-oriented to have a a visual of this. This is a heme group. Um there's the iron right in the middle of the heme group. That gets taken out, uh goes through a few transformations, and then this is the part that I can't use this for anything. I just have to get rid of this somehow. That's the bilirubin. And the bilirubin has some color to it. Which explains uh why we see it in people's skin. Um so, some terminology related to bilirubin um Bilirubin is not really water soluble, and so uh Think about the spleen and it being in the spleen, the red blood cells are getting broken up. Um and that uh bilirubin has to travel from the spleen into the liver, and it's going to do it in the blood. Um so, it kind of hitches a ride on the albumin that's already in the blood. At this point, we call it unconjugated bilirubin. Uh sometimes you'll see it on lab reports as indirect uh bilirubin. So then, uh the liver takes it up. And um conjugates it to this other acid. Once it's conjugated, it is uh easier to dissolve in the Uh so, conjugated bilirubin is also known as direct bilirubin. You may see it called that on lab reports. Um And so, it can travel in the blood and uh comes out in the urine. Some of it comes out in the urine. A lot of it a lot of the bilirubin um ends up in the bile. Because there's so much of it, it gives the bile this really You know, it sounds crazy, but this dark yellow uh going to green color. Um that's where that a lot of that color comes from. All right. So, this is All right, secretion, defecate. Okay. So, it's getting into the intestines. Then some of it um gets processed um into these other molecules until finally it becomes sterco- uh bilin. This is brown. And it's because of the stercobilin, the presence of this stuff, that that our our waste is brown-colored. So, if somebody's having a problem with getting the bile from the liver into the small intestine, one of the the signs of this is a pale the pale stool. So, cholestasis is what I'm talking about. Um if there's some kind of blockage that's not allowing the the the bile to get into the the intestinal tract. And I think there's we're almost done. Um a little bit more uh filter and kitchen. The drugs that come in through the oral route, um they get processed and um they get metabolized. They're different kinds of waste products. If it's nonpolar, that is if it's lipid soluble, it's going to go out in the bile. It's going to go in the out in the trash that way, and that's going to be eliminated in the stool. If it's polar, if it's something can that can dissolve in water, that's going to go into the plasma, and then it gets to excreted by the kidneys. But the liver wants this stuff out of the body. All right. So, this is why the difference between orally administered medications versus IV medications. Um for orally administered medications, things have to come in through the digestive system, through GI tract. That's going to uh get recollected Blood's going to get recollected into this portal vein that goes to the liver. And the liver's going to get first crack at that blood. And so, it's going to have some uh metabolic enzymes that that work on those drugs. So, what we end up with what we end up with as effective circulating concentration of the drug depends on what the liver does with it. It's the so-called first-pass metabolism. That's that blood that first got into the body, the liver's going to try to neutralize a lot of that stuff. And that's why with IV administered medications, you bypass all of this. And so, action of the drugs is faster, and um the less of it gets metabolized, less of it gets broken down. Because it gets right into circulation without going through this portal vein. And then this is the final slide. Um we did uh filter, we did kitchen, and now let's talk about storage. The things that get stored for the long term, um vitamins, the fat-soluble ones. All of them, A, D, E, K. Um and then the water-soluble ones are the primarily the two that we've talked about before, the folate B9 and B12. These are the ones that um when a patient is low in these, they end up um making red blood cells really slowly, and so the end the red blood cells end up being really big, macrocytic cells. It's a kind of anemia. And then the minerals that get stored are iron, which we've talked about in some detail. Um they're stored attached to ferritin. Hundreds of iron atoms get stored in ferritin. Um Um and the liver also is responsible for making the proteins that transfer the iron from the liver to the bone marrow, and that's the transferrin. And then the other mineral that's stored here is copper. That is the end of part one. See you in part two.