Digestive part 2 wk2 flashcards ( 2 days revision)

So onwards and upwards then. So for today, what we're going to do is we're going to continue with the stomach. So if you were to have seen the, um, recording, we covered nutrition, a little bit of nutrition, um, last week. We looked at the role of the mouth in digestion. We looked at the esophagus in conveying the food to the stomach.

And then I covered the stomach as well, whereby we look at some mechanical and chemical digestion. And we also looked at all the different types of cells in the stomach and also what is secreted there. So of course today we're going to continue with the regulation of this gastric secretion, how these secretions are regulated, because they're not constantly produced all the time.

Otherwise it will be quite wasteful and also really dangerous to your stomach. The other bit is, of course, to look at the small intestine. So, obviously, we are now following the journey of the food, which is now called the chyme. After it gets processed in the stomach, it will get passed on to the small intestine, and we're going to look at the small intestine from its structure to its role to the different types of secretions.

And then we are going to look at the pancreas. and the liver. Both of them are accessory organs. They are both endocrine and exocrine organs. And they are really important in producing a variety of secretions that is required for the process of digestion. So we're going to cover those things today as well.

Right, so as I said before, gastric secretion is highly regulated. You can't have gastric juices being produced all the time. It is wasteful, and it is also very dangerous. So the regulation of gastric secretion occurs in three different phases. Alright, you have the cephalic phase, gastric phase, and the intestinal phase.

Now the numbers that you see over here in percentages, are basically the result of this regulation, whereby 35 percent of gastric juices are produced in each phase, I mean, sorry, in the cephalic phase, and then 60 percent of gastric juices is produced during the gastric phase and 5 percent during the intestinal phase.

So the cephalic phase is when you start to think about food, even the thought of it, the sight of it, the smell of it, will start to simulate the cephalic phase. Alright, so that is when your stomach gets ready for the food to arrive. After that, you have, of course, the gastric phase, where the food has then arrived, and the distention of the stomach will cause the gastric phase to kick off, and that produces about 60 percent of the juices.

And finally, you have the intestinal phase, whereby the chyme is moving out of the stomach and kind of going towards the intestine. And that means that you're slowly reducing the amount of gastric juices in the stomach to about 5%, okay? So what we're going to look at is we're going to look at each of this phase, and then we're going to look at how the regulation works.

So please make sure you recall what is in the recording, because I'm going to refer to some of the different, some of the cells in the stomach, and what it produces, alright? So as I said, the first part is the cephalic phase. So that is when the sight, the smell, the taste, or the thought of food, especially when you're hungry and, of course, you know, thinking about tea time now, maybe building up to dinner, that will already kick off this phase, okay?

So your central nervous system will then send a message down the vagus nerve to the submucosal plexus. Now the submucosal plexus is responsible for the sensory regulation. So, it basically will send a message by, uh, what we call acetylcholine, which is a neurotransmitter, and that neurotransmitter will stimulate all these cells in the stomach, okay?

So you have the mucous cell, the chief cells which produce pepsinogen, and you have the parietal cells which, which is responsible for the production of hydrochloric acid and intrinsic factor. Okay. Okay, so G cells and parietal cells are what we call exocrine cells because it produces secretions that then gets, um, kind of, uh, put into the stomach or into the lumen.

You also have G cells and G cells are what we call entero end cream cells. So they produce hormones and these hormones are secreted into the bloodstream and it will circulate around the body and it will target whichever cells that it targets. So the submucosal plexus will stimulate all these cells to produce their products.

So you have mucus, which then protects the stomach from the acid. Okay, and then you of course have pepsinogen, which is a pro enzyme. It's not active yet, it needs to be activated in the right pH. And then, of course, you have hydrochloric acid, which is really important, firstly, to activate pepsinogen, to produce, to become pepsin.

And also, hydrochloric acid is really important in breaking down complex macromolecules. Right, so, after it stimulates this, at the same time, what you have is the production of gastrin by G cells, and the hormone gastrin further acts on these cells. So it stimulates parietal cells further, it stimulates chief cells as well, and it also helps with peristalsis.

Now, when preparing for digestion to happen, you don't want these cells to produce somatostatin, okay? So what happens in the sepalic phase is that the D cells are inhibited. Somatostatin is a hormone that actually reduces, um, digestion. So basically the whole cephalic phase is, um, getting the stomach ready for the arrival of food.

So what happens next is what we call the gastric phase, and this is where most of the gastric juices is produced. So as you can see, food has now arrived in the stomach, and the stomach will then distend, and then the pH will go up. Okay, meaning that it will be less acidic because the food is not as acidic yet.

Now, this distension and elevation of pH will stimulate the stretch receptors in the stomach because obviously when the food arrives, the stomach will stretch out. And then also the elevated pH will stimulate the chemoreceptors. This in turn will stimulate the submucosal plexus and the myenteric plexus.

So the myenteric plexus is different from the submucosal plexus. The myenteric plexus is involved in the mechanical regulation of the stomach. Okay, so all the muscle movements, the grinding motion, the propulsion, the peristalsis, they are all regulated by the myoenteric plexus. So what happens is that, of course, you know, the mucous cell, the G cell, the parietal cells and the G cells are continuously stimulated because now there's food in the stomach and you need all these products.

Okay? At the same time, the myoenteric plexus will stimulate the mixing waves in the stomach, The propulsion, the grinding, and the retropulsion in the stomach to break down the food into much smaller particles, to what we call chyme, okay? So the partially digested peptides which are present in the food will further stimulate the G cells, and of course as I said, the hormone gastrin is important in stimulating all these cells as well, okay?

So as the food passes through the stomach, The drop in the pH in the duodenum will stimulate the D cells. That means that the food is starting to exit the stomach. So that's fine. It stimulates the D cell to produce somatostatin, which then will start to inhibit the G cells to start slowing down the production of these gastric juices.

Okay? Right, oh dear. That is not good. Hold on a second. Okay. Right, so what we have now is the, um, intestinal phase. So this is when the chyme has been digested and it's now moving towards the duodenum. Okay, so it's exiting the stomach. So what happens is of course the duodenal stretch and chemoreceptors will now be stimulated because this chyme is now going into the duodenum and the duodenum is starting to stretch.

This will, uh, produce an enterogastric reflex, which will then inhibit the myenteric plexus, which then will stop the mixing, um, in the stomach. Okay, because there's no longer any food, you don't want the stomach to keep on grinding and mixing, which can be quite, um, uh, problematic. At the same time, this number three here, what I'm trying to say is, is that the stretch receptors in the stomach will also begin to relax.

So without the stomach being stretched, it will also reduce the production of the hormone gastrin, because you no longer need it. So after that, the presence of lipids and carbohydrates and even proteins in the duodenum will simulate the production of more enteroendocrine products. So this is cholecystokinin.

The gastric inhibitory peptides, so cholecystokinin and GIP will be, um, produced and secreted via the circulation and it will act on the chief cells and parietal cells. So it will inhibit these cells, stopping it from producing pepsinogen, stopping the parietal cells from producing hydrochloric acid, and at the same time it also inhibits the process of peristalsis in the stomach.

Now, of course, the pH in the duodenum is also going to decrease. That is because chyme is highly acidic. It's mixed with all this hydrochloric acid. So as it moves into the duodenum, it's going to decrease the pH over there. That drop in pH is going to stimulate the production of secretin, which will also inhibit B cells and peristalsis.

So that means that the process of digestion in the stomach is coming to an end. And it is now kicking off the process of digestion in the duodenum and the rest of the smaller intestine. Okay, you will soon come across CCK, GIP, and secretin again when we talk about the smaller intestine and the regulation of the various products in there.

Right, so just a quick summary or a simplification, if I can get there. There we go. So, So basically, the sight, the sound, the thought of food will stimulate the production of gastric juices. So here you see Homer Simpson, um, you know, taking his donut, and that itself will stimulate the cephalic phase. Now, of course, as I said earlier, you know, G cells will produce the hormone gastrin, and as all hormones go, it is not secreted into the lumen of the stomach, it is always secreted into the bloodstream.

The hormone gastrine will act on the parietal cell, which is involved in the production of hydrochloric acid, and also the intrinsic factor. It will also act on a cell called the enterochromaffin like cell. That is a paracrine cell. So paracrine cells produce a product which will then act on the neighboring cell.

So in the case of the enterochromaffin cell, it produces histamine. That will act on the parietal cell to further stimulate the production of hydrochloric acid. Okay, so as I said, par, the parietal cell will produce hydrochloric acid to then help with the digestion of food. And as the process of digestion continues it, the acid condition will continue to, um, go down.

So the pH will go further down and that will, um, stimulate the D cell to produce somatostatin. which then inhibits the G cell. So that closes the loop. So, before we move on, I have to touch a little bit on the chief cells as well, because as I've shown you earlier, the hormone gastrin will act on the chief cell.

And as I've said before, the chief cell is responsible for the production of a proenzyme called pepsinogen. So always remember when pepsinogen is produced, it's not active pepsin yet. So when pepsinogen is produced, and when the pH goes down, that is when it activates pepsin. And of course, pepsin will act on the peptide bonds in proteins to further digest the protein.

So this here is a summary of what I've just talked about. So this can be quite useful for when you are, you know, carrying out your revision. So, as I said earlier, gastric juice production depends on the food, or the concentration, or the arrival of food in your stomach, okay? Hydrochloric acid is vital for stomach function.

Not only does it activate, um, pepsin, or pepsinogen, it is also important for breaking down complex macromolecules. So, gastrin is a key regulator of parietal cells, which obviously produces hydrochloric acid, and chief cells that produces pepsinogen. Now proteins will of course stimulate G cells and not only proteins, other, um, nutrients as well like carbohydrates or lipids.

And that will produce the hormone gastrin and as I've shown you, gastrin is released into the blood and from the blood it acts on the parietal cell and, um, the entrochromaffin like cells to produce, um, hydrochloric acid and histamine. Okay, and then of course, gastrin also promote the chief cells to secrete pepsinogen, and the high, um, sorry, the low pH will then stimulate these cells to secrete somatostatin, which then goes on to inhibit everything, okay?

So I'm just kind of recapping so hopefully you'll understand what is going on in terms of the regulation, but if you still do not understand that, I would highly recommend just going back to this recording and have a go at listening to it again. So as you can see, the process of digestion is highly regulated, and this is no different elsewhere in the digestive tract.

So we're now going to move on to the small intestine. So we've talked about the stomach now, we've seen the process of digestion in the stomach, so now the food, which is called chyme, has arrived in the smaller intestine. Now the smaller intestine is actually the region of the greatest It's part of digestion and absorption, okay?

So a lot of the macromolecules that you see in your food are broken down and absorbed into the blood and the lymph. More specifically, um, glucose or monosaccharides and amino acids are absorbed into the blood. Lipids, triglycerides, they're all absorbed into the lymph, okay? So they have different destinations.

Now, the process of digestion in the smaller intestine is of course facilitated by secretions that will change the pH of chyme. So remember, chyme is highly acidic when it arrives in the duodenum, therefore the pH of chyme has to be changed in order to first, uh, in order to allow the enzymes that are in the smaller intestine to work, okay?

The optimal condition for those enzymes are not in an acidic condition. They can't work like that. It has to be in an alkali condition. Okay, so that is what you can see in the small intestine. The average length of the small intestine in an adult human male is about 6. 9 meters and about 7. 1 meters in an adult female.

So the small intestine is actually divided into three key regions. Now you first have the duodenum. Which is the shortest region. It's about 0. 27 meters long, and it is the part that is attached to the stomach. So it is the part that gets the most, um, kind of exposed to most, to the most acidic conditions.

Okay. Then of course you have the jejunum, and then followed by the ileum, and the part with the most absorption and digestion is actually in the jejunum. So in total, the maximum diameter of the smaller intestine is only 4 centimeters, and this is only half the large intestine, which is 8 centimeters.

However, there's a lot of modifications in the smaller intestine that increases its surface area, and we'll talk about that shortly. Also, what is interesting about the smaller intestine is that as you go through the smaller intestine, from the jejunum, I mean, sorry, from the duodenum, to the jejunum, to the ileum, you'll see various modifications.

Firstly, the folds, and then also the length of the villi. Okay, and also they have various, um, additions to the different parts of the small intestine, depending on the function of that region. Okay? Right, so like the stomach, the small intestine, um, is responsible for the motility of the food. Um, of chyme, and also for, um, mechanical digestion as well.

So you have chemical digestion, but also you have mechanical digestion happening in the smaller intestine. So there are two key types of movement that you will see in the smaller intestine. So one is segmentation. The other one is peristalsis. So segmentation is exclusively found in the smaller intestine.

Peristalsis is throughout the gastrointestinal tract. Okay, so segmentation is actually the slow contraction of the circular muscle layer and what it does is it occludes the lumen and drives the content forward and back. So it's about one to four centimetres each time. So think about it as a, as the, the chyme getting squashed and then moved back and forth.

So it keeps getting rolled over, basically. So this is to mix the chyme with the digestive enzymes, and also it is to increase the surface area of the chyme to the mucosa layer of the digestive tract. And this will help with the process of digestion, but also the process of absorption. So it's an increase in its surface area or contact point.

So all absorbable molecules will be removed from the lumen in this kind of movement. Okay, so the strength of contraction or segmentation is of course regulated by food content. So the more food there is in there, the higher the contraction that you will see in the smaller intestine. Now of course there's the process of peristalsis because you need to And we've moved this kind along and I touched on this in the recording, but I will cover it again just in case you have not listened to it.

So peristalsis is something that you will see in the esophagus. You will see again in the small intestine, you see in the stomach. So it is basically the alternate movement of the longitudinal muscle on the outer side and the circular muscle on the inner side of the digestive tract. So what happens is that When the longitudinal muscle contracts, the circular muscle relaxes.

So this alternate movement will slowly move. So basically you have this movement, and then this one relaxes, and the food will move here, and then this will squash it, and then the food will keep moving. So this alternate movement will help the kind to move along in one direction. Okay? So this is a rhythmic movement, of course, and it just moves it all the way to the large intestine.

Now, this movement, apart from moving it along the digestive tract, it allows the chyme to mix with the digestive enzymes as well. And of course, it ensures an adequate exposure of the chyme to the mucosal surface for absorption. So the frequency of the contraction will vary in the small intestine. You have a higher frequency in the duodenum, followed by the jejunum, followed by the ileum.

Do you know why it's in such an order? This is something that you can use logic to think about this. What if the frequency is higher in the ileum? What do you think is going to happen?

No? I don't think you want antiperistalsis to happen. So if the frequency is higher in the ileum, it's going to push everything the other way. So that is why you have a higher frequency in the jejunum. to push the chyme towards, sorry, the duodenum to push the chyme towards the duodenum, towards the ileum in one direction.

You don't want it the other way around because it will push the chyme back into your stomach and that is not something that you want. Alright? So as I said before, um, the small intestine has a lot of modifications to increase the surface area because one of the key functions of the small intestine is of course to absorb all the nutrients.

So, what we have here is 20 feet worth of smaller intestine. However, there are some modifications that increases the surface area. The first one is Plicae Circularis. So, if you zoom into the smaller intestine, you'll see these folds. Um, Plicae Circularis, if you translate it, it means circular folds. And this will increase the surface area of the smaller intestine by three folds.

Now, if you zoom in further, to a plecate circularis, what you will see are these finger like projections called villi. Plural, um, singular, villus. Okay? And that will increase the surface area by tenfold. And again, if you were to zoom in further onto one of these projections, what you will see are microvilli.

Okay, so there's little brushy structures, and they are also called the brush border, and that will increase the surface area by 20 to 30 fold. Now the brush border is not just about increasing the surface area, you'll find a lot of different types of enzymes which are located there, that is important for breaking down, um, your sugars and the, um, and also protein, which we'll look at in, um, I think in the next lecture.

Right, so all these modifications, if you were to iron out the small intestine as you would if you iron out your t shirt or the creases on your t shirt, it will be about 300 square meters in size if you were to iron out all these folds. So it is well equipped for maximum absorption, okay? So as I said before, um, all this changes in the small intestine is to increase the surface area.

However, there are some differences between the jejunum, the duodenum, and the ileum, especially in terms of the number of folds, or the number of plicae circularis, and also the length of the villi. So what you want to do is you want to think about it as the function of those things. So the, the plicae circularis is all about absorption.

The more folds there are, the higher the absorption, um, is in that particular region. Okay, so in the jejunum, that's where the maximum absorption happens, so you get a lot more folds over there. And then compared to ileum, compared to the duodenum, of course the duodenum is where the chyme first arrives in the smaller intestine, so the absorption is not that high over there.

Now in terms of the length of the villi, think about it again as maximum absorption but also at the same time maximum secretion, okay? So again, the jejunum has the most absorption and some secretion, so you have a much longer villi over there. The duodenum has a high amount of secretion, the reason being that the acidic chyme when it arrives in the duodenum has to be neutralized quite quickly.

So the duodenum is equipped to produce a lot of bicarbonate and it's then secreted into the lumen. Therefore, the duodenum has a lot, um, has a longer villi compared to the ileum. Okay, so this is how you can try and remember the kind of modifications you see in the smaller intestine. And of course, the most straightforward one is that the epithelial surface, um, is columnar and its luminal surface has microvilli, or the brush border, which then increases the surface area, but at the same time functions as a location for a lot of enzymes.

Right, so, the small intestine is covered by columnar epithelial cells and they're all responsible for, um, nutrient absorption. So you also get crypt cells, which is around this crypt here, and these crypts are known as the crypt of Lieberkuhn. If you look at some textbooks, they'll call it, um, the crypt of Lieberkuhn.

And you will see that a lot of these crypt cells are involved in the production of a variety of secretions. Now, the epithelium of the small intestine is self renewing. It tends to renew itself, um, every six days or so. Okay? Right, so let's have a look at the individual function of these cells. So, the muc the villus absorptive cell has a mucosal surface that has a lot of microvilli, and that constitutes what we call the brush border.

Again, as I said, it's important for enzymes over there, but also the modification is important for absorption. . Then you have the goblet cell, which is responsible for the secretion of mucin, which is a major component of mucus. And if you recall from the previous lecture, um, the mucus is really important in protecting the, um, digestive tract, especially from acid or, and, um, other kind of enzymatic activities.

Now, what you have next is the enteric endocrine cell or enteroendocrine cell, which produces hormone. So you have, um, these cells producing polycystokinin, dextrin, secretin, and, um, glucose dependent insulinotropic, and they're all involved in the regulation of the production of, um, various secretions. Um, then after that you have what we call the stem and progenitor cell, which can differentiate into other specialized cells that will then migrate out of the crypt and into the surface of the villi.

Next is Pana cells and those synthesize antimicrobial peptides, so they tend to synthesize things like lysozyme, and you know, lysozyme can be found in your saliva, it can be found in tears, it can be found in egg white, and what it does is it cleaves the peptidoglycan layer, so if you recall from microbiology, um, the cell wall of some types of bacteria will have The peptidoglycan layer.

Can you all remember which one they are? Like, is it gram positive or gram negative bacteria that has a thick peptidoglycan layer? You've just done your exam. Button? Absolutely right. So it tends to target the gram positive bacteria. So lysozymes is really important in terms of managing the microbial population in the digestive tract.

Now, you of course have some undifferentiated crypt cells which will proliferate to replace lost enterocytes. As I mentioned, we get quite a quick turnaround in the replacement of, um, these enterocytes. So about six days, you get a whole new layer in the small intestine. Right, so there's a variety of secretions in the small intestine.

What is interesting is that the small intestine actually do not secrete enzymes. Okay, the digestive enzymes that you get inside the small intestine, apart from the brush border region, all come from the pancreatic juices that you get. So, what they actually produce in the small intestine are things like mucus, water, and bicarbonate.

So mucus, as I've shown you earlier, is produced by goblet cells. So these cells will produce, uh, mucin, and the mucus will then protect the mucosa from the action of acid and proteases. Because the smaller intestine is, of course, an area of high digestion, it needs protection from all these substances. Um, and as said, it is most needed in the duodenal, uh, portion because the acidic time is gonna arrive over there and it needs the most protection.

Then, of course, you have cells in the Crip that produces water, and water's really important because the water that is produced will combine with the mucus that's produced by the goblet cells and make it runny for movement to coat the, the smaller intestine or to coat the lumen of the smaller intestine.

And as you all know, water is really an important environment for enzymes. So the process of hydrolysis, as the name goes, requires water. Next is bicarbonate, and this is primarily produced by what we call Brunner's glands. And these glands are mostly found in the duodenum. Again, because of its exposure to an acidic environment.

So these glands produce mucus rich bicarbonate secretion that will then protect The, um, lumen or the helium from the acidic kind and give an alkaline condition for the enzymes. So all these secretions are important, namely protection and creating the right environment for enzymatic activity. So on top of those secretions, um, basically you will have, um, other things that are important for the immune function of the smaller intestine.

So, chyme, when it arrives in the duodenum, is near sterile, because it's so acidic. So a lot of microbes cannot, um, tolerate that kind of pH. Now, there are still a lot of bacteria that are found in your gut. As you all know now, the gut microbiome is a very important, um, ecosystem. Now, a large proportion is actually found in the larger intestine.

So we need to keep that in check, especially keeping those, So a lot of microbes cannot, um, tolerate that kind of pH. Now, there are still a lot of bacteria that are found in your gut. As you all know now, the gut microbiome is a very important, um, ecosystem. Now, a large proportion is actually found in the larger intestine.

So we need to keep that in check, especially keeping those microbes. away from invading the other parts of your digestive system. So the spread from the distal portion is controlled by secretion of antibacterial enzymes, um, such as lysozymes, and then of course immunoglobulins and lymphocytes that is dotted throughout the smaller intestine.

Okay? There are, there are a few introductions, um, into the smaller intestine that's important for this management of microbes. The first one is Peyer's patches. It's found specifically in the ileum, and that is because the ileum sits right next to the large intestine. So there's a huge population of microbes in the large intestine.

So Peyer's Patches is a bit like tonsils, basically. So it, it's a checkpoint, or a guard point, where it keeps any of those microbes from invading the smaller intestine. Okay, so there's small masses of lymphatic tissues that keep the microbial population in check. On top of that, you have panocells that are dotted throughout the small intestine.

And these cells are responsible for the secretion of antimicrobial peptides, primarily lysozyme. Sorry, lysozyme. Alright? So let's have a look at these things. I mean, I've talked about them, but I have not shown you what they actually look like in the smaller intestine. So, what we have here is the duodenum.

And you have the classical arrangement. Of the tissues in the, um, digestive tract. So what you have here is the mucosal layer. Okay? And then you have muscularis mucosal, which is actually in the mucosal layer. And this muscles are important for the movement of the vii, and also to help with the agitation of it, to allow the secretion to move into the lumen.

After muscularis mucosa or the mucosal layer, you have the submucosal region, which is not labeled in this diagram. But then you have muscularis externa, and as you can see, the longitudinal muscle is on the outer side, followed by the circular muscle. Okay? Now the stomach has an additional muscle. Can you guys remember what it's called?

Oblique. I heard that. Good. So the oblique, oblique layer. So what is different with the stomach is it has an additional muscle layer and that is because of the amount of mechanical digestion that happens in the stomach compared to the other parts of the digestive tract. So this too is found throughout.

So you can see in the duodenum you have your longitudinal muscle and your circular muscle and then outside you will have your cirrhosis. Okay. So, what is interesting about the duodenum is this glance here, Brunner's glance, once you see a cross section of the small intestine and you spot this, you know you are exactly in the duodenum.

And as I said before, this is responsible for the secretion of, um, bicarbonate rich alkaline fluid that helps to neutralize the chyme and prepare the, um, the chyme for the next process of digestion. Right, so, let's have a look at another picture. So here we have the villi, and if we were to zoom into that particular section over there, you'll see all the cells, but then this weird one here looks quite different.

What do you think that one is? So I've shown you all the different types of cells that are found in the smaller intestine, so what cell do you think this one is?

It has a nucleus, but the nucleus is quite squashed. No? No guesses? Go on.

So as I said before, you need a lot of mucus in the digestive tract, so the cell that produces this mucin is the goblet cell. Okay, so this here is the goblet cell, and what you're seeing, if I were to put it under an electron microscope, are all these capsules of mucin. Okay, that is ready to be released.

So once this mucin is released, the water from the crypt cells that washes over the goblet cells will dilute it to form mucus, which will then coat the smaller intestine. And you'll find these cells in your nose as well, so you probably have millions of them. So one of them may produce a little tiny bit of mucin, but if you have millions of them, that's where you get a lot of mucus being formed.

So that, you see, is the goblet cell. So I'm just going to summarise, um, the different kind of features that you will see in a smaller intestine, and this is quite useful, especially if you are, um, doing a quick revision and trying to understand what I've just talked about. So as I've said before, there are lots of modifications in the smaller intestine, and the jejunum is different from the duodenum, and it's different from the ileum.

And these modifications are quite obvious if you know what you're looking for. So in the duodenum, the defining feature is these duodenal glands, or Brunner's glands, okay? So that is for neutralizing the acid, and as I said, for creating the right condition for enzymatic activities. Now, in the ileum, because it borders the large intestine, I've mentioned K is patches, and that is only found in the ileum, and it prevents any invasion of microbes coming from the larger intestine, okay?

And then we talked about the number of folds, plicae circularis, and also the length of the villi, and how the folds are proportional to the amount of absorption that happens in the smaller intestine. So the jejunum has the most folds because it has the highest amount of absorption, followed by the ileum, followed by the duodenum.

The villi and the length of the villi is proportional to the amount of absorption and the amount of secretion. So again, jejunum has the longest villi, but then that is followed by the duodenum, and then the ileum, okay? So that is how you can remember, you can use this for your revision as well. Right, so moving swiftly on, apart from just um, exocrine functions, or you know, the secretion of water, bicarbonate, and mucus, there are other types of secretions as well, in the case of hormonal secretions, so the enteroendocrine function of the smaller intestine.

So you get cholecystokinin, you get secretin being, um, produced, you get somatostatin and gastric inhibitory peptides when I've shown you the function of all these things in relation to, um, the regulation of the production of the gastric juice in the stomach. However, these things are also important when the food arrives in the smaller intestine.

Okay, so in the case of Secretin, hydrochloric acid or the low pH in the duodenum will stimulate the enteroendocrine cells to produce secretin. Secretin will act on the pancreas and also the liver. It'll act on the pancreatic duct to produce bicarbonate, and it'll act on the liver to produce bile. Okay, and the whole idea is to neutralize the acid in the duodenum or the rest of the smaller intestine.

The next one is called cysto kinin. As the name goes, Cole means bile. Cyst means bladder, and kin means means moving or mover. So cysto kinin means that it moves the gallbladder, so the presence of fat or other types of nutrients in the smaller intestine will stimulate the anterial endocrine cell to produce cholecystokinin.

And if you recall, in the stomach cholecystokinin. Basically inhibits the T cells and the parietal cells from producing pepsinogen and hydrochloric acid. However, in the smaller intestine, what cholecystokinin does is that it actually induces the production of enzymes by the pancreas. And also, it will act on the gallbladder and cause it to contract and the sphincter of the gallbladder to relax.

So that then the bile that is stored in the gallbladder can be released into the duodenum, and then you get a higher production of digestive enzymes, meaning that it will increase the digestion of products within the duodenum. So slightly different from what you see in the stomach. Right, so I'm going to cover a little bit of the accessory glands before we have a break.

So we take a little bit of a sidestep because these glands are really important. As I said, the smaller intestine doesn't produce a lot of enzymes, however, the enzymes are produced by the accessory glands. So what we have here is of course the liver, which sits under our diaphragm and is really important in the process of digestion, but also in the metabolism of carbohydrates, lipids.

And, um, proteins, and also detoxification of alcohol and, um, drugs. And then what we have here is the gallbladder, which is tucked underneath, underneath the liver. It is very important, not only for the storage of bile, but it is important for the concentration of bile. Okay? And then finally we have the pancreas, which sits under the stomach, and that is important for the production of a host of enzymes.

So you can see over here in terms of the anatomy, the pancreas have a pancreatic duct that then, um, will channel all the products that is produced by the pancreas into the duodenum. At the same time, you have the bowel duct here, which leads from the gallbladder that will then take it to meet the pancreatic duct.

And here you have the hepato pancreatic ampu, or what they call the ampu of Vata. Okay, that's where they join. And what is controlling the release of these products is what we call the hepatopancreatic sphincter. Okay, or sometimes they call it the sphincter of Odi, which I will refer to time and time again.

So these are the key features of all the different accessory glands. Of course it doesn't always look that good. If you were to look at a textbook you'll probably see the one before, but if you were to carry out a dissection you'll probably see something like this. So this here is of a model organism, particularly an omnivore.

It's from a pig. Um, we don't pick a, um, herbivore because it's quite different. You have the four different sections of the stomach in herbivores. So you have omasum, abomasum. So we can't study that if you want to study, um, the human digestive tract. So what you have here is of course your stomach. And then you have the pylorus, which is part of the stomach.

And that leads to the duodenum here. So you can spot the liver and the gallbladder, which is tucked nicely into the liver. And then you have your gall, uh, your bowel duct over here, and the pancreas. And here, this tiny little thing here is the pancreatic duct, okay? So I don't have any videos of a dissection, particularly for this, but if you like videos of, like, cadavers and human dissection, have a look at the video that I posted.

last week. Right, so let's move on to the pancreas then. So the pancreas have several functions. It's a known endocrine gland because it secretes insulin and glucagon that is very important for regulating your blood sugar levels. So when times are good, when you have lots of carbohydrates and blood sugar, I mean the blood sugar is high, Then insulin is secreted in order for your body to carry out, um, glycogenesis and the sugar can be stored in the form of glycogen in your muscles, alright?

When times are bad, when blood sugar, the blood sugar is low, glucagon is secreted and of course your body will undergo glycogenolysis, breaking down the glycogen stores or you undergo gluconeogenesis where you convert, um, sugars from other, um, nutrients like protein. Okay, so I think this is going to be covered in your biochemistry class.

I'm not going to go into too much detail. This is beyond the scope of what you need to know here. So what we're going to cover really, it's, it's role as an accessory, digestive, and exocrine organ, whereby it produces enzymes and secrete this enzyme rich fluid into the duodenum, and that is the role of the pancreas that we're going to cover today.

Now, of course, the, the fluids that is produced is rich in bicarbonate because it's required to neutralize the acidic gastric contents that enter, um, the duodenum. And then, of course, the enzymes, together with the brush border enzymes, will complete the digestion of, um, the carbohydrates, proteins, and fat that has been ingested.

Right, so let's have a quick look at the pancreas again. Um, so as I've shown you earlier, you saw in the picture of the model organism, the pancreatic duct. So the pancreatic duct is, um, how to say, there's lots of acinar cells around the pancreatic duct, and these are the key cells of the pancreas, and they are important in the production of those enzymes.

Now of course on top of that you get your pancreatic islet or the islet of Langerhans. You probably have heard about that. And that is made out of alpha cells and beta cells. So alpha cells are responsible for the production of glucagon. And beta cells are responsible for the production of insulin.

However, we're not going to focus too much on that. We're going to focus on these acina cells, which are responsible for the production of digestive enzymes. So they're gathered around these ducts, and they're, uh, the enzymes and secretion that they produce is then channeled out of the pancreas. into the duodenum.

And as I've said before, this release of the pancreatic juices mixed with bile is um, regulated or controlled by the, um, sphincter of Odi, or the hepato pancreatic sphincter. Okay? So again, as I said, the key unit in the pancreas is the acina cells, or in plural, it's called acini. They normally gather around the pancreatic duct.

As you can see, you can, there's lots of acina cells, about 15 to 100 cells per duct, and you can see here that these ducts are all connected to an interlobular duct, which then goes into an interlobular duct, and then finally the pancreatic duct. Now these acina cells are highly modified for its role in secreting enzymes, or producing enzymes.

So you can see over here a collection of zymogen granules, and again, zymogens are inactive enzymes, or they call it pro enzymes. So you can see the zymogen granules collected at the apical side of the cell. On top of that, what is quite obvious in the cell is the, um, how much recti uh, rough endoplasmic reticulum there is, and also the Golgi body, because they are equipped, again, for protein production and secretion.

Okay, so having a quick look at the cross section of the pancreas, you'll probably spot the interlobular duct, and then the key thing is you get lots and lots of the senor cells kind of gathered around all these ducts, and then if you see a region which is quite different to the rest, that is the islet of Langerhans, your alpha and beta cells.

Don't have to worry in memorizing what it looks like in a cross section, I thought I'll just show you what it looks like. When you don't look at the text, the classic textbook image. Right, so as I said before, acina cells are key in the production of enzymes. So they produce and export a large quantity of protein.

You're talking about more than 20 different types of enzymes. So they contain secretory granules at the apical pole, and that is a mixture of zymogens, um, of the enzymes that are required for digestion. So they have lots of, um, rough endoplasmic reticulum. They got lots of Golgi body for that particular function.

They also secrete isotonic plasma like fluid, which are rich in chlorides. Now, aside from the acina cells, what is important to know is the duct cells. So the duct cells line the pancreatic duct. Now, it's, it's actually quite important, these duct cells. The function is to produce a lot of bicarbonate. Okay, so that is important in, again, neutralizing acid and creating the condition for enzymatic activity.

So let's talk a bit about the composition of the pancreatic juice. So the pancreas secrete about 1, 500 milliliter of fluid each day, so this has been covered a little bit in the previous lecture. And it is rich in bicarbonate thanks to the duct cells. And the whole idea is, again, to neutralize acidic chyme in the duodenum.

I know I sound like a broken tape recorder, I keep saying this, but it's so important. And it produces a high amount of protein. Um, and it's the highest in, uh, compared to any other organ in the body. And this, the proteins that they produce are basically enzymes that are required to digest fats, proteins, and carbohydrates.

And we're going to look at this suite of enzymes. So, this is not all the enzymes that are found in the pancreatic juice. These are some key ones that I'll touch on, and probably some of them you might have already heard of. So what we have here is trypsin, chemo trypsin, elastase, and carboxy peptidase.

They're all involved in, um, breaking down protein. However, when they are produced, they are produced in the form of a zymogen, meaning that they're not active. This is to prevent any auto digestion of the organ. If you produce a, an active enzyme, like for example, Pepin, it will digest your stomach. Same goes for these things if they produce it.

In an active form, it'll start digesting the pancreas itself. So it normally is an enzymogen, and it needs to be activated. So you can see over here, trypsinogen is activated either by the alkali conditions in the duodenum itself, so there's an auto activation going on there, but at the same time, it can be activated by an enzyme known as enteropeptidase.

And this enzyme is found on the brush border of the small intestine. So once it's activated, it becomes trypsin, and these, and this enzyme can then activate all the other zymogens by cleaving the protein, okay? So once activated, it can cleave the internal peptide bonds of your protein molecule. Now on top of that, what is also present in the pancreatic juice is amylase, which digests starch, especially the glycosidic bonds, so you see amylase in your saliva as well.

It also contains lipase, which will cleave the ester bonds in the glycerides to release fat. And then you have colipase which will interact with lipase to make it more hydrophobic, thereby allowing lipase to interact with micelles, okay? So that is the function of colipase, and you will have RNAs and DNAs, and as the name goes, it cleaves RNA and DNA.

So these are just a few of the key enzymes. Now, on top of enzymes, we also have hormones and chemical modulators, again. So, again, you have cholecystokinin, gastrin, and acetylcholine, and what they do to the pancreas is to increase the secretion of the enzymes and, um, bicarbonate rich fluid. Okay? So, again, to get it ready to, um, act on the chyme that has arrived in the duodenum.

The next thing is of course secretin, and again, whenever you see secretin, it normally responds to the drop in pH. Okay, so you have secretin here, and you have the presence of amino acids. And the whole idea is to increase the secretion of bicarbonate rich fluid from the duct cells to help reduce the um, acidity in the duodenum.

Next you have insulin, and normally you get insulin when the conditions are good, right, when you have lots of glucose in your body. So the presence of insulin will signal to the pancreas to increase its enzyme synthesis and secretion because obviously the food, there's lots of food in your digestive tract.

And finally somatostatin is all about inhibition. So somatostatin, as you can remember, is released when, um, The, the acidic conditions are high and it basically inhibits things. So in this case, it inhibits the secretion from the Athena and duct cells signifying the end of the digestive period. So whenever you see somatostatin, it is normally at the end of the digest digestive period, because you don't want to waste all these gastric juices or the, um, juices from the smaller intestine or the pancreatic juice, um, production.

Right, so just a quick summary of what we've talked about in terms of the regulation. So, basically the stimulation by vagal nerves, especially in the presence of food, will cause the production of these various hormones by the enteroendocrine cells. Okay, so the chyme entering the duodenum will cause these cells to produce things like cholecystokinin and secretin.

Cholecystokinin, as I said, is produced in the presence of lipids and also carbohydrates and proteins, whereas secretin is produced when the pH drops. What cholecystokinin does is that it will act on the gallbladder. It will cause the gallbladder to contract and the sphincter of Odi to, um, relax, and thereby allowing, um, bowel to be released in the duodenum.

At the same time, cholecystokinin will act on the pancreas and it will cause the acina cells to produce lots of enzymes, alright? And then the enzymogens will be released into the duodenum and eventually activated. Secretin responds to the drop in pH, so what secretin does is it acts on the liver and gets the liver to produce lots of bile.

Because bowel is alkali. And then it will also act on the duct cells of the pancreas to produce lots of bicarbonate. Thereby releasing this bicarbonate into the duodenum as well. Okay? So that, in a way, is how these, um, the secretion of the pancreas is regulated by cholecystokinin and secretin. Right, so with that, we're gonna take a quick break.

'Moving swiftly on to the other accessory gland, which is the liver. So hopefully we'll be able to wrap things up by six o'clock today and let you guys get off a bit earlier, hopefully. Right, so after the pancreas, we're going to have a bit of a chat about the liver, and the liver is a really important organ, as most of you probably know from your A-levels.

The liver is one of the largest organs in the body, of course, after the skin and the brain. The average weight of the liver is about 1.3 kg. It sits right under our diaphragm, and it is one of the, well, it is the only human organ that is capable of natural regeneration.

So if you have any liver damage, you only need 25% of the liver in order to regenerate to its complete form. When I say complete form, I just say the mass, not the shape itself, okay? Now, the liver performs many metabolic and homeostatic functions. So it is the place where carbohydrates, proteins, lipids, that's where they are interconverted, synthesized, broken down.

It also is very important in the detoxification of alcohol and also drugs. So we are going to touch on those things today. Now, as I said, there's lots and lots of different functions in the liver.

I'm not going to cover all of them. I'm just going to briefly go through some of them, but the ones in orange are the ones that we're going to cover today. So it is particularly important in terms of filtering out any foreign particulate.

And when I say foreign particulate, it's things like bacteria. It's also things like parasites. It contains cells known as Kapha cells, which has the ability to filter out these things.

It is responsible for the synthesis and secretion of bile. So bile is made out of several different ingredients, namely cholesterol, bile salts, which is also made out of cholesterol, and bilirubin, which is made out of broken down red blood cells. As I said earlier, the liver is important in terms of the metabolism of carbohydrates, protein, and fat.

However, this is beyond the scope of this lecture. For those of you who are doing biochemistry or fundamentals of biochemistry, you'll probably go through that in more detail. The liver has an endocrine function like the pancreas.

So it produces a variety of hormones, ranging from things that control the production of platelets, for example. But again, we're not going to cover that in this particular lecture. It is important in iron, copper, vitamin A, B12, D, E, K, starch.

And as I've said before, it plays a really important role in the detoxification of ammonia, alcohol, and drugs, which again, as I said, is something that we will cover today. Now, in terms of its anatomy, the chief functional cell of the liver are known as hepatocytes. So let's take a look at these two figures over here.

When you look at the anterior surface of the liver, you can see the right lobe and the left lobe. When you flip it around to the posterior surface, what you'll see is the quadric lobe and also the caudate lobe. The liver is wrapped, there's kind of a film around the liver known as Gleason's capsule.

And then of course, the liver is split into two here by a forciform ligament. And that ligament attaches the liver to the diaphragm and also the anterior abdominal wall. So it keeps it in place.

Right in the bottom part of the liver here, in the posterior surface, you should be able to see the gallbladder. That's about seven to 10 centimeters in size. It almost looks like a little pear.

And as I've said earlier, the gallbladder is really important as a storage for bile, but at the same time, it concentrates the bile that is produced by the hepatocytes. Right. So if you take a cross section of the liver, you should be able to see the liver lobules.

And normally it has a polyhedral structure, but if it's cut right across, it does look quite hexagonal and it is bordered by these connective tissues. And in the middle of the lobule is your central vein. Now, this here is a nice little cartoon of what a liver lobule looks like.

And as I said before, it's quite hexagonal in structure, but at the border of the lobule, you should be able to see what we call the portal triad. And that is made up of the bile duct, the hepatic portal vein, and also the hepatic artery. And arranged radiating out of the central vein is the hepatocyte.

So you can see there's lots of space amongst the hepatocytes. These are called the sinusoids, and that's why the liver has a spongy type of texture. OK.

So again, zooming into the portal triad, just to remind you, it's made out of three things. You have your portal vein, the hepatic artery and the bile duct. And around it, you can see all the hepatocytes.

Right. So just to orientate you again, I'm going to talk you through the structure. So what we're seeing here is, again, your liver lobule and then the portal triad here where you have the bile duct, your hepatic portal vein and the hepatic artery.

And as I said earlier, the hepatocytes radiate from the central vein. And between the hepatocytes, you have your sinusoids, which is this space. And then you get these cover cells which are attached to the walls of the sinusoids.

And as I said before, these cells are important in its filtering mechanism. So it's a bit phagocytic. So it kind of feeds on the bacteria or any parasites floating around.

Now, within the sinusoids itself, you should be able to see the venules that will have the deoxygenated blood and you should have arterioles as well. And then you also have what we call the bile caneliculi, which then, of course, drains the freshly synthesized bile into the bile duct, which is then taken to the gallbladder. So the liver is quite unusual because it has two sources of blood here.

So it has the blood, 25% of the blood comes via the hepatic artery. That's oxygenated blood. It also contains what we call chylomicrons and lipids.

And then, of course, you have 75% of blood going towards the liver via the hepatic portal vein. And this is deoxygenated blood. But this blood has flowed through the capillaries of the digestive tract, the stomach, the intestines, the pancreas, and the spleen.

So it's nutrient rich. So this blood will then converge in the liver. And what you'll see is, of course, you send the sinusoid and the hepatic artery will empty its content into the arterioles.

And of course, you have the venules as well. And all of the blood will then converge in the central vein. Now, this deoxygenated blood will be taken back into the heart via the hepatic vein and the vena cava.

And it gets reoxygenated over there. So the key thing here is that the liver receives two sources of blood. Now, we cannot talk about the liver without talking about the gallbladder.

And as I said before, the gallbladder sits right under the liver. And it is important for the storage of bile that is not required immediately for digestion. So it stores bile.

And it can expand itself to accommodate up to 60 mils of bile. It has folds within the gallbladder. So like the stomach, if you remember, the stomach is normally quite small.

But then it has these folds called the rugae, which then allows the stomach to expand. Same goes for the gallbladder. It's a lot smaller.

But then it can expand because it has these folds. Now, what the gallbladder does is that it can concentrate the bile by 20 fold. That is done by absorbing sodium chloride, bicarbonate, and water.

So sodium chloride gets transported out of the gallbladder. And water will diffuse through with sodium chloride. So just a quick overview of what the gallbladder looks like.

So the gallbladder sits over here. And you have your right hepatic duct and the left hepatic duct that drains the bile that's synthesized by the hepatocytes. And it's taken into the gallbladder via the cystic duct.

So when the bile is transported, it will then go through the common bile duct. And you will meet the pancreatic juices via the pancreatic duct here. And as I've said before, where it joins the pancreatic duct, this here is the ampulla of vata.

And the release of pancreatic juices and bile into the duodenum is controlled by the sphincter of Odi, or your hepatopancreatic sphincter. Bile is not continuously released all the time. So during what we call the interdigestive period, the bile is actually sent back into the gallbladder.

And that is because the sphincter of Odi is constricted. So it sends a pressure and the bile will be sent back into the gallbladder. As it stays there, it gets concentrated.

Now when you're eating or during the digestive period, what happens is cholecystokinin will act on the gallbladder. And it also will act on the sphincter. So the gallbladder will be constricted.

And that will push the bile all the way to the cystic duct via the common bile duct. And then the sphincter of Odi will relax, also because of cholecystokinin. And then bile and pancreatic juices can be released into the duodenum.

So what is bile made of then? As I said before, bile contains cholesterol, but it also contains bilirubin and cholesterol in the form of bile salts. So bile is used for the promotion of digestion, and it is also used to emulsify lipids. So it helps with the digestion of lipids.

Now the production of bile happens in three steps. Of course, hepatocytes will produce bile from cholesterol, bilirubin, and bile salts and other ingredients. And then the bile will be secreted into the bile canaliculi.

And the ductal epithelial cells, you saw all the different ducts, they will secrete bicarbonate into bile to modify the secretion. And then in between meals, half of the hepatic bile is diverted back to the gallbladder, and it stays there and gets concentrated. And then during meals, when cholecystokinin acts on the gallbladder, it will constrict, and then the sphincter of odi will relax, and bile will then be secreted into the duodenum, as you can see over here.

So bile is made out of a variety of things. As I said before, we're not going to cover every single ingredient in bile. That's not the point of the lecture.

What we'll focus on are three key things. Bile acids, which is used to make bile salts. And then you have bilirubin, which is made out of hemoglobin from all red blood cells.

And then, of course, cholesterol. And what you can see here is that hepatic bile is actually quite diluted. So this is bile that is freshly made from the hepatocytes.

And then gallbladder bile is when it gets concentrated. You can see the concentration is much higher in terms of bile acids, bilirubin, and cholesterol in gallbladder bile. So one of the ingredients, or one of the things that you find in bile is cholesterol.

And cholesterol is something that we can acquire via our diet. But at the same time, cholesterol is also synthesized de novo by the liver. So the liver is actually primarily responsible for a large proportion of the cholesterol that we have in our body.

So the cholesterol that's synthesized is important for a variety of things, including cell membranes, because it acts as a scaffold and prevents our cell membrane from being too fluid. But it's also important for the synthesis of a variety of hormones, such as estrogen and progesterone. You get cholesterol in there.

Now, cholesterol serves as a precursor for bile acids, which is the ingredient for bile salts that you see inside bile. And then any excess cholesterol will be excreted via bile, along with phospholipids and particularly lecithin. So lecithin is an amphiphatic molecule.

So have you guys heard of the word amphiphatic before? Yes? In chemistry, perhaps? So what is amphiphatic then? Right. It's a very important thing, this amphiphatic molecule, because it has a hydrophilic site and a hydrophobic site. So it has two sites.

And because it's amphiphatic, it allows lecithin to interact with a hydrophobic molecule and the hydrophilic surrounding. So it's important that way. And bile salts are also amphiphatic molecules.

And you'll see why they are important later. So as I said before, cholesterol is the precursor for bile acids. So cholesterol will be acted upon by an enzyme known as C27B hydroxylase in your intestine.

And then what happens is that it is converted to colic acid or chenodeoxycholic acid. Now, some intestinal bacteria will act on it to form a secondary bile acid, as you can see over here. But actually, what is key here is that bile acids are conjugated with some molecules known as glycine and taurine.

And these molecules are hydrophilic. So by conjugating with a hydrophilic molecule, it produces the end product, which is amphiphatic. So you have the hydrophobic end, which is from cholesterol, and you have the hydrophilic side, which is from glycine or taurine.

Now, small amounts of these secondary bile acids, which are formed in the intestine, are taken back to then be reconjugated with amino acids to form bile salts. Now, the whole point is that these amphiphatic molecules are really important because it can interact with dietary fats, and that allows it to be made into micelles. So as I said before, our bile salt has the hydrophobic side here and the hydrophilic bit.

So if you have a fat globule, the hydrophobic side of the bile salt will interact with the fat, and then the hydrophilic side, which is polar, will interact with its watery aqueous surrounding. So what happens is when bile salts interact with the fat globule, what happens is it allows it to remain in what we call little tiny micelles. So then lipase can then interact with it and break it down further.

Now, bile salts, as I said, is synthesized and it gets released into the duodenum via bile, and then what happens is that it can be recycled by our body. So 95% of bile salts are then reabsorbed by the small intestine, particularly the terminal ileum. So this 95% will enter the hepatic portal vein and it's then recycled, and it's then stored in the gallbladder again.

Only 5% are lost in your feces, and that is because the bile salt is acted on by the bacteria in the small intestine. So it deconjugates these bile salts, so it makes it hydrophobic by removing the hydrophilic region. So because it's hydrophobic, it cannot be recycled any further, and therefore it is lost.

So this recycling can happen up to 20 times. Now, for a person who has lost the terminal ileum, it then of course means that they will have to increase the synthesis of bile salts, so the liver will have to work doubly hard to produce it. So the amphiphytic nature of bile salts are really important, because as you can see over here, any excess cholesterol in our body that cannot be dispersed into my cells will form crystals in the bowel.

So I'm sure a lot of you have heard about cases of gallstones. So how does this work and why does it happen? So mycelation allows cholesterol to remain in solution, and how does that work? So here you see a droplet or a cholesterol, and then what you have is, as I said before, lecithin, which is an amphiphytic molecule, and then you have bile salts, which is also an amphiphytic molecule. So what happens is the hydrophobic domains of this molecule will interact with cholesterol, and its hydrophilic domain will face the aqueous surrounding, thereby keeping cholesterol in solution.

However, if there's too much cholesterol, you will outnumber the amount of lecithin and bile salts there is in the bile solution. So what happens is that if cholesterol is not bound by this amphiphytic molecule, it will start to precipitate calcium carbonate, or it will also precipitate phosphate salts, thereby producing these stones. And as the stones build up in the gallbladder, what will happen is there will be a lot of pain.

So normally it's treated by either the excision of the gallbladder itself, or they can use certain drugs to dissolve these precipitates, or they can also use ultrasonic waves to break it down further. So for those of you who have never seen gallstones, I mean actually this picture was taken by a student of ours a couple of years ago. So gallstones that you see in this picture are about four centimeters in size.

It's actually quite big, and there's two different varieties here. This one is what we call a cholesterol gallstone, which is like full of cholesterol. That's why you get this yellowish tinge.

And then this one actually has been stained by bilirubin, so it's kind of brownish. This was actually taken in the Royal Berkshire Hospital. So we do have some replacements at the Royal Berkshire Hospital, especially in the histopathology unit and the blood sciences unit.

So the histopathology unit so happened is actually on campus in the Harborne building. So I normally tend to advertise this towards the end of the semester. So keep an eye out for this.

It's about a six week long placement. You get to work on things like that. Right, moving swiftly on to bilirubin synthesis then.

So the other ingredient in bile is of course bilirubin, and I think a lot of you know that bilirubin gives you this distinct colour. It's a distinct pigment that gives urine your yellow colour, it gives colour to your faeces, and it also gives bile its distinct greenish yellowish colour as well. Now the breakdown of heme actually produces bilirubin, and bilirubin is actually an insoluble waste product.

You can see here it's quite hydrophobic. So bilirubin must be made water-soluble by conjugating with other molecules before it gets excreted. So this transformation of bilirubin occurs in five different steps.

So first it is formed in the spleen where the red blood cells are broken down, and then what happens is then bilirubin is transported in the plasma in conjugation with another protein to ensure that it is soluble. Once it gets into the liver, it gets de-conjugated from that protein and re-conjugated to another molecule, and I'll show you how that works shortly. And once that happens, it can then be excreted.

So let's take a look at the process in more detail then. So as I said before, bilirubin is formed from old red blood cells. So you have hemoglobin, which is then broken down to heme and globin.

Heme is acted on by heme oxygenase to form bilirubin. Now bilirubin doesn't hang around for long. It gets reduced quite quickly to form bilirubin.

So bilirubin is kind of a greenish colour, whereas bilirubin is yellowish. So one way of remembering this is like if you have a bruise on your arm. So a fresh bruise is normally quite greenish, and that is bilirubin.

And then as your bruise recovers, it gets a bit more yellowish, therefore that is bilirubin. So that's one way of remembering it. So as I said before, bilirubin is not very soluble.

So it has to be conjugated to something in order to increase its solubility to be transported in your plasma. So what it binds to is albumin. So once it binds to albumin, it can then be transported to the liver, whereby it is de-conjugated.

And in the liver, it gets conjugated to glucuronic acid, thereby increasing its solubility again. So bilirubin diglucuronide is then able to be transported in bile. So when it gets into the intestine, it's acted on by bacterial flora to then form urobilinogen.

Now urobilinogen is a colourless substance, and that can be transported back into the liver by your portal circulation, or it can enter the general circulation and is excreted via the kidney in the form of urine. Now if urobilinogen is reduced, it gets converted into stercobilin. Now stercobilin is a brownish colour, and it gives your feces its distinct colour, whereas urobilin is an oxygenated form of urobilinogen, and that gives your urine that kind of colour as well.

So that's where the pigments of your urine and feces come from. So a lot of you would have heard about jaundice, and that's where you get high concentrations of unconjugated bilirubin in the blood, so about 34 micromole per litre. And that causes this classic yellow discolouration of the skin, the sclera of the eyes, and the deeper tissues.

There are many causes to cause jaundice, one of them being excessive destruction of red blood cells. So this is what we call hemolytic jaundice. So if you have a blood transfusion and it's the wrong type of blood, you have this excessive destruction of red blood cells, thereby increasing the amount of bilirubin in your body.

There's not enough albumin or what do you call it, glucuronic acid to conjugate it, therefore it basically hangs around your system, causing jaundice. Sometimes you also get jaundice in babies, newborn babies, and that's because the haemoglobin is converted from neonatal haemoglobin to adult haemoglobin, therefore the premature liver is not able to cope with that, therefore you have lots of bilirubin hanging around, causing jaundice. So this is treated by UV light, and that helps with the isomerisation of bilirubin.

So it transforms it from trans to cis, therefore solubilising it. Now the other bit is cases where there's an impaired uptake of bilirubin by hepatocyte, that causes hepatic jaundice. Sometimes you get decreased conjugation of bilirubin, either because of the lack of albumin or the lack of glucuronic acid, that also is called hepatic jaundice, and when there's an obstruction of bowel flow, most of the bilirubin is conjugated with albumin and glucuronic acid, thereby reducing the albumin and glucuronic acid stores, therefore new bilirubin being introduced to the system have nothing to conjugate with.

So that will also cause jaundice, and of course naturally any form of liver damage will cause jaundice as well. Right, so like any other secretion in the digestive system, bowel secretion is also tightly regulated. So as you can see again, the presence of fatty acids, amino acids and chyme will stimulate the production of cholecystokinin, and the drop of the pH will stimulate the production of secretin.

Cholecystokinin, as I said, as the name goes, is supposed to act on the gallbladder, so it will act on the gallbladder and it will cause it to contract, and the sphincter of odi to relax, thereby releasing bile into the duodenum. Secretin will act on the liver and stimulate bowel production. So this here is a very simple slide that captures the whole thing, and again it's quite useful for revision.

Right, so as I said before, the liver is really important in the detoxification of a variety of things. We're talking about ammonia here, and later you'll look at alcohol, and of course drugs. So in the case of amino acid catabolism, the breakdown of amino acid that occurs via transamination and deamination will lead to the production of ammonia, and ammonia is really toxic and it needs to be removed via the Muir cycle, or sometimes it's referred to as the Ornithin cycle.

So the first step is of course transamination, and a group of enzymes known as transaminases are involved in this, and most of them are found in the liver. So here you can see alpha-ketoglutarate acts as an amino group acceptor, so you can see an amino acid here, and when it's acted on by an amino transfer rate, it transfers the amino group to this particular amino acceptor, thereby producing glutamate and alpha-ketoacid. Now alpha-ketoacid can be a variety of things, such as acetoacetal-CoA, citric acid cycle intermediates, or even pyruvate.

Again, I'm not going into any details here because we're not going to talk too much about biochemistry. Now what happens is that the L-glutamate will undergo the process of deamination, where the amino group is then liberated, and what you have is the production of the acceptor molecule again, alpha-ketoglutarate and ammonia, and that ammonia is highly toxic, it needs to be removed. So the process of removing this is carried out by what we call the Ornithin or urea cycle, and this is carried out in the liver.

So ammonia that's released in the process of deamination is rapidly removed, and what happens is this ammonia is bound to carbon dioxide in the presence of an enzyme known as carbamyl phosphate synthetase, and what happens is that you get this production of carbamyl phosphate, which can then enter the Ornithin cycle. You don't have to remember every single step of the Ornithin cycle, just remember that when carbamyl phosphate enters the cycle, it's bound to L-ornithin, it undergoes several steps, and you get urea produced at the very end of that cycle, and L-ornithin is then recovered to bind to carbamyl phosphate again. That urea is then of course excreted by the kidney, in some cases some of it may diffuse back into the intestine and that's converted to ammonia by enteric bacteria, and that ammonia can enter the portal circulation again and go back into the liver to re-enter this Ornithin cycle.

Now as I said, the liver is super important when it comes to removing drugs and poisons, so substances that are not normally found in our body is known as xenobiotics, we talk about things like aspirin, paracetamol, warfarin, all sorts of painkillers, they all need to be detoxified. So the liver is responsible for neutralizing these things, and that is done by modifying the chemical constitution, and this process is called biotransformation. Biotransformation occurs in two steps, the first step is to reduce the toxicity of the molecule, and the second step is to increase the solubility so that that molecule can be removed from the body.

So the liver plays an important role in the inactivation and excretion of hormones as well, such as steroids, and also all the things like insulin and glucagon, they undergo proteolysis and deamination in the liver. Right, so the process of biotransformation is quite straightforward, as I said, the first step is to reduce the toxicity, and that can be done by oxidation, reduction, hydrolysis, or acetylation, so you change the chemical.