Liver Physiology Lecture Notes PDF

Liver physiology Oleg Osadchiy 1 Learning objectives ✓ Describe the structure of the liver lobule. ✓ Explain the blood supply of the liver. ✓ Outline the main functions of the liver. ✓ Describe the composition of bile. ✓ Outline the structure of the biliary system. ✓ Explain the role of bile in inte...

Liver physiology Oleg Osadchiy 1 Learning objectives ✓ Describe the structure of the liver lobule. ✓ Explain the blood supply of the liver. ✓ Outline the main functions of the liver. ✓ Describe the composition of bile. ✓ Outline the structure of the biliary system. ✓ Explain the role of bile in intestinal digestion of fats. 2 Learning objectives ✓ Describe the functions of the gallbladder. ✓ Explain the mechanisms that regulate the bile secretion by hepatocytes and the bile release into the duodenum. ✓ Describe metabolism of bilirubin. ✓ Explain the main types of jaundice and the contributing pathophysiological mechanisms. ✓ Outline the role of liver in detoxification of blood, protein synthesis, and metabolism of carbohydrates and lipids. 3 Overview of GIT. Location of the liver in the abdomen. Hepatobiliary system. Overview of the liver ✓ The liver is the the largest gland of the body, weighing about 1.4 kg in an average adult. ✓ It is located below the diaphragm, on the right side of the body. ✓ The main function of liver is a secretion of bile. ✓ Consequently, the liver is part of the hepatobiliary system, which includes, apart from the liver, the gallbladder and bile ducts. 7 Plate The liver lobule. Organization of liver lobule. CV is central vein. PS is portal space. Each PS contains a portal tract, which includes branches of the bile duct (green), portal vein (blue), and hepatic artery (red). Lobules of the liver ✓ Liver is organized into many functional units called lobules. ✓ Each lobule is a six-sided structure (hexagon) that consists of multiple plates of hepatocytes arranged around a central vein. ✓ Each plate includes few cords of hepatocytes radiating towards a central vein. ✓ At each corner of the liver lobule, there is a portal space which contains branches of bile duct, portal vein, and hepatic artery. ✓ Bile duct, portail vein, and hepatic artery form the portal tract (or portal triad). 10 Plate The liver lobule. Structure of the hepatic plate. Hepatic plate ✓ Within a hepatic plate, there are two structures that lie in between the adjacent cords of hepatocytes. (i) The bile canaliculus that accumulates bile from the hepatocytes and drains it into the bile duct in the portal space. (ii) The sinusoid vessel that receives blood from the portal vein and the hepatic artery, and drains the blood into the central vein. ✓ The direction of bile flow in the canaliculus (from center towards the periphery) is opposite to the direction of blood flow in the sinusoid (from periphery to the center). 13 Directions of the bile flow and blood flow within a hepatic plate. Liver sinusoids. Liver sinusoids ✓ Liver sinusoids are wide, highly permeable capillaries that contain a mixture of venous blood from the portal vein and the arterial blood from the hepatic artery. ✓ They deliver the blood to the central vein. ✓ The wall of sinusoids is made of fenestrated endothelial cells, without a basement membrane. ✓ Hepatocytes are separated from the sinusoids by the space of Disse which contains loose connective tissue. ✓ Kupffer cells reside in the lumen of sinusoids, and act as macrophages that kill bacteria through phagocytosis. 16 The Kupffer cells. Hepatic artery Portal vein Sources of blood supply of the liver. Blood supply of the liver ✓ The liver receives blood from two sources – the hepatic artery and the portal vein. ✓ From the hepatic artery, the liver obtains oxygenated blood. ✓ From the portal vein, the liver receives venous blood that contains newly absorbed nutrients, drugs, and possibly microbes and toxins from GIT. ✓ The liver serves as a filter that can remove potentially harmful substances before they get into the systemic circulation. ✓ From sinusoids, oxygen, nutrients, and toxic substances are taken up by the hepatocytes. 19 Sources of blood supply of the liver. Functions of the liver ✓ Secretion of bile for fat digestion. ✓ Detoxication of blood. ✓ Synthesis of plasma proteins and clotting factors. ✓ Storage of blood. ✓ Metabolism of carbohydrates. ✓ Metabolism of lipids. 21 Secretion of bile 22 Bile ✓ Each day, hepatocytes secrete about 1 liter of bile, a yellow-green liquid. ✓ Bile has a pH of 7.6-8.6 and is isotonic to blood plasma. ✓ Bile is released into the duodenum. ✓ Because the bile has alkaline pH, it contributes to neutralization of the gastric acid that was expelled to the duodenum upon gastric emptying. 23 The bile secreted by hepatocytes enters the bile canaliculus, and then goes to the bile ductule. Biliary tract. Bile ducts ✓ Between the hepatocytes are small ducts called canaliculi, which collect bile produced by the hepatocytes. ✓ From canaliculi, bile passes into the bile ducts. Small bile ducts merge to form larger ducts, i.e. the left and the right hepatic ducts, which give rise to the common hepatic duct. ✓ The common hepatic duct joins the cystic duct from the gallbladder to form the common bile duct, which drains the bile into the duodenum. 26 Bile ducts ✓ Bile drainage into the duodenum is controlled by the sphincter of Oddi. ✓ When there is no chyme in the duodenum, the sphincter Oddi closes, and the bile backs up into the gallbladder for storage. 27 Bile composition (i) Water (ii) Bile pigments (iii) Bile salts (iv) Cholesterol (v) Lecithin (phospholipid) (vi) Several ions (Na+, bicarbonate, etc) 28 29 Bile acids ✓ Bile acids are subdivided into the primary and secondary. ✓ Primary bile acids (cholic acid and chenodeoxycholic acid) are synthesized by liver from cholesterol. ✓ Secondary bile acids (e.g. deoxycholic acid) are produced in the duodenum once the primary bile acids are processed by the intestinal microflora. 30 Bile acids are conjugated with glycine and taurine to produce bile salts (glycocholate and taurocholate). Bile salts are present in the ionized form, so they are more soluble in water than the bile acids. Glycocholate Taurocholate Bile salts. Bile and digestion of fat ✓ In the duodenum, the bile assists to pancreatic lipase in digesting of fat. (i) Bile salts make fat water-soluble (meaning it can be accessed by the lipase present in the intestinal fluid). (ii) Bile salts contribute to the emulsification of fat – a large lipid globule is split into multiple smaller droplets. This markedly increases the surface area for the action of lipase, which accelerates digestion of fat. 33 Bile salt (hydrophilic regions are shaded). Bile salt Bile salts contain both hydrophobic and hydrophilic regions. The bile makes fat water-soluble. Fat globule with bile salts attached to its surface is called micelle. Cholesterol Lecithin Simple micelle (left) and mixed micelle (right). How to make fat water-soluble? ✓ In contrast to proteins and carbohydrates, dietary lipids are insoluble in water. This complicates their digestion by pancreatic lipase in the watery intestinal lumen. ✓ Bile salts are amphipathic, which means they have a hydrophobic region (lipid-soluble) and a hydrophilic region (water-soluble). ✓ Hydrophobic regions of the bile salts interact with a large lipid globule, and hydrophlic regions interact with the watery intestinal chyme. ✓ In this way, the fat is solubilized in the watery intestinal chyme and can be digested by enzymes (lipase). 38 Types of micelle ✓ The micelle could be of two types – simple micelle and mixed micelle. ✓ Simple micelle is made of a lipid droplet and the bile salts attached to its surface. ✓ Mixed micelle incorporates cholesterol and lecithin molecules inside the lipid droplet. 39 Bile and digestion of fat ✓ In the duodenum, the bile assists to pancreatic lipase in digesting of fat. (i) Bile salts make fat water-soluble (meaning it can be accessed by the lipase present in the intestinal fluid). (ii) Bile salts contribute to the emulsification of fat – a large lipid globule is split into multiple smaller droplets. This markedly increases the surface area for the action of lipase, which accelerates digestion of fat. 40 Surface tension is the force that holds molecules of liquid together. Bile salts reduce the surface tension (detergent action). Drops of oil (fat). Emulsification of a large lipid globule is due to reduction of surface tension by bile salts. Why tiny lipid droplets cannot coalesce and re-form a large lipid globule? The hydrophilic part of the bile salt molecule which projects to solution is charged negatively. Emulsification of fat. Emulsification of fat ✓ When the bile salts adsorb on the surface of small lipid droplets, they create shells of the negative charge, which cause the droplets to repel each other. ✓ This action holds the fat droplets apart and prevents them from recoalescing. ✓ Consequently, the surface area available for digestion by pancreatic lipase is markedly increased. 47 Bile and digestion of fat ✓ In the duodenum, the bile assists to pancreatic lipase in digesting of fat. (i) Bile salts make fat water-soluble (meaning it can be accessed by the lipase present in the intestinal fluid). (ii) Bile salts contribute to the emulsification of fat – a large lipid globule is split into multiple smaller droplets. This markedly increases the surface area for the action of lipase, which accelerates digestion of fat. 48 Basic digestive processes. Bile salts Bile salts also aid in absorption of the products of lipid hydrolysis, such as free fatty acids and glycerol, in the small intestine. 50 Glycerol and fatty acids need to diffuse from the intestinal lumen to the enterocytes for absorption. Free fatty acids and glycerol cannot diffuse through the watery layer covering the absorptive surface of the small intestine, because they are not water-soluble. Fatty acid Glycerol Micelle can incorporate free fatty acids and glycerol. Micelle can carry fatty acids and glycerol through the watery layer that covers the absorptive surface of the intestine. Fatty acid Glycerol Once the micelle has crossed the watery layer that covers the absorptive surface of the intestine, the fatty acids and glycerol are released out, and can be taken up by the enterocytes for transporting to the blood. Intestinal lumen Micelle Micelle is working as a shuttle that is moving back and forth between the intestinal lumen and the intestinal mucosa. The passengers are fatty acids and glycerol. 56 Micelle and fat absorption ✓ Once the fat is digested by lipase, glycerol and free fatty acids are released into the luminal fluid. ✓ Neither glycerol nor the free fatty acids are water-soluble. So these molecules, once they are released from the fat droplet, cannot diffuse through the watery luminal fluid to the intestinal surface (mucosal cells), where they are supposed to be absorbed. ✓ Consequnetly, the glycerol and free fatty acids are re-cycled into the lipid droplet (micelle). As the micelle is water-soluble, it can carry the products of the lipid hydrolysis through the watery luminal content to the absorptive surface of the small intestine. 57 Gallbladder 58 Gallbladder functions as a bile storage. The gallbladder ✓ The gallbladder is a pear-shaped sac located just beneath the liver. ✓ Its major function is to store the bile. ✓ Bile is continuously secreted by liver. However, between meals, the sphincter of Oddi is closed, which prevents bile from entering the duodenum. Any bile secreted at this point backs up into the gallbladder, where it is stored. ✓ Another function of the gallbladder is to concentrate the bile while it is being stored (through absorption of water). 60 Differences in characteristics of the hepatic bile vs. the gallbladder bile. Epithelial cells of the gallbladder absorb water through aquaporins and secrete H+ ions through the Na+-H+ exchanger. Regulation of the bile secretion by liver and its release into the duodenum. 63 Stimulation of the bile secretion into the duodenum (i) Bile acids absorbed from the duodenum into the blood. (ii) Hormones secretin and cholecystokinin (CCK) released from the endocrine cells in the duodenum. (iii) Stimulation of the vagus nerve. 64 Enterohepatic circulation of the bile salts. Effects of secretin and CCK on the bile secretion Vagus nerve stimulates bile release similar to CCK, but the vagal effect is smaller. Jaundice 69 Jaundice is a yellow discoloration of the skin and sclera caused by hyperbilirubinemia. Bilirubin is a bile pigment that gives it yellow-green colour. There are two types of bilirubin – conjugated and unconjugated (free). Stercobilin Metabolism of bilirubin in normal conditions. Bilirubin ✓ Bilirubin is the principal bile pigment, which has a yellow color. ✓ Phagocytosis of aged erythrocytes liberates heme and globin. Heme is converted to biliverdin, and then to free bilirubin. ✓ Free bilirubin is insoluble in water, so in order to be carried by the blood plasma, it binds to plasma proteins. ✓ In the liver, free bilirubin is conjugated with glucuronic acid. The conjugated bilirubin (bilirubin glucuronide) is watersoluble, so it can be excreted with bile into the duodenum. 73 Urobilinogen ✓ In the duodenum, bilirubin is converted to urobilinogen by the intestinal microflora, which then can follow three pathways – (i) Urobilinogen can be coverted to urobilin, and then to stercobilin, which is released with feces and accounts for its normal brown colour. (ii) Urobilinogen can be absorbed to portal circulation, reach liver, and then be re-cycled into the bile. (iii) Urobilinogen can be absorbed to systemic circulation, reach kidney, and be excreted with urine. 74 Three types of jaundice (i) Prehepatic (ii) Hepatic iii) Extrahepatic 75 Prehepatic jaundice ✓ This type of jaundice is seen upon excessive hemolysis of red blood cells (hemolytic anemia). ✓ Heme released from the destroyed red blood cells is metabolized to form the excess amounts of free bilirubin. ✓ Hyperbilirubinemia causes yellow discoloration of the skin and sclera. ✓ Because free bilirubin is not water-soluble, it is not excreted in the urine, so the urine colour is not changed. 76 Hepatic jaundice ✓ Liver disease (hepatitis, cirrhosis) induces injury of the hepatocytes. ✓ Both free bilirubin and conjugated bilirubin leak from the damaged hepatocytes into the blood plasma. ✓ Hyperbilirubinemia causes yellow discoloration of the skin and sclera. 77 Extrahepatic jaundice ✓ This type of jaundice is caused by obstruction of the common bile duct by a gallstone or tumor. ✓ Bilirubin is conjugated by the hepatocytes, but cannot flow into the duodenum. ✓ Hence conjugated bilirubin accumulates in the liver and enters the bloodstream. ✓ Because conjugated bilirubin is water-soluble, it appears in urine (which becomes dark-coloured). ✓ Because conjugated bilirubin does not enter the duodenum, the stools are light-coloured because they lack bile pigments. 78 Obstructive jaundice. Light-coloured stool. Dark urine Other functions of the liver 80 Detoxification of blood ✓ All substances are absorbed from GIT to the portal circulation, and are brought to the liver. ✓ Liver is acting as a filter that clears the blood via the following mechanisms – (i) Phagocytosis by Kupffer cells. (ii) Chemical modification of absorbed molecules (e.g. alcohol, medications), which are subsequently released into the bile. (iii) Conversion of toxic substances to less toxic substances. For example, ammonia is converted to urea and uric acid. 81 Synthesis of proteins by liver (i) Plasma proteins (albumin, globulins, and fibrinogen). (ii) Clotting factors (fibrinogen, prothrombin, and others). (iii) Transporting proteins (corticosteroid-binding globulin, thyroid-binding globulin, transferrin, ceruloplasmin). (iv) Peptide prohormones (angiotensinogen). (v) Lipoproteins. 82 Carbohydrate metabolism ✓ Liver is a storage of glycogen. ✓ As such, the liver is important for maintaining normal blood glucose levels. ✓ When blood glucose is low, the liver breaks down glycogen, and releases glucose into the bloodstream. ✓ The liver can also convert amino acids, lactic acid, and glycerol to glucose (gluconeogenesis). ✓ In contrast, when blood glucose is high, as occurs after a meal, the liver converts glucose to glycogen and triglycerids for storage. 83 Lipid metabolism (i) Hepatocytes synthesize and store triglycerids and cholesterol. (ii) Hepatocytes break down fatty acids to generate ATP. (iii) Hepatocytes synthesize lipoproteins, which transport fatty acids, triglycerids, and cholesterol to body cells. 84 After this lecture you are able to ✓ Describe the structure of the liver lobule. ✓ Outline the main functions of the liver. ✓ Describe the composition of bile and its role in digestion and absorption of fat. ✓ Explain the mechanisms that regulate the bile secretion by hepatocytes and its release into the duodenum. ✓ Explain the main types of jaundice. 85