P1 B1 CTB Liver Physiology PDF

Liver Physiology Dr Seley Gharanei, Assistant Professor Cell and Tissue Biomedicine [email protected] MB ChB Phase I Block 1 Health, Metabolism and Homeostasis  Learning outcomes  Describe the blood supply to the liver  Describe the organisat...

Liver Physiology Dr Seley Gharanei, Assistant Professor Cell and Tissue Biomedicine [email protected] MB ChB Phase I Block 1 Health, Metabolism and Homeostasis  Learning outcomes  Describe the blood supply to the liver  Describe the organisation of the liver  Describe the major cell types of the liver  Outline the major functions of the liver  Describe the production, storage and secretion of bile  Describe the composition of bile  Explain the function of bile salts  Describe the enterohepatic circulation The Liver  Is located mainly in the right upper quadrant of the abdomen  Weighs approximately 1.4 kg  Receives nearly 25 % of the cardiac output Basic Overview of Blood Supply to the Liver * This image is not a very accurate anatomic representation of the blood supply to the liver, please refer to your anatomy teachings in this area. The liver receives: 1. Venous flow from the hepatic portal vein 2. Arterial flow from the proper hepatic artery Basic overview to illustrate overall routes of circulation through liver Please refer to CAI theme learning outcomes and materials for the greater detail of learning required. The hepatic portal vein carries venous blood draining from the stomach, small intestine, large intestine, pancreas and spleen. Basic overview to illustrate overall routes of circulation through liver Please refer to CAI theme learning outcomes and materials for greater detail of learning required. Organisation of the Liver: Hepatocytes are arranged in lobules branch of hepatic vein central vein bile duct hepatic artery portal vein Functional Zonation of Liver Lobules III II I Zone I periportal hepatocytes: most oxygenated, specialize in oxidative metabolism, gluconeogenesis and urea synthesis. Zone II Zone III pericentral hepatocytes: least oxygenated, specialize in drug metabolism, glycolysis and lipogenesis.  Organisation of the Liver: Liver Lobule  Liver lobule is organized into plates of hepatocytes, lying in a cage of reticuloendothelial cells.  The plates are separated by vascular spaces called sinusoids.  Blood from the sinusoids converges on the central vein.  In turn, the central veins converge on the hepatic vein. Major Cell Types of the Liver  hepatocytes  cholangiocytes The reticuloendothelial cell meshwork includes diverse cell types:  endothelial cells  Kupffer cells Space of Disse  lipocytes (stellate cells)  Major Functions of the Liver The liver performs more than 500 functions. These include: 1. Production of bile 2. Cholesterol processing 3. Synthesis of plasma proteins 4. Energy metabolism and substrate interconversion 5. Drug metabolism and detoxification 6. Immune functions 7. Storage of vitamins and minerals 8. Excretion of bilirubin  Production, Storage and Secretion of Bile  The liver produces bile.  The liver secretes bile (0.7- 1.2 l per day), which drains into the main bile duct from the liver to the duodenum.  The gall bladder stores and Davies et al, Human Physiology (Churchill Livingstone) concentrates bile. P1 B1 CTB Physiology of the Small Intestine CCK AND SECRETIN REGULATE PANCREATIC AND BILIARY SECRETION bile prod ucti on e cre tion nz y me s ll ga dder on e i bla tract con HCO3- CCK secretion secretin P1 B1 CTB Physiology of the Small Intestine  Bile Composition Bile contains 6 major components: 1. Bile salts (bile acids conjugated with taurine) 2. Lecithin (a phospholipid) 3. HCO3- and other salts 4. Cholesterol 5. Bile pigments and small amounts of other metabolic end-products. 6. Trace metals Q1 : What is the major physiological role of bile salts in the small  Bile Composition Bile contains 6 major components: 1. Bile salts } Solubilize fat (bile acids conjugated with taurine) in small intestine 2. Lecithin (a phospholipid) 3. HCO3- and other salts Neutralizes acid in duodenum 4. Cholesterol 5. Bile pigments and small amounts of other metabolic end-products. 6. Trace metals Bile Production and Secretion Hepatocytes secrete: bile salts cholesterol lecithin bile pigments Cholangiocytes secrete: bicarbonate Water Components of bile are secreted into the bile canaliculus and drain into the bile duct.  Bile Acid Formation, Conjugation, Secretion and Recycling primary cholesterol bile acids taurine secondary glycine bile acids from entero -hepatic circulation bile canaliculus conjugated bile salts 5% 95% faeces  The Enterohepatic Circulation  Bile salts are released into the small intestine.  95 % are continuously recycled via the enterohepatic circulation and returned to the liver for reuse.  5 % are lost in faeces. The liver synthesizes new bile salts to replace them. Davies et al, Human Physiology (Churchill Livingstone)  95 % of bile salts are returned to the liver via the enterohepatic Of these: circulation:  75 % are recycled as intact bile salts.  25 % are deconjugated by bacteria in the terminal ileum and colon to yield primary bile acids, some of which are dehydroxylated by bacteria to yield secondary bile acids.  The primary and secondary bile acids thus formed are also recycled.  The primary and secondary bile acids are reconjugated in the liver to form bile salts. The bile salts are released in bile into the small intestine.  Bile Acid Formation, Conjugation, Secretion and Recycling primary cholesterol bile acids taurine secondary glycine bile acids from entero -hepatic circulation bile canaliculus conjugated bile salts 5% 95% faeces  The Enterohepatic Circulation  Bile salts are released into the small intestine.  95 % are continuously recycled via the enterohepatic circulation and returned to the liver for reuse.  5 % are lost in faeces. The liver synthesizes new bile salts to replace them. Q2 : Damage to the ileum (by, for example, ileal resection or Crohn’s Davies et al, Human Physiology (Churchill Livingstone) disease) can result in the symptom steatorrhoea, owing to malabsorption Q4: Absorption of which other dietary of which main dietary component? component is also likely to be impaired? Q3: Why?  Bile Salts: Main Functions  Emulsification of dietary lipids, rendering them accessible to pancreatic lipases, and presenting fat digestion products for absorption.  Elimination of cholesterol.  Prevention of cholesterol precipitation in the gall bladder.  Facilitation of the absorption of fat-soluble vitamins.  2. Cholesterol Processing  Cholesterol is a lipid molecule that has many important functions: plasma membranes component of bile salts precursor for steroid hormones myelin (neuron axonal “wrapping”)  15% of cholesterol comes from diet  85% of cholesterol is synthesized within the body (mostly in the liver)  Is transported in plasma in complexes with lipoproteins (that are synthesized mainly in liver). Roles of the Liver in Cholesterol Processing  Synthesizes cholesterol from acetyl CoA.  Synthesizes lipoproteins, which transport cholesterol in plasma.  Exports cholesterol via circulation to body cells for synthesis of key products e.g. steroid hormones.  Utilises cholesterol for synthesis of bile salts.  Extracts excess cholesterol from plasma.  Exports excess cholesterol in bile for excretion in faeces.  Cholesterol Processing LIVER Cholesterol synthesis Uptake from plasma BILE P1 B1 CTB Carbohydrates DIET and Lipids PLASMA Cholesterol transport on lipoproteins GI TRACT CELLS membrane s hormones FAECES Plasma cholesterol: etc. Phase 2 Synthesis of Plasma Proteins Major plasma proteins e.g. albumin Factors involved in haemostasis/ fibrinolysis coagulation e.g. fibrinogen coagulation inhibitors e.g. a1-antitrypsin fibrinolysis e.g. plasminogen Carriage proteins (binding proteins) e.g. transferrin sex hormone binding globulin (SHBG) thyroid-binding globulin (TBG) Pro-hormones, apolipoproteins P1 B1 CTB Introduction to Endocrinology 4. Energy Metabolism and Substrate Interconversion Carbohydrate Metabolism  Glycogenolysis  Gluconeogenesis  Glycogen synthesis  Glycolysis, citric acid cycle and fatty acid synthesis Lipid metabolism  Ketogenesis  Triglyceride synthesis from fatty acids Protein metabolism  Deamination  Urea formation P1 B1 CTB Carbohydrates and P1 B1 CTB Energy Lipids Metabolism Drug Metabolism and Detoxification  The liver is the major site of drug metabolism. For information on P1 BO PPT Principles of drug metabolism: Pharmacology Part 2: Pharmacokinetics P1 B1 PPT Hepatic Drug Metabolism 6. Immune Functions: Kupffer Cells  Tissue macrophages located in hepatic sinusoids attached to endothelial cell lining.  Ingest bacteria (by phagocytosis) and inflammatory mediators. 7. Storage of Vitamins and Minerals The liver stores:  Fat soluble vitamins A, D, E and K  Minerals (iron and copper) which are released when needed.  8. Excretion of Bilirubin  Bile pigments are excretory products being disposed of by the liver via the gut.  The main bile pigment is bilirubin, formed from the breakdown of haem in the spleen and bone marrow.  Hepatocytes conjugate bilirubin with glucuronic acid to form a polar, water-soluble molecule, which is exported into bile. Despopoulos & Silbernagl, Color Atlas of Physiology (Thieme) Excretion of Bilirubin https://ahdc.vet.cornell.edu/clinpath/modules/chem/tbili.htm  Recommended Reading Medical Sciences, Naish and Syndercombe Court, Chapter 15: The Alimentary System https://0-www-clinicalkey-com.pugwash.lib.warwick.ac.uk/ student/content/book/3-s2.0-B9780702073373000158#hl0003408 Section: The Liver and Biliary System  Answers Q1 : What is the major physiological role of bile salts in the small intestine? Bile salts serve as EMULSIFYING agents, so they convey FATS and the digestion products into water soluble structures that enable them to be digested and absorbed in the small intestine. Bile salts emulsify fats into emulsion droplets so solublising them and presenting them for digestion by the pancreatic lipase enzyme, which digests them into the fat digestion products. What bile salts also do is they emulsify fat digestion products into these smaller structures called micelles, which present the fat digestion products to the intestinal epithelial cells so they can be absorbed. Q2 : Damage to the ileum (by, for example, ileal resection or Crohn’s disease) can result in the symptom steatorrhoea, owing to malabsorption of which main dietary component? Fat Q3: Why? Extensive damage to the ileum can impair its ability to recycle bile salts by the enterohepatic circulation. Because we've seen that the terminal ileum is the region from which the bile salts are reabsorbed and returned to the liver. So if the bile salts can't be reabsorbed. Then more of them will be lost in the faeces. But we know that the liver can make new bile salts. But we also said a few slides back that they can't make enough bile salts from scratch. The liver relies on the enterohepatic circulation to recycle the bile salts so that it has enough to carry out its digestive and absorptive functions. Now, if the daily loss of bile salts exceeds the ability of the liver to synthesise new bile salts, then the size of the circulating bile salt pool is going to be diminished. So in other words, a bile salt deficiency. And we know that bile salt deficiency is going to lead to impaired digestion and absorption of fat because it relies on the bile salts to emulsify both fat and the digestion products for the processes that happen. So if that can't be digested and absorbed, instead it's going to be excreted in the faeces. So we're going to get excess unabsorbed dietary fat excreted in the faeces, which leads to large, very fatty, foul-smelling stools. And that's steatorrhea. Q4: Absorption of which other dietary component is also likely to be impaired? fat soluble vitamins Q5: Why? The reason for that is, as we said in the session on the physiology of small intestine, the fat soluble vitamins follow the same pathway for absorption as do the fat digestion products. So if