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020112.Rvandyke.Liverphysiology.Pdf Author(s): Rebecca W. Van Dyke, M.D., 2012 License: Unless otherwise noted, this material is made available under the terms of the Creative Commons Attribution – Share Alike 3.0 License: http://creativecommons.org/licenses/by-sa/3.0/ We have reviewed this material in accordance with U.S. Copyright Law and have tried to maximize your ability to use, share, and adapt it. The citation key on the following slide provides information about how you may share and adapt this material. Copyright holders of content included in this material should contact [email protected] with any questions, corrections, or clarification regarding the use of content. For more information about how to cite these materials visit http://open.umich.edu/education/about/terms-of-use. 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To use this content you should do your own independent analysis to determine whether or not your use will be Fair. M2 GI Sequence Liver Physiology Rebecca W. Van Dyke, MD Winter 2012 Learning Objectives • At the end of this presentation students should be able to: • 1. Describe the basic organization of the liver cell plate and its functional • consequences: • a. Blood supply • b. Configuration of hepatocytes • c. Configuration of other liver cells • d. Concentration gradients in sinusoidal blood. • 2. Describe the basic physiological processes the liver utilizes to accomplish function: • a. transport • b. metabolism • c. biotransformation • d. synthesis • e. secretion • 3. Be able to give examples of the consequences of liver damage on above processes. • 4. Be able to give examples of possible consequences of liver disease/injury on liver barrier function and hepatic regeneration. Industry Relationship Disclosures Industry Supported Research and Outside Relationships • None Cystic artery sole supply to bile duct Anatomy of Liver Acinus bile duct hepatic artery portal vein blood flow portal triad bile sinusoids Michigan Histology Collection central vein Dual Blood Supply of Liver liver Hepatic artery: 20% Portal vein: 80% spleen pancreas Liver has dual blood Regents of the University of Michigan supply: 80% portal vein 20% hepatic artery What are the Functional Consequences of….? • Increased vena caval pressure/hepatic vein obstruction? • Decreased hepatic artery blood flow? and/or Decreased portal vein blood flow? • Effects on the bile duct? Budd-Chiari Syndrome: Obstruction of the Hepatic Vein(s) Normal Budd-Chiari Hemorrhage in Dilated upstream pericentral area; sinusoids; hepatic vein atrophic/ischemic obscured hepatocytes Decreased inflow: ischemic infarction Bile Duct • Sole blood supply to the bile duct is through the hepatic artery via the cystic artery • Reduced blood flow through the hepatic artery causes ischemic injury to the extrahepatic bile ducts • Ischemia or damage to the bile duct often leads to injury, fibrosis, stricture Liver Cell Anatomy: Consider functional consequences Image showing relationship between sinusoid, sinusoid lining cells, and hepatocyte removed. Scanning Electron micrograph of Liver Cells in Liver Sinusoid American Gastroenterological Association Functional Consequences of Fenestrated Sinusoidal Endothelium? Space of Disse Other serum proteins Albumin Kupffer Cell Tissue macrophage Filtration device bacteria, endotoxin Releases inflammatory mediators that influence hepatocytes positively or negatively Looking Down a Sinusoid at a Kupffer Cell Poised to Grab Passing Bacteria Kupffer cells (red) Ito Cell/Fat-storing Cell Rare cell, located in sinusoids under endothelium Stores lipophilic materials such as Vitamin A Stimulated by chronic inflammation/alcohol converts to myofibroblast produces collagen and extracellular matrix Responsible for much of the excess fibrotic material in cirrhosis Ito Cell (Fat-storing Cell) on a Sinusoid (S) Hepatic Stellate (Ito) Cell (arrows) The Liver: The Body’s Refinery Defects in Glucose Metabolism in Liver Disease Acute liver failure: Hypoglycemia (rapid neuronal death) Chronic liver disease: Insulin resistance and diabetes (unknown mechanism) UREA Fatty acid metabolism within hepatocytes albumin hepatocyte FABP free fatty acid pool excess esterification to glucose, to mitochondria TAG amino acids for energy Apo cholin B100 e VLDL cholesterol esters Regents of the University of Michigan Greater Role of the Liver in Production and Metabolism of Lipoproteins and Lipids LDL HDL Chol. Cholesterol Gut Liver Chylomycrons CM remnants TG TG VLDL-TG BILE Cholesterol Bile acids Phospholipids Fatty Liver with Inflammation Liver as Protein Synthetic Machine Vena cava systemic outflow Liver synthesizes and secretes: Lipoproteins Albumin Clotting factors Anti-proteases (α1-anti-trypsin) Fibrinogen Complement factors Ceruloplasmin Transferrin and other binding proteins Hepatic artery carries arterial blood with blood proteins Portal vein carries venous blood from intestine, spleen and pancreas Protein Secretion Defects in Liver Disease Example Clinical Consequence Albumin Decreased plasma oncotic pressure/ edema Decreased binding of hydrophobic compounds Clotting factors : Decreased factors II, VII, IX and X Increased bleeding Fibrinogen Decreased fibrin formation in clotting Defects in Protein Synthesis/release also cause liver disease: Alpha1-Anti-trypsin Deficiency Image of pathophysiology of alpha-1- anti-trypsin deficiency removed PAS Stain Showing Retained Globs of Mutant Alpha1 Anti-trypsin Protein in Hepatocyte ER Lipoprotein release: another liver synthetic function VLDL: a combination of fat and protein The unique position and blood supply of the liver also affect liver physiology Anatomy of Liver Acinus bile duct hepatic artery portal vein blood flow portal triad bile sinusoids Michigan Histology Collection central vein Consequences of Changes in Hepatic Blood Flow and/or Oxygen Delivery? Peri-central vein (hepatic vein) clotted off with ischemic damage to hepatocytes Peri-central ischemia HV clot Peri-portal normal tissue Not all liver cells are alike. Substances found in higher concentrations in the portal vein • Albumin • CPS • FABP • HMG CoA Substances found in higher concentrations in the hepatic vein • P450s • ADH • C7αH • Cysteine • GR • Gluatamate •α 2µG • GS • GLUT-1 •α -KG Periportal Necrosis from Allyl Formate Toxicity HV PV Pericentral Necrosis from Carbon Tetrachloride Toxicity Normal cells PV HV Necrosis Bile Formation Functions of Bile • Transports material to the intestine for excretion – Drugs, toxins, xenobiotics – Cholesterol – Bilirubin – Copper • Transports bile acids to the intestine to aid in fat absorption Bile Acids • Organic acid synthesized in liver from cholesterol • Conjugated to amino acids • Secreted in bile - essential for fat digestion/absorption • Reabsorbed in distal ileum and returned to liver via portal vein Bile Acid Cholesterol OH Cholesterol: Flat (planar) hydrophobic compound compound hydrophobic (planar) Flat Cholesterol: Metamorphosis to a bile acid OH OH Lose the double bond Metamorphosis to a bile acid OH OH Shorten the side chain Metamorphosis to a bile acid COOH OH OH Add a carboxylic acid group and bend this below the plane of the rings Metamorphosis to a bile acid COOH OH OH OH Add a hydroxyl group that is bent down Metamorphosis to a bile acid Add another hydroxyl group OH COOH OH OH OH Metamorphosis to a bile acid you now have a tri-hydroxy bile acid: cholic acid OH COOH OH OH OH One more change - conjugation of an amino acid to the side chain yields Taurocholate (taurine conjugated cholic acid) OH CO NH COOH OH OH OH Conjugated tri-OH Bile Acid Hydrophobic side OH- OH- OH- COO- Hydrophilic side Biliary Lipids Bile acids from intestine To intestine for fat digestion Enterohepatic Circulation of Bile Acids: recycling is efficient Bile acids cycle between the liver and the small Bile acid synthesis
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