Author(s): Rebecca W. Van Dyke, M.D., 2012
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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
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: Lose the double bond bond double the Lose
OH Metamorphosis to a bile acid acid bile a to Metamorphosis Shorten the side chain chain side the Shorten
OH Metamorphosis to a bile acid acid bile a to Metamorphosis
plane of the rings rings the of plane
and bend this below the the below this bend and Add a carboxylic acid group group acid carboxylic a Add
OH
COOH COOH Metamorphosis to a bile acid acid bile a to Metamorphosis
that is bent down down bent is that
Add a hydroxyl group group hydroxyl a Add OH OH
OH
COOH COOH Metamorphosis to a bile acid acid bile a to Metamorphosis OH OH
OH
COOH COOH
hydroxyl group group hydroxyl
OH OH
Add another another Add Metamorphosis to a bile acid acid bile a to Metamorphosis OH OH
OH
COOH COOH
OH OH
you now have a tri-hydroxy bile acid: cholic acid acid cholic acid: bile tri-hydroxy a have now you Metamorphosis to a bile acid acid bile a to Metamorphosis OH OH
OH
NH NH COOH COOH CO
OH OH
Taurocholate (taurine conjugated cholic acid) acid) cholic conjugated (taurine Taurocholate
conjugation of an amino acid to the side chain yields yields chain side the to acid amino an of conjugation One more change - - change more One 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 intestine.
Total bile acid pool is about 3 grams. Liver About 90% of bile acids are reabsorbed in the terminal ileum.
However about 5-10% of bile acids are lost daily into the colon. Effect?
Small bowel Liver synthesizes about Colon 5-10% of the total bile acid pool each day. Enterohepatic Circulation of Bile Acids: Ilial loss
Bile acid Resection of 40 cm of synthesis the terminal ileum will result in what problem?
Bile acid loss into the cecum Liver will increase. What will this cause?
Liver upregulates bile acid synthesis and bile acid pool remains normal. Fat absorption remains the same.
Colon 40 cm resection of terminal ileum Enterohepatic Circulation of Bile Acids: Loss of most of the ileum
Bile acid synthesis Resection of >100 cm of the terminal ileum will result in what problem? Liver Initially, bile acid loss into the colon will be massive. What will be the initial effect of this loss of bile acids into the colon?
Colon >100 cm resection of terminal ileum Enterohepatic Circulation of Bile Acids: Lost of Ileum Resection of > 100 cm of the terminal ileum will Bile acid synthesis result in what problem over time?
Liver upregulates bile Liver acid synthesis but cannot keep up with loss rate. Bile acid pool is reduced Fat is malabsorbed.
As the bile acid pool falls, loss into the colon is less per day and secretory diarrhea due to bile acids converts to steatorrhea Colon (+ secretory diarrhea > 100 cm resection from fatty acids). of terminal ileum Enterohepatic Circulation of Bile Acid: Cholestyramine
Bile acid Cholestyramine: synthesis bile acid binding resin that removes bile acids from the enterohepatic circulation Liver Liver upregulates bile acid synthesis (using up what compound in the process?)
If liver cannot keep up, what happens?
Small bowel Less free bile acid in Colon the colon causes what? Liver takes up and excretes many other organic compounds: bilirubin is the classic and historic example
Hepatic Bilirubin Transport
SER UDP-glucuronide RBC + breakdown Unconj BR in RES Conj BR Unconj BR Bile Unconj Canaliculus Bilirubin Conj BR MRP-2: Multispecific organic anion transporter Conj Conjugated bilirubin BR Glutathione S-conjugates other organic anions ATP
Blood Hepatocyte Jaundice of the Neonate
• Newborn infants have poorly developed bilirubin conjugation enzymes and jaundice is common.
• Premature infants are even more affected
• Unconjugated bilirubin in the brain causes permanent damage (kernicterus)
• How to prevent brain damage in neonates?
Regents of the University of Michigan Phototherapy for Unconjugated Hyperbilirubinemia of the Neonate Martybugs, Wikimedia Commons. Hepatic Bilirubin Transport and Mechanisms of Hyperbilirubinemia
Gilbert's syndrome (mild) Crigler-Najjar syndrome (severe)
SER Hemolysis
Unconj BR Bile Unconj Canaliculus Bilirubin Conj BR Multispecific organic anion transporter
Conj Conjugated bilirubin BR Glutathione S-conjugates other organic anions ATP
Blood Hepatocyte
Dubin-Johnson syndrome Rotor's syndrome ?estrogen/cyclosporin Consequences of Liver Disease
for Bilirubin Handling?
Bilirubin: Jaundice
The first liver disease test CDC Liver Biotransformation/Excretion of Endogenous/Exogenous Compounds
• Bilirubin conjugation is an example
• Many other organic compounds undergo two- step biotransformation – Example: cholesterol to bile acids
• After biotransformation, metabolites excreted – Larger, lipophilic molecules excreted in bile – Smaller (<400 Da) transported to blood and excreted by kidneys
Step-wise Synthesis of Bile Acids from Cholesterol Steps are analogous to Phase I and Phase II steps of drug/xenobiotic metabolism Cholesterol
P450- mediated hydroxylations
Conjugation OH group of side chain to glycine or amino acid taurine Liver and Gut Barrier Functions
Insoluble,Liver helps to remove/eliminate: nonabsorbable compounds Xenobiotics Xenobiotics: metabolism, excretion Liver RES/filter Drugs Metabolism Bacteria Drugs (acid, : physical metabolism, excretion Biliary excretion barrier, Bacteria gut immune : Kupfer cells system, liver RES)
Intestine mucosal barrier Pancreas Liver’s Magic Trick: Regeneration
Image of liver regeneration process removed Prometheus Bound
P.P.Reubens
An early case of of hepatic regeneration
P. P. Rubens Functional Consequences of Losing a Large Amount of Liver Due to Resection/Necrosis?
• Hypoglycemia • Poor blood clotting • Cholestasis and jaundice • Increased blood ammonia - affects cognitive function • Decreased drug disposition • Abnormal lipid metabolism Summary
• Liver exhibits a wide range of functions • Liver diseases may cause malfunction of one or more normal function • Functions regulated separately so any one liver disease can affect each to a different extent • Liver diseases cause: – Altered liver functions – Altered tests of liver injury Additional Source Information for more information see: http://open.umich.edu/wiki/AttributionPolicy
Slide 73, Image 1 (top): Martybugs, "Jaundice phototherapy," Wikimedia Commons, http://commons.wikimedia.org/wiki/File:Jaundice_phototherapy.jpg, CC; BY-SA 3.0, http://creativecommons.org/licenses/by-sa/3.0/.