Liver Anatomy and Function

• The liver is the largest organ in the body
• The liver weighs 1.2-1.6 kg
• The liver represents 25% of cardiac output at rest
• It can regenerate if damaged
• The liver performs over 500 different functions

Liver Anatomy

• The liver has 4 lobes
• The major lobes are the left and right
• The minor lobes are caudate and quadrate
• It has common hepatic ducts, cystic and common bile ducts
• The cystic duct comes from the gallbladder
• The common bile duct joins the pancreatic duct at the hepatopancreatic ampulla
• Glisson's capsule is connective tissue surrounding the liver

Anterior View

• The falciform ligament holds the left and right lobes in place
• The inferior vena cava returns blood to the heart
• The teres ligament is a ligament on the anterior of the liver

Blood Supply

• The liver receives two blood supplies, detoxifying organs
• It receives the hepatic artery bringing oxygen rich supply
• It receives the hepatic portal vein bringing nutrient rich supply
• All blood draining from the GI tract goes to the liver

Hepatic Portal Vein

• The hepatic portal vein is the main vessel carrying blood from the digestive organs to the liver
• The liver is the major site for absorption

Liver Lobule

• Liver lobules, hexagonal structures consisting of hepatocytes
• Hepatocytes radiate outward from a central vein
• At each of the six corners of a lobule is a portal triad
• Structures in the portal triad include branches of bile duct, hepatic artery and hepatic portal vein

Liver Anatomy Cells

• The hepatic cells are hepatocytes
• Sinusoids are specialized capillaries, large and fenestrated
• Kupffer cells are fixed macrophages that have phagocytic function

Space Of Disse

• Stellate or Ito cells store vitamin A
• These cells become fibrous when activated as a result of liver damage
• The basolateral membrane is between the hepatocytes and space of Disse
• Microvilli increases basolateral membrane surface area
• The apical membrane makes up the bile canaliculi, located between hepatocytes

Lobular Models

• Portal lobule connects to central venules
• The hepatic acinus/acinus lobule has separate zones

Oxygen Gradient

• Periportal cells are high in O2 but pericentral cells are low in O2
• Know which dominates: gluconeogenesis, B-oxidation, nutrients, O2
• Autoimmune hepatitis, iron-overload injury/billary cirrhosis are more periportal
• NAFLD, Drug/alcohol toxicity, Parasite infection fibrosis are more central lobule related

Bile

• Composed of bile salts, bile pigments, cholesterol, neutral fats, phospholipids and electrolytes
• The liver produces 0.4-0.8 liters of bile daily
• Bile flows through canals called bile canaliculi to a bile duct
• Bile ducts leave the liver via the common hepatic duct
• Bile salts emulsify fats

Gallbladder Anatomy

• The gallbladder is a thin-walled green muscular sac
• Located on the inferior surface of the liver
• It stores bile that is not immediately needed for digestion
• When the muscular wall of the gallbladder contracts, bile is expelled into the bile duct
• Stimulated by cholecystokinin (CCK) and secretin causing contractions
• This produces more bile and increases flow.
• Hormones released in response to a fatty meals, bile is released into GI tract to aid fat absorbtion

Bile Acids

• Bile acids are derived from cholesterol
• Conjugated to taurine and glycine to increase polarity
• Increases polarity of bile acids because bile acids are Lipophilic (fat-loving)

Sinusoidal Transporters

• NTCP - sodium taurocholate transporter
• Transports bile acid symport with sodium, between hepatocyte + blood
• OATP - organic anion transporter protein
• OCT - organic cation
• MRP4 - - transport drug and metabolites back into the blood then into urine

Biliary Transporters

• Biliuribin transported to bile by MRP-2
• Transport between hepatocyte + Bile canaliculus
• ABCG 5/8-transport cholesterol
• MDR3 - PC
• BSEP - Bile Salts -drugs developed nacted w/BSFP (Removed from market)
• MDR1 - P Glycoprotein, transports Drug and metabolites
• BCRP - breast cancer resistant protein that transports steroid derivatives

P-Glycoprotein

• It uses ATP and is an Efflux transporter
• Found in Liver, Gl tract, Kidneys and Brain
• Protects brain: Pumps material out of body, away from brain
• Pumps material out of the body.
• Activity can be increased with induction and decreased with inhibition
• Altered activity can change drug concentration in the body

Bilirubin

• The break down product from heme
• Urobilinogen, (80%) - excreted in feces (stercobilin)
• Urobilinogen, (2%) excreted in urine
• The liver carries out enterohepatic circulation

Enterohepatic Circulation

• Key components: liver, gallbladder, common hepatic duct, intestine Enterohepatic circulation is the reabsorption of bile salts
• Involves enteric system and the liver
• Know its association w/ distribution of drugs
• 5% of bile salts are excreted in feces

Functions of the Liver

• Performs metabolic functions
• Synthesizes proteins and important macromolecules
• Carries out breakdown of proteins
• Storage of vitamins A and B12 and Fe
• Excretion of waste products from bloodstream into bile

Carbohydrate Metabolism

• Gluconeogenesis is making new glucose
• Glycogenolysis is splitting of Glycogen
• Glycogenesis is making new Glycogen

Lipid Metabolism

• Cholesterol synthesis is making Cholesterol
• Lipogenesis is making lipids

Liver Metabolism Diagram, Fed State

• Know the key enzymes involved in the different processes

Liver Metabolism Diagram, Basal State

• Note the release of urea and release of lactate

Liver Metabolism Diagram, Starved State

• Note the presence of Keytone Bodies (KB)

Glycolysis

• know the control mechanisms behind ATP and more

Glycogen

• Glycogen is made up of glucose with a-1,4-Glycosidic bonds
• Branching occurs at the a-1,6 positions in Glycan polymers

Glycogen Mobilisation Control

• Hormones involved:
  • Insulin - released from the B-cells of the pancreas
  • Glucagon - released from the a-cells of the pancreas
  • Adrenaline - released from the adrenal medulla
• Target organs:
  • Liver - glucagon
  • Muscle - adrenaline ####Key enzymes are regulated
• Glycogen phosphorylase - breaks down glycogen
• Glycogen synthase - Makes glycogen

Glycogen Phosphorylase

• Function is to break down Glucose
• Removal of glucose residues from glycogen Active form: Phosphorylase a (Phosphorylated) Inactive form: Phosphorylase b (Dephosphorylated)
• Pyruvate is metabolized Liver generates much more glucose
• Enzymes such as Phosphorylase Kinase activated adds Phosphate groups
• Enzymes such as Phosphorylase Phosphatase deactivates Phosphorylase Kinase as Phosphatase enzymes remove Phospahte groups
• (adding/removing Phosphate groups)

Enzymes in Liver

• Glucagon activates Phosphorylase kinase. Activated Phosphorylase converts phosphorylase b into a and leads to glycogen degradation
• Insulin stimulates phosphodiesterase that degrades cAMP

Glycogen Synthase

• If glycogen is to be mobilized, glycogen synthase must be switched off, otherwise a "futile cycle" will ensue
• Glycogen synthase I (a) is active
• Glycogen synthase D (b) is inactive because it is phosphorylated
• A phosphorylation/dephosphorylation cycle regulates the synthesis of glycogen

Protein Synthesis

• Carried out by the liver
• It synthesis of amino acids
• Produces albumin, the major osmolar component of blood serum
• Synthesizes Alpha and beta globulins
• The liver will carry out Tranferrin for iron transport/storage
• The liver will carry Production of coagulation factors
• Coagulation factors include protein C protein S and antithrombin (III), plasminogen
• Hormone production includes; angiotensino­gen, thrombopoietin, insulin like growth factor
• Part of the Within immune system as it produces Complement proteins, C-reactive peptide

Liver Breakdown

• Breaks down insulin and other hormones
• Breaks down or modifies toxic substances which sometimes results in toxication
• Role in Amino acid metabolism
• Convertes ammonia to urea
• Plays a role in Drug Metabolism

Amino Acid Metabolism

• Glutamic acid plays roles in Transamination
• Is a byproduct that causes brain and liver damage
• Role in generating urea for asmolatity

Transanimation

• If Liver is damaged Enzymes increases the number that are around
• Alanine Amino Transaminase – ALT
• Aspartate Amino Transferase –AST
• Markings for Liver for issue damage to cordiac and muscle

Trans Animation

• Enzyme in Liver
• Cofactor
• Oxidative Deamination, removes Ammonia to help Balance
• Glutamined to Ammonia

Glutaminate Production

• Most abundant amino acid
• Amino acid helps transfer Ammonia

Urea Cycle

• Catalolathy: removal of ammonia
• Removes Ammonia from body
• Ammonia is toxic, causes cerebral oedema
• Cathalolathy: removal of ammonia

Urea Cycle

• Cycle with all it's components

OTC Deficiency

• Involves Treatment: Benzoate, Phenyl butarate - bind to glutamine/glycine
• Benzoate, Pheny; excreted and Decreases osmotic pressure via Kidneys
• Late onset OTC deficiency can present as nausea, vomiting, delayed growth and a variety of psychiatric symptoms