Liver Anatomy, Blood Supply and Function

• The liver is the largest organ
• Weighs 1.2-1.6 Kg on average in adults
• Receives 25% of cardiac output when the body is at rest
• Capable of regenerating if damaged
• Involved in over 500 different functions

Liver Anatomy

• Has four lobes
• Two major lobes: left and right
• Two minor lobes: caudate and quadrate
• The Glisson’s capsule is a connective tissue surrounding the liver

Ducts

• Common hepatic duct
• Cystic duct from the gallbladder
• Common bile duct which joins the pancreatic duct at the hepatopancreatic ampulla

Anterior Liver

• The ligaments hold the Liver in place

Blood Supply

• Receives two blood supplies for detoxification
• Hepatic artery, which supplies oxygen-rich blood
• Hepatic portal vein, which supplies nutrient-rich blood from the GI tract

Arterial Blood Supply

• Coeliac Trunk branches into the Right and Left Hepatic Arteries

Hepatic Portal Vein

• All blood passes from the GI tract before entering the liver for absorption

Liver Lobule

• It is a hexagonal structure consisting of hepatocytes
• Hepatocytes radiate outward from a central vein
• Located at each of the six corners of a lobule exists a portal triad
• Liver sinusoids are specialized capillaries, large and fenestrated

Space of Disse

• The Stellate Cells (ITO cells) have the function of storing vitamin A
• When activated due to the liver being damaged, they become fibrous
• The basolateral membrane is between hepatocytes and the space of Disse
• Microvilli increase surface area of the basolateral membrane
• Apical membranes are what make up the bile canaliculi, and they are positioned between hepatocyte

Lobular Models

• Portal lobule connects the central venules

Oxygen Gradient and Zonation of Metabolism

• Portal vessels have high O2
• The central vein has low O2

Bile

• Consists of bile salts, bile pigments, cholesterol, neutral fats, phospholipids and electrolytes
• The liver produces 0.4-0.8 l of bile daily
• Bile flows through canals called bile canaliculi to a bile duct
• Bile ducts exit the liver via the common hepatic duct
• Bile salts emulsify fats by breaking them down from larger to smaller droplets, which increases surface area

Gallbladder Anatomy

• Thin-walled green muscular sac
• Attached to the inferior surface of the liver
• Stores bile that is not immediately needed for digestion
• When the muscular wall contracts, bile is expelled into the bile duct
• Stimulated by cholecystokinin (CCK) and secretin which both cause contraction, thereby producing more bile

Bile Acids

• Derived from cholesterol
• Conjugation to taurine and glycine increases polarity of molecules
• This is due to them being lipophilic

Sinusoidal Transporters

• Exist between the hepatocyte and blood
• NTCP is a sodium taurocholate transporter or bile acid transporter that is symport with sodium
• OATP carries organic anions
• OCT carries organic cations
• MRP4 transports drug metabolites back into the blood and then to urine

Biliary Transporters

• Transport between hepatocyte and Bile canaliculi
• Biliuribin is transported to bile by MRP-2
• ABCG 5/8 transports cholesterol
• MDR3 transports PC
• BSEP bile salts are drugs that developers acted with BSEP but were removed from market
• MDR1 (P Glycoprotein) transports drugs and metabolites
• BCRP (breast cancer resistant protein) transports steroid derivatives

P-Glycoprotein (MDR1, ABCB1)

• The name for a type of protein that functions as an energy-dependent efflux transporter
• Found in the liver, GI tract, kidneys, and brain
• Pumps material out of the body, including outside of the brain
• Activity can be increased or decreased
• Altered activity can change drug concentration in the body

Bilirubin

• The break down product from heme
• Converted to urobilinogen by gut bacteria

Enterohepatic Circulation

• Refers to the recycling of bile salts and other compounds between the liver and the small intestine
• Five percent of bile salts are excreted in feces

Functions

• The liver is involved in metabolic processes, synthesis, and breakdown
• Functions to store of vitamins A and B12 and iron (ferritin)
• Excretion of waste products from bloodstream into bile

Carbohydrate Metabolism

• Gluconeogenesis involves making new glucose
• Glycogenolysis involves splitting off glycogen
• Glycogenesis involves making new Glycogen

Lipid Metabolism

• Cholesterol synthesis involves making cholesterol
• Lipogenesis involves making lipids

Starved State

• Ketone bodies are metabolized in the brain to produce energy

Glycogen

• Refers to the storage of glucose primarily in the liver and muscle
• A way glucose molecules that are joined together produce beta bonds

Glycogen Mobilization

• Is controlled by various hormone
• Insulin is released from the β-cells of the pancreas
• Glucagon is released from the α-cells of the pancreas
• Adrenaline is released from the adrenal medulla

Target Organs

• Liver is the target during glucagon release
• Muscle is targeted during adrenaline release

Key Enzymes

• Glycogen phosphorylase, an enzyme that breaks down glycogen
• Glycogen Synthase makes glycogen

Glycogen Phosphorylase

• Involved in breaking down glucose
• Involves removal of glucose residues
• Phosphorylase b dephosphorylated is the inactive from
• Phosphorylase a phosphorylated is the active form
• Activated by phosphorylase kinase
• Deactivated by phosphorylase phosphatase

Glycogen Synthase

• Unless glycogen synthesis is switched off, a futile cycle will ensue during synthesis
• In the active state it is Glycogen synthase 1
• In the inactive state it is Glycogen synthase D - phosphorylated

Protein Synthesis

• The liver facilitates this effect
• Synthesis of amino acids
• Produces albumin, which reduces the pressure needed for serum
• Production of various coagulation factors is handled by the Liver

Breakdown

• The liver facilitates this as well
• Insulin and other hormones are broken down during detoxication
• Toxic substances in the Liver are metabolized, sometimes with negative effect
• Converts ammonia to urea, a toxic compound
• Drug metabolism

Amino Acid Metabolism

• Liver is key for this activity
• Byproducts results in brian or liver damage

Transamination

• If liver is damaged, number of enzymes increase, indicating an issue
• ALT or alanine amino transaminase indicate liver issues
• AST or aspartate amino transferase also point to damaged tissues
• Such markers also are linked to cardiac malfunction

Glutamate Dehydrogenase

• An enzyme used in energy cycle
• Liver's oxidative deamination is critical
• Liver also releases ammonia and generates NAD(P)H as reducing agents

Glutamine Production

• Transfers ammonia out of the body
• Glutamate converts Glutamine

Urea Cycle

• A cycle involving cathalolathy, or removal of ammonica occurring in the liver
• Bloodstream, kidneys, and intestines involved
• Ammonia is toxic in the body and may cause cerebral complications; or cause Liver or Kidney Damage
• Treatment:
  • Sodium benzoate combines with Glycine to form hippuric acid and is excreted in the urine.
  • Phenylbutyrate reacts with glutamine to form phenylacetylglutamine and is excreted
  • Both lead, by different mechanism to lower the blood concentration of ammonia.