Liver Anatomy and Function

Liver Facts

• It is the largest organ in the body
• The liver weighs 1.2-1.6 kg on average in an adult
• Around 25% of cardiac output when the body is at rest goes to the liver
• There are more than 500 different functions
• Notably, it can regenerate if damaged

Liver Anatomy

• It has 4 lobes: major (left and right) and minor (caudate and quadrate)
• There are common hepatic ducts
• There are cystic ducts from the gallbladder
• Common bile duct joins the pancreatic duct which is at the hepatopancreatic ampulla
• Connective tissue surrounding the liver is called Glisson's capsule

Anterior View of the Liver

• Ligaments hold the liver in place

Posterior View of the Liver

• The inferior vena cava returns blood to the heart
• The blood leaves the liver via the teres ligament, and falciform ligament

Blood Supply to the Liver

• It is a detoxifying organ
• It receives two blood supplies:
  • Hepatic artery with oxygen rich blood
  • Hepatic Portal Vein with nutrient rich blood and all blood that drains from the GI tract

Arterial Blood Supply

• Coeliac Trunk supplies arterial blood to the liver
  • The hepatic artery is the only artery to know

Hepatic Portal Vein

• Vessels from the stomach, spleen, pancreas, small intestine, and colon drain into the hepatic portal vein

Liver Lobule

• The liver lobules are hexagonal structures consisting of hepatocytes
• Hepatocytes radiate outward from a central vein
• There is a portal triad at the six corners of a lobule
• The branches of the portal triad are a bile duct away from the venule, a hepatic artery bringing blood to liver, and the hepatic portal vein that also brings blood to the liver
• There are liver sinusoids

Liver Anatomy Microstructure

• Hepatic cells are equal to hepatocytes
• Sinusoids are specialized capillaries that are large and fenestrated with veins
• Kupffer cells are fixed macrophages with phagocytic function

Space of Disse

• Stellate Cells (ITO cells) store vitamin A and when activated by liver damage, become fibrous
• Basolateral membrane is between hepatocytes and the space of Disse
• This membrane has microvilli that increase the surface area
• Apical membrane makes up bile canaliculi between hepatocytes

Lobular Models

• Connect central venules, portal lobule, and separate zones

Oxygen Gradient and Zonation of Metabolism

• Periportal cells have a high 02 start and Mid-lobular and Pericentral cells have a low 02 end
• Periportal cells dominate with gluconeogenesis, B-oxidation, nutrients, and oxygen
• Pericentral cells dominate with glycolysis and lipogenesis
• Central lobule is associated with NAFLD, drug/alcohol toxicity, and parasite infection fibrosis

Bile

• Bile includes 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 leave the liver via the common hepatic duct
• Bile salts emulsify fats into small droplets and increase the surface area

Gallbladder Anatomy

• Thin-walled green muscular sac on the inferior surface of the liver stores bile
• Stores bile that is not immediately needed for digestion
• Muscular bladder contracts to expel bile into the bile duct when the muscular wall of the gallbladder is contracted
• Stimulated by cholecystokinin (CCK) and secretin, which increases bile flow
• These hormones are released in response to a fatty meal to aid the fat in the GI tract

Bile Acids

• Are derived from cholesterol
• Conjugation to taurine and glycine increases polarity of molecules due to being lidophilic

Sinusoidal Transporters

• Located between Hepatocyte and Blood
• NTCP (sodium taurocholate transporter) bile acid transporter (symport with sodium)
• OATP (organic anion transporter protein)
• OCT (organic cation)
• MRP4 transports the drug and metabolites back into the blood and then into urine

Biliary Transporters

• Transport between hepatocyte and Bile canaliculus
• Biliuribin is transported in bile by MRP-2
• ABCG 5/8-transports cholesterol
• MDR3 - PC
• BSEP - transports Bile Salts
  • drugs developed, inacted with BSFP, are no longer on the market)
• MDR1 (P Glycoprotein)–transports metabolites
• BCRP (breast cancer resistant protein) - steroid derivatives

P- Glycoprotein (MDR1, ABCB1)

• Uses energy (ATP)
• Is an efflux transporter found in the liver, GI tract, kidneys, and brain
• Pumps material out of the body, and out of the brain
• The activity can be increased (induction) and decreased (inhibition)
• Altered activity can change drug concentration in the body

Bilirubin

• Is the break down product from haeme/heme from RBC
• Bloodstream, Liver, Gut, Reticuloendothelial, Excreted

Enterohepatic Circulation

• Essential for drug distribution
• Enteric system is for reabsorption

Functions of the Liver

• Metabolic
• Synthesis
• Breakdown
• Storage of vitamins (A, B12) and Fe ()
• Excretion of waste products from bloodstream into bile

Metabolism

• Carbohydrate metabolism: includes gluconeogenesis and glycogenesis
• Lipid metabolism: Cholesterol synthesis

Dietary Fat and Cholesterol

• Resynthesis and storage, mainly in adipose tissue through transport by serum albumin
• Returned to liver for glucose synthesis

Fed/Absorptive State

• Insulin is high
• Glucose starts as Glycogen with Acetyl CoA used as the building blocks
• Protein is AA
• Acetyl CoA is a natural building block

Basal State

• Glucose is low
• Insulin is low
• Glucagon is high

Starved State

• Ketone bodies are metabolised in brain
• Glycogen is deplete with use of Acetyl CoA

Liver Glycolisis and Gluconeogenesis

• Glycolysis
• Is the oxidative phosphorylation
• Gluconeogenesis

Glycogen

• Glucose molecules joined together by way of bonds
• Glycogen is related to control metabolism
• Glycogen G (glucose storage) mostly in liver and muscle

Control of Glycogen Mobilisation

• Hormones are involved:

  • Insulin released from the β-cells of the pancreas
  • Glucagon released from the α-cells of the pancreas
  • Adrenaline released from the adrenal medulla

• Target organs:

  • Liver from glucagon
  • Muscle from Adrenaline

• Key enzymes regulated:

  • Glycogen phosphorylase breaks down glycogen
  • Glycogen synthase makes glycogen

Glycogen Phosphorylase

• Glycogen Phosphorylase breaks down glucose Residues
• Active form is Phosphorylase a (Phosphorylated)
• Inactive form is Phosphorylase b
• Activated by Phosphorylase Kinase
• Deactivated by Phosphorylase Phosphatase

How to Activate Kimase: The Enzyme Cascade Cycle

• Amplifies signals
• Control mechanisms
• Glucagon generates cAMP, the activates Protein Kinase A
• Phosphorylase Kinase then actibvates Glycogen Phosphorylase

Glycogen Synthase

• Glycogen synthase must be switched off to mobilise glycogen
• If not mobilised, it induces a futile cycle
• Glycogen synthase is either form i-active of D-inactive

Protein Synthesis

• Synthesis of amino acids
• Produces albumin, the major osmolar component of blood serum
• Effects include producing osmotic pressure and not causing edema
• Alpha and beta globulins
• Tranferrin – iron transport/storage
• Production of (coagulation factors) I, II, V, VII, IX, X and XI, and protein C, antithrombin II, and plasminogen
• Hormone synthesis – angiotensinogen, thrombopoetin, insulin like growth factor
• Complement proteins, C-reactive peptide – within immune system

Breakdown

• Breaks down insulin and other hormones for detoxication, as well as toxic substances
• Amino acid metabolism
• Converts ammonia (toxic) to urea
• Drug Metabolism

Amino Acid Metabolism

• Has liver, kidney, and brain benefits and risks
• Product causes brain/liver damage
• Glutamate Dehydrogenase

Transamination

• Liver damage increases number of enzymes
• Alanine Amino Transaminase – ALT
• Aspartate Amino Transferase –AST

Glutamate Dehydrogenase

• Enzyme is in the liver- oxidizes deamination

Glutamine Production

• Most abundant amino acid, helps transfer ammonia out of the body
• This leads to synthesis of glutamine

Urea Cycle

• Cathalolathy (removal of ammonica) in liver
• Removal of Ammonia is essential
• Urea Cycle involved
• Ammonia is toxic and leads to cerebral edema

Deficiency

• OTC Deficiency is related to ornathine
• Decreases the amount of amino acids needed to assist in Urea recycling