Briefly describe anatomy and architecture of liver
Anatomy
- About 20% body weight
- Large R lobe: main part
- Blood in:
- 70% from portal vein
- 30% hepatic artery
- Blood out: hepatic vein
- Bile drains into the gallbladder and into the duodenum
Hepatic architecture
- Hepatocyte cords - crucial to function, associated with sinusoid…
- Central vein
- Portal tract
In liver disease this is lost.
Hepatocyte architecture
- Highly polarized cells
- Apical surfaces of each cell: bile canalicula. Markedly increases surface area.
- Villi. Secretory functions
- Basolateral surfaces in association with sinusoids
- Bile-blood barrier by tight junctions between cells
- Sophisticated transportation mechanisms
Porto-systemic shunting
- The portal circulation is connected in key places with the systemic circulation
- An increase in the pressure within the portal circulation can lead to portal hypertension
- This results in newly circulatory pathways opening up
List liver functions
- Carbohydrate metabolism
- Protein metabolism
- Lipid metabolism
- Storage
- Bile formation and secretion
- Chemical processing and excretion
Functions of the liver
Homeostasis
- immune function
- clotting
- energy supply
- growth/healing
- digestion
- drug metabolism
Describe carbohydrate metabolism
Carbohydrate metabolism
- Glycogenesis
- Glycogenolysis
- Gluconeogenesis
- Glycolysis: cellular respiration
Some cells can’t use other energy sources: brain, blood, retina cells
#### Glycolysis: cellular respiration
- Process of glucose being used to make energy in the presence of oxygen
- EVERY CELL IN THE BODY
- OBLIGATORY IN BRAIN & RETINA (blood cells)
- Costs 2 ATP to run the reaction, creates 4 ATP = Net 2 ATP per reaction
- Also generates NADH: source of more energy
Glycogenesis
- Glycogen, from
- UDP-glucose
- by glycogen synthase
-
Glycogenolysis
- Glycogen: Polysaccharide globule
- 10-18 hours max of glucose. Liver, muscle
- Central glycogenin, 3x105 glucose each
- Utilisation of glycogen to form glucose
- Sequentially the monomers are removed and converted to glucose
- Stimulated by glucagon, adrenaline. Inhibited by insulin
Gluconeogenesis
- Glycolysis:
- obligates glucose
- brain, retina, BRBC
- Gluconeogenesis:
- Produce glucose from non-carbohydrate sources (FAs, proteins)
- Pyruvate/lactate or amino acids are converted to oxaloacetate to enter the pathway
Describe regulation of carbohydrates
- Fed: BSL high. Insulin release. Stimulates glycolysis, glycogenesis, down-regulates gluconeogenesis.
- Fasted: BSL low. Glucagon release. Stimulates glycogenolysis, gluconeogenesis, down-regulates glycolysis, switches off glycogenesis.
Describe protein metabolism
List protein functions
- Albumin: Main carrier protein of the body. Osmotic pressure in the blood
- Immune system proteins: Igs, CRP, Complements 1-9, opsonin
- Anticoagulants: Fibrinogen, clotting factors, prothrombin, anti-thrombin
- Hormones: angiotensinogen, thrombopoietin
- Carrier proteins: transferrin, ceruloplasmin, IGF-binding protein
Protein metabolism
- AA made by the liver: glycine, alanine, serine, asparagine, aspartic acid, glutamine, glutamic acid, proline, cysteine, tyrosine, and arginine
- “Essential” AA: have to be eaten, can’t make them: valine, leucine, isoleucine, phenylalanine, methionine, tryptophan, threonine, lysine, and histidine
- Formation of amino acids
- Transamination: amino group added to a keto-acid. Uses aminotransferases
- Alanine aminotransferase (ALT) makes alanine
- Aspartate aminotransferase (AST) makes aspartate
- Hydroxylation
Protein metabolism
- Biogenic amines:
- Formed by dehydroxylation of AA: renders it very active
- Amino acids from SI -> protein synthesis, catabolism, or conversion to glycogen or triacylglyceride or transport to muscle
- Fasted state: AA from muscle breakdown
- <15% of ATP source- poor energy source
- Carbon of the AA decides if carb (glucogenic AA) or fat synthesis (ketogenic AA) pathway
Describe protein catabolism
Oxidative Deamination
- Process:
- Amino acids broken down: Oxidated, then hydrated, releasing amine groups and hydrogen. Forms ammonia (2NH₃)
- Forms α-ketoacid: Carbons that can enter the fat or carbohydrate cycle to make ATP.
Protein Catabolism
- Ammonia (NH₃): Toxic. Crosses blood-brain barrier. Causes confusion and brain damage. Must be removed.
- Sources of Urea: Breakdown of amino acids (AA), absorbed from the small intestine (SI): bacteria.
- Urea Cycle:
- NH₃ enters a complex series of biochemical reactions involving citrullination, condensation, and cleavage. The process is energy-dependent (requires ATP) and releases energy.
- Creates UREA.
- UREA is secreted into the circulation and is removed by the kidneys.
- Amino Acids:
- Made in the liver or absorbed from the small intestine.
- Formed into proteins.
- Transported out of the liver.
- Broken down into glucose.
- Removed via the Urea cycle.
Describe lipid metabolism
Process:
- Ingested Fat:
- Broken down into fatty acids in the small intestine.
- Ingested and packed into lipoproteins: hydrophilic. Chylomicron. Thoracic duct. Transported to tissues and liver via arteries.
- Adipocytes:
- Release fatty acids into the blood (glucagon).
- Liver:
- Remnant chylomicrons back to liver
- receptor-mediated uptake: salvage cholesterol and left-over FA
- repackaged along with newly made FA
- Makes fatty acids from excess glucose.
Pathways:
- mitochondria process
Palmitic acid is Hydrophobic: A solid oil, liquid at 63°C. Must package these into lipoproteins for delivery.
Discusslipid protein carriers
Apolipoproteins:
- Made in the liver. Associated with lipoproteins.
- Ligand for the receptors for lipoproteins.
- Regulate lipoprotein function and some enzymes of the pathway.
- Example: Apo-lipoprotein A-1 makes up 70% of HDL.
Lipoproteins:
- Phospholipid-rich, cholesterol-rich molecules.
- Form the polar structure.
- Make fatty acids water-soluble for transport in the blood.
Types of Lipoproteins:
- Chylomicrons, very low-density lipoprotein (VLDL), LDL, IDL, and HDL.
- Amount of fatty acids determines the formation of VLDL.
- LDL regulates cholesterol activity and enzyme activity in the hepatocyte, determined by receptor density per cell.
- Atherogenic particles: chylomicron remnants, IDL, LDL.
HDL Function:
- Apo-A1 circulates and collects cholesterol, phospholipids into the core.
- Esterifies the cholesterol in its core.
- Liver delivery and secretion into the bile.
- Regulation: Hepatic lipase in the liver breaks down HDL. Increased activity with insulin resistance.
Describe lipid storage and excretion
- Lipids can be stored in adipocytes.
- Lipids can be used to form glucose through gluconeogenesis, with Acetyl CoA forming oxaloacetate.
- Lipids can be excreted into the intestine via bile (400-800 ml/day).
Bile Composition:
Contains: Bile salts, Bilirubin, Cholesterol, Amino acids, Steroids, Enzymes, Porphyrins, Vitamins, Heavy metals, Drugs, Xenobiotics
Discuss functions of bile
- Bile salts emulsify dietary fats and fat-soluble vitamins (clotting factor synthesis) and facilitate their intestinal absorption.
- Elimination of cholesterol: 500 mg/day.
- Major excretory route for bilirubin.
- Excretion of fat-soluble substrates.
- Secretion of igA.
- Bile is an essential component of the enterohepatic circulation.
Bile Salts:
- Primary bile salts: cholic acid & chenodeoxycholic acid, conjugated with taurine and glycine.
- Excreted bile salts are incorporated into mixed micelles in bile with phospholipid (phosphatidylcholine) and cholesterol.
- Gut Bacteria:
- Convert cholic acid to deoxycholic acid.
- Convert chenodeoxycholic acid to lithocholic acid.
Discuss secretion of bile
- Cholecystokinin:
- Released by enterochromaffin cells in the duodenum in response to FAT.
- Causes gallbladder (GB) contraction and common bile duct (CBD) contraction.
- Secretin:
- Released by S cells in the duodenum in response to ACID.
- Stimulates biliary duct cellular secretion of bicarbonate (bicarb) and water.
- Bile Flow:
- Bile enters the duodenum, aiding in the digestion of fat and metabolism by bacteria in the intestine.
Enterohepatic Circulation
- Bile Circulation:
- 2-4g of bile circulates 10 times per day.
- Primary Bile Acids:
- Cholic acid & chenodeoxycholic acid, 95% reabsorbed in the terminal ileum.
- Bacterial conversion to deoxycholic acid & lithocholic acid.
Discuss bile duct obstruction
- Causes:
- Mechanical, usually caused by stones, resulting in inflammation and stone formation.
- Possible imbalance of bile acids vs cholesterol, leading to crystal formation of bile acid.
Describe bilirubin metabolism
- Heme Breakdown:
- Produces bilirubin, which is insoluble and deposited in skin and eyes.
- Crosses the blood-brain barrier.
- Transport and Excretion:
- Bound to albumin, transported to the liver.
- Bile is the major route of excretion for bilirubin.
- Bilirubin is conjugated with glucuronic acid by uridine glucuronyl transferase in the liver microsomes to become water-soluble.
- Excreted into bile by multidrug resistance protein MRP2.
Discuss cholestasis
- Definition: Failure of bile secretion.
- Manifestation of many liver diseases, bile secretion is the rat e limiting step
- Clinical Manifestation:
- Jaundice (excess bilirubin), pale stool (insufficient biliverdin), fatty stool (insufficient bile salts), dark urine (excess bilirubin).
- Causes: Obstruction, drugs, infection.
Discuss drug metabolism
- Environment:
- Drugs active in hydrophobic environments like tissues, cells, and membranes. Excretion is hydrophilic in bile or urine.
- Detoxification Phases:
- Phase 1: Oxidation, usually by Cytochrome P450.
- Phase 2: Conjugation, including glucuronidation and sulfation.
- Influences:
- Genetic polymorphisms- leading to variability in expression
- enzyme induction, age, disease, competition.
Drug Metabolism: First Pass Effect
- Effect:
- Only 15% of a drug is metabolized when 100% is ingested and 75% is absorbed.
- Examples: Propranolol, morphine, glycerol trinitrate.
- **Avoidance Strategies? different routes of administration vs oral
Discuss alcohol metabolism
- Breakdown Factors:
- ADH expression in stomach and liver.
- ALDH deficiency in some genetic groups.
- Chronic ingestion induces Cytochrome P450.
- incd Glycolysis and fatty acid synthesis.
Discuss the components of the liver function tests and their associations
- Key Markers:
- Bilirubin (total).
- Alanine aminotransferase (ALT).
- Aspartate aminotransferase (AST).
- Alkaline phosphatase (ALP).
- Gamma-Glutamyl transferase (GGT).
- Albumin.
- Globulins.
- Activated partial thromboplastin time (APTT).
- Blood sugar level (BSL).
- Iron metabolism.
- Interpretation:
- Bilirubin (total) biliary, hepatocellular function
- Alanine aminotransferase ALT hepatocellular damage
- Aspartate aminotransferase AST hepatocellular damage
- Alkaline phosphatase ALP biliary
- Gamma-Glutamyl transferase GGT biliary
- Albumin hepatocellular function
- Globulins hepatocellular function
- Activated partial thromboplastin time APTT hepatocellular function
- BSL hepatocellular function
- Iron and ferritin hepatocellular damage
Discuss immune function of the liver
- Overview:
- Liver has both innate and adaptive immune functions with significant overlap.
- Liver disease often involves a state of immune suppression.
- The liver is a highly immunologically tolerant organ.
- Chronic hepatitis involves low-grade inflammation controlled by the liver.
Innate Immunity
- Acute Phase Proteins:
- Manufacture and export of proteins like amyloid A, fibrinogen, C-reactive protein (CRP), haptoglobin, complement factors C3 and C9, hemopexin, ceruloplasmin, α2-macroglobulin, CD14, α1-antichymotrypsin, α1-cysteine proteinase inhibitor, and α1-antitrypsin.
- Modulate immune response and indicate inflammation.
- Immune Cells in the Liver:
- Kupffer cells (macrophages) phagocytose and remove antigen-antibody complexes.
- Liver NK/T cells have non-specific cell killing and anti-tumor effects.
Adaptive Immunity
- Antigen Presentation:
- Directed by antigen-presenting cells like dendritic cells (DC) of the liver (MHCII).
- Non-specific (MHCI) presentation in the liver may lead to tolerance.
- Lymphocytes:
- Main immune cells in the liver with many CD8:CD4 and high numbers of γδ phenotype.
- Dependent on longevity and activation based on distribution in the microarchitecture.
- Extensive ongoing research in this area.
