8.5 - Hepatobiliary System

LECTURE NOTES

  • Two lobes - falciform ligament down the middle

  • Blood supply by both hepatic artery and portal vein

  • Outflow contains bile and blood (leaves by 3 hepatic veins)

    • Right, middle and left hepatic vein

  • Two lobes of kidney divided by middle hepatic vein (which sits further left on image than the falciform ligament)

  • Liver is divided into segments - left has segments 1-4 and right hsa segments 5-8

  • Liver technically curls around your body - right posterior section is around your back

  • Hepatic lobule

    • Hexagonal structural unit

    • Sensor of each lobule has a central vein → connects blood from hepatic sinusoids → hepatic vein → systemic veinous system

    • Each lobule has numerous rows of hepatocytes - each has a sinusoid facing side and bile canaliculi-facing side

  • Portal triad

    • Branch of hepatic artery - brings oxygen rich blood into the liver to support hepatocytes increased energy demands

    • Branch of portal vein - mixed venous blood from GI Tract containg nutrients, bacteria and toxic and spleen containing waste products come.

      • Hepatocytes process nutrients, detoxift blood and excrete blood

    • Bile duct - bile produced by hepatocytes drains into bile canaliculi → coaelsce with cholangiocyte-lined bile ducts around lobule perimeter

  • Three zone model

    • Blood into hepatic acinus via Point A

    • Blood drains out of hepatic acinus via Point B

    • Zone 1 - high oxygen and high toxin risk

    • Zone 2 - medium oxygen and medium toxin risk

    • Zone 3 - low oxygen and low toxin risk

  • Hepatic Acinus

    • Functional unit of liver

    • Consists of two adjacenet 1/6th hepatic lobules - sharing 2x portal triads and extend into hepatic lobules as far as the central vein

    • Acinus ais made up of three zones…

  • Liver cell types

    • Sinusoidal endothelial cells

      • No basement membrane

      • Fenestrated - discontinuous endothelium

      • Allow lipids and large molecule movement to and from hepatocytes

    • Kuppfer cells

      • Sinusoidal macrophages

      • Attached to endothelial cells

      • Phagocytosis

    • Hepatic stellate cells

      • Exist in a dormant state

      • Essentially fibroblasts which get activated in response to liver damage

      • Store vitamin A in liver cytosolic droplets

      • Proliferate, chemotactis and deposit collagen in ECM

    • Hepatocytes

      • 80% of liver mass

      • Cubical shaped

      • Syntehsise albumin, clotting factors and bile ssalts

      • Recieve nutrients and building blocks from sinusoids

      • Drug metabolism

    • Cholangiocytes

      • Secrete bicarbonate and water into bile

  • Hepatocyte functions - numerous including:

    • Metabolic and catabolic: synthesise and utilise carbs, lipids and proteins

    • Secretory and excretory functions: synthesis and secretion of proteins, bile and waste products

    • Detoxification and immunological functions: breakdown of ingested pathogens and processing of drugs

  • Carbohydrate metabolism: glycolysis, glycogenesis, glycogenolysis, gluconeogenesis, lipolysis and lipogenesis

    • Glucose undergoes glycolysis to produce pyruvate

    • Pyruvate enters TCA cycle to produce more ATP

    • Oxygen is rate-limiting and therefore pyrvate is fermented to lactate

    • Lactate is reconverted into pyruvate in the liver

    • Gluconeogenesis of pyruvate which can be metabolised

    • This is known as the cori cycle

  • Protein Synthesis

    • Amino acids go

  • Synthesis of non-essential Amino Acids

    • Process known as transamination

    • Alanine shuttled to liver and amide moved to alpha keto glutarate

    • Forms glutarate and pyruvate

  • Transamination - differnt keto acids can be converted into multiple amino acids depending on the transaminase enzyme, which are vital for the production of non-essential amino acids)

    • Examples…

  • Glucose-alanin cycle - deamination

    • One method of gluconeogenesis

    • One problem is the msucle can potentially utilise the amino acids to produce gllucose to release energy

    • But…

      • Conversion of pyruvate to glucose requires energy

      • Nitrogen removal as urea requires energy

    • Solution…. transfer problem to liver for the glucose- alanine cycle

    • Pyruvate from glycolysis and glutamate

      • Glutamate transfers amine to pyruvate

      • Alanine forms and is formed and shuttled to liver

      • At the liver alanine broken down to pyruvate

      • Amine transferred back to alpha ketoglutarate to form glutamate

      • Amine taken off to form urea

      • Pyruvate used to produce glucose → shuttled back to muscle cell for glycolyssi

  • Triglyceride metabolism

    • Triglyceride conversion into fatty acids

    • Fatty acids shuttled to liver

    • Beta oxidation of fatty acids to acetyl CoA

    • Acetyl CoA enters the TCA cycle

  • Lipoprotein Synthesis

    • Glucose taken into the liver can be converted to glycerol, fatty acids (via malnoyl coA or cholesterol by HMG CoA reductase)

      • Glycerol and fatty acids forms triglycerides

      • Add phospholipids or apoproteins or cholesterol to form lipoproteins

    • Lipoproteins used as VLDL to transport fatty acids to tissues

    • At tissues fatty acids are converted to tri-glycerides

    • Lipoproteins can also form HDL - which is empy and picks up excess cholesterol

    • LDL formed from VLDL to transport cholesterol to tissues

  • Hepatocyte Storage Functions

    • Fat soluble vitamins (A, D, E, K)

      • Stores sufficient 6-12 month except Vitamin K where store is small)

      • Vitamin K is essential for blood clotting

    • Storage of iron as ferritin

      • Available for erythropoesis

  • Detoxification

    • Anything that is not produced by the body and shouldn’t be there is removed

    • P450 enzymes

      • Phase 1 - modification - become mor hydrophilic

      • Phase 2 - conjugation - attach water soluble side chains to make it less reactive.

  • Biliary System:

  • Bile is mainly composed of water

  • Small amount of bile salts present

  • Uses of bile are:

    • Cholesterol homoeostasis

    • Absorption of lipids and lipid soluble vitamins

    • Excretions of xenobiotics, cholesterol metabolites, adenocorticoids and other steroid hormones, alkaline phosphatase

  • Hepatocytes secrete 60% of total bile

    • Primary secretion - bile secertions reflect serum concentrations

    • Secretion of bile salts (acids), lipids and organic ions

  • Cholagniocytes secrete 40% of total bile

    • Alteration of pH

    • Water drawn into bile by osmosis via paracellular junctions

    • Luminal glucose and organic acids reabsorbed

    • Bicarbonate and chloride actively secreted into bile by CFTR

    • IgA is exocytos

  • Bile flow

    • Biliary excretion of bile salts and toxins performed by biliary transporters

    • Main transporters include:

      • Basolateral membrane (importing)

        • OATPS - bile salt uptake (organic anion transporting peptide)

        • NTCP - bile salt uptake (sodium taurocholate-cotransporting polypeptide)

      • Apical surface (exporting)

        • Bile salt excretory pump (BSEP) - active transport of bile acids into bile

        • MDR related proteins (MRP2 & MRP3) - negatively charged metabolites

        • Products of multidrug resistance genes

          • MDR1→ excretion of neutral and positive xenobiotics and cytotoxins

          • MDR3 → phospatidylcholine

  • Bile salts

    • Main component is bile acids

    • Bile acids syntehsised from cholesterol

    • Sodium and potassium salts of bile acids connjugated in liver to glycine and taurine

    • 2 primary bile acids are synthesised in the liver

      • Cholic acid and chenodeoxycholic acid

      • These can be converted to secondary acids by gut bacteria

      • Cholic → deoxycholic

      • Chenodeoxycholic → Lithocolic

  • Bile salts function

    • Reduce surface tension of fats

    • Emulsify fat prior to its digestion and absorption

    • Bile salts form Micelles

      • Steroid nucleus planar has 2x faces (amphipathic)

      • 1x surface hydrophilic

  • Regulation of bile flow and secretion

    • Between meals sphincter of Oddi is closed

    • When you eat, the sphincter relaxes and it opens allowing bile to flow through

    • Gastric contents enter duodenum causing release of cholecytsokinin which causes gall bladder to contract

  • Enterohephatic circulation

    • 95% of bile salts are reabsorbed from the terminal ileum

      • Na+/bile co-transport system

    • 5% converted into secondary acids in the colon

      • Deoxycholic acid is reabsorbed

      • 99% of lithocolic acid excreted in stool absorbed B. salta back to liver and re-excreted in bile.

  • Gall Bladder Functions

    • Gall bladder stores and concentrated bile and acidifies it

    • Gall bladder contraction is triggered by CCK

      • CCKA receptors and neuronal plexus of GB wall (innervated by preganglionic parasympathetic fibres of vagus nerve)

  • Bilirubin

    • Free bilirubin is insoluble and a yellow pigment

    • 75% from haemoglobin breakdown, 22% from catabolism of other haemoproteins and 3% from ineffective BM erythropoiesis

    • Free Bilirubin is bound to albumin in the blood

    • Most dissociates in liver and enters hepatocytes

    • BR conjugated with 2x molecules of UDP-glucoronate → bilirubin diglucuronide

    • Secreted ACROSS concentration gradient into biliary canaliculi → Gastrointestinal tract

    • 200-250mg of BR excreted into bile/day

      • 85% in faeces

        • BR → urobilinogen → stercobilinogen → stercobilin

      • 15% enters enterohepatic circulation

        • BR → deconjugated → lipophilic form

        • Urobilinogen and stercobilinogen

      • 1% enters systemic circulation and is excreted by kidneys

  • Jaundice

    • Post-hepatic jaundice - known as obstructive jaundice