Why do we produce bile?
Cholesterol homeostasis, dietary lipid/vitamin absorption, removal of xenobiotics/drugs/endogenous waste products (cholesterol metabolites, adrenocortical. other steroid hormones)
What is the composition in human bile?
What other substances are excreted into bile?
Adrenocortical and other steroid hormones, drugs/xenobiotics, cholesterol and alkaline phosphatase
How much bile is produced daily?
500ml produced/secreted daily
What colour is bile?
Green/yellow due to glucoronides of bile pigments
Where is bile secreted from?
60% by hepatocytes and up to 40% by cholangiocytes
Where does bile drain from?
Liver through bile ducts, into duodenum at duodenal papilla
What is the role of the biliary tree?
Alters pH, fluidity and modifies bile as it flows through H2O is drawn into bile (via osmosis through paracellular junctions) Luminal glucose and some organic acids are also reabsorbed HCO3- and Cl- are actively secreted into bile by CFTR mechanism Cholangiocytes contribute IgA by exocytosis
What is bile flow closely related to?
It is closely related to conc of bile acids and salts in blood
What excretes bile salts and toxins?
Transporters on apical surface of hepatocytes and cholangiocytes
What governs rate of bile flow?
Biliary transporters Dysfunction is a cause of cholestasis
What are the main transporters of bile?
Bile salt excretory pump (BSEP), MDR related proteins (MRP1/3), products of familial intrahepatic cholestasis gene (FIC1) and multidrug resistance genes (MDR1/3)
What is the function of BSEP?
Active transport of bile acids across hepatocyte canalicular membranes into the bile and secretion of bile acids is a major determinant of bile flow
What is the function of MDR1?
Mediates canalicular excretion of xenobiotics, cytotoxins
What is the function of MDR3?
Encodes a phospholipid transporter protein that translocates phosphatidylcholine from inner to outer leaflet of canalicular membrane
How are bile salts made - what are their components?
Na/K salts of bile acids are conjugated in the liver to glycine and taurine Bile acids synthesised from cholesterol
What are the 4 bile acids in humans?
Primary acids (formed in liver): Cholic acid and chenodeoxycholic acid Both converted by colonic bacteria into 2 secondary acids: Deoxycholic acid and lithocholic acid
What is the function of bile salts?
Reduce surface tension of fats and emulsify fat preparatory to its digestion/absorption
What do bile salts form?
Micelles - amphipathic, transport to GIT epithelial cells
What is a negative of bile salts?
They have detergent-like actions which could make them cytotoxic in high concentrations
What controls the Ampulla of bile duct?
Sphincter of Oddi
What is the anatomy of the biliary system?
Each hepatocyte is apposed to several bile canaliculi which drain into intralobular bile ducts, which coalesce into interlobular ducts, then R/L hepatic ducts which all join outside liver to form Common Hepatic Duct Cystic duct drains the gall bladder and unites with common hepatic duct to form the Common Bile Duct, whihc is joined by Pancreatic duct prior to entering duodenal papilla
How is the bile flow/secretion regulated?
Between meals duodenal orifice is closed, so bile is diverted into gall bladder for storage Eating causes sphincter of Oddi to relax Gastric contents enter duodenum causing release of cholecystikinin which causes the gall bladder to contract
Functional diagram of bile formation - FITB
What is cholestasis?
Slowing/stopping of movement of bile in the biliary tree/duct
Structured schematic showing the different receptors on the cholangiocytes
What is the enterohepatic circulation?
Liver cells transfer various substances from plasma to bile and many hydrophilic drug conjugates are concentrated in bile -> gut -> glucoronide hydrolysed -> active drug re-released -> reabsorbed -> cycle repeated
What happens to the bile salts?
95% of bile salts absorbed from small ileum by Na/bile salt co-transport Na/K ATPase system 5% converted into 2ary bile acids in colon Absorbed bile salts are taken to the liver HPV and reexcreted in bile
What is the anatomy of the gall bladder and biliary tree? FITB
What is the importance of the enterohepatic circulation with drug circulation?
There is a reservoir of recirculating drugs so it can prolong action of dugs