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
What does the enterohepatic circulation look like? FITB
What are the 2ndary bile acids that are produced and what happens to them in the enterohepatic circulation?
Deoxycholate absorbed Lithocholate 99% excreted in stool
How much bile salts are recycled in the enterohepatic circulation?
3g - 2 times per meal, 6-8x/day
What is caused by terminal ileal resection/disease?
Decreased bile salt reabsorption and increased stool [fat] as enterohepatic criculation is interrupted and liver can't increase rate of bile salt production enough to make it up
What happens if bile is stopped from entering the gut?
Up to 50% ingested fat appears in faeces and fat soluble vitamins are malabsorbed
What are the functions of the gall bladder?
Stores bile (50g) released after meal for fat digestion Acidifies bile Concentrates bile by H2O diffusion following net absorption of Na, Cl, Ca2+, HCO3
What is the difference between hepatic duct bile and gall bladder bile?
What effects does a cholecystectomy have on the patient?
Bile discharge (periodically) aids digestion but isn't essential - normal health and nutrition can exist with continuous slow bile discharge into duodenum BUT avoid foods high fat content
What is bilirubin?
H2O-insoluble yellow pigment
Where does bilirubin come from?
75% from Hb breakdown 22% from catabolism of haem proteins 3% from ineffective bone marrow eryhtropoiesis
How is BR metabolised and excreted?
BR bound to albumin, where mostly dissociates in liver Free BR enters hepatocytes, binds to cytoplasmic proteins, conjugated to glucoronic acid (UDPGT) forming diglucoronide-BR which is transported across conc grad into bile canaliculi and back into GIT
Fill in the blanks of BR metabolism in the liver
What are urobilinogens?
H2O-soluble, colourless derivatives of BR formed by GIT bacteria
Where is urobilinogen formed?
Mainly in intestines by bacterial action on BR
What happens to urobilinogen?
1/2 formed is reabsorbed and taken up via HPV to liver, enters circulation, excreted by the kidney 20% reabsorbed into general circulation Some passed in stool as Stercobilinogen
What is the GIT mucosa permeable to, in terms of BR?
Impermeable to conjuated BR, but permeable to unconjugated BR and urobilinogens
What happens to unconjugated BR?
Some enters the enterohepatic circulation and some forms urobilinogens
FITB of the bilirubin metabolism and excretion pathway
Why are faeces brown?
Oxidation of stercobilinogen to stercobilin
What is jaundice?
Excess BR in blood >34-50microM/L Yellow tinge to skin, sclerae, mucous membranes
What does cholestasis normally result in?
Jaundice - but not necessarily the other way round
What are the 3 types of jaundice?
Pre-hepatic, hepatic and post-hepatic/obstructive
What are the causes of pre-hepatic jaundice?
Increased quantity of BR: Haemolysis, massive transfusion, haematoma resorption, ineffective erythropoiesis
What are signs of pre-hepatic jaundice?
Hb drop wihout overt bleeding
Where is the problem occurring in pre-hepatic jaundice?
Where is the problem occurring in hepatic jaundice?
Where is the problem occurring in post-hepatic jaundice?
What are the causes of hepatic jaundice?
Defective uptake - defective conjugation or BR excretion Liver failure - acute/fulminant, acute on chronic, viral hep Intrahepatic cholestasis
What are the causes of hepatic jaundice if there is high unconjugated BR?
Decreased BR uptake: Drugs and CCF Decreased BR conjugation: hypothyroidism, gilbert's, Crigler-Najjar
What are the causes of hepatic jaundice if there is high conjugated BR?
Heptocellular dysfunction: Congenital, infection (Hep A/B/C), toxin (drugs), AI, neoplasia, vascular Decreased hepatic BR excretion: Dubin-johnson, rotor's
What are the causes of obstructive jaundice?
Defective transport of BR by biliary duct system - bile duct stones, HepPancBil malignancy, local lymphadenopathy Sepsis
What is Gilbert's syndrome?
Common hereditary cause of increased bilirubin - up to 5% of popn Autosomal recessive Elevated UNconjugated bilirubin in bloodstream
What is the cause of Gilbert's?
70-80% reduction in glucuronidation activity of enzyme UDPGT-1A1
What are the symptoms of Gilbert's?
No serious consequences, but mild jaundice may appear under exertion/stress/fasting/infections but otherwise asymptomatic
What is the cell turnover like during liver failure?
More hepatocytes destroyed than regenerated
What is acute liver failure and what are the 2 causes?
ALF - when rate of hepatocyte death > regeneration and combination of apoptosis and/or necrosis Apoptosis - nuclear shrinkage but no cell membrane rupture so no 2ndary inflammation Necrosis - ATP exhaustion resulting in swollen cell, which eventually lyses so 2ndary inflammation present
What is the result of ALF?
Catastrophic illness which can rapidly lead to death/coma due to multiorgan failure
What triggers apoptosis in ALF?
Activation of caspases (cysteine proteases) which is activated cytokines
Which other factors regulate pathways of hepatocyte death?
Cellular nitric oxide, antioxidants, various pro-/anti-inflammatory cytokines
What is fulminant hepatic failure?
Rapid development (
What is sub-fulminant?
Less than 6 months
What are the differences between subfulminant and fulminant?
Cerebral oedema is common in fulminant, rare in subfulminant Renal failure and portal hypertension more frequent in subfulminant
What are the classifications of fulminant hepatic failure?
Hyperacute Hepatic Failure (0-7 days) Acute Hepatic Failure (8-28 days) Subacute Hepatic Failure (29 days to 12 weeks)
What is the commonest cause of ALF in UK?
What are the toxins that causes ALF?
Paracetamol, amanita phalloides, bacillus cereus
What are the other causes of ALF?
Diseases of pregnancy (AFLOP, Hep infarction) Idiosyncratic drug reactions (single agent [NSAID's], drug combinations [amoxicillin/clavulanic acid]) Vascular diseases (ischaemic hepatitis) Metabolic causes (Wilson's disease)
What are the dosages of paracetamol that are dangerous and cause acute fulminant liver failure?
Toxicity=10g Severe toxicity= 25g Lowe doses can be hepatotoxic in chronic alcoholics, malnutrition/fasting, tegretol, phenobarbital, rifampacin
What are the results of hepatocellular failure compared to normal liver function?
What are the consequences of liver failure?
Diminished protein synthesis - decreased: albumin (oedema/ascites), clotting factors (bruising/bleeding), complement (infection/sepsis) Defective metabolism: Carbs (hypoglycaemia), protein catabolism (low urea), ammonia clearance (encephalopathy and coma)
What are the symptoms of ALF?
Initially non-specific - malaise, nausea, lethargy Jaundice Then encephalopathy
What are the causes of death in those with ALF?
Bacterial and fungal infections Circulatory instability Cerebral Oedema Renal failure Respiratory failure Acid-base and electrolyte disturbance Coagulopathy
What is the only beneficial therapeutic intervention for ALF?
Liver transplantation but need to be selected carefully otherwise commits patient to immmunosuppression, expensive, precious graft wasted