Jaundice & Liver Failure Flashcards
List 3 important roles of bile?
Bile has 3 important roles:
o Cholesterol homeostasis
o Dietary lipid/vitamin absorption
o Removal of xenobiotics(foreign substance)/drugs/endogenous waste products E.g.
cholesterol metabolites,
adrenocortical
other steroid hormones
Xenobiotics – exogenous compounds e.g. food additives, which we are exposed to
Composition of human bile?
Other Substances Excreted into Bile
- Adrenocortical and other steroid hormones
- Drugs/Xenobiotics
- Cholesterol
- Alkaline Phosphatase (ALP)
Bile Production
Bile drains from the liver, through the bile ducts, into the duodenum at …………… ……………….
•500ml produced/secreted daily
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•Green/yellow colour glucoronides of bile pigments
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•60% bile secreted by hepatocytes (liver cells)
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•Up to 40% secreted by cholangiocytes (biliary epithelial cells)
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•Bile drains from liver, through bile ducts, into duodenum at duodenal papilla
What is the role of the biliary tree in bile production?
•40% bile secreted by …………………….. (biliary epithelium)
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•Alters ….., ……………… and modifies bile as it flows through
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•………. drawn INTO bile (osmosis through paracellular junctions)
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•Luminal ……….. and some organic acids also reabsorbed
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•…………. and ……. actively secreted INTO bile by CFTR mechanism (Cystic Fibrosis Transmembrane Regulator)
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•Cholangiocytes contribute ….. by exocytosis
•40% bile secreted by cholangiocytes (biliary epithelium)
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•Alters pH, fluidity and modifies bile as it flows through
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•H20 drawn INTO bile (osmosis through paracellular junctions)
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•Luminal glucose and some organic acids also reabsorbed
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•HCO3- and Cl- actively secreted INTO bile by CFTR mechanism (Cystic Fibrosis Transmembrane Regulator)
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•Cholangiocytes contribute IgA by exocytosis
Cholistasis
Choli=bile
Stasis=slow
Common in what disease?
Cystic fibrosis
Bile Formation
Bile Flow
•Bile flow closely related to ……………. of bile acids and salts in blood
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•Biliary excretion of bile salts and toxins performed by ………….. on apical …………… of hepatocytes + cholangiocytes
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•These biliary transporters also govern ………. of bile flow
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•Dysfunction of the transporters is a cause of …………….
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•Main transporters include the:
– ………. …………. …………. ………….. (BSEP)
–……….. ………………. ……………. (MRP1 & MRP3)
–products of the…………… ……………… ……………….. gene (FIC1) and …………. …………… …………… (MDR1 & MDR3).
Bile Flow
•Bile flow closely related to concentration of bile acids and salts in blood
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•Biliary excretion of bile salts and toxins performed by transporters on apical surface of hepatocytes + cholangiocytes
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•These biliary transporters also govern rate of bile flow
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•Dysfunction of the transporters is a cause of cholestasis
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•Main transporters include the:
– Bile Salt Excretory Pump (BSEP)
–MDR related proteins (MRP1 & MRP3)
–products of the familial intrahepatic cholestasis gene (FIC1) and multidrug resistance genes (MDR1 & MDR3).
Mutations can lead to gentic diseases which lead to choliostasis
Bile flow
- BSEP (ABCB11 gene): active transport of ………… …………. across hepatocyte canalicular membranes into bile, and secretion of ………… …………. is a major determinant of ………… ………….
- MDR1: mediates canalicular excretion of …………., ………….
- MDR 3: encodes a phospholipid transporter protein that translocates …………………….. from inner to outer leaflet of canalicular membrane
Bile flow
- BSEP (ABCB11 gene): active transport of bile acids across hepatocyte canalicular membranes into bile, and secretion of bile acids is a major determinant of bile flow
- MDR1: mediates canalicular excretion of xenobiotics, cytotoxins
- MDR 3: encodes a phospholipid transporter protein that translocates phosphatidylcholine from inner to outer leaflet of canalicular membrane
Bile salts and Bile …… basically mean the same thing
Bile salts and Bile Acid basically mean the same thing
What are Bile salts?
Name the two primary acids formed by the liver?
What happens to these bile acids and state the substances produced?
What is the purpose of conjugation?
Bile salts
Bile salts are sodium + potassium salts of bile acids conjugated to glycine + taurine
Bile acids are synthesis from cholesterol; 4 acids in humans o 2 primary acids are formed in the liver:
Cholic acid
Chenodeoxycholic acid
o These are then converted by colonic bacteria:
Cholic acid to deoxycholic acid
Chenodeoxycholic acid to lithocholic acid
The prupose of the conjugation is to make the initial compounds more easily absorbed + metabolised
Composition of bile
Water, bile salts, inorganic salts, bile pigments (bilirubin, bilivirden), fatty acids, lethicin, fat, cholesterol, alkaline phosphatase, drug metabolites + trace metals
All components form an alkaline electrolyte solution There are also other substances excreted into bile:
Andrenocortical + other steroid hormones
Drugs/xenobiotics
Cholesterol
Alkaline phosphatase (ALP)
what causes the golden-yellow colour of bile?
What is there an increase of in duct obstruction?
What is there an increase of in hepatic illnesses?
Clinical correlation: in duct obstruction, there is an increase in cholesterol + ALP, which may result in jaundice. However in hepatic illness, the increase is NOT in ALP, but rather ALT + AST (alanine transaminase + aspartate transaminase)
The golden-yellow colour of bile is due to gluconorides of bile pigments
What is the function of Bile salts?
How are they able to do this?
The detergent-like actions make bile salts potentially cytotoxic in high concentrations.
What protects the cell’s cell membrane?
Function
Fats are water insoluble, and bile consists of predominantly water, therefore bile salts allow emulsion of the lipids in the water by reducing the surface tension of the fat and forming micelles in the water
They are able to do this by forming micelles – due to their amphipathic nature they form a lipid hydrophobic core with a hydrophilic surface – allowing the lipids to be transported to the GI tract epithelial cells for absorption
The detergent-like actions make bile salts potentially cytotoxic in high concentrations, but cell membranes are protected by other intraluminal lipids and their own membrane content of cholesterol + glycolipids. However they are thought to contribute to liver cancer at very high concentrations.
Anatomy of the Biliary System
•Each hepatocyte is apposed to several bile …………..
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•these drain into ………….. ………….. ………….., coalesce
………….. ………….. —– into …………../………….. …………..Ducts
join outside liver to form ………….. ………….. Duct
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•………….. ………….. drains the gall bladder
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•………….. ………….. unites with ………….. ………….. Duct to form ………….. ………….. DUCT (CBD)
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•CBD joined by………….. Duct prior to entering duodenal papilla
Anatomy of the Biliary System
•Each hepatocyte is apposed to several bile canaliculi
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•these drain into intralobular bile ducts, coalesce
interlobular ducts —– into Right/Left Hepatic Ducts
join outside liver to form Common Hepatic Duct
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•Cystic Duct drains the gall bladder
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•Cystic Duct unites with Common Hepatic Duct to form COMMON BILE DUCT (CBD)
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•CBD joined by Pancreatic Duct prior to entering duodenal papilla
What is the sphincter of oddi?
The sphincter of Oddi (also hepatopancreaticsphincter or Glisson’s sphincter), abbreviated as SO, is a muscular valve that controls the flow of digestive juices (bile and pancreatic juice) through the ampulla of Vater into the second part of the duodenum
cholecystokinin effect on the bile duct and the sphincter of oddi?
cholecystokinin causes the bile duct to contract and the sphincter of oddi to open (relax)
CCK is released when you eat food?
What is the enterohepatic circulation and state why it is important?
Enterohepatic circulation
Liver cells transfer various substances from plasma to bile; many of which are then concentrate in bile e.g. gluconuride, which is hydrolysed then reabsorbed into the circulation – i.e. the cycle repeats itself
This can prolong the action of different drugs, e.g. morphine
Summary = GI tract – portal blood – uptake by hepatocyte + excretion into canaliculus – bile duct – GI tract – reabsorption into terminal ileum + transport out of enterocytes
95% bile salts absorbed from small (………….) ………….
by Na+/bile salt co-transport Na+-K+ ATPase system
5% converted to 2o bile acids in …………. ( where the primary bile acids are converted into secondary bile acids):
- deoxycholate absorbed
- lithocholate 99% excreted in stool
absorbed B.salts back to liver
re-excreted in bile
95% bile salts absorbed from small (terminal) ileum
by Na+/bile salt co-transport Na+-K+ ATPase system
5% converted to 2o bile acids in colon ( where the primary bile acids are converted into secondary bile acids):
- deoxycholate absorbed
- lithocholate 99% excreted in stool
absorbed B.salts back to liver
re-excreted in bile
List 3 functions of the bile duct?
1.Stores bile (50ml), released after meal for fat digestion
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2.Acidifies bile
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3.Concentrates bile by H20 diffusion following net absorption of Na+, Cl-, Ca2+, HCO3 ( intra-cystic pH)
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- Gall bladder can reduce volume of its stored bile by 80 – 90%
What is bilirubin?
List 3 sources of bilirubin?
What happens once bilirubin is in the hepatocytes and why does this happen?
Bilirubin
Water insoluble yellow pigment
Source:
o Hb breakdown in spleen
o Catabolism of haem proteins o Ineffective bone marrow erythropoiesis
Bilirubin is produced in spleen then bound to albumin where it dissociates in the liver and enters hepatocytes
In the hepatocytes, it binds to cytoplasmic proteins and is conjugated to glucoronic acid to form diglucoronide-BR
o This is more soluble than free bilirubin
The conjugated molecule is then transported across conc gradient into bile canaliculi and into the GI tract
Total BR = free unconjugated BR + conjugated BR
Why Faeces is Brown:
Oxidation of stercobilinogen to stercobilin
What does jaundice cause a yellow tinge to?
What is pre-hepatic jaundice?
List 4 reasons that may cause it?
What is a marker in the blood for it and expain why it is a marker?
Pre-hepatic
o Problem is before the liver, i.e. BR production in the spleen is too high
o May be due to haemolysis, massive transfusion, haematoma reansorption, ineffective erythropoiesis
o BR production is too great for conjugation in the liver, therefore predominantly unconjugated BR in the blood
o Look for HB drop without overt bleeding
MASS DEATH OF RBC MORE RAPIDLY THEN 120 Days
What is hepatic jaundice and state 3 causes of hepatic jaundice?
What can hepatic jaundice lead to?
Hepatic/hepatocellular
o Spleen production of BR normal, but the hepatocytes of the liver not functioning properly, either defective uptake, conjugation or excretion
o May cause liver failure (which may be acute, chronic, caused by viral hep etc) and intrahepatic cholestasis
What is gilberts sundrome?
What causes it?
What is it an elevated version of?
What is its mode of inheritance?
UDPGT-1A1 conjugates bilirubin
With Gilberts syndrom they have a slow isoform of UDPGT-1A1
Gilbert’s caused by AGT deficiency (polymorphism less effective enzyme in 2% of population) slightly increased BR which may spike during illness or stress
What is Fulminant hepatic failure?
What is sub fulminant?
What are their clinical differences?
Lsit some causes of acute liver failure?
•Toxins
–Paracetamol
–Amanita phalloides
–Bacillus cereus
•Diseases of pregnancy
–AFLOP, HELLP, hepatic infarction, HEV, Budd-Chiari
•Idiosyncratic drug reactions
–Single Agent: Isoniazid, NSAID’s, valproate
–Drug combinations: Amoxicillin/clavulanic acid, trimethoprim/sulphamethoxazole, rifampicin/isoniazid
•Vascular Diseases
–Ischaemic hepatitis, post-OLT hepatic artery thrombosis, post-arrest, VOD
•Metabolic causes
–Wilson’s disease, Reye’s syndrome
Liver failure
What can dimished protein syntheisis of the liver cause?
What can defctive metabolism of the liver cause?
•Diminished Protein Synthesis
–¯ Albumin ® ascites and oedema
–¯ Clotting factors ® bruising and bleeding
–¯ Complement ® infection and sepsis
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•Defective Metabolism
–Carbohydrate ® hypoglycaemia
–Protein catabolism ® low urea
–Ammonia Clearance ® encephalopathy and coma
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•May be acute or chronic
HEpatic encephalopathy
Aetiopathogenesis?
- accumulated neurotoxic substances in brain.?
- Affecting astrocyte function?
- e.g.
–Short-chain fatty acids
–False neurotransmitters, such as tyramine, octopamine, and beta-phenylethanolamines;
–Manganese
–Ammonia
–Gamma-aminobutyric acid (GABA).
