Liver failure and Jaundice Flashcards
Reasons for producing bile
Cholesterol homeostasis
Dietary lipid/ vitamin absorption
Removal of xenobiotics/ drugs/ endogenous waste products e.g. cholesterol metabolites, adrenocortical, other steroid hormones
Composition of bile
97% water
Alkaline
How much bile is produced
500ml daily
% of bile secreted by what?
60% by hepatocytes
40% by cholangiocytes (cells that line biliary tree/ cells that line canaliculi)
Where does bile drain from liver?
From liver
through bile ducts
into duodenum at duodenal papilla
Role of biliary tree
40% bile secreted by cholangiocytes (biliary epithelium)
Alters pH, fluidity and modifies bile as it flows through
H20 drawn INTO bile (osmosis through paracellular junctions)
Luminal glucose and some organic acids also reabsorbed
HCO3- and Cl- actively secreted INTO bile by CFTR mechanism (Cystic Fibrosis Transmembrane Regulator)
Cholangiocytes contribute IgA by exocytosis
Biliary excretion of bile salts and toxins performed by
Examples?
If mechanisms stop?
transporters on apical surface of hepatocytes + cholangiocytes- govern rate of bile flow
If transporters stop, cholestasis
Bile Salt Excretory Pump (BSEP)
active transport of bile acids across hepatocyte canalicular membranes into bile, which is a major determinant of bile flow
MDR related proteins (MRP1 & MRP3)
products of the familial intrahepatic cholestasis gene (FIC1)
multidrug resistance genes (MDR1 & MDR3)
MDR1- mediates canalicular excretion of xenobiotics (foreign compounds that could potentially be toxic), cytotoxins
MDR3- encodes a phospholipid transporter protein that translocates phosphatidylcholine (phospholipids) from inner to outer leaflet of canalicular membrane
Bile acids synthesised from
cholesterol
Bile acids in humans
2 primary acids formed in liver by hepatocytes:
Cholic acid+ Chenodeoxycholic acid
converted by colonic bacteria into:
2 secondary acids
Deoxycholic acid+ Lithocholic acid (respectively)
Function of bile salts
1) Reduce surface tension of fats
2) Emulsify fat preparatory to its digestion/absorption
3) Form micelles:
Bile salts amphipathic
One surface has hydrophilic domains, facing OUT
2nd has hydrophobic domains, facing IN
free Fatty Acids and Cholesterol INSIDE
thus transported to GIT epithelial cells for absorption
Danger of bile salts
Detergent-like actions make bile salts potentially cytotoxic in high concentrations
Anatomy of biliary tree R lobe of liver- bile drains out into? L lobe of liver- bile drains out into? Both of these drain to? Gall bladder function? bile goes through? Final duct joining before duodenum? When not eating? When eating?
Right hepatic duct
Left hepatic duct
R+ L hepatic ducts+ drains into common hepatic duct
Gall bladder stores bile+ pumped through cystic duct
Cystic duct+ common hepatic duct join to form common bile duct prior to entering duodenal papilla into duodenum to secrete bile into intestine
When not eating, sphincter of oddi= closed+ goes down cystic duct into gall bladder
When you eat+ , gastric contents triggers release of CCK which relaxes sphincter of Oddi= opens hole+ causes gall bladder contraction, pumps bile into duodenum
Enterohepatic Circulation of a drug, e.g. glucoronide
Liver cells transfer glucoronide from plasma to bile→ concentrated in bile→ glucoronide hydrolysed→ active drug re-released→ reabsorbed through portal blood, cycle repeated
Drugs with high enterohepatic circulation= not a lot is lost as it goes into intestine
Enterohepatic circulation of bile salts % absorbed from ileum? Method? From where? How much re-cycles?
95%
by Na+/bile salt co-transport Na+-K+ ATPase system
Terminal ileum
3g bile salt pool re-cycles repeatedly in enterohepatic circulation (2x/meal; 6 – 8x/day)
Disease of enterohepatic circulation
If bile stopped from entering gut?
Terminal Ileal Resection/Disease:
less bile reabsorption+ more fat in stool
(because enterohepatic circulation interrupted and liver can’t increase rate of bile salt production enough to make it up)
Up to 50% ingested fat appears in faeces+ malabsorption fat soluble vitamins (A,D,E,K)
Functions of Gall Bladder
How can you see this is measurements?
Stores bile (50ml) released after meal for fat digestion Acidifies bile Concentrates bile by H2O diffusion following net absorption of Na+, Cl-, Ca2+, HCO3-= decreased intra-cystic pH- Gall bladder can reduce volume of its stored bile by 80%-90%
Difference from hepatic duct bile to Gallbladder Bile:
Increase % of solids
Increase Bile Salts
Decrease pH
Effect of Gall bladder remova
Bile still being made by liver but trickling consistently into intestine- Normal health and nutrition exist with continuous slow bile discharge into duodenum
But:
Avoid foods with high fat content: don’t have enough concentrated bile to digest it
Bilurubin (BR) properties
H20 insoluble, yellow pigment
Sources of BR
75% BR from Hb breakdown from RBC breakdown in spleen
22% from catabolism of other haem proteins
3% from ineffective bone marrow erythropoiesis
Transport of BR
From spleen, transported to liver when bound to albumin (because H20= insoluble) → Most dissociates in liver→ Free BR enters hepatocyte, binds cytoplasmic proteins→Conjugated to glucoronic acid (UDPGT enzyme used from smooth ER)→ diglucoronide-BR (conjugated= more soluble than free BR)→ transported ACROSS concentration gradient into bile canaliculi
Total BR=?
Free BR (unconjugated)+ Conjugated BR (smaller amount)
BR metabolism+ excretion pathway
Urobilinogens = H2O-SOLUBLE, colourless derivatives of BR formed by action of gut bacteria urobilinogen is formed mainly in the intestines by bacterial action on bilirubin. About half of the urobilinogen formed is reabsorbed and taken up via the portal vein to the liver, enters circulation and is excreted by the kidney GIT mucosa (relatively) IMpermeable to CONJUGATED BR but is PERMEABLE to UNCONJUGATED BR and Urobilinogens 20% urobilinogens reabsorbed into gen.circulation: urine excretn Some urobilinogens passed in stool as Stercobilinogen
In the colon, BR reduced by gut bacteria to stercobilinogen which is oxidised to stercobilin which is brown= stool= brown
Cholestasis
Slow/ cessation of bile flow
Jaundice parameters
Normal?
Excess BR in blood
(>34-50 microM/L)
Normal= less than 21
Cholestasis and Jaundice
Cholestasis normally results in jaundice
Jaundice does not necessarily mean there is cholestasis
Symptoms of Jaundice
Whites of eyes yellow then skin yellow
Pre-hepatic Jaundice description+ causes
Prehepatic:
Increased quantity of BR more than the downstream path can deal with, causes:
Heamolysis (RBCs dying quicker than normal (less than 120 days age), can be caused by lots of things)
Massive Transfusion- not all RBCs get into blood, so some die
Haematoma resorption- cells die quickly in the haematoma
Ineffective erythropoiesis
Subtypes of Jaundice
Prehepatic
Hepatic
Post-hepatic/ Obstructive
Jaundice test for differentiation
Split BR test= if there is a high unconjugated BR, jaundice= pre hepatic/ hepatic
Split BR test= if there is high conjugated BR, jaundice= post-hepatic + dark urine
To distinguish between pre-hepatic+ hepatic by looking at liver: liver tests show liver failure= hepatic
Hepatic Jaundice
Hepatocytes not working: Defective uptake Defective conjugation Defective BR excretion Liver failure, causes: Acute/Fulminant- (sudden) Acute on Chronic Viral hepatitis, EtOH (alcohol), Autoimmune disease etc. Intrahepatic cholestasis: sepsis, TPN (Total parental nutrition), Drugs
Post-hepatic/ Obstructive Jaundice
Physical obstruction reducing bile flow into duodenum, defective Transport of BR by Biliary duct system e.g. common bile duct stones, HepPancBil malignancy, local LNpathy
Look out for sepsis (cholangitis)
Dilated bile ducts on scans (swollen up just before blockage)
Jaundice genetic condition
% of population?
Inheritance?
Gilbert’s Syndrome
Up to 5% of the population
Autosomal recessive inheritance
Elevated unconjugated bilirubin in bloodstream
Cause: 70%-80% reduction in glucuronidation activity of the enzyme Uridine-diphosphate-glucuronosyltransferase isoform 1A1 (UDPGT-1A1). Mild jaundice may appear under:
exertion, stress, fasting, infections
otherwise usually asymptomatic
Acute liver failure pathophysiology
Definition?
Defined as – the rate of hepatocyte death > regeneration rate, various aetiologies and a combination of necrotic and/or apoptotic cell death.
1) Apoptotic – e.g. paracetamol – NO inflammation.
▪ Cytokines active Caspase cascade after oxidative mitochondrial damage.
2) Necrotic – e.g. ischaemia – INFLAMMATION.
▪ If mitochondria badly damaged so no ATP left.
Types of Acute Liver failure
1) Fulminant/Acute Hepatic Failure = rapid development (<8 weeks) of severe liver injury with impaired synthetic
function (such as albumin) and encephalopathy.
o Hyper-acute Hepatic Failure – 0-7 days.
o Acute hepatic failure – 8-28 days.
o Sub-acute hepatic failure – 29days-12weeks.
2) Sub-fulminant = less rapid (<6 months).
o Clinical differences:
▪ Cerebral oedema common in fulminant.
▪ Renal failure and portal hypertension common in sub-fulminant.
Acute Liver Failure (ALF) – Epidemiology and Causes
▪ Causes – commonest cause is paracetamol overdose (70% of ALF):
▪ Paracetamol – 10g+ = possible toxicity, >25g = severe toxicity.
Normal Liver function vs Consequence of Hepatocyte Failure
Normal Liver function: Detoxification Glycogen storage Production of clotting factors Immunological function and globulin production Maintainance of homeostasis
Encephalopathy and cerebral oedema Hypoglycaemia Coagulopathy and bleeding Increased susceptibility to infection Circulatory collapse, renal failure