liver failure and jaundice lecture

Question 1

3 bile functions

Answer 1

cholesterol homeostasis, dietary lipid and vitamin absorption, removal of xenobiotics, drugs, endogenous waste products (e.g. cholesterol metabolites, adrenocortical, other steroid hormones)

Question 2

what does bile contain

Answer 2

bilirubin in alkaline electrolye secretion

Question 3

what is bile made and secreted by

Answer 3

most from hepatocytes, then some from cholangiocytes (biliary epithelium)

Question 4

where does bile drain

Answer 4

from liver, through bile duct into duodenum at duodenal papilla

Question 5

roles of cholangiocytes in biliary tree in modifying bile

Answer 5

alters pH, fluidity; draws H2O into bile through paracellular junctions; luminal glucose and some organic ions reabsorbed; HCO3- and Cl- actively secreted into bile by CFTR; cholangiocyte contribute IgA by exocytosis

Question 6

bile flow

Answer 6

closely related to concentration of bile acids and salts in blood; excretion of bile salts and toxins performed by transporters on apical surface of hepatocytes and cholangiocytes (transporters govern rate of flow, and dysfunction causes cholestasis)

Question 7

transporters

Answer 7

bile salt excretory pump (BSEP), MDR related proteins (MRP1 and MRP3), products of familial intrahepatic cholestasis gene (FIC1) and multidrug resistance genes (MDR1 and MDR3)

Question 8

what are bile salts

Answer 8

Na and K salts of bile acids synthesised from cholesterol

Question 9

primary bile acids

Answer 9

made in liver by hepatocytes (cholic acid, deoxycholic acid)

Question 10

what are primary bile acids converted to in gut

Answer 10

secondary bile acids (chenodeoxycholic acid, lithocholic acid)

Question 11

function of bile salts

Answer 11

reduce surface tension of fats, emulsify fat preparatory to its digestion and absorption (97% water)

Question 12

bile salts as amphipathic to from micelles

Answer 12

outer is hydrophilic, inner hydrophobic, free FA and cholesterol inside - transported to GIT epithelial cells for absorption

Question 13

bile salts at high concentrations

Answer 13

cytotoxic in high concentrations as have detergent-like actions

Question 14

hepatocytes apposed to

Answer 14

several bile canaliculi

Question 15

fate of bile

Answer 15

these drain into intralobular ducts, which coalesce into interlobular ducts; these go into right/left hepatic ducts and join outside liver to form common hepatic duct

Question 16

sphincter of oddi

Answer 16

closed between meals so when not eating bile goes down cystic duct into meals; when eating (esp. FA and amino acids), cholecystikinin (CCK) released and causes gall bladder to pump and sphincter of oddi to open, allowing bile into duodenum

Question 17

what does cystic duct drain

Answer 17

gall bladder

Question 18

what does cystic duct unite with

Answer 18

common hepatic duct to form common bile duct, which is joined by pancreatic duct prior to entering duodenal papilla

Question 19

enterohepatic circulation

Answer 19

liver to gut then reabsorbed to liver - constant cycle (not necessarily 100%)

Question 20

bile salts undergoing enterohepatic circulation

Answer 20

95% undergo enterohepatic circulation; most reabsorption from terminal ileum (if Crohn’s disease etc and not functional, bile salt reabsorption doesn’t occur and cause irritation and damage to colon (bile acid malabsorption diarrhoea) and increased fatty stool; less in circulation so ADEK vitamins malabsorbed as fat soluble so deficient)

Question 21

functions of gall bladder

Answer 21

stores, acidifies and concentrates bile (more solid, far more concentrated bile salts, lower pH vs hepatic bile duct)

Question 22

cholecystectomy (removal of gall bladder)

Answer 22

gall bladder not essential as continuous slow bile discharge into duodenum, so must avoid foods with high fat content - cause diarrhoea after

Question 23

bilirubin

Answer 23

water-insoluble, yellow pigment; most from breakdown of Hb (spleen), some from catabolism of other haem proteins, or very few from ineffective bone marrow erthropoiesis

Question 24

fate of bilirubin

Answer 24

as water insoluble, gets to liver from spleen by binding to albumin (still unconjugated); bilirubin enters liver and albumin releases; bilirubin enters hepatocyte and made soluble by conjugation with glucoronic acid (via UDPGT from smooth ER), forming diglucoronide-blirubin; total BR = unconjugated BR + conjugated BR; carried into duodenum

Question 25

urobiliogens

Answer 25

formed by gut bacteria from bilirubin (water soluble); some unconjugated enter enterohepatic circulation; some urobilinogens passed in stool by being reduced to stercobilinogen, then oxidised to stercobilin (brown - causes brown faeces); slide 29

Question 26

causes of jaundice

Answer 26

excess BR in blood (>34-50microM/L) causing yellowing of white of eyes then skin; can be caused by cholestasis (slow/cessation of bile flow)

Question 27

causes of jaundice

Answer 27

pre-hepatic, hepatic/hepaticellular, post-hepatic - depends on where in pathway occurs

Question 28

pre-hepatic jaundice

Answer 28

spleen; problem in formin/transporting bilirubin before liver (too much produced if RBCs dying quicker than 128 days - haemolysis); massive transfusion in short space of time; haematoma resorption; ineffective erythropoiesis; too high for liver to cope with; most bilirubin unconjugated

Question 29

hepatocellular jaundice

Answer 29

hepatocytes not working; defective uptake, conjugation or BR excretion; any liver disease/failure causing death of hepatocytes (acute/fulminant - sudden insult, acute on chronic, viral hepatitis, EtOH (alcohol), autoimmune disease); intrahepatic cholestasis (sepsis, TPN (IV feeding), drugs); predominantly unconjugated; distinguish from pre-hepatic by liver blood test and history

Question 30

post-hepatic jaundice (obstructive)

Answer 30

defective transport of BR by biliary duct system (e.g. bile duct stones, HepPancBil malignancy, local LNpathy); look out for sepsis (cholangitis); dilate bile ducts on scans above blockage; bilirubin is conjugated; amount of bilirubin entering gut goes down, so amount of stercobilin decreases, so faeces are less brown; body tries to reroute bile to kidneys so urine can be dark

Question 31

other cause of jaundice

Answer 31

Gilbert’s syndrome (commonest and benign)

Question 32

autosomal recessive inheritance

Answer 32

elevation in unconjugated bilirubin due to reduction in activity of UDPGT; usually asymptomatic but mild jaundice appears under exertion, stress, fasting, infections

Question 33

BSEP transporter

Answer 33

active transport of bile acids across hepatocyte canalicular membranes into bile; secretion of bile acid major detriment to bile flow

Question 34

MDR1 transporter

Answer 34

mediates canalicular excretion of xenobiotics, cytotoxins

Question 35

MDR3 transporter

Answer 35

encodes phospholipid transporter protein that translocates phophatidylcholine (phospholipids) from inner to outer leaflet of canalicular membrane