Liver failure and jaundice Flashcards
Is Liver failure the only cause of jaundice
No
List the functions of bile
Cholesterol homeostasis
Dietary lipid (bile salts solubilise lipids and vit A/D/E/K) / vitamin absorption
Removal of xenobiotics/ drugs/ endogenous waste products
e. g. - cholesterol metabolites - adrenocortical - other steroid hormones
Describe the composition of human bile
Water- 97% Bile salts- 0.7% Inorganic salts- 0.7% Bile pigments (Bilirubin, Bilverdin)- 0.2% Fatty acids- 0.15% Lecitihin- 0.1% Cholesterol- 0.06% Drug metabolites- higher molecular weight- ones that can't be filtered Trace metals- Fe, Zn, Mn, Pb, Cu
What other substances may be secreted into bile
Adrenocortical and other steroid hormones
Drugs/Xenobiotics- for excretion in faeces with bilirubin
Cholesterol- to fine tune serum concentrtions
Alkaline Phosphatase (ALP)
Summarise the composition of bile
Bile is 97% water and exists in an alkaline solution
How much bile is produced each day
500ml produced/secreted daily
What is the colour of bile
Green/yellow colour due to glucoronides of bile pigments
Where is bile produced
Bile is produced from 2 distinct areas:
o 60% by hepatocytes.
o 40% by Cholangiocytes (biliary epithelial cells) in the biliary tree.
Where does bile drain
Bile drains from liver, through bile ducts, into duodenum at duodenal papilla
Explain the role of the biliary tree in bile production
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
What governs bile flow
Bile flow closely related to concn of bile acids and salts in blood
Biliary excretion of bile salts and toxins performed by transporters on apical surface of hepatocytes + cholangiocytes
These biliary transporters also govern rate of bile flow
Dysfunction of the transporters is a cause of cholestasis
Pump bile acids in and out of tree changing pH, HCO3- and cl- facilitating flow of bile
What are the main transporters of the biliary tree
Bile Salt Excretory Pump (BSEP)
MDR related proteins (MRP1 & MRP3)
products of the familial intrahepatic cholestasis gene (FIC1) and multidrug resistance genes (MDR1 & MDR3).
Describe the role of BSEP
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
Describe the role of MDR1
MDR1: mediates canalicular excretion of xenobiotics, cytotoxins
Describe the role of MDR3
MDR 3: encodes a phospholipid transporter protein that translocates phosphatidylcholine from inner to outer leaflet of canalicular membrane
Describe the importance of these transporters
if they stop working (genetic mutations)- abnormal bile flow- too thick- cholestasis
What are bile salts produced from
Na and K salts of bile acids (conjugated in liver) to glycine and taurine (cysteine derivative)
Bile acids synthesised from cholesterol
Four bile acids in humans:
Describe how secondary bile acids are produced from primary bile acids
§ There are 4 bile salts in humans:
o 2 Primary Acids: 2 Secondary Acids: Cholic Acid à Deoxycholic Acid
Chenodeoxycholic Acid à Lithocholic Acid
§ The conversion of primary (formed in the liver) to secondary occurs via colonic bacteria.
Describe the functions of bile acids
Reduce surface tension of fats
Emulsify fat preparatory to its digestion/absorption
Remember bile is watery and fats are insoluble in water- bile salts envelope around them to allow them to be carried in bile
Describe bile salt 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
What is the danger of high concs of bile salts
Detergent-like actions make bile salts potentially cytotoxic in high concentrations
What is the ampulla of the bile duct controlled by
The sphincter of oddi
This is normally closed- so the bile produced from the liver is stored in the gall bladder
Describe the anatomy of the biliary tree
Each hepatocyte is apposed to several bile canaliculi
these drain into intralobular bile ducts, coalesce
interlobular ducts —– Right/Left Hepatic Ducts
join outside liver to form Common Hepatic Duct
Cystic Duct drains the gall bladder
Cystic Duct unites with Common Hepatic Duct to form COMMON BILE DUCT (CBD)
CBD joined by Pancreatic Duct prior to entering duodenal papilla
What happens in response to eating
Between meals duodenal orifice closed, therefore bile diverted into gall bladder for storage
Eating causes sphincter of Oddi to relax
Gastric contents (F.As, A.As > CHOs) enter duodenum causing release of cholecystikinin, CCK (Gut mucosal hormone)
Cholecystikinin causes gall bladder to contract and to relax sphincter of oddi
Describe the roles of the enterohepatic circulation in prolonging drug action
Liver cells transfer various substances, including drugs, from plasma to bile
Many hydrophilic drug conjugates (esp. glucoronide) are concentrated in bile – GUT
Glucoronide hydrolysed in gut — active drug released — reabsorbed- - cycle repeated
“reservoir” of re-circulating drug
can prolong action e.g. morphine
therefore we need to adjust dose- but not all the compound enters the enterohepatic circulation
Describe the enterohepatic circulation of bile salts
o 95% of bile salts reabsorbed in the terminal ileum by Na+/bile-salt co-transport. (Na+/K+ ATPase system )
§ Terminal ileum disease/resection – less resorption = more fatty stool as less bile salt excreted (liver cannot sustain production) and malabsorption of fat-soluble vitamins (A, D, E, K).
o 5% are converted to secondary bile acids in the colon by colonic bacteria:
§ Deoxycholate absorbed.
§ Lithocholate excreted in stool (99% of it).
o Reabsorbed salts go via the portal veins, back to the liver to be re-excreted in bile.
o 3g of bile salts at any one time, secreted 2x a meal.
0.2 g excreted each day
How many times is bile released a day
3g bile salt pool re-cycles repeatedly in enterohepatic circulation (2x/meal; 6 – 8x/day)
Describe the consequence of Terminal Ileal Resection/Disease
bile salt reabsorption and stool [fat] (because
decreased bile reabsorption and increased stool (fat)
enterohepatic circulation interrupted and liver can’t increase rate of bile salt production enough to make it up)
could be chron’s disease or an abscess
sometimes misdiagnosed as I.B.S
What happens if bile is stopped from entering the gut
If bile stopped from entering Gut:
Up to 50% ingested fat appears in faeces
malabsorption fat soluble vitamins (A,D,E,K)
Describe the functions of the gall bladder
Stores bile (50ml), released after meal for fat digestion
Acidifies bile
Concentrates bile by H20 diffusion following net absorption of Na+, Cl-, Ca2+, HCO3 (decreasing intra-cystic pH)
- Gall bladder can reduce volume of its stored bile by 80 – 90%
Compare hepatic duct bile to gallbladder bile
Gallbladder bile- greater percentage of solids
Greater conc of bile salts
lower pH
What are the effects of cholecystectomy
Periodic discharge of bile from GB aids digestion BUT is NOT ESSENTIAL
Normal health and nutrition exist with continuous slow bile discharge into duodenum
Avoid foods with high fat content
Summarise bilirubin conjugation
Bilirubin is derived predominantly from haemoglobin breakdown in the spleen and carried in the blood, bound to albumin.
BR-albumin in blood dissociates at the liver and free BR enters the hepatocyte and joins to P protein (intracellular binding proteins) to form bilirubin P
Bilirubin P joins to UPGDA (uridine diphospho-glucoronic acid)
this is broken down:
Glucuronyl transferase catalyses production of bilirubin diglucuronide and UDP
transported ACROSS concentration gradient into
bile canaliculi GIT
What is the total BR in the blood equal to
TOTAL BR = FREE BR (UNCONJUGATED) + CONJUGATED BR
What are urobilinogens
Urobilinogens = H2O-SOLUBLE, colourless derivatives of BR formed by action of GIT bacteria
What can happen to urobilinogens
urobilinogen is formed mainly in the intestines by bacterial action on bilirubin glucoronides . 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
Therefore some UNCONJUGATED BR enters enterohepatic circulation; and some forms urobilinogens
20% urobilinogens reabsorbed into gen.circulation urine excretn
What can urobilinogen be converted into
Some urobilinogen is reabsorbed and excreted by the kidneys in urine. Urobilinogen is also converted by bacteria in the gut to stercobilinogen . Most of the stercobilinogen is oxidized to stercobilin (responsible for the brown colour of faeces) within the gastrointestinal tract. Roughly 10% of the stercobiliogen is reabsorbed and returned to the liver via the portal circulation - enterohepatic circulation
How are urobilinogens passed in stool
Some urobilinogens passed in stool as Stercobilinogen
How much urobilinogen is reabsorbed
§ Half of urobilinogen (UBR) formed is reabsorbed –portal vein to liver – circulation– kidney – excreted.
o 50% formed is reabsorbed from the gut, 50% is excreted in stool.
§ 20% of the 50% reabsorbed into the general circulation is excreted in urine.
§ 50% of urobilinogen is passed in the stool as Stercobilinogen.
· Faeces are brown as Stercobilinogen is oxidised to stercobilin
What is cholestasis
Cholestasis: slow/cessation of bile flow
What is meant by jaundice
Jaundice: Excess BR in blood (> 34 – 50microM/L)
Normal BR <21 microM/L
(yellow tinge to skin, sclerae, mucous membranes)
Describe the relationship between cholestasis and jaundice
Cholestasis normally results in jaundice
Jaundice does not necessarily mean there is cholestasis
Describe pre-hepatic jaundice
Increased quantity of BR: Haemolysis Massive Transfusion Haematoma resorption Ineffective erythropoiesis
RBCs dying quicker than 120 days due to haemolysis (drugs, leukaemia, sepsis, infection)
BR goes up faster than downstream path can deal with
What is pre-hepatic jaundice characterised by
§ Hb drop without overt bleeding.
Haemolytic anaemias eg sickle cell disease.
↑ breakdown of red blood cells → ↑ production of bilirubin → jaundice.
Remember this is unconjugated bilirubin, which is not water soluble, therefore does not pass into the urine.
↑ serum urobilinogen but otherwise normal liver biochemistry.
Describe the investigations for pre-hepatic jaundice
Blood film: haptoglobins, LDH.
Describe intra-hepatic jaundice
Normal BR entering liver
Defective uptake
Defective conjugation
Defective BR excretion
due to disease killing hepatocytes
high unconjugated bilirubin
What can cause hepatic jaundice
Liver Failure: Acute/Fulminant- sudden- often due to paracetamol overdose Acute on Chronic Viral hepatitis, EtOH (ethanol) , Autoimmune disease etc.
Intrahepatic cholestasis:
sepsis, TPN (total parenteral nutrition- I.V nutrition), Drugs
Describe post-hepatic/obstructive jaundice
Defective Transport of BR by Biliary duct system e.g. common bile duct stones, HepPancBil malignancy, local LNpathy, cholangiocarcinoma (cancer of bile duct)
Look out for sepsis (cholangitis)
Dilated bile ducts on scans
What is post-hepatic/obstructive jaundice characterised by
§ Very usually by cholangitis.
§ Stool pale – as less stercobilin.
§ Urine dark as more BR sent to kidneys.
Predominately conjugated BR
How is post-hepatic/obstructive jaundice caused
Blockage blocks bile duct- above blockage- bile duct dilates
less enters colon and duct- less stercobilin- faeces will be pale
Describe Gilbert’s syndrome
Commonest hereditary cause of increased bilirubin
Up to 5% of the population
Autosomal recessive inheritance
Elevated unconjugated bilirubin in bloodstream
What causes Gilbert’s syndrome
Cause: 70%-80% reduction in glucuronidation activity of the enzyme Uridine-diphosphate-glucuronosyltransferase isoform 1A1 (UDPGT-1A1).
Converts bilirubin to bilirubin diglucuronide more slowly- especially under stress
When is Gilbert’s syndrome symptomatic
No serious consequences
Mild jaundice may appear under:
exertion, stress, fasting, infections
otherwise usually asymptomatic
How is Gilbert’s syndrome diagnosed
Raised unconjugated hyperbilirubin .
Otherwise normal liver biochemistry.
Normal full blood count, smear and reticulocyte count (thus excluding haemolysis)
Absence of signs of liver disease
Describe the management for Gilbert’s syndrome
Reassure the patient that no further investigation or treatment is necessary
List some other congenital abnormalities that can result in Jaundice
Crigler-Najjar, Dubin Johnson, Rotor’s syndromes are rare.
What are the investigations for obstructive jaundice
§ CT or MRCP, ultrasound etc.
MRCP = magnetic resonance cholangiopancreatography
Describe cholestatic jaundice
Cholestatic jaundice is caused by the failure of bile secretion by the liver or bile duct obstruction. This is divided into intrahepatic and extrahepatic cholestasis.
Intrahepatic cholestasis is caused by hepatocellular swelling or abnormalities at cellular lever of bile excretion.
Extrahepatic cholestasis results from the obstruction of bile flow at any point distal to the bile canaliculi.
It is important to differentiate between intrahepatic and extrahepatic cholestatic jaundice as management is quite different.
How does the liver balance the loss of bile salts
Bile salts may be recycled up to 10 times per day with loss of only 5% into the faeces. To balance the loss, the liver produces 0.1-0.5mg per day of new (primary) bile salts.
95% recycled and 5% made in pool
