Liver failure and Jaundice

Question 1

Reasons for producing bile

Answer 1

Cholesterol homeostasis
Dietary lipid/ vitamin absorption
Removal of xenobiotics/ drugs/ endogenous waste products e.g. cholesterol metabolites, adrenocortical, other steroid hormones

Question 2

Composition of bile

Answer 2

97% water

Alkaline

Question 3

How much bile is produced

Answer 3

500ml daily

Question 4

% of bile secreted by what?

Answer 4

60% by hepatocytes

40% by cholangiocytes (cells that line biliary tree/ cells that line canaliculi)

Question 5

Where does bile drain from liver?

Answer 5

From liver
through bile ducts
into duodenum at duodenal papilla

Question 6

Role of biliary tree

Answer 6

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

Question 7

Biliary excretion of bile salts and toxins performed by
Examples?
If mechanisms stop?

Answer 7

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

Question 8

Bile acids synthesised from

Answer 8

cholesterol

Question 9

Bile acids in humans

Answer 9

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)

Question 10

Function of bile salts

Answer 10

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

Question 11

Danger of bile salts

Answer 11

Detergent-like actions make bile salts potentially cytotoxic in high concentrations

Question 12

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?

Answer 12

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

Question 13

Enterohepatic Circulation of a drug, e.g. glucoronide

Answer 13

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

Question 14

Enterohepatic circulation of bile salts
% absorbed from ileum?
Method?
From where?
How much re-cycles?

Answer 14

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)

Question 15

Disease of enterohepatic circulation

If bile stopped from entering gut?

Answer 15

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)

Question 16

Functions of Gall Bladder

How can you see this is measurements?

Answer 16

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

Question 17

Effect of Gall bladder remova

Answer 17

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

Question 18

Bilurubin (BR) properties

Answer 18

H20 insoluble, yellow pigment

Question 19

Sources of BR

Answer 19

75% BR from Hb breakdown from RBC breakdown in spleen
22% from catabolism of other haem proteins
3% from ineffective bone marrow erythropoiesis

Question 20

Transport of BR

Answer 20

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

Question 21

Total BR=?

Answer 21

Free BR (unconjugated)+ Conjugated BR (smaller amount)

Question 22

BR metabolism+ excretion pathway

Answer 22

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

Question 23

Cholestasis

Answer 23

Slow/ cessation of bile flow

Question 24

Jaundice parameters

Normal?

Answer 24

Excess BR in blood
(>34-50 microM/L)
Normal= less than 21

Question 25

Cholestasis and Jaundice

Answer 25

Cholestasis normally results in jaundice

Jaundice does not necessarily mean there is cholestasis

Question 26

Symptoms of Jaundice

Answer 26

Whites of eyes yellow then skin yellow

Question 27

Pre-hepatic Jaundice description+ causes

Answer 27

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

Question 28

Subtypes of Jaundice

Answer 28

Prehepatic
Hepatic
Post-hepatic/ Obstructive

Question 29

Jaundice test for differentiation

Answer 29

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

Question 30

Hepatic Jaundice

Answer 30

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

Question 31

Post-hepatic/ Obstructive Jaundice

Answer 31

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)

Question 32

Jaundice genetic condition
% of population?
Inheritance?

Answer 32

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

Question 33

Acute liver failure pathophysiology

Definition?

Answer 33

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.

Question 34

Types of Acute Liver failure

Answer 34

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.

Question 35

Acute Liver Failure (ALF) – Epidemiology and Causes

Answer 35

▪ Causes – commonest cause is paracetamol overdose (70% of ALF):
▪ Paracetamol – 10g+ = possible toxicity, >25g = severe toxicity.

Question 36

Normal Liver function vs Consequence of Hepatocyte Failure

Answer 36

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