Lecture 7: Bilirubin lecture Flashcards
Where is bile generated?
In the liver
Where is bile stored?
In the gall bladder
What are the 5 components of bile?
Bicarbonate
Cholesterol
Phospholipids
Bile pigments
Bile salts
Which vessels collect bile secreted by hepatocytes?
Bile cannaliculi, which combine to form bile duct
Name the predominant bile pigment?
Bilirubin
How are bile pigments generated?
formed from the haem portion of haemoglobin (porphyrin ring) when odd or damanged erthyocytes are broken down in the spleen and liver.
What is the functional unit of the liver?
Hepatic lobule
What are the 3 parts of the portal triad?
Branches of the bile duct
Portal veins
Hepatic artery
Describe the flow of blood out of the liver?
Central vein drains the blood from each hepatic lobule.
The central veins converge creating hepatic veins.
Hepatic veins drain directly into the inferior vena cava
What are the 3 hepatic veins?
Right, left and intermediate
What is the enterohepatic circulation?
Recycled pathway from the liver to the intestine and back to the liver
How many days is an erthyrocyte lifespan?
120 days
Describe the steps of haem breakdown in the reticulo-endothelial system?
Step 1:
Haem converted to Biliverdin
Broken down by haem oxygenase
This is the point where the iron is removed
Step 2:
Biliverdin converted to unconjugated bilirubin
Broken down by biliverdin reductase
Key characteristics of bilirubin?
Hydrophobic
Cannot be transported without albumin bound
Describe what happens when the unconjugated bilirubin is bound with albumin and is transported out of the reticulo-endothelial system?
It is transported to the hepatocytes in the liver (the portal triad).
In the liver it is converted to conjugated bilirubin by UDP glucuronyl transferase (adding glucuronic acid)
Which vessel transports unconjugated bilirubin/albumin to the liver from the reticulo-endothelium system?
Portal vein
This carries the blood from the gastrointestinal tract, gallbladder, pancreas and spleen to the liver
Name these vessels?
Why does the unconjugated biliruibin be transformed into conjugated bilirubin?
Makes it hydrophilic so it can be transported out of the liver
Describe the route from conjugated bilirubin to the small bowel?
It is accumulated in bile
Bile is removed from the left and right bile ducts, which converge the become the common hepatic duct.
Bile can either be stored in the gallbladder (via cystic duct) or travels down the common bile duct.
The common bile duct converge with the pancreatic duct and becomes the hepatopancreatic ampulla.
This empties into the ilieum of the small bowel
What colour is bilirubin?
Yellow
What happens to conjugated bilirubin once it has entered the ileum of the small intestine?
Initially it is converted to unconjugated bilirubin by ß-glucoronidase
The intestinal microflora modifies the U-bilirubin into urobilinogens.The urobilinogens are not absorbed in the small intestine.
What happens to urobilinogens once it has entered the large intestines?
When they enter the large intestine, the intestinal microflora convert them into mesobilin, sterobilin and urobilin.
urobilin are absorbed into the blood stream and excreted by the kidneys i.e. in urine.
The mesobilin and sterobilin are insoluble and therefore are excreted in faeces.
What is the main two functions of bile salts?
- Act as surfactant aiding the absorption of fats and lipid-soluble vitamins e.g. vit K
- Excretion of bilirubin
Describe the structure of bile salts?
Ionically charged
Hydrophobic end
Hydrophilic end
Describe how bile salts aid the absorption of fat?
The bile salts congregate around a fat droplet
The hydrophobic side pointing towards the fat droplet
The hydrophilic side points towards the water
Thus increasing the surface area of the fat droplet for the action of triglyercide lipase
What does it mean by emulsification?
Breakdown of large lipid droplets into small uniform droplets
Describe the 3 stages of lipid metabolism with the aid of bile salts?
Stage 1:
Emulsify the fat globules in the intestines
Bile salts surround the lipid droplets aiding the lipase activity.
Fat droplets gets broken down into free fatty acids and bile salts
Stage 2:
Bile salts form micelle the free fatty acids
This allows it to be absorbed into the epithelial cell layer
Stage 3:
Absorbed free fatty acids form triglycerides and are packaged into chylomicrons for secretion in lacteals
What is the interdigestive period and what happens to the sphincter of oddi?
Period between meals
Sphincter is contracted preventing the release of bile from the hepatopancreatic ampulla.
What happens in the gallbladder during the interdigestive period?
Pressure in the common bile duct increases. Hence, the bile moves through the cystic duct into the gallbladder.
In the gallbladder, the epithelial cells reabsorbs water and electrolytes concentrating the bile
What stimulates the enteroendocrine cells to secrete cholecystokinin (CCK)?
Fatty acids and amino acids that enter the duodenum (occurs after a meal)
What does the cholecytokinin (CCK) do?
Stimulates the contraction of the smooth muscle of the gallbladder
Relaxes the Sphincter of Oddi.
Bile is released as a result
What stimulates the enteroendocrine cells to secrete secretin?
Acidic chyme in the duodenum stimulates the secretion of secretin
What does the secretin do?
Stimulates duct cells to release bicarbonate into the bile and stimulates bile production
Which cells in the liver secrete the bile salts and bile pigment?
Hepatocytes
Which cells in the liver secrete bicarbonate?
The epithelial cells lining the bile ducts
Describe the enterohepatic circulation for bile salts?
Bile salts present in the body are not enough to fully process the fats in a typical meal.
The bile salts are absorbed by sodium coupled transporters in the ileum
These absorbed bile salts are returned via the portal vein, back to the liver.
Once back in the liver, they are once again secreted into the bile.
A small amount of bile salts escape and are excreted in faeces
What percentage of bile salts are recycled in the enterohepatic circulation?
95%
the rest (5%) are lost in faeces
Define the term hyperbilirubinaemia?
Too much bilirubin in the blood
In what way is bilirubin excreted?
Mostly in faeces
A bit in the urine
A bit reabsorbed as urobilinogen
Define jaudice?
Defined as elevated levels of bilirubin (hyperbilirubinaemia)
Where are the two clinical signs of jaudice?
Yellowing of the sclera
Yellowing of the skin
What is the normal level of total bilirubin?
< 21 µmol/L
At what level of total bilirubin will jaudice be visible in the sclera
>30 µmol/L
At what level of total bilirubin will jaudice be visible in the skin
> 100 µmol/L
What are the two components of total bilirubin?
Unconjugated bilirubin
Conjugated bilirubin
What are the 3 groupings of jaudice?
- Pre-hepatic jaudice
- Hepatic jaudice
- Post-hepatic jaudice
What are the possible causes of pre-hepatic jaudice?
Trophical disease e.g. malaria, yellow fever
Sickle cell anemia or other genetics disorder
What is pre-hepatic jaudice associated with?
Associated with elevated haemolysis (breakdown of RBCs)
The liver cannot cope with the high levels of unconjugated bilirubin
What are the levels of conjugated:unconjugated bilirubin for pre-hepatic jaudice?
very high levels of unconjugated
high levels of conjugated
What are the two causes of neo-natal jaudice?
Physiological and haemolytic causes
Physiological: too high a level of fetal haemoglobin
Haemolytic; Incompatilibity between fetus and mother
What type of jaudice is neo-natal jaudice?
Pre-hepatic jaudice (i.e. too much erthryocyte breakdown)
Describe the physiological cause of neo-natal jaudice?
Common and usually harmless
After birth, newborns but destroy fetal haemoglobin and replace with adult haemoglobin
Undeveloped liver (with lack of glucuronyltransferase) is not able cope with the high haemolysis
Last approx 14 days
What is the treatment of physiological neo natal jaudice?
Treat with phototherapy- blue light
How does phototherapy work?
Blue light changes unconjugated bilirubin to a water-soluble form
This water-soluble form can be excreted
Describe the haemolytic cause of neo-natal jaudice?
rhesus incompability between mother and featus
If maternal blood is rhesus -ve, the blood can be sensitised by a previous rhesus +ve fetus or by a blood transfusion which has rhesus +ve (very rare).
Thus, when the mother has another baby who is rhesus +ve, the mother will have the antibodies and will start attacking the foetus blood
What is the treatment of haemolytic neo natal jaudice?
High dose of phototherapy and blood transfusion
What are the 3 points in the hepatic system that can go wrong to cause hepatic jaudice?
- Impaired uptake of unconjugated bilirubin
- Impaired conjugation of bilirubin
- Impaired transport of conjugated bilirubin into the bile caniculi
Define Gilberts?
Condition that results in a reduction in glycuronyl transferase activity (the enzyme that converts unconjugated bilirubin to conjugated bilirubin in the liver)
Results in hepatic jaudice
What are the 3 major causes of hepatic jaudice?
Cirrhosis (e.g. alcohol-induced)
Hepatotoxic drugs e.g. paracetamol overdose
Viral hepatitis
What are the 3 vessels that are associated in getting obstructed resulting in post-hepatic jaudice?
Hepatic veins
Cystic duct
Common bile duct
Name these vessels
Cholestasis meaning
Reduction or stoppage of bile flow
What conditions are associated with post-hepatic jaudice?
Conditions associated with obstruction of the hepatic veins, cystic duct or common bile duct.
e.g. Gallstones, pancreatitis and pancreatic tumours
Describe gallstones?
Small pebbles of cholesterol which move from the gall bladder into duct and obstruct the flow of bile (i.e. causing cholestasis).
It arises if the capacity of bile salts and phospholipids to solubilise cholesterol is exceeded
Can cause post-hepatic jaudice if bile flow is completely obstructed
Define pancreatitis?
Acute or chronic inflammation of the pancreas following infection or damage
Swelling of the pancreas can block the flow resulting in post-hepatic jaudice
What are the symptoms associated with gallstones in area 1
Gallstones in the cystic duct
Painful contractions
No jaudice and bile can still move from the liver
How does gallstones move down the bile ducts?
As the gallbladder contracts it forces the stones to move further along the bile duct
What are the symptoms associated with gallstones in area 2
Gallstones in the common bile duct
Staeorrhea
Post-hepatic jaundice
Pale stool
Dark urine
What colour would the urine and stool be for post-hepatic jaudice?
Pale stool
Dark urine
Define steaorrhea?
Fatty faeces as the fat cannot be broken down by bile salts
What are the symptoms associated with gallstones in area 3
Gallstones in the duodenal papilla, the opening of the pancreatic duct into the duodenum
Acute pancreatitis
Malnutrition- as both bile and exocrine pancreatic secretions cannot be excreted
Why are bile salts so important?
Required for efficient digestion and absorption of lipids
Required for absorption of lipid soluble vitamins
Name some of the lipid soluble vitamins that bile salts aid in absorbing?
Vitamins A, D, E and K
Vitamin K is important for coagulation
What coagulation factors is vitamin K a cofactor?
Coagulation factors 2, 7, 9 and 10
Why must vitamin K be administered to post-hepatic jaudice patients prior to surgery?
Patients who have post-hepatic jaudice are not able to absorb lipid-soluble vitamins (including Vitamin K).
Therefore, must be given Vitamin K to prevent haemorrhage during surgery
Describe the pathway for urobilinogens to be excreted in the urine?
Urobilinogens in the small intestine are absorbed by the portal vein and taken to the liver.
From the liver they go to the kidney and are excreted in urine in the urobilin form
How do we test for conjugated bilirubin?
Add diazo reagent to serum
Conjugated bilirubin is converted into a blue product
The wavelength can be measured.
NOTE: unconjugated will not react
How do we measure to total bilirubin levels?
Add diazo and caffeine
The caffeine will displace the unconjugated bilirubin from albumin.
Once displaced, both the conjugated and unconjugated bilirubin can react to the diazo and become converted to a blue product.
The wavelength is measured
Add diazo only is used to measure which bilirubin(s)?
Conjugated bilirubin only
Add diazo and caffeine to measure which bilirubin(s)?
Total bilirubin
Both conjugated and unconjugated
What is the best way to measure bile pigments in urine?
MultiStix urinalysis
Dip the stick in urine and see a colour change
The percentage of colour change depends on the percentage of amylase present
Which bilirubin(s) does the MultiStix urinalysis measure?
Conjugated bilirubin only (because this is the soluble one)
Define hyperbilirubinuria and what does this tell you?
Detection of conjugated bilirubin in the urine
Always pathological!!!
No C-bilirubin should be present in the urine
NOTE: urobilin are present normally but not C-bilirubin
What are the two key components of bile?
Bile salts
Bile pigments
Where are bile pigments generated?
Generated in the reticulo-endothelial system from haem breakdown
Is it conjugated or unconjugated bilirubin that needs to be bound to albumin?
Unconjugated
What comes first the common hepatic duct or the common bile duct?
Common hepatic (comes from the liver)
Common bile duct (the pathway for all of the bile)
What is the function of bile salts?
Emulsify lipids
Incerase pancreatic lipase activity to ensure efficient digestion and absorption of fats and fat-soluble vitamins
What is the enzyme that converts haem to biliverdin?
Haem oxygenase
What is the enzyme that converts biliverdin into unconjugated bilirubin?
Biliverdin reductase
What is the enzyme that converts U-bilirubin into C-bilirubin in the liver?
UDP glucuronyl transferase
What is the enzyme that converts C-bilirubin in the small intestine to U-bilirubin?
ß-glucornoidase
Name the 3 urobilinogens?
Stercobilinogen
Urobilinogen
Mesobilinogen
Draw the flowchart of the bilirubin metabolism
Which enzyme acts on haem to remove Fe2+ ions?
Haem oxygenase
In physiological neonatal jaundice, which enzyme is in too little quantity to cope with the increased haemolysis of fatal haemoglobin?
UDP Glucoronyltransferase
