Lecture 37: Bilirubin, Jaundice and Gallstones Flashcards
Where does HEME come from?
- 80% from senescent RBCs
- 20% from heme (produced by hepatic enzymes)
From these two sources, the enzye HEME OXYGENASE in the reticuloendothelial cells breaks down heme to
i. Biliverdin
ii. CO
iii. Fe
Biliverdin is then broken down to bilirubin
What are the characteristics of unconjugated bilirubin?
Very water INSOLUBLE
Because its proprionic acid groups (polar groups) are hidden by H-bonding…weird huh?
How is unconjugated bilirubin transported?
Bound by albumin because unconjugated bilirubin is water insoluble
At the hepatocyte membrane, they are split apart
Bilirubin is then taken up by the hepatocyte
What is the Space of Disse?
The space at which the bilirubin and albumin dissociate so that bilirubin can be transported into the hepatocyte membrane
Where does unconjugated bilirubin get conjugated?
In the hepatocyte
Gets conjugated with glucuronide in the ER by UDP Glucuronosyltransferase or UDP-GTransferase
Where does bilirubin get secreted?
Into the canaliculus against its concentration gradient
Most are secreted as diglucuronide
What is the transporter in the hepatocyte that carries glucuronides (hence bilirubin) into the lumen of the canaliculus?
MRP2
What are the organic components of bile?
- bilirubin (1%)
- bile salts (66%)
- phospholipid (22%)
- cholesterol
- protein
What is the point of glucuronidation of bilirubin?
It makes bilirubin water soluble
So conjugated bilirubin is water soluble
Found in bile not blood
What are the toxic effects of unconjugated bilirubin?
Neurotoxic lipid
So it is bound to albumin and inactivated by conjugation, excretion and blood brain barrier
These protective mechanisms may be defective in newborn
What is delta bilirubin?
A CONJUGATED bilirubin that is COVALENTLY BOUND to albumin (different from unconjugated albumin that is H-bond to albumin)
Only found in patients with protracted hyperbilirubinemia
Very strongly bound together
How is bilirubin broken down?
Bacteria convert bilirubin to colorless urobilinogen
Urobilinogen is then converted into pyrroles by bacteria to give stool its color
Where can you find urobilinogen?
In urine because some of it is absorbed and passed to the urine via the serum
What is urobilinogen?
Breakdown product of bilirubin
What is icterus?
Jaundice, yellowing of the eye
What are the different types of jaundice?
- Unconjugated (“indirect”) jaundice
2. Conjugated (“direct”) jaundice
What are the characteristics of indirect jaundice?
Unconjugated hyperbilirubinemia
H-bond of albumin prevents passage into urine
What are the characteristics of conjugated jaundice?
Direct jaundice
Mixture of conjugated and unconjugated bilirubin in serum
Water soluble conjugated bilirubin passes into urine
May have some delta bilirubin
If you see bilirubin in the urine, what type of
Bilirubinemia is it?
“direct’ hyperbilirubinemia because this is the
“conjugated” hyperbilirubinemia
Only conjugated is water soluble
What causes unconjugated jaundice?
OVERPRODUCTION of bilirubin
Reduced uptake of bilirubin by liver
Defects on bilirubin conjugation
What are the types of overproduction of bilirubin?
- Hemolysis
- Extravasation into tissue (hematoma)
- Ineffective EPO
What are the types of defects of conjugation?
- Crigler Najjar types I & II
- Gilbert’s (common, benign) Gil bearrrrrsssss
- Drugs
- Wilson’s
- Hyperthyroidism
- Newborn
What are the types of reduced hepatic uptake?
- altered circulation
- drug effect
Example: RIFAMYCIN
Why are newborns prone to unconjugated bilirubinemia?
- immature transport
- immature conjugation
- hemolysis
Treated by phototherapy
