This document discusses bilirubin metabolism and jaundice. It outlines that bilirubin is produced from the breakdown of heme and is metabolized in the liver and excreted in bile and feces. Jaundice occurs when there is an increase in unconjugated bilirubin in the blood, which can be caused by increased hemolysis, liver disease, or obstruction of bile flow. Lab tests and imaging may be used to investigate the underlying cause of jaundice.
3. BILIRUBIN METABOLISM
• Bilirubin is a tetrapyrrole pigment, a result of a break down of heme
(ferroprotoporphyrin IX)
• About 250-300mg of Bilirubin is produced everyday, 70-80% of this is
from breakdown of Hb
• The remaining is from :
1. Premature destruction of erythroid cells from the bone marrow
2. Hemoprotein turnover eg myoglobin, cytochromes
The formation of bilirubin occurs in the reticuloendothelial cells,
primarily in the liver and the spleen
4. Bilirubin metabolism
1. Heme oxygenase
(a microsomal enzyme) cleaves the
alpha bridge of the porphyrin
group and opens up the heme ring
forming:
• biliverdin,
• Iron and
• Carbon monoxide
5. 2. Biliverdin reductase
(a cytosolic enzyme) reduces the
central methylene bridge of the
biliverdin and converts it to
unconjugated bilirubin which in
insoluble in water because of the
string hydrogen bonds between the
water soluble moieties of bilirubin,
propionic acid carboxyl group of
one dipyrrolic half of the molecule
with the Imino and lactam groups
of the opposite half
6. 3. Since unconjugated bilirubin is insoluble in water, it binds to Albumin
and transported into the liver where it is conjugated
7. 4. In the liver, the unconjugated bilirubin is taken up by Hepatocytes partly
by a process that involves a carrier mediated membrane transport
5. After entering the hepatocytes , it is bound to a number of cytosol
protein including glutathione-s-transferase superfamily, this prevents the
efflux back into serum and presents the bilirubin for conjugation
In the liver……
8. In the liver……
6. In the endoplasmic reticulum, bilirubin is solubilized by conjugation
with glucuronic acid which destroys the Hydrogen bonds and yields:
• Diglucuronide
• Monoglucuronide
This is catalyzed by Bilirubin Uridin Diphosphate Glucuronosly
Transferase (UDPGT)
9. Transport to the small Intestine….
7. The Diglucuronide and Monoglucuronide are then transported into
the canalicular bile by an energy dependent mechanism involving Multi
drug resistance Transporter 2
10. In the small intestine..
• The conjugated bilirubin in the canalicular bile drains the small
intestine (duodenum)
• The conjugated bilirubin remains unchanged in the proximal part of
the small intestine until it reaches the terminal ileum.
• In the terminal ileum:
1. Bilirubin is hydrolyzed by bacterial Beta glucuronidase into
unconjugated bilirubin
2. Unconjugated bilirubin is then reduced by normal gut flora to form
colorless tetrapyrroles called Urobilinogen
11. Excretion
• 80-90% is excreted in feces either
unchanged or oxidized to orange
derivates called urobilins
• 10-20% is passively absorbed,
enter the portal venous blood
and excreted by the liver
• A small fraction(less than
3mg/dl) escapes the hepatic
uptake, filters across the renal
glomerulus and excreted in urine
12. JAUNDICE
• What is Jaundice?
Is a yellow discoloration of the skin or
sclera of the eyes caused by an
increase bilirubin in the blood which
can be by:
1. Increased hemolysis
2. Liver diseases
3. Obstruction of bile outflow
16. :Caused by mutations of MDRT-2 protein
: caused by defects of storage in the liver
17.
18.
19.
20. AST:ALT more than 2 suggestive of Alcoholic hepatitis and less than 1 suggestive of viral hepatitis
AST, ALT levels more than 25 times normal are suggestive of hepatocellular injury
