1. Bilirubin metabolism and jaundice

2. Objectives Bilirubin metabolism and pathophysiological mechanism.
Bilirubin uptake and transport.
Jaundice condition and types.

3. Pathophysiological importance of bilirubin metabolism
It is the end product of heme degradation.
Serum bilirubin level is an important clinical marker of hepatobiliary excretory function.
Hepatic uptake, storage, conjugation and excretion of bilirubin are finely balanced. Therefore, enhancement of bilirubin throughput requires coordinated induction of multiple genes, which may be mediated by nuclear receptors.

4. Sources of bilirubin Erythroid Non-erythroid (80%) (20%) Normal:
(80%) (20%)
Normal:
Senescent erythrocytes Free heme
Abnormal:
Hemolysis: Extravascular Intravascular
Ineffective erythropoiesis
Cytochromes
Catalase
Peroxidase
Tryptophane pyrrolase
Myoglobin

5. Opening of the heme ring and Enzyme-catalyzed formation of bilirubin

6. The linear structure of bilirubin:
Two dipyrroles joined by a central methene bridge N H M V O
CH2 OH OH O C C
CH2 V
CH2 M M N N
CH2 H H O

7. Bilirubin contains several polar groups (shown in red):
Yet, it is insoluble in water. O O OH OH C C
CH2
CH2 V V M M
CH2
CH2 M M N N N N O H H
CH2 H H O

8. Conjugation with glucuronic acid
makes bilirubin water soluble

9. The internal hydrogen bonds of bilirubin are
disrupted by conjugation of the propionic acid
carboxyl group with glucuronic acid
CH2 C V M M OH
CH2 O H H O N N N N O H H
CH2 OH O
CH2 M M
CH2 V C

10. The internal hydrogen bonds of bilirubin are
disrupted by conjugation of the propionic acid
carboxyl group with glucuronic acid
CH2
-GlucA C O V M M
CH2 H H O N N N N O H H
CH2
CH2 M M
CH2 V
GlucA- O C

11. Phototherapy changes the configuration of bilirubin making it transiently water soluble

12. Bilirubin throughput: schema of a hepatocyte
Tight
junction
Liver
sinusoid
Fenestrated
endothelium
Sinusoidal
surface
Canalicular
surface

13. B alb Bilirubin circulates bound to serum albumin. Albumin- binding:
Keeps bilirubin soluble
Prevents tissue deposi- tion.
Prevents renal excretion
Drugs that displace bilirubin from albumin may precipitate kernicterus: Sulfonamides Coumadin, etc. B
alb

14. B alb Bilirubin circulates bound to serum albumin.
At the sinusoidal surface of hepatocytes, it dissociates from albumin. B
alb

15. B alb Bilirubin circulates bound to serum albumin.
At the sinusoidal surface of hepatocytes, it dissociates from albumin. B
alb

16. B alb Bilirubin circulates bound to serum albumin.
At the sinusoidal surface of hepatocytes, it dissociates from albumin.
alb B

17. B alb Bilirubin circulates bound to serum albumin.
At the sinusoidal surface of hepatocytes, it dissociates from albumin.
alb B

18. Bilirubin enters through the sinusoidal surface, probably by facilitated diffusion.
Uptake is energy independent and bidirectional.
Bilirubin uptake is reduced:
In neonates
In cirrhosis
From drug effect: novobiocin
In some cases of Gilbert syndrome B B

19. What is the mechanism of facilitated diffusion of bilirubin?
Zucker has proposed that no transporter protein is needed.
In a recent report, organic anion transport protein 2 (oatp2) has been implicated in bilirubin uptake.
However, oatp2 transports organic anions, such as BSP, it is not sufficient for bilirubin transport.

20. Inside the hepatocyte, bilirubin binds to cytosolic proteins termed ligandins, which are the same as glutathione-S transferases (GSTs).
GST binding inhibits the efflux of bilirubin, thereby increasing its net uptake
GSTs B B

21. GSTs B B

22. Conjugation of bilirubin with glucuronic acid is catalyzed by UGT1A1, which transfers glucuronic acid from UDP-glucuronic acid to bilirubin
Conjugation with glucuronic acid makes bilirubin water-soluble and non-toxic.
Glucuronidation is essential for biliary excretion of bilirubin.
GSTs
UDP
UDPGA B B B GA
UGT1A1

23. UDP-glucuronosyltransferases (UGTs)
UDPGA
UDP
Substrate
Glucuronide
UGT
UGTs are ER proteins that convert many internal and exogenous toxins to non-toxic metabolites.
UGT’s are a family of enzymes concentrated in the liver.
One UGT isoform, UGT1A1, conjugates bilirubin and is essential for its excretion.
Inherited UGT1A1 deficiency causes jaundice.

24. Jaundice:
It is a medical term describes the elevation of bilirubin in blood result in yellow color of skin and sclera.
Other symptoms include nausea, vomiting, dark- colored urine and Types of Jaundice:
fatigue.
according to the cause of jaundice
it is classified to three main types:
Pre-hepatic jaundice
Hepatic jaundice
Post-hepatic (most common type)

25. Post-hepatic jaundice
hemolytic jaundice
hepatocellular jaundice
obstructive jaundice
Post-hepatic jaundice
Hepatic jaundice
Pre-hepatic jaundice
Due to obstruction of bile duct which prevents passage of bilirubin into intestine.
D.Bil will back to liver and then to circulation elevating its level in blood and urine.
Occur in:
Biliary stricture
Cancer of the pancreas or gallbladder
Gallstones
Due to liver cell damage (cancer, cirrhosis or hepatitis)
Conjugation of bilirubin decreased (ID.Bil. ).
Blilirubin that is conjugated is not efficiently secreted into bile but leaks to blood (D.Bil. )
Occur in :
Cirrhosis (scarring of the liver)
Hepatitis
Gilbert's disease
Due to increase in RBCs breakdown due to hemolytic anemia.
The rate of RBCs lysis and bilirubin production more than ability of liver to convert it to the conjugated form
Erythroblastosis fetalis
Hemolytic anemia
Transfusion reaction
Causes
D.Bil (High)
D.Bil, ID.Bil, T.Bil all (High)
ID.Bil > D.Bil
Type of Bil.
ALP ( High)
ALT, AST (High)
K+ ( High) Hematology:
CBC (low Hb)
Conformational test

26. Thank you for
your attention!