1. HYPERBILIRUBINEMIA TREATMENT and its
By: Evgenia Klourfeld
Candy Pletzer
Jane Lui
Jan. 27, 2004
PHM 226, Example
Instructor: Dr. Jeffrey Henderson

2. Is a product of heme metabolism
What is Bilirubin?
Is a bile pigment
Is lipid soluble
Is a product of heme metabolism

3. Macrophage of the reticuloendothelial system
Heme Metabolism
Fe3+ + CO
NADP+
Hemoglobin – 80%
Myoglobin
Cytochrome P450s
Hemoproteins O2
NADPH + H+
Heme
Biliverdin
Bilirubin
Heme Oxygenase
Biliverdin Reductase
Macrophage of the reticuloendothelial system
Blood
Modified from Ganon, W.F. Review of Medical Physiology, (6th ed.).

4. The Fate of Bilirubin… ? Alb B B B CB B + GST MRP2 :GST sER Plasma
Hepatic Cell
Bile
Alb B ? B
+ GST
MRP2 B CB
+ UDPGA
:GST B
UGT1A1
sER
Alb = albumin B = bilirubin GST = glutathione-S-transferase
UDPGA = uridine diphosphoglucuronic acid; CB = conjugated bilirubin
UGT1A1 = UDP-glucuronosyltransferase 1A1
MRP2 = Multi-drug Resistance Protein 2
Adapted from Harrison’s 15th Ed. “Principles of Internal Medicine”, 2001.

5. Bilirubin Excretion B CB B CB Liver Enterohepatic circulation Bile
B-glucoronidase
bacteria B CB ox
Urobilin
Urobilinogen
Stercobilin
Stercobilingogen
bacteria
feces
Intestines

6. Bilirubin Excretion B CB B CB Liver Urobilin Kidney ox Urobilinogen
Urine
Enterohepatic circulation
Bile
B-glucoronidase
bacteria B CB ox
Urobilin
Urobilinogen
Stercobilin
Stercobilingogen
bacteria
Intestines
feces

7. Hyperbilirubinemia
Interferences at any one of the points of bilirubin processing described above can lead to a condition known as HYPERBILIRUBINEMIA.
As the name implies this disease is characterized by abnormally elevated levels of bilirubin in the blood.

8. SYMPTOMS
Yellowing of the skin, scleras (white of the eye), and mucous membranes (jaundice)
Detectable when total plasma bilirubin levels exceed 2mg/100mL
AHHH!!! I have symptoms of hyperbilirubinemia!!!

9. Causes: Increased bilirubin production
Reduced bilirubin uptake by hepatic cells
Disrupted intracellular conjugation
Disrupted secretion of bilirubin into bile canaliculi
Intra/extra-hepatic bile duct obstruction
Lead to increases in free (unconj.) bilirubin
Result in rise in conj. bilirubin levels

10. INCREASED BILIRUBIN PRODUCTION (unconj. Hyperbilirubinemia)
Hemolysis
Increased destruction of RBCs
eg sickle cell anemia, thalassemia
Drastic increase in the amount of bilirubin produced
Unconj. bilirubin levels rise due to liver’s inability to catch up to the increased rate of RBC destruction
Prolonged hemolysis may lead to precipitation of bilirubin salts in the gall bladder and biliary network
result in formation of gallstones and conditions such as cholecystitis and biliary obstruction
Other
Degradation of Hb originating from areas of tissue infarctions and hematomas
Ineffective erythropoiesis

11. DECREASED HEPATIC UPTAKE (unconj. Hyperbilirubinemia)
Several drugs have been reported to inhibit bilirubin uptake by the liver
e.g. novobiocin, flavopiridol
Bile
MRP2 B
+ GST CB
Plasma
Hepatic cell
Alb
:GST
sER
+ UDPGA
UGT1A1

12. 3) DISRUPTED INTRACELLULAR CONJUGATION (unconj. Hyperbilirubinemia)
Neonatal jaundice
occurs in 50% of newborns
fetal bilirubin is eliminated by mother’s liver
causes:
hepatic mechanisms are not fully developed resulting in decreased ability to conjugate bilirubin
rate of bilirubin production is increased due to shorter lifespan of RBCs
Acquired disorders
hepatitis, cirrhosis
impaired liver function

13. 3) DISRUPTED INTRACELLULAR CONJUGATION (unconj. Hyperbilirubinemia)
Crigler-Najjar Syndrome, Type I (CN-I)
recessive allele; mutation-induced loss of conjugating ability in the critical enzyme glucuronosyltransferase
CN-II
greatly reduced but detectable glucuronosyltransferase activity due to mutation (predominantly recessive); enzymatic activity can be induced by drugs
Gilbert’s Syndrome
glucuronosyl transferase activity reduced to 10-30% of normal; also accompanied by defective bilirubin uptake mechanism
Plasma
Hepatic cell
Bile
Alb B B
+ GST
MRP2 B
+ UDPGA CB
Alb
UGT1A1
:GST B
sER

14. 4) DISRUPTED SECRETION OF BILIRUBIN INTO BILE CANALICULI (conj
4) DISRUPTED SECRETION OF BILIRUBIN INTO BILE CANALICULI (conj. Hyperbilirubinemia)
Dubin–Johnson Syndrome
mild conj. hyperbilirubinemia, but can increase with concurrent illness, pregnancy, and use of oral contraceptives; otherwise asymptomatic
Inability of hepatocytes to secrete CB after it has formed
Due to mutation in the MRP2 gene (autosomal recessive trait)
Rotor Syndrome
Autosomal recessive condition characterized by increased total bilirubin levels due to a rise in CB
Caused by a defect in transport of bilirubin into bile
Hepatic cell
Bile
Plasma
Alb B B
+ GST
MRP2 B
+ UDPGA CB
Alb
UGT1A1
:GST B
sER

15. 5) Intra/extra-hepatic bile duct obstruction
Intra-hepatic
Obstruction of bile canaliculi, bile ductules or hepatic ducts
Extra-hepatic
Obstruction of cystic duct or common bile duct
Cholecystitis
Obstruction causes backup and reabsorption of CB which
results in increased blood levels of CB

16. Treatment & Therapeutic Considerations
**PHOTOTHERAPY**
Through absorption of the wavelengths at the blue end of the spectrum (blue, green and white light), bilirubin is converted into water-soluble photoisomers. This transformation enhances the molecule’s excretion into bile without conjugation.
PHENOBARBITAL
This drug is not approved by FDA for use in neither adult nor pediatric hyperbilirubinemia patients, due to possibility of significant systemic side-effects.
Exact pathway is not known, but it is believed to act as an inducing agent on UDP-glucuronosyltransferase, thereby improving conjugation of bilirubin and its excretion.
ALBUMIN
A 25% infusion can be used in treating hyperbilirubinemia (esp. due to hemolytic disease).
It is used in conjunction with exchange transfusion to bind bilirubin, enhancing its removal.
CLOFIBRATE (ATROMID-S)
This drug has been shown to reduce bilirubin levels via an unknown mechanism.
Clofibrate is also associated with increased risk of developing cholelithiasis, cholecystitis, as well as functional liver abnormalities, which can worsen hyperbilirubinemia.
**PERCUTANEOUS TRANSHEPATIC CHOLANGIOGRAPHY**
Allows extraction of stones and thus removal of the source of obstruction when present.

17. ADVERSE THERAPEUTIC EFFECTS
Flavopiridol – can induce hyperbilirubinemia. It shares the glucuronidation pathway that is involved in bilirubin conjugation, effectively reducing the amount of bilirubin that can be processed by the hepatic cells at any given time.
Novobiocin – inhibits the UDP-glucuronosyltransferase activity, leading to hyperbilirubinemia.
Valspodar – causes an increase in bilirubin levels by P-glycoproteins in the biliary canaliculi, thus interfering with bilirubin transport.

18. REFERENCES
Braunwald, E., Fauci, A.S., Kasper, D.L. Harrison’s Principles of Internal Medicine, (15th ed.). McGraw-Hill Medical Publishing Division: New York, 2001.
CPS Compendium of Pharmaceuticals and Specialties, (32nd ed.). Canadian Pharmaceutical Association: Ottawa, 1997.
Ganong, W.F. Review of Medical Physiology, (6th ed.). Lange Medical Publications: Los Altos, 1973.
MICROMEDEX.
Mims, L., Gooden, D.S. Phototherapy for neonatal hyperbilirubinemia: a dose response relationship. Phys. Med. Biol. 1974;19: 263.