HYPERBILIRUBINEMIA

and its

TREATMENT

By: Evgenia Klourfeld (evrblu@hotmail.com)

Candy Pletzer (pletzerc@hotmail.com)
Jane Lui (janelui@hotmail.com)
PHM 226, Example
Jan. 27, 2004 Instructor: Dr. Jeffrey Henderson
 What is Bilirubin?
Is a bile pigment
Is lipid soluble
Is a product of heme metabolism
 Heme Metabolism

Hemoglobin 80% Fe3+ + CO NADP+

O2
Myoglobin NADPH + H+

Cytochrome P450s Heme Biliverdin Bilirubin

Heme Biliverdin
Hemoproteins Oxygenase Reductase

Macrophage of the
reticuloendothelial system Blood

Modified from Ganon, W.F. Review of Medical Physiology, (6th ed.).

 The Fate of Bilirubin
Plasma Hepatic Cell Bile
Alb
B

? B + GST
MRP2
B + UDPGA CB
Alb B :GST 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 Harrisons 15th Ed. Principles of Internal Medicine, 2001.

Liver
Bilirubin Excretion
Enterohepatic
circulation
B CB

Bile

B-glucoronidase bacteria
B
CB Urobilinogen
ox Urobilin
Stercobilingogen Stercobilin
bacteria

Intestines feces
Liver
Bilirubin Excretion
Urobilin
B CB Kidney
ox
Urobilinogen
Enterohepatic Urine
Bile circulation

B-glucoronidase bacteria
B
CB Urobilinogen
ox Urobilin
Stercobilingogen Stercobilin
bacteria

Intestines

feces
 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.
 SYMPTOMS

o Yellowing of the skin, scleras (white of the eye), and

mucous membranes (jaundice)

o Detectable when total plasma bilirubin levels exceed

2mg/100mL

AHHH!!! I have symptoms

of hyperbilirubinemia!!!
Causes:
1. Increased bilirubin
production
Lead to increases in
2. Reduced bilirubin uptake
free (unconj.) bilirubin
by hepatic cells
3. Disrupted intracellular
conjugation
4. Disrupted secretion of
bilirubin into bile
canaliculi Result in rise in conj.
5. Intra/extra-hepatic bile bilirubin levels
duct obstruction
 1) 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 livers 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
 2) DECREASED HEPATIC UPTAKE
(unconj. Hyperbilirubinemia)

Several drugs have been reported to inhibit bilirubin

uptake by the liver
e.g. novobiocin, flavopiridol

Plasma Hepatic cell Bile

Alb
B

B + GST
MRP2
B + UDPGA CB

Alb B :GST UGT1A1

sER
3) DISRUPTED INTRACELLULAR CONJUGATION
(unconj. Hyperbilirubinemia)

Neonatal jaundice
occurs in 50% of newborns
fetal bilirubin is eliminated by mothers 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
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
Gilberts 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
B :GST

sER
4) DISRUPTED SECRETION OF BILIRUBIN INTO
BILE CANALICULI
(conj. Hyperbilirubinemia)
DubinJohnson 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
Plasma Hepatic cell Bile
Alb
B

B + GST
MRP2
B + UDPGA CB

Alb UGT1A1
B :GST

sER
 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

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 molecules 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.
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.
REFERENCES

1. Braunwald, E., Fauci, A.S., Kasper, D.L. Harrisons Principles of

Internal Medicine, (15th ed.). McGraw-Hill Medical Publishing
Division: New York, 2001.
2. CPS Compendium of Pharmaceuticals and Specialties, (32nd ed.).
Canadian Pharmaceutical Association: Ottawa, 1997.
3. Ganong, W.F. Review of Medical Physiology, (6th ed.). Lange
Medical Publications: Los Altos, 1973.
4. MICROMEDEX.
5. Mims, L., Gooden, D.S. Phototherapy for neonatal
hyperbilirubinemia: a dose response relationship. Phys. Med. Biol.
1974;19: 263.
6. www.aw-bc.com/mathews/ch21/bilirubi.htm
7. www.emedicine.com/med/topic1065.htm
8. www.emedicine.com/med/topic1066.htm
9. www.rxlist.com/cgi/generic2/clofibrate_wcp.htm#P