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HYPERBILIRUBINEMIA
and its
TREATMENT
By: Evgenia Klourfeld ([email protected])
Candy Pletzer ([email protected])
Jane Lui ([email protected])
Jan. 27, 2004
PHM 226, Example
Instructor: Dr. Jeffrey Henderson
What is Bilirubin?
Is a bile pigment
 Is lipid soluble
 Is a product of heme metabolism

Heme Metabolism
Hemoglobin – 80%
O2
Myoglobin
Cytochrome P450s
Hemoproteins
Heme
Fe3+ + CO
NADP+
NADPH + H+
Heme
Oxygenase
Biliverdin
Biliverdin
Reductase
Macrophage of the
reticuloendothelial system
Modified from Ganon, W.F. Review of Medical Physiology, (6th ed.).
Bilirubin
Blood
The Fate of Bilirubin…
Plasma
Hepatic Cell
Bile
Alb
B
?
Alb
B + GST
B :GST
B
+ UDPGA
UGT1A1
CB
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.
MRP2
Bilirubin Excretion
Liver
B
Enterohepatic
circulation
CB
Bile
B-glucoronidase
CB
bacteria
Intestines
B
bacteria
Urobilinogen
ox
Urobilin
Stercobilingogen Stercobilin
feces
Bilirubin Excretion
Liver
B
CB
Kidney
Enterohepatic
circulation
Bile
B-glucoronidase
CB
Urobilinogen
B
bacteria
bacteria
Urobilinogen
Urobilin
ox
Urine
ox
Urobilin
Stercobilingogen Stercobilin
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.
2.
3.
4.
5.
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
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 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
2)

DECREASED HEPATIC UPTAKE
(unconj. Hyperbilirubinemia)
Several drugs have been reported to inhibit bilirubin
uptake by the liver

e.g. novobiocin, flavopiridol
Hepatic cell
Plasma
Alb
Bile
B
B + GST
Alb
B :GST
B + UDPGA
CB
UGT1A1
sER
MRP2
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
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
Alb
Hepatic cell
Bile
B
B + GST
B
Alb
B :GST
CB
+ UDPGA
UGT1A1
sER
MRP2
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
Alb
Hepatic cell
Plasma
Bile
B
B + GST
B
Alb
B :GST
+ UDPGA
CB
UGT1A1
sER
MRP2
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 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 UDPglucuronosyltransferase, 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

Novobiocin – inhibits the UDP-glucuronosyltransferase

Valspodar – causes an increase in bilirubin levels by P-
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.
activity, leading to hyperbilirubinemia.
glycoproteins in the biliary canaliculi, thus interfering
with bilirubin transport.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
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.
www.aw-bc.com/mathews/ch21/bilirubi.htm
www.emedicine.com/med/topic1065.htm
www.emedicine.com/med/topic1066.htm
www.rxlist.com/cgi/generic2/clofibrate_wcp.htm#P