HYPERBILIRUBINEMIAHYPERBILIRUBINEMIA

and itsand its

TREATMENTTREATMENT

By: Evgenia Klourfeld (By: Evgenia Klourfeld (evrblu@hotmail.com))

Candy Pletzer (pletzerc@hotmail.com)Candy Pletzer (pletzerc@hotmail.com)

Jane Lui (janelui@hotmail.com)Jane Lui (janelui@hotmail.com)

Jan. 27, 2004Jan. 27, 2004PHM 226, ExampleInstructor: Dr. Jeffrey Henderson

What is Bilirubin?What is Bilirubin?

Is a bile pigment Is lipid soluble

Is a product of heme metabolism

Heme MetabolismHeme Metabolism

Hemoglobin – 80%

Myoglobin

Cytochrome P450s

Hemoproteins

Macrophage of the reticuloendothelial system

HemeHeme

Oxygenase

BiliverdinBiliverdin Reductase

Bilirubin

Blood

O2

Fe3+ + CO

NADPH + H+

NADP+

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

The Fate of Bilirubin…The Fate of Bilirubin…

Alb = albumin B = bilirubin GST = glutathione-S-transferaseUDPGA = uridine diphosphoglucuronic acid; CB = conjugated bilirubinUGT1A1 = UDP-glucuronosyltransferase 1A1MRP2 = Multi-drug Resistance Protein 2

Adapted from Harrison’s 15th Ed. “Principles of Internal Medicine”, 2001.

MRP2

BB+ + GSTGST CBCB

Plasma Hepatic Cell Bile

AlbAlbBB

AlbAlb

?:GSTBB

sER

BB + UDPGA UGT1A1

Bilirubin ExcretionBilirubin Excretion

Intestines

Liver

BB CBCB

CBCB BBUrobilinogen

B-glucoronidase bacteria

bacteria

Bile

Enterohepatic circulation

ox Urobilin

Stercobilin

Stercobilingogen

feces

Bilirubin ExcretionBilirubin Excretion

Intestines

Liver

BB CBCB

CBCB BBUrobilinogen

B-glucoronidase bacteria

bacteria

BileEnterohepatic circulation

KidneyUrobilin

ox

Urobilinogen

Urobilin

Stercobilin

Stercobilingogen

feces

Urine

ox

HyperbilirubinemiaHyperbilirubinemia

Interferences at any one of the points of Interferences at any one of the points of bilirubin processing described above can bilirubin processing described above can lead to a condition known as lead to a condition known as HYPERBILIRUBINEMIAHYPERBILIRUBINEMIA..

As the name implies this disease is As the name implies this disease is characterized by abnormally elevated characterized by abnormally elevated levels of bilirubin in the blood.levels of bilirubin in the blood.

SYMPTOMSSYMPTOMS

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

o Detectable when total plasma bilirubin levels Detectable when total plasma bilirubin levels exceed 2mg/100mLexceed 2mg/100mL

AHHH!!! I have symptoms of hyperbilirubinemia!!!

CausesCauses::

1.1. Increased bilirubin Increased bilirubin production production

2.2. Reduced bilirubin Reduced bilirubin uptake by hepatic cellsuptake by hepatic cells

3.3. Disrupted intracellular Disrupted intracellular conjugationconjugation

4.4. Disrupted secretion of Disrupted secretion of bilirubin into bile bilirubin into bile canaliculicanaliculi

5.5. Intra/extra-hepatic bile Intra/extra-hepatic bile duct obstructionduct obstruction

Lead to increases in Lead to increases in free free (unconj.)(unconj.) bilirubinbilirubin

Result in rise in Result in rise in conj.conj. bilirubin levels bilirubin levels

1)1) INCREASED BILIRUBIN PRODUCTIONINCREASED BILIRUBIN PRODUCTION(unconj. Hyperbilirubinemia)(unconj. Hyperbilirubinemia)

HemolysisHemolysis Increased destruction of RBCs Increased destruction of RBCs

eg sickle cell anemia, thalassemiaeg sickle cell anemia, thalassemia Drastic increase in the amount of bilirubin producedDrastic increase in the amount of bilirubin produced Unconj. bilirubin levels rise due to liver’s inability to Unconj. bilirubin levels rise due to liver’s inability to

catch up to the increased rate of RBC destructioncatch up to the increased rate of RBC destruction Prolonged hemolysis may lead to precipitation of Prolonged hemolysis may lead to precipitation of

bilirubin salts in the gall bladder and biliary network bilirubin salts in the gall bladder and biliary network result in formation of gallstones and conditions such as result in formation of gallstones and conditions such as

cholecystitis and biliary obstructioncholecystitis and biliary obstruction

OtherOther Degradation of Hb originating from areas of tissue Degradation of Hb originating from areas of tissue

infarctions and hematomasinfarctions and hematomas Ineffective erythropoiesisIneffective erythropoiesis

2)2) DECREASED HEPATIC UPTAKEDECREASED HEPATIC UPTAKE(unconj. Hyperbilirubinemia)(unconj. Hyperbilirubinemia)

Several drugs have been reported to inhibit Several drugs have been reported to inhibit bilirubin uptake by the liver bilirubin uptake by the liver

e.g. novobiocin, flavopiridole.g. novobiocin, flavopiridol

Bile

MRP2

BB + GST+ GST

CBCB

Plasma Hepatic cell

AlbBB

Alb :GSTBB

sER

BB + UDPGA UGT1A1

3) DISRUPTED INTRACELLULAR 3) DISRUPTED INTRACELLULAR CONJUGATIONCONJUGATION

(unconj. Hyperbilirubinemia)(unconj. Hyperbilirubinemia)

Neonatal jaundiceNeonatal jaundice occurs in 50% of newbornsoccurs in 50% of newborns fetal bilirubin is eliminated by mother’s fetal bilirubin is eliminated by mother’s

liver liver causes:causes:

hepatic mechanisms are not fully developed resulting in hepatic mechanisms are not fully developed resulting in decreased ability to conjugate bilirubin decreased ability to conjugate bilirubin

rate of bilirubin production is increased due to shorter rate of bilirubin production is increased due to shorter lifespan of RBCslifespan of RBCs

Acquired disordersAcquired disorders hepatitis, cirrhosishepatitis, cirrhosis impaired liver functionimpaired liver function

3) DISRUPTED INTRACELLULAR CONJUGATION3) DISRUPTED INTRACELLULAR CONJUGATION (unconj. Hyperbilirubinemia)(unconj. Hyperbilirubinemia)

Crigler-Najjar Syndrome, Type I (CN-I)Crigler-Najjar Syndrome, Type I (CN-I)

recessive allele; mutation-induced loss of conjugating ability in recessive allele; mutation-induced loss of conjugating ability in the the critical enzyme glucuronosyltransferasecritical enzyme glucuronosyltransferase CN-IICN-II

greatly reduced but detectable glucuronosyltransferase greatly reduced but detectable glucuronosyltransferase activity activity due to mutation (predominantly recessive); due to mutation (predominantly recessive); enzymatic activity can be enzymatic activity can be induced by drugsinduced by drugs

Gilbert’s SyndromeGilbert’s Syndrome

glucuronosyl transferase activity reduced to 10-30% of normal; glucuronosyl transferase activity reduced to 10-30% of normal; also also accompanied by defective bilirubin uptake accompanied by defective bilirubin uptake mechanismmechanism

Bile

MRP2

BB + GST+ GST

CBCB

Plasma Hepatic cellAlb

BB

Alb :GSTBB

sER

BB + UDPGAUGT1A1

4) DISRUPTED SECRETION OF BILIRUBIN 4) DISRUPTED SECRETION OF BILIRUBIN INTO BILE CANALICULIINTO BILE CANALICULI(conj. Hyperbilirubinemia)(conj. Hyperbilirubinemia)

Dubin–Johnson SyndromeDubin–Johnson Syndrome mild conj. hyperbilirubinemia, but can increase with concurrent mild conj. hyperbilirubinemia, but can increase with concurrent

illness, pregnancy, and use of oral contraceptives; otherwise illness, pregnancy, and use of oral contraceptives; otherwise asymptomaticasymptomatic

Inability of hepatocytes to secrete CB after it has formedInability of hepatocytes to secrete CB after it has formed Due to mutation in the MRP2 gene (autosomal recessive trait)Due to mutation in the MRP2 gene (autosomal recessive trait)

Rotor SyndromeRotor Syndrome Autosomal recessive condition characterized by increased total Autosomal recessive condition characterized by increased total

bilirubin levels due to a rise in CBbilirubin levels due to a rise in CB Caused by a defect in transport of bilirubin into bile Caused by a defect in transport of bilirubin into bile Bile

MRP2

BB + GST+ GST

CBCB

Plasma Hepatic cellAlb

BB

Alb :GSTBB

sER

BB + UDPGAUGT1A1

5) Intra/extra-hepatic bile duct 5) Intra/extra-hepatic bile duct obstructionobstruction

Intra-hepaticObstruction of bile canaliculi, bile ductules or hepatic ducts

Extra-hepaticObstruction of cystic duct or common bile duct

Cholecystitis

Obstruction causes backup and reabsorption of CB which

results in increased blood levels of CB

TreatmentTreatment & Therapeutic Considerations & 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.

ADVERSE THERAPEUTIC EFFECTSADVERSE THERAPEUTIC EFFECTS

FlavopiridolFlavopiridol – can induce hyperbilirubinemia. It – can induce hyperbilirubinemia. It shares the glucuronidation pathway that is shares the glucuronidation pathway that is involved in bilirubin conjugation, effectively involved in bilirubin conjugation, effectively reducing the amount of bilirubin that can be reducing the amount of bilirubin that can be processed by the hepatic cells at any given time.processed by the hepatic cells at any given time.

NovobiocinNovobiocin – inhibits the UDP- – inhibits the UDP-glucuronosyltransferase activity, leading to glucuronosyltransferase activity, leading to hyperbilirubinemia.hyperbilirubinemia.

ValspodarValspodar – causes an increase in bilirubin levels – causes an increase in bilirubin levels by P-glycoproteins in the biliary canaliculi, thus by P-glycoproteins in the biliary canaliculi, thus interfering with bilirubin transport.interfering with bilirubin transport.

REFERENCESREFERENCES

1. Braunwald, E., Fauci, A.S., Kasper, D.L. Harrison’s 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.htm7. www.emedicine.com/med/topic1065.htm8. www.emedicine.com/med/topic1066.htm9. www.rxlist.com/cgi/generic2/clofibrate_wcp.htm#P