HYPERBILIRUBINEMIA TREATMENT and its By: Evgenia Klourfeld (evrblu@hotmail.com) Candy Pletzer (pletzerc@hotmail.com) Jane Lui (janelui@hotmail.com) Jan. 27, 2004 PHM 226, Example Instructor: Dr. Jeffrey Henderson

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

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.).

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.

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

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

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 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!!!

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

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

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

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 Hepatic cell Bile Alb B B + GST MRP2 B + UDPGA CB Alb UGT1A1 :GST B sER

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

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 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 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