Presentation on theme: "HYPERBILIRUBINEMIA TREATMENT and its"— Presentation transcript:
1HYPERBILIRUBINEMIA TREATMENT and its By: Evgenia KlourfeldCandy PletzerJane LuiJan. 27, 2004PHM 226, ExampleInstructor: Dr. Jeffrey Henderson
2Is a product of heme metabolism What is Bilirubin?Is a bile pigmentIs lipid solubleIs a product of heme metabolism
3Macrophage of the reticuloendothelial system Heme MetabolismFe3+ + CONADP+Hemoglobin – 80%MyoglobinCytochrome P450sHemoproteinsO2NADPH + H+HemeBiliverdinBilirubinHeme OxygenaseBiliverdin ReductaseMacrophage of the reticuloendothelial systemBloodModified from Ganon, W.F. Review of Medical Physiology, (6th ed.).
4The Fate of Bilirubin… ? Alb B B B CB B + GST MRP2 :GST sER Plasma Hepatic CellBileAlbB?B+ GSTMRP2BCB+ UDPGA:GSTBUGT1A1sERAlb = albumin B = bilirubin GST = glutathione-S-transferaseUDPGA = uridine diphosphoglucuronic acid; CB = conjugated bilirubinUGT1A1 = UDP-glucuronosyltransferase 1A1MRP2 = Multi-drug Resistance Protein 2Adapted from Harrison’s 15th Ed. “Principles of Internal Medicine”, 2001.
5Bilirubin Excretion B CB B CB Liver Enterohepatic circulation Bile B-glucoronidasebacteriaBCBoxUrobilinUrobilinogenStercobilinStercobilingogenbacteriafecesIntestines
6Bilirubin Excretion B CB B CB Liver Urobilin Kidney ox Urobilinogen UrineEnterohepatic circulationBileB-glucoronidasebacteriaBCBoxUrobilinUrobilinogenStercobilinStercobilingogenbacteriaIntestinesfeces
7HyperbilirubinemiaInterferences 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.
8SYMPTOMSYellowing of the skin, scleras (white of the eye), and mucous membranes (jaundice)Detectable when total plasma bilirubin levels exceed 2mg/100mLAHHH!!! I have symptoms of hyperbilirubinemia!!!
9Causes: Increased bilirubin production Reduced bilirubin uptake by hepatic cellsDisrupted intracellular conjugationDisrupted secretion of bilirubin into bile canaliculiIntra/extra-hepatic bile duct obstructionLead to increases in free (unconj.) bilirubinResult in rise in conj. bilirubin levels
10INCREASED BILIRUBIN PRODUCTION (unconj. Hyperbilirubinemia) HemolysisIncreased destruction of RBCseg sickle cell anemia, thalassemiaDrastic increase in the amount of bilirubin producedUnconj. bilirubin levels rise due to liver’s inability to catch up to the increased rate of RBC destructionProlonged hemolysis may lead to precipitation of bilirubin salts in the gall bladder and biliary networkresult in formation of gallstones and conditions such as cholecystitis and biliary obstructionOtherDegradation of Hb originating from areas of tissue infarctions and hematomasIneffective erythropoiesis
11DECREASED HEPATIC UPTAKE (unconj. Hyperbilirubinemia) Several drugs have been reported to inhibit bilirubin uptake by the livere.g. novobiocin, flavopiridolBileMRP2B+ GSTCBPlasmaHepatic cellAlb:GSTsER+ UDPGAUGT1A1
123) DISRUPTED INTRACELLULAR CONJUGATION (unconj. Hyperbilirubinemia) Neonatal jaundiceoccurs in 50% of newbornsfetal bilirubin is eliminated by mother’s livercauses:hepatic mechanisms are not fully developed resulting in decreased ability to conjugate bilirubinrate of bilirubin production is increased due to shorter lifespan of RBCsAcquired disordershepatitis, cirrhosisimpaired liver function
133) DISRUPTED INTRACELLULAR CONJUGATION (unconj. Hyperbilirubinemia) Crigler-Najjar Syndrome, Type I (CN-I)recessive allele; mutation-induced loss of conjugating ability in the critical enzyme glucuronosyltransferaseCN-IIgreatly reduced but detectable glucuronosyltransferase activity due to mutation (predominantly recessive); enzymatic activity can be induced by drugsGilbert’s Syndromeglucuronosyl transferase activity reduced to 10-30% of normal; also accompanied by defective bilirubin uptake mechanismPlasmaHepatic cellBileAlbBB+ GSTMRP2B+ UDPGACBAlbUGT1A1:GSTBsER
144) DISRUPTED SECRETION OF BILIRUBIN INTO BILE CANALICULI (conj 4) DISRUPTED SECRETION OF BILIRUBIN INTO BILE CANALICULI (conj. Hyperbilirubinemia)Dubin–Johnson Syndromemild conj. hyperbilirubinemia, but can increase with concurrent illness, pregnancy, and use of oral contraceptives; otherwise asymptomaticInability of hepatocytes to secrete CB after it has formedDue to mutation in the MRP2 gene (autosomal recessive trait)Rotor SyndromeAutosomal recessive condition characterized by increased total bilirubin levels due to a rise in CBCaused by a defect in transport of bilirubin into bileHepatic cellBilePlasmaAlbBB+ GSTMRP2B+ UDPGACBAlbUGT1A1:GSTBsER
155) Intra/extra-hepatic bile duct obstruction Intra-hepaticObstruction of bile canaliculi, bile ductules or hepatic ductsExtra-hepaticObstruction of cystic duct or common bile ductCholecystitisObstruction causes backup and reabsorption of CB whichresults in increased blood levels of CB
16Treatment & 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.PHENOBARBITALThis 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.ALBUMINA 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.
17ADVERSE 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.
18REFERENCESBraunwald, 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.