Bilirubin metabolic disordersnew.pptVIP

Bilirubin metabolic disorders Dr. Gwiria Satti Dr. Ahmed EL Tahir Dec.2009 Objectives: Formation of bilirubin List of biliruibin metabolic disorders Molecular basis of: Gilberts syndrome Crigler-Najjar syndrome Dubin-Johnson syndrome Rotor’s syndrome Questions Formation of bilirubin The hemoglobin is degraded or broken into: Globin, the protein part, Heme part. Heme initially breaks apart into: biliverdin (a green pigment) bilirubin, (an orange-yellow pigment), reduced form of Biliverdin iron (conserved for latter use) The bilirubin is then transported to the liver where it reacts with a solubilizing sugar glucuronic acid. Soluble form of bilirubin (conjugated) is excreted into the bile. Heme degradation Genetic of bilirubin metabolic disorders Several inherited chronic conditions includes: Gilbert’s syndrome Dubin-Johnson syndrome Rotor’s syndrome Crigler-Najjar syndrome The first three are usually mild, chronic conditions that can be aggravated under certain conditions, but in general cause no significant health problems. Crigler-Najjar is the most serious and may result in death.  Gilberts syndrome The most common hereditary cause of increased bilirubin. Found in up to 5% of the population. Caused by elevated levels of unconjugated bilirubin in the bloodstream hyperbilirubinemia. The source of this hyperbilirubinemia is reduced activity of the enzyme glucuronyltransferase which conjugate bilirubin and some other lipophilic molecules. Conjugation renders the bilirubin water-soluble, after which it is excreted in bile into the duodenum. Molecular basis of Gilberts syndrome The gene that expreses bilirubin-UGT is located on chromosome2 There are 5 exons. 2 to 5 are at the 3’ end are are constant components of all isoforms of the enzyme Exon1 encodes a unique region within each UGT and confers substrate specificity However multiple exon 1s (ones) at least 13 exist. To complete the gene one of these has to be recruited Expression of UGT1*1 (