 Tetrapyrrole pigment- a breakdown product of heme  About mg is produced per day primarily in R.E cells of Spleen and Liver  Sources- Breakdown of Hb in senescent R.B.C Prematurely destroyed erythroid cells Turnover of Hemoproteins Unconjugated Bilirubin is insoluble in water due to tight internal hydrogen bonding

 Hepatocellular uptake-Albumin bound unconjugated bilirubin is taken up by Hepatocytes mediated by Bilirubin transporter protein  Intracellular binding-Bilirubin is kept in solution by binding to Glutathione-S- transferases

 Bilirubin conjugation is catalysed by the enzyme UDP-glucuronosyl transferase resulting in formation of mono and diglucuronides  These molecules are highly soluble in water facilitating their excretion through bile

In distal ileum and colon hydrolysis Conj Bilirubin Unconj Bilirubin gut bact reduction Urobilinogen 80-90% 10-20% Unchanged urobilin portal blood faeces liver kidney

 Excessive production of bilirubin  Reduced hepatocyte uptake  Impaired conjugation  Decreased hepatocellular excretion  Impaired bile flow The first three mechanisms lead to unconjugated hyperbilirubinemia and the latter two produce conjugated hyper bilirubinemia

UNCONJUGATED HYPERBILIRUBINEMIA  Hemolytic disorders  Ineffective Erythropoiesis  Drugs  Inherited conditions CONJUGATED HYPERBILIRUBINEMIA  Inherited conditions

 Inherited conditions like Spherocytosis,elliptocytosis,G6PD and pyruvate kinase deficiencies  Acquired conditions like Microangiopathic hemolytic anemias,PNH,Spur cell anemia,Immune hemolysis  Excessive hemolysis Inc Bilirubin turnover Unconjugated Hyperbilirubinemia

 In Thalassemia major,Megaloblastic anemia,Porphyrias,Lead poisoning abnormal R.B.C’ are produced and are destroyed in bone marrow  Excessive unconjugated Bilirubin(70% of total ) is formed resulting in Unconjugated hyper Bilirubinemia

 Rifampicin, probenecid, ribavirin cause decreased uptake of Unconjugated Bilirubin by hepatocytes  Gentamicin, Pregnanediol, Chloramphenicol inhibit UGT 1 A 1

 Autosomal recessive  Liver incapable of synthesising Functional enzyme UGT1A1  Colorless Bile containing trace amount of unconjugated bilirubin  Serum Bilirubin can reach very high levels producing severe Jaundice and Icterus  Death within 18 months after birth is common if no Liver transplantation is done

 Autosomal dominant  Mutation in UDPGT gene causes reduced activity and affinity but not complete absence of enzyme  Capable of forming only Monoglucoronide Bilirubin  TREATMENT: Phenobarbitone-improves Bilirubin Glucuronidation by inducing hypertrophy of the hepatocellular E.R. Liver Transplantation

 Reduction in Hepatic glucuronidating activity.  In most cases two extra bases(TA) are found in TATAA element of 5’Promotor region  Reduced expression of UGT1A1  It is found in association with stress,severe exercise and fasting

 Autosomal recessive  Hereditary defect in Hepatocellular excretion of Bilirubin Glucuronide across canalicular membrane  It is due to absence of canalicular protein,Multi-drug resistance protein2.  Asymptomatic apart from chronic or recurrent Jaundice of fluctuating intensity

 Autosomal dominant  Decreased Bilirubin uptake  Decreased biliary excretion  Patients exhibit Jaundice but otherwise lead normal lives

 Almost every newborn develops transient andmild unconjugated hyperbilirubinemia  Bilirubin conjugating and excreting machinery is not fully mature until about 2 weeks of age  Breast milk contains Beta glucuronidase  Deconjugation of bilirubin glucuronide  Increases intestinal reabsorption of unconjugated bilirubin