2 Formation of Bilirubin from Heme Heme is degraded in RE system (esp. liver & spleen)85% from RBCs15% from turnover of immature RBCs & cytochromesHemeheme oxygenasebiliverdin (green)bilirubin (red-orange)bile pigmentsIn Blood with albuminUNCONJUGATED BILIRUBIN(or INDIRECT BILITUBIN)Salicylates & sulfonamides can displacebilirubin from albumin & so bilirubin enters CNS causing neural damage
3 Bilirubin Metabolism in the Liver Uptake of Bilirubin by hepatocytes:Bilirubin dissociates from its carrier albumin & enters hepatocytesConjugation of Bilirubin:In hepatocytes, bilirubin is conjugated with two molecules of glucuronicacid by the enzyme glucuronyl transferaseExcretion of bilirubin into bile:Conjugated bilirubin (bilirubin diglucuronide) is transported into bile canalculi& then into bile.Process is energy dependent & is impaired in liver diseases
4 Bilirubin Metabolism in the Intestine Conjugated bilirubin bacteria in the intestine Urobilinogen Stercobilin Reabsorbed in stool (brown) Kidney Urine Urobilin (yellow)
6 JAUNDICE IS NOT A DISEASE Yellow color of skin, nail beds & sclera caused by deposition of bilirubin secondary to increased bilirubin levels in blood (hyperbilirubinemia)JAUNDICE IS NOT A DISEASEHOWEVER,IT IS A SIGN OFAN UNDERLYING DISEASE
8 Hemolytic Jaundice Massive lysis of RBCs in hemolytic anemia e.g. sickle cell anemiaBilirubin is produced in a rate faster than rate ofconjugation by the liverBlood:Increased blood unconjugated (indirect) bilirubinUrine:Urobilinogen is increasedNo bilirubin in urine (Color of urine is normal)as it is bound to albuminStoolDark colorIncreased stercobilin (produced from increased urobilinogen)
9 Obstructive JaundiceIn bile duct obstruction: Conjugated bilirubin is prevented from passing to the intestine. Thus, it is regurged to blood increasing conjugated (direct) bilirubin in blood Excessive conjugated bilirubin is excreted in urine giving the yellowish brown color of urine Blood: Increased conjugated (direct) bilirubin GGT & ALP are markedly elevated (ALT is normal or mildly elevated) Urine: Bilirubin appears in urine Thus, color is yellowish brown Urobilinogen is reduced Stool Pale (low stercobilin)
10 Hepatocellular Jaundice First Liver damage (by hepatitis or hepatitis) causes low conjugation efficiency leading to increased unconjugated (indirect) bilirubin in blood Second Conjugated bilirubin is not efficiently secreted into bile. Instead, diffuses to blood increasing conjugated (direct) bilirubin in blood Blood Increased BOTH unconjugated (indirect) & conjugated (direct) bilirubin ALT & AST levels are markedly elevated Urine: Bilirubin is present in urine So, urine color is yellowish brown Stool Pale (low stercobilin)
11 LABORATORY INVESTIGATIONS IN TYPES OF JAUNDICE BLOODURINEGGT & ALPALT & ASTCONJUGATEDBILIRUBINUNCONJUGATEDUROBILINOGENNORMALN: mg/dlN: 0.2 – 1 mg/dlNILTRACEINCREASEDINCREASDHEMOLYTICJAUNDICEMARKEDINCREASENormalormild increasePRESENTDecreased or absentOBSTRUCT.HEPATOCEL. JAUNDICE
12 Jaundice in Newborns In newborns (especially premature), Bilirubin accumulates as the liver enzyme bilirubin glucuronyl transferase(responsible for conjugation of bilirubin) is low at birth. (The enzymes reachesadult levels in about 4 weeks)Accordingly, unconjugated bilirubin is increased in blood.Elevated bilirubin in excess of the binding capacity of albumin can diffuseinto basal ganglia & cause toxic encephalopathy (kernicterus)TreatmentExposure of the newborn skin to blue fluorescent light which convertsbilirubin to more polar & hence water-soluble isomersThese isomers can be excreted into bile without conjugation to glucuronicacid.
14 Congenital hyperbilirubinemia Bilirubin is elevated in blood due to inherited defects in the bilirubin metabolic pathwayCrigler-Najjar syndromeLow activity of glucoronyltransferase (conjugating enzyme)Rare Inherited l diseaseSevere hyperbilirubinemia in neonates (unconjugated bilirubin)Complicated by kernicterus & early deathGilbert`s syndromeDecreased production (expression) of glucoronyltransferaseRare autosomal dominant traitMore common menOccurs in 2-3 % of menUsually asymptomatic hyperbilirubinemiaLiver function tests are normalDubin-Johnson syndromeDefect in transfer of conjugated bilirubin into the biliary canalculiConjugated hyperbilirubinemia.