Liver Bilirubin Metabolism Jaundice

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  • 1.Evaluation of jaundice Bilirubin metabolism - Physiology and Biochemistry Clinical evaluation adult, child, infant, and pregnant woman Post-operative jaundice 1www.medicinemcq.com

2. Bilirubin formation 80% of bilirubin Degradation of the hemoglobin 2Old or injured RBCswww.medicinemcq.com 3. Major source of bilirubin Old RBC 380%www.medicinemcq.com 4. 20% Breakdown of hemoproteins in the liver Catalase Cytochrome oxidases 4www.medicinemcq.com 5. Ineffective erythropoiesis Destruction of newly formed erythrocytes 5Bone marrow itselfNormally account for 50% of the total serum bilirubin Regurgitation of conjugated bilirubin from hepatocytes into the serumwww.medicinemcq.com 75. Physiologic Neonatal Jaundice Neonatal liver Incompletely developed at birth 75Levels of UDP-glucoronyltransferase enzymes are lowwww.medicinemcq.com 76. Most neonates Mildunconjugated hyperbilirubinemia 762 to 5 days after birthwww.medicinemcq.com 77. Physiologic Neonatal Jaundice Bilirubin level is low at birthBilirubin produced by the fetusCleared by the placenta 77Eliminated by the maternal liverJaundice at birth is pathologicalwww.medicinemcq.com 78. Peak levels < 15 mg/dL Normal serum bilirubin Within 2 weeksMay last for up to 4 weeks Premature infants Exclusively breast fed babies 78www.medicinemcq.com 79. Premature babies Liver Immaturity is more severe 79Higher levels of unconjugated hyperbilirubinemia developwww.medicinemcq.com 80. Risk for kernicterus Bilirubin >20 mg/dL Uncongugated bilirubin crosses immature blood-brain barrier 80Precipitates in the basal gangliawww.medicinemcq.com 81. Treatment 81Physiologic Jaundice usually does not need treatmentwww.medicinemcq.com 82. Phototherapy Converts bilirubin into photoisomers Soluble 82Can be excreted in bile without conjugationwww.medicinemcq.com 83. Conditions that can exaggerate physiologic Jaundice 1. 2. 3. 4. 5.83Diabetes in mother Polycythemia in infant Delayed cord clamping Cephalhematoma Intraventricular hemorrhagewww.medicinemcq.com 84. Conditions that can exaggerate physiologic Jaundice 6.7. 8. 9. 10.84Hypothyroidism (decreased UDPglucoronyl transferase activity) Congenital infections (decrease hepatic excretion of bilirubin) Hypoxia Congenital heart disease (decrease hepatic perfusion) Unfed babies (Increased enterohepatic circulation)www.medicinemcq.com 85. Jaundice at birth Pathological 85Hemolytic disease Infectionwww.medicinemcq.com 86. Breast milk jaundice Pregananediol breast milk Interfere with bilirubin conjugation Temporary interruption of breast feeding 86Jaundice in second week of life.Reduce the bilirubin levelswww.medicinemcq.com 87. Lucey-Driscoll syndrome UGT1A1 inhibitor is found in maternal serum. 87Transient familial neonatal hyperbilirubinemiawww.medicinemcq.com 88. Type I Crigler-Najjar syndrome Bilirubin UGT-1 activity is absentSevere unconjugated hyperbilirubinemia of about 20 to 45 mg/dLAppears in the neonatal period 88Persists for lifewww.medicinemcq.com 89. Crigler-Najjar Unconjugated hyperbilirubinemia Abnormal UDP-glucuronyl transferase activity Type I Type II Crigler-Najjar 89Absent (severe) < 10% (mild)www.medicinemcq.com 90. Many die of kernicterus in the neonatal period Phototherapy Liver transplantation 90Required to prevent this complication Lifesavingwww.medicinemcq.com 91. LFTs are normal Liver biopsy 91NormalNo hemolysiswww.medicinemcq.com 92. Bile is colorless Bilirubin glucuronides Markedly reduced or absent.Serum bilirubin concentration does not respond to enzyme inducers92www.medicinemcq.com 93. No bilirubin in urine 93Unconjugated bilirubin accumulates in plasmawww.medicinemcq.com 94. Phototherapy For about 12 hours daily 94From birth throughout childhoodwww.medicinemcq.com 95. Complications of phototherapy Dehydration Retinal damage 95Increased insensible water loss Result from increase in environment and body temperature. Baby should be weighed twice daily. May occur after several days Eyes should be kept coveredwww.medicinemcq.com 96. Exchange transfusion 96May be needed in the immediate neonatal periodwww.medicinemcq.com 97. Liver transplantation 97Indicated prior to the onset of brain damagewww.medicinemcq.com 98. Type II Crigler-Najjar syndrome UGT-1 activity < 10% of normal Not ill during the neonatal period May not be diagnosed until early childhood 98www.medicinemcq.com 99. Bile Deeply colored Increase in monoglucuronides 99Bilirubin glucuronides are present Characteristicwww.medicinemcq.com 100. Phenobarbital Increases UGT-1 activity Fall in serum bilirubin concentration to 2 to 5 mg/dL 100Distinguishes CN-II from CN-I.Normal life expectancieswww.medicinemcq.com 101. kernicterus 101Rare in CN 2www.medicinemcq.com 102. Transmission of Crigler-Najjar Type I RecessiveType II Predominantly recessive (Harrison) Autosomal dominant (Sleizenger) 102www.medicinemcq.com 103. Gilbert's Syndrome UGT1A1 activity 103Reduced to < 35%Defect in conjugation Defect also in bilirubin uptakewww.medicinemcq.com 104. Gilberts syndrome 104Isolated uncongugated hyperbilirubinemia (< 4 mg/dL) Benignwww.medicinemcq.com 105. Fasting Serum bilirubin rise 105Twofold to threefoldwww.medicinemcq.com 106. Phenobarbital Normalizes 106Serum bilirubin concentrationwww.medicinemcq.com 107. CPT-11 (irinotecan) Topoisomerase 1 inhibitor Useful in Colorectal cancer Uterine cancer Small cell lung cancer 107www.medicinemcq.com 108. CPT-11 (irinotecan) 108Glucuronidated by bilirubin-UDPglucuronosyltransferasewww.medicinemcq.com 109. Irinotecan in GS May cause 109Myelosuppressionwww.medicinemcq.com 110. Dubin-Johnson Syndrome MRP2 is defectiveATP-dependent canalicular membrane transporter110Defective hepatic secretion of conjugated bilirubinwww.medicinemcq.com 111. Dubin-johnson syndrome 111Autosomal recessive Conjugated hyperbilirubinemia in childhood or early adult lifewww.medicinemcq.com 112. Cardinal feature Liver is black. Accumulation of dark, melanin-like pigment Epinephrine metabolites that are not excreted normally. Substrates for MRP2 112www.medicinemcq.com 113. Liver biopsy Unnecessary Not associated with an adverse clinical outcome 113www.medicinemcq.com 114. Diagnostic of Dubin-Johnson syndrome Dubin-Johnson syndrome Two naturally occurring coproporphyrin isomers in urine 114Total coproporphyrin is normal > 80% is isomer II 25% III - 75%www.medicinemcq.com 115. Rotor syndrome Milder Dubin-johnson syndrome Conjugated hyperbilirubinemiaLiver histology Normal 115No black pigmentwww.medicinemcq.com 116. Hyperbilirubinemia Increased by Oral contraceptive use Pregnancy Intercurrent illness 116www.medicinemcq.com 117. Hyperbilirubinemia 117May be subclinical until the patient becomes pregnant or receives oral contraceptiveswww.medicinemcq.com 118. Bile acid metabolism 118Normal Do not have prurituswww.medicinemcq.com 119. Congugation abnormal 1. 2. 3.119Neonatal jaundice Crigler-najjar syndrome Gilbert syndromewww.medicinemcq.com 120. Secretion of bilirubin into bile Abnormal 120Dubin-johnson syndrome Rotor syndromewww.medicinemcq.com 121. Abnormalities - Summary Secretion into bileDubin-johnson and Rotor CongugationUDP-GT abnormal 1. 2. 3.121MRP 2 protein abnormalCrigler-najjar - congugation Gilbert congugation and uptake Neonatal jaundice - congugationwww.medicinemcq.com 122. Carotenoderma Yellow color of the skin Due to caroteneOccurs in normal persons who ingest excessive amounts of carotene Vegetables Carrots Oranges 122www.medicinemcq.com 123. Carotene Concentrated on the Palms Soles Forehead 123Carotenoderma spares the scleraewww.medicinemcq.com 124. Quinacrine 124Can cause discoloration of the scleraewww.medicinemcq.com 125. Intrahepatic cholestasis of pregnancy Third trimester. 125Presents with pruritus Jaundice infrequentResolves within 2 weeks of deliverywww.medicinemcq.com 126. Intrahepatic cholestasis of pregnancy 126Tends to recur with subsequent pregnancies Caused by an unusual sensitivity to circulating estrogenswww.medicinemcq.com 127. Acute fatty liver of pregnancy Third trimester Encephalopathy HypoglycemiaMay be fatal 127Markedly increased levels of bilirubin and ammoniaUnless delivery is promptly performedwww.medicinemcq.com 128. Preeclampsia Microvascular disorder BP> 140/90 mmHg Proteinuria >300 mg per 24 h 128www.medicinemcq.com 129. Vasospasm and endothelial injury in multiple organs 129Affects the liver in about 10 %www.medicinemcq.com 130. Roll-over test" Change the position from lateral recumbent to supine Increase in diastolic BP of 20 mmHg or more 130Due to increased sensitivity to angiotensin IIwww.medicinemcq.com 131. HELLP Severe form and requires prompt delivery Hemolysis Elevated Liver function tests Low Platelet count 131www.medicinemcq.com 132. IV labetalol Most commonly used to control blood pressure. Calcium channel blockers may also be used 132www.medicinemcq.com 133. ACE inhibitors Avoided in the second and third trimesters of pregnancy Oligohydramnios 133Decreased fetal renal functionwww.medicinemcq.com 134. Magnesium sulfate 134For eclamptic seizureswww.medicinemcq.com 135. Postoperative jaundice Predisposing factors 135Inhalational anesthetic agents Hepatotoxic drugs Impaired hepatic perfusion Blood transfusions Occult sepsiswww.medicinemcq.com 136. Benign postoperative cholestasis Self-limited