Liver Bilirubin Metabolism Jaundice
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Liver Bilirubin Metabolism Jaundice
- 1. Evaluation of jaundice Bilirubin metabolism - Physiology and Biochemistry Clinical evaluation – adult, child, infant, and pregnant woman Post-operative jaundice 1 www.medicinemcq.com
- 2. Bilirubin formation 80% of bilirubin Degradation of the hemoglobin 2 Old or injured RBCs www.medicinemcq.com
- 3. Major source of bilirubin Old RBC 3 80% www.medicinemcq.com
- 4. 20% Breakdown of hemoproteins in the liver Catalase Cytochrome oxidases 4 www.medicinemcq.com
- 5. Ineffective erythropoiesis Destruction of newly formed erythrocytes 5 Bone marrow itself Normally account for <15% of bilirubin produced www.medicinemcq.com
- 6. Ineffective erythropoiesis Increased in 1. 2. 3. 4. 5. 6 Thalassemia major Megaloblastic anemias Congenital erythropoietic porphyria Lead poisoning Dyserythropoietic anemias www.medicinemcq.com
- 7. How much bilirubin is produced daily? 7 250 to 300 mg www.medicinemcq.com
- 8. Site of bilirubin synthesis Reticuloendothelial cells 8 Spleen Liver Bone marrow www.medicinemcq.com
- 9. Formation of bilirubin Heme Heme ----------------------→ CO + Biliverdin ( green color) + Iron oxygenase ↓ ↓ Biliverdin reductase ↓ Bilirubin (released into blood) 9 www.medicinemcq.com
- 10. Bilirubin Not soluble in water Potentially toxic 10 Made soluble by its reversible, binding to albumin www.medicinemcq.com
- 13. Bilirubin Insoluble 13 Made soluble by its reversible, binding to albumin www.medicinemcq.com
- 14. Bilirubin in plasma <2mg% 14 Tightly but reversibly bound to albumin www.medicinemcq.com
- 15. Bilirubin bound to albumin Transported to the liver Bilirubin taken up by liver cells 15 Albumin not taken by liver www.medicinemcq.com
- 16. Liver Conjugates bilirubin Water-soluble 16 Excreted into bile www.medicinemcq.com
- 17. Bilirubin uptake Bilirubin taken up across the sinusoidal (basolateral) membrane 17 Carrier-mediated mechanism www.medicinemcq.com
- 18. Conjugation in liver With glucuronic acid Bilirubin UDP-glucuronyl transferase (UGT1A1) 18 Monoglucuronide (BMG) www.medicinemcq.com
- 20. BMG Majority converted to BDG 20 Actively excreted in bile www.medicinemcq.com
- 22. Conjugated bilirubin Directed toward the canalicular (apical) membrane Transported into the bile canaliculus ATP-dependent export pump 22 Canalicular membrane protein called multidrug resistance-associated protein 2 www.medicinemcq.com
- 24. Dubin-Johnson syndrome 24 Results from mutations in MRP2 www.medicinemcq.com
- 25. BMG and BDG Transported into plasma also 25 < 5% of total serum bilirubin www.medicinemcq.com
- 27. Conjugated bilirubin 27 Not absorbed up by intestinal mucosa www.medicinemcq.com
- 28. Distal ileum and colon Conjugated bilirubin hydrolyzed to unconjugated bilirubin 28 By bacterial glucuronidases www.medicinemcq.com
- 29. Unconjugated bilirubin Reduced by normal gut bacteria 29 Colorless urobilinogen www.medicinemcq.com
- 30. Urobilinogen 85% Excreted in feces unchanged Oxidized to orange derivatives (urobilins) 15% Enterohepatic circulation Up to 20% passively absorbed 30 Enter the liver through portal venous blood Re-excreted by liver www.medicinemcq.com
- 31. Urobilinogen Small fraction escapes hepatic uptake Reaches systemic circulation < 3 mg/dL filtered by renal glomerulus 31 Excreted in urine. www.medicinemcq.com
- 32. Rate-limiting step in bilirubin metabolism 32 Hepatic excretion www.medicinemcq.com
- 33. Normal serum concentration of bilirubin 33 < 1 mg/dL www.medicinemcq.com
- 34. Normal serum concentration of bilirubin < 1 mg/dL Almost entirely unconjugated 34 When measured with sensitive techniques www.medicinemcq.com
- 35. Serum bilirubin 98 % Unconjugated 2% Conjugated bilirubin 35 Bound to albumin Water-soluble www.medicinemcq.com
- 36. Conjugated bilirubin Cleared 36 by the kidney www.medicinemcq.com
- 37. BMG and BDG in plasma Also bind reversibly to albumin When present in abnormally high concentrations for a long time BMG or BDG bind irreversibly with albumin 37 BR-albumin conjugates www.medicinemcq.com
- 38. BMG and BDG Loosely Filtered at the glomerulus 38 bound to albumin Appear in urine www.medicinemcq.com
- 39. UCB, BMG, BDG, and BR-albumin conjugates All enter the kidney via the bloodstream Only BMG and BDG appear in urine. 39 www.medicinemcq.com
- 40. How much bilirubin can be tightly bound in 100 ml of plasma? 25 mg Bilirubin in excess of this is bound only loosely Detach easily 40 Can diffuse into tissues www.medicinemcq.com
- 41. Terminal ileum and large intestine Bacterial beta-glucoronidase Remove glucoronide 41 Colorless urobilinogen form www.medicinemcq.com
- 42. Urobilinogen Oxidized in the colon to colored stercobilinogen 42 Excreted in the feces www.medicinemcq.com
- 43. Enterohepatic circulation Small amount of urobilinogen is reabsorbed Re-excreted through the liver Small amount bypass the liver and enter systemic circulation 43 Excreted in urine as urobilinogen www.medicinemcq.com
- 44. Urobilinogen in urine 44 Present normally www.medicinemcq.com
- 45. Urobilinogen Absent in urine Complete obstruction of the bile duct 45 Since no bilirubin reaches the intestine. www.medicinemcq.com
- 46. Urobilinogen in urine increased in hemolytic jaundice Due to increased production of bilirubin Bilirubin is not present in urine 46 Unconugated bilirubin does not appear in the urine www.medicinemcq.com
- 47. Unconjugated bilirubin Bound to albumin Not filtered by the normal glomerulus 47 Normally not present in urine www.medicinemcq.com
- 48. Bilirubin in the urine Always conjugated form 48 Water soluble Indicates hepatobiliary disease www.medicinemcq.com
- 49. Normal bilirubin concentration < 1.5 mg/dL Jaundice 49 Serum bilirubin > 4 mg/dL www.medicinemcq.com
- 50. Van den Bergh reaction Bilirubin cleaved by diazotized sulfanilic acid Colored azo-dipyrole formed 50 Assayed by spectrophotometry www.medicinemcq.com
- 51. Conjugated bilirubin Water soluble Reacts rapidly (“directly”) with diazo reagents 51 www.medicinemcq.com
- 52. Unconjugated bilirubin Not water soluble Reacts quite slowly with diazo reagents 52 www.medicinemcq.com
- 53. “Accelerator” compound Ethanol or urea 53 Facilitates the reaction of unconjugated bilirubin with the diazo reagent www.medicinemcq.com
- 54. Indirect bilirubin fraction Subtract direct bilirubin concentration (i.e., accelerator compound absent) from that of the total concentration (i.e., accelerator compound present) 54 www.medicinemcq.com
- 55. Direct bilirubin concentration Not equivalent to conjugated bilirubin levels Similarly, indirect bilirubin is not equivalent to unconjugated bilirubin Many laboratories 55 Now not doing direct and indirect bilirubin measurements www.medicinemcq.com
- 56. Free bilirubin 56 Same as uncongugated Free bilirubin is going to the liver from reticuloendothelial cells www.medicinemcq.com
- 57. Delta bilirubin 57 Conjugated bilirubin bound to albumin Also called biliprotein Does not appear in the urine www.medicinemcq.com
- 58. Half-life of albumin-bound bilirubin 2 58 weeks www.medicinemcq.com
- 59. Half-life Albumin = 2 to 3 weeks Delta bilirubin = 15 days Bilirubin = 4 h 59 www.medicinemcq.com
- 60. Delta bilirubin 60 Bilirubinuria may disappear before hyperbilirubinemia www.medicinemcq.com
- 61. Choluria 61 Presence of bile pigments in urine www.medicinemcq.com
- 62. Acholuric jaundice 62 Occur only in uncogugated hyperbilirubinemia www.medicinemcq.com
- 63. Unconjugated hyperbilirubinemia 63 Increased bilirubin production Hemolysis Ineffective erythropoiesis Resorption of a hematoma www.medicinemcq.com
- 64. Hemolysis Increased destruction of erythrocytes Bone marrow Unconjugated hyperbilirubinemia. Capable of only eightfold increase in erythrocyte production in response to a hemolytic stress If the liver function is normal Hyperbilirubinemia is mild 64 < 4 mg% www.medicinemcq.com
- 65. Jaundice may follow massive transfusion 65 Shortened lifespan of transfused erythrocytes www.medicinemcq.com
- 66. Major trauma Hyperbilirubinemia Resorption of hematomas Blood transfusions 66 www.medicinemcq.com
- 67. Prolonged hemolysis Bile stones Precipitation of bilirubin salts within the gall bladder or biliary tree 67 Cholecystitis Biliary obstruction www.medicinemcq.com
- 68. Physiological jaundice Most common cause of unconjugated hyperbilirubinemia Immature liver bilirubin metabolism 68 UDP-glucoronyltransferase activity reduced www.medicinemcq.com
- 69. Kernicterus Occur only with uncongugated hyperbilirubinemia 69 Only unconjugated bilirubin can cross the blood brain barrier www.medicinemcq.com
- 70. Kernicterus Unconjugated bilirubin Penetrates BBB When the plasma level exceeds that which can be tightly bound by albumin i.e., > 25 mg/dl 70 www.medicinemcq.com
- 72. Phototherapy Blue light Increases conversion of uncongugated bilirubin to maleimide fragments 72 Can be excreted into the bile www.medicinemcq.com
- 74. Conjugated hyperbilirubinemia Direct bilirubin fraction Due to defects in hepatic excretion 74 > 50% of the total serum bilirubin Regurgitation of conjugated bilirubin from hepatocytes into the serum www.medicinemcq.com
- 75. Physiologic Neonatal Jaundice Neonatal liver Incompletely developed at birth 75 Levels of UDP-glucoronyltransferase enzymes are low www.medicinemcq.com
- 76. Most neonates Mild unconjugated hyperbilirubinemia 76 2 to 5 days after birth www.medicinemcq.com
- 77. Physiologic Neonatal Jaundice Bilirubin level is low at birth Bilirubin produced by the fetus Cleared by the placenta 77 Eliminated by the maternal liver Jaundice at birth is pathological www.medicinemcq.com
- 78. Peak levels < 15 mg/dL Normal serum bilirubin Within 2 weeks May last for up to 4 weeks Premature infants Exclusively breast fed babies 78 www.medicinemcq.com
- 79. Premature babies Liver Immaturity is more severe 79 Higher levels of unconjugated hyperbilirubinemia develop www.medicinemcq.com
- 80. Risk for kernicterus Bilirubin >20 mg/dL Uncongugated bilirubin crosses immature blood-brain barrier 80 Precipitates in the basal ganglia www.medicinemcq.com
- 81. Treatment 81 Physiologic Jaundice usually does not need treatment www.medicinemcq.com
- 82. Phototherapy Converts bilirubin into photoisomers Soluble 82 Can be excreted in bile without conjugation www.medicinemcq.com
- 83. Conditions that can exaggerate physiologic Jaundice 1. 2. 3. 4. 5. 83 Diabetes in mother Polycythemia in infant Delayed cord clamping Cephalhematoma Intraventricular hemorrhage www.medicinemcq.com
- 84. Conditions that can exaggerate physiologic Jaundice 6. 7. 8. 9. 10. 84 Hypothyroidism (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 85 Hemolytic disease Infection www.medicinemcq.com
- 86. Breast milk jaundice Pregananediol breast milk Interfere with bilirubin conjugation Temporary interruption of breast feeding 86 Jaundice in second week of life. Reduce the bilirubin levels www.medicinemcq.com
- 87. Lucey-Driscoll syndrome UGT1A1 inhibitor is found in maternal serum. 87 Transient familial neonatal hyperbilirubinemia www.medicinemcq.com
- 88. Type I Crigler-Najjar syndrome Bilirubin UGT-1 activity is absent Severe unconjugated hyperbilirubinemia of about 20 to 45 mg/dL Appears in the neonatal period 88 Persists for life www.medicinemcq.com
- 89. Crigler-Najjar Unconjugated hyperbilirubinemia Abnormal UDP-glucuronyl transferase activity Type I Type II Crigler-Najjar 89 Absent (severe) < 10% (mild) www.medicinemcq.com
- 90. Many die of kernicterus in the neonatal period Phototherapy Liver transplantation 90 Required to prevent this complication Lifesaving www.medicinemcq.com
- 91. LFTs are normal Liver biopsy 91 Normal No hemolysis www.medicinemcq.com
- 92. Bile is colorless Bilirubin glucuronides Markedly reduced or absent. Serum bilirubin concentration does not respond to enzyme inducers 92 www.medicinemcq.com
- 93. No bilirubin in urine 93 Unconjugated bilirubin accumulates in plasma www.medicinemcq.com
- 94. Phototherapy For about 12 hours daily 94 From birth throughout childhood www.medicinemcq.com
- 95. Complications of phototherapy Dehydration Retinal damage 95 Increased 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 covered www.medicinemcq.com
- 96. Exchange transfusion 96 May be needed in the immediate neonatal period www.medicinemcq.com
- 97. Liver transplantation 97 Indicated prior to the onset of brain damage www.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 98 www.medicinemcq.com
- 99. Bile Deeply colored Increase in monoglucuronides 99 Bilirubin glucuronides are present Characteristic www.medicinemcq.com
- 100. Phenobarbital Increases UGT-1 activity Fall in serum bilirubin concentration to 2 to 5 mg/dL 100 Distinguishes CN-II from CN-I. Normal life expectancies www.medicinemcq.com
- 101. kernicterus 101 Rare in CN – 2 www.medicinemcq.com
- 102. Transmission of Crigler-Najjar Type I Recessive Type II Predominantly recessive (Harrison) Autosomal dominant (Sleizenger) 102 www.medicinemcq.com
- 103. Gilbert's Syndrome UGT1A1 activity 103 Reduced to < 35% Defect in conjugation Defect also in bilirubin uptake www.medicinemcq.com
- 104. Gilbert’s syndrome 104 Isolated uncongugated hyperbilirubinemia (< 4 mg/dL) Benign www.medicinemcq.com
- 105. Fasting Serum bilirubin rise 105 Twofold to threefold www.medicinemcq.com
- 107. CPT-11 (irinotecan) Topoisomerase 1 inhibitor Useful in Colorectal cancer Uterine cancer Small cell lung cancer 107 www.medicinemcq.com
- 108. CPT-11 (irinotecan) 108 Glucuronidated by bilirubin-UDPglucuronosyltransferase www.medicinemcq.com
- 109. Irinotecan in GS May cause 109 Myelosuppression www.medicinemcq.com
- 110. Dubin-Johnson Syndrome MRP2 is defective ATP-dependent canalicular membrane transporter 110 Defective hepatic secretion of conjugated bilirubin www.medicinemcq.com
- 111. Dubin-johnson syndrome 111 Autosomal recessive Conjugated hyperbilirubinemia in childhood or early adult life www.medicinemcq.com
- 112. Cardinal feature Liver is black. Accumulation of dark, melanin-like pigment Epinephrine metabolites that are not excreted normally. Substrates for MRP2 112 www.medicinemcq.com
- 113. Liver biopsy Unnecessary Not associated with an adverse clinical outcome 113 www.medicinemcq.com
- 114. Diagnostic of Dubin-Johnson syndrome Dubin-Johnson syndrome Two naturally occurring coproporphyrin isomers in urine 114 Total coproporphyrin is normal > 80% is isomer I I – 25% III - 75% www.medicinemcq.com
- 115. Rotor syndrome Milder Dubin-johnson syndrome Conjugated hyperbilirubinemia Liver histology Normal 115 No black pigment www.medicinemcq.com
- 116. Hyperbilirubinemia Increased by Oral contraceptive use Pregnancy Intercurrent illness 116 www.medicinemcq.com
- 117. Hyperbilirubinemia 117 May be subclinical until the patient becomes pregnant or receives oral contraceptives www.medicinemcq.com
- 118. Bile acid metabolism 118 Normal Do not have pruritus www.medicinemcq.com
- 119. Congugation abnormal 1. 2. 3. 119 Neonatal jaundice Crigler-najjar syndrome Gilbert syndrome www.medicinemcq.com
- 120. Secretion of bilirubin into bile Abnormal 120 Dubin-johnson syndrome Rotor syndrome www.medicinemcq.com
- 121. Abnormalities - Summary Secretion into bile Dubin-johnson and Rotor Congugation UDP-GT abnormal 1. 2. 3. 121 MRP 2 protein abnormal Crigler-najjar - congugation Gilbert – congugation and uptake Neonatal jaundice - congugation www.medicinemcq.com
- 122. Carotenoderma Yellow color of the skin Due to carotene Occurs in normal persons who ingest excessive amounts of carotene Vegetables Carrots Oranges 122 www.medicinemcq.com
- 123. Carotene Concentrated on the Palms Soles Forehead 123 Carotenoderma spares the sclerae www.medicinemcq.com
- 124. Quinacrine 124 Can cause discoloration of the sclerae www.medicinemcq.com
- 125. Intrahepatic cholestasis of pregnancy Third trimester. 125 Presents with pruritus Jaundice infrequent Resolves within 2 weeks of delivery www.medicinemcq.com
- 126. Intrahepatic cholestasis of pregnancy 126 Tends to recur with subsequent pregnancies Caused by an unusual sensitivity to circulating estrogens www.medicinemcq.com
- 127. Acute fatty liver of pregnancy Third trimester Encephalopathy Hypoglycemia May be fatal 127 Markedly increased levels of bilirubin and ammonia Unless delivery is promptly performed www.medicinemcq.com
- 128. Preeclampsia Microvascular disorder BP> 140/90 mmHg Proteinuria >300 mg per 24 h 128 www.medicinemcq.com
- 129. Vasospasm and endothelial injury in multiple organs 129 Affects 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 130 Due to increased sensitivity to angiotensin II www.medicinemcq.com
- 131. HELLP Severe form and requires prompt delivery Hemolysis Elevated Liver function tests Low Platelet count 131 www.medicinemcq.com
- 132. IV labetalol Most commonly used to control blood pressure. Calcium channel blockers may also be used 132 www.medicinemcq.com
- 133. ACE inhibitors Avoided in the second and third trimesters of pregnancy Oligohydramnios 133 Decreased fetal renal function www.medicinemcq.com
- 134. Magnesium sulfate 134 For eclamptic seizures www.medicinemcq.com
- 135. Postoperative jaundice Predisposing factors 135 Inhalational anesthetic agents Hepatotoxic drugs Impaired hepatic perfusion Blood transfusions Occult sepsis www.medicinemcq.com
- 136. Benign postoperative cholestasis Self-limited <2 weeks Transient hyperbilirubinemia Normal LFT 136 www.medicinemcq.com