Liver Bilirubin Metabolism Jaundice

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Liver Bilirubin Metabolism Jaundice

  1. 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. 2. Bilirubin formation  80% of bilirubin  Degradation of the hemoglobin  2 Old or injured RBCs www.medicinemcq.com
  3. 3. Major source of bilirubin Old RBC   3 80% www.medicinemcq.com
  4. 4. 20%  Breakdown of hemoproteins in the liver Catalase  Cytochrome oxidases  4 www.medicinemcq.com
  5. 5. Ineffective erythropoiesis  Destruction of newly formed erythrocytes   5 Bone marrow itself Normally account for <15% of bilirubin produced www.medicinemcq.com
  6. 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. 7. How much bilirubin is produced daily?  7 250 to 300 mg www.medicinemcq.com
  8. 8. Site of bilirubin synthesis Reticuloendothelial cells     8 Spleen Liver Bone marrow www.medicinemcq.com
  9. 9. Formation of bilirubin Heme Heme ----------------------→ CO + Biliverdin ( green color) + Iron oxygenase ↓ ↓ Biliverdin reductase ↓ Bilirubin (released into blood) 9 www.medicinemcq.com
  10. 10. Bilirubin Not soluble in water  Potentially toxic   10 Made soluble by its reversible, binding to albumin www.medicinemcq.com
  11. 11. www.medicinemcq.com 11
  12. 12. www.medicinemcq.com 12
  13. 13. Bilirubin Insoluble   13 Made soluble by its reversible, binding to albumin www.medicinemcq.com
  14. 14. Bilirubin in plasma  <2mg%  14 Tightly but reversibly bound to albumin www.medicinemcq.com
  15. 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. 16. Liver  Conjugates bilirubin  Water-soluble  16 Excreted into bile www.medicinemcq.com
  17. 17. Bilirubin uptake  Bilirubin taken up across the sinusoidal (basolateral) membrane  17 Carrier-mediated mechanism www.medicinemcq.com
  18. 18. Conjugation in liver  With glucuronic acid  Bilirubin UDP-glucuronyl transferase (UGT1A1)  18 Monoglucuronide (BMG) www.medicinemcq.com
  19. 19. Glucoronyltransferase  19 Induced by phenobarbitone www.medicinemcq.com
  20. 20. BMG  Majority converted to BDG  20 Actively excreted in bile www.medicinemcq.com
  21. 21. Bilirubin in bile 85%   15%   21 Diglucuronides Monoglucuronide www.medicinemcq.com
  22. 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
  23. 23. www.medicinemcq.com 23
  24. 24. Dubin-Johnson syndrome  24 Results from mutations in MRP2 www.medicinemcq.com
  25. 25. BMG and BDG  Transported into plasma also  25 < 5% of total serum bilirubin www.medicinemcq.com
  26. 26. www.medicinemcq.com 26
  27. 27. Conjugated bilirubin  27 Not absorbed up by intestinal mucosa www.medicinemcq.com
  28. 28. Distal ileum and colon Conjugated bilirubin hydrolyzed to unconjugated bilirubin   28 By bacterial glucuronidases www.medicinemcq.com
  29. 29. Unconjugated bilirubin  Reduced by normal gut bacteria  29 Colorless urobilinogen www.medicinemcq.com
  30. 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. 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. 32. Rate-limiting step in bilirubin metabolism  32 Hepatic excretion www.medicinemcq.com
  33. 33. Normal serum concentration of bilirubin  33 < 1 mg/dL www.medicinemcq.com
  34. 34. Normal serum concentration of bilirubin  < 1 mg/dL  Almost entirely unconjugated  34 When measured with sensitive techniques www.medicinemcq.com
  35. 35. Serum bilirubin  98 %  Unconjugated   2%  Conjugated bilirubin  35 Bound to albumin Water-soluble www.medicinemcq.com
  36. 36. Conjugated bilirubin  Cleared 36 by the kidney www.medicinemcq.com
  37. 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. 38. BMG and BDG  Loosely  Filtered at the glomerulus  38 bound to albumin Appear in urine www.medicinemcq.com
  39. 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. 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. 41. Terminal ileum and large intestine  Bacterial beta-glucoronidase  Remove glucoronide  41 Colorless urobilinogen form www.medicinemcq.com
  42. 42. Urobilinogen  Oxidized in the colon to colored stercobilinogen  42 Excreted in the feces www.medicinemcq.com
  43. 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. 44. Urobilinogen in urine  44 Present normally www.medicinemcq.com
  45. 45. Urobilinogen  Absent in urine  Complete obstruction of the bile duct  45 Since no bilirubin reaches the intestine. www.medicinemcq.com
  46. 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. 47. Unconjugated bilirubin  Bound to albumin  Not filtered by the normal glomerulus  47 Normally not present in urine www.medicinemcq.com
  48. 48. Bilirubin in the urine  Always conjugated form   48 Water soluble Indicates hepatobiliary disease www.medicinemcq.com
  49. 49. Normal bilirubin concentration < 1.5 mg/dL  Jaundice  49 Serum bilirubin > 4 mg/dL www.medicinemcq.com
  50. 50. Van den Bergh reaction  Bilirubin cleaved by diazotized sulfanilic acid  Colored azo-dipyrole formed  50 Assayed by spectrophotometry www.medicinemcq.com
  51. 51. Conjugated bilirubin Water soluble  Reacts rapidly (“directly”) with diazo reagents  51 www.medicinemcq.com
  52. 52. Unconjugated bilirubin Not water soluble  Reacts quite slowly with diazo reagents  52 www.medicinemcq.com
  53. 53. “Accelerator” compound  Ethanol or urea  53 Facilitates the reaction of unconjugated bilirubin with the diazo reagent www.medicinemcq.com
  54. 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. 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. 56. Free bilirubin   56 Same as uncongugated Free bilirubin is going to the liver from reticuloendothelial cells www.medicinemcq.com
  57. 57. Delta bilirubin    57 Conjugated bilirubin bound to albumin Also called biliprotein Does not appear in the urine www.medicinemcq.com
  58. 58. Half-life of albumin-bound bilirubin 2 58 weeks www.medicinemcq.com
  59. 59. Half-life Albumin = 2 to 3 weeks  Delta bilirubin = 15 days  Bilirubin = 4 h  59 www.medicinemcq.com
  60. 60. Delta bilirubin  60 Bilirubinuria may disappear before hyperbilirubinemia www.medicinemcq.com
  61. 61. Choluria  61 Presence of bile pigments in urine www.medicinemcq.com
  62. 62. Acholuric jaundice  62 Occur only in uncogugated hyperbilirubinemia www.medicinemcq.com
  63. 63. Unconjugated hyperbilirubinemia  63 Increased bilirubin production  Hemolysis  Ineffective erythropoiesis  Resorption of a hematoma www.medicinemcq.com
  64. 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. 65. Jaundice may follow massive transfusion  65 Shortened lifespan of transfused erythrocytes www.medicinemcq.com
  66. 66. Major trauma  Hyperbilirubinemia Resorption of hematomas  Blood transfusions  66 www.medicinemcq.com
  67. 67. Prolonged hemolysis Bile stones  Precipitation of bilirubin salts within the gall bladder or biliary tree    67 Cholecystitis Biliary obstruction www.medicinemcq.com
  68. 68. Physiological jaundice Most common cause of unconjugated hyperbilirubinemia  Immature liver bilirubin metabolism   68 UDP-glucoronyltransferase activity reduced www.medicinemcq.com
  69. 69. Kernicterus Occur only with uncongugated hyperbilirubinemia   69 Only unconjugated bilirubin can cross the blood brain barrier www.medicinemcq.com
  70. 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
  71. 71. www.medicinemcq.com 71
  72. 72. Phototherapy  Blue light  Increases conversion of uncongugated bilirubin to maleimide fragments  72 Can be excreted into the bile www.medicinemcq.com
  73. 73. www.medicinemcq.com 73
  74. 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. 75. Physiologic Neonatal Jaundice  Neonatal liver  Incompletely developed at birth  75 Levels of UDP-glucoronyltransferase enzymes are low www.medicinemcq.com
  76. 76. Most neonates  Mild unconjugated hyperbilirubinemia  76 2 to 5 days after birth www.medicinemcq.com
  77. 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. 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. 79. Premature babies  Liver  Immaturity is more severe  79 Higher levels of unconjugated hyperbilirubinemia develop www.medicinemcq.com
  80. 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. 81. Treatment  81 Physiologic Jaundice usually does not need treatment www.medicinemcq.com
  82. 82. Phototherapy  Converts bilirubin into photoisomers  Soluble  82 Can be excreted in bile without conjugation www.medicinemcq.com
  83. 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. 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. 85. Jaundice at birth Pathological    85 Hemolytic disease Infection www.medicinemcq.com
  86. 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. 87. Lucey-Driscoll syndrome  UGT1A1 inhibitor is found in maternal serum.  87 Transient familial neonatal hyperbilirubinemia www.medicinemcq.com
  88. 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. 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. 90. Many die of kernicterus in the neonatal period  Phototherapy   Liver transplantation  90 Required to prevent this complication Lifesaving www.medicinemcq.com
  91. 91. LFTs are normal Liver biopsy    91 Normal No hemolysis www.medicinemcq.com
  92. 92. Bile is colorless Bilirubin glucuronides   Markedly reduced or absent.  Serum bilirubin concentration does not respond to enzyme inducers 92 www.medicinemcq.com
  93. 93. No bilirubin in urine  93 Unconjugated bilirubin accumulates in plasma www.medicinemcq.com
  94. 94. Phototherapy For about 12 hours daily   94 From birth throughout childhood www.medicinemcq.com
  95. 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. 96. Exchange transfusion  96 May be needed in the immediate neonatal period www.medicinemcq.com
  97. 97. Liver transplantation  97 Indicated prior to the onset of brain damage www.medicinemcq.com
  98. 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. 99. Bile  Deeply colored   Increase in monoglucuronides  99 Bilirubin glucuronides are present Characteristic www.medicinemcq.com
  100. 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. 101. kernicterus  101 Rare in CN – 2 www.medicinemcq.com
  102. 102. Transmission of Crigler-Najjar  Type I   Recessive Type II Predominantly recessive (Harrison)  Autosomal dominant (Sleizenger)  102 www.medicinemcq.com
  103. 103. Gilbert's Syndrome  UGT1A1 activity    103 Reduced to < 35% Defect in conjugation Defect also in bilirubin uptake www.medicinemcq.com
  104. 104. Gilbert’s syndrome   104 Isolated uncongugated hyperbilirubinemia (< 4 mg/dL) Benign www.medicinemcq.com
  105. 105. Fasting Serum bilirubin rise   105 Twofold to threefold www.medicinemcq.com
  106. 106. Phenobarbital  Normalizes  106 Serum bilirubin concentration www.medicinemcq.com
  107. 107. CPT-11 (irinotecan) Topoisomerase 1 inhibitor  Useful in  Colorectal cancer  Uterine cancer  Small cell lung cancer  107 www.medicinemcq.com
  108. 108. CPT-11 (irinotecan)  108 Glucuronidated by bilirubin-UDPglucuronosyltransferase www.medicinemcq.com
  109. 109. Irinotecan in GS  May cause  109 Myelosuppression www.medicinemcq.com
  110. 110. Dubin-Johnson Syndrome MRP2 is defective  ATP-dependent canalicular membrane transporter   110 Defective hepatic secretion of conjugated bilirubin www.medicinemcq.com
  111. 111. Dubin-johnson syndrome   111 Autosomal recessive Conjugated hyperbilirubinemia in childhood or early adult life www.medicinemcq.com
  112. 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. 113. Liver biopsy Unnecessary  Not associated with an adverse clinical outcome  113 www.medicinemcq.com
  114. 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. 115. Rotor syndrome  Milder Dubin-johnson syndrome   Conjugated hyperbilirubinemia Liver histology  Normal  115 No black pigment www.medicinemcq.com
  116. 116. Hyperbilirubinemia  Increased by Oral contraceptive use  Pregnancy  Intercurrent illness  116 www.medicinemcq.com
  117. 117. Hyperbilirubinemia  117 May be subclinical until the patient becomes pregnant or receives oral contraceptives www.medicinemcq.com
  118. 118. Bile acid metabolism   118 Normal Do not have pruritus www.medicinemcq.com
  119. 119. Congugation abnormal 1. 2. 3. 119 Neonatal jaundice Crigler-najjar syndrome Gilbert syndrome www.medicinemcq.com
  120. 120. Secretion of bilirubin into bile Abnormal    120 Dubin-johnson syndrome Rotor syndrome www.medicinemcq.com
  121. 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. 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. 123. Carotene  Concentrated on the Palms  Soles  Forehead   123 Carotenoderma spares the sclerae www.medicinemcq.com
  124. 124. Quinacrine  124 Can cause discoloration of the sclerae www.medicinemcq.com
  125. 125. Intrahepatic cholestasis of pregnancy  Third trimester.    125 Presents with pruritus Jaundice infrequent Resolves within 2 weeks of delivery www.medicinemcq.com
  126. 126. Intrahepatic cholestasis of pregnancy   126 Tends to recur with subsequent pregnancies Caused by an unusual sensitivity to circulating estrogens www.medicinemcq.com
  127. 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. 128. Preeclampsia  Microvascular disorder BP> 140/90 mmHg  Proteinuria >300 mg per 24 h  128 www.medicinemcq.com
  129. 129. Vasospasm and endothelial injury in multiple organs  129 Affects the liver in about 10 % www.medicinemcq.com
  130. 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. 131. HELLP  Severe form and requires prompt delivery Hemolysis  Elevated Liver function tests  Low Platelet count  131 www.medicinemcq.com
  132. 132. IV labetalol Most commonly used to control blood pressure.  Calcium channel blockers may also be used  132 www.medicinemcq.com
  133. 133. ACE inhibitors  Avoided in the second and third trimesters of pregnancy  Oligohydramnios  133 Decreased fetal renal function www.medicinemcq.com
  134. 134. Magnesium sulfate  134 For eclamptic seizures www.medicinemcq.com
  135. 135. Postoperative jaundice  Predisposing factors      135 Inhalational anesthetic agents Hepatotoxic drugs Impaired hepatic perfusion Blood transfusions Occult sepsis www.medicinemcq.com
  136. 136. Benign postoperative cholestasis  Self-limited  <2 weeks Transient hyperbilirubinemia  Normal LFT  136 www.medicinemcq.com

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