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Bilirubin and Jaundice

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Bilirubin and Jaundice Bilirubin and Jaundice Pathways of Bilirubin Synthesis and Catabolism Bone Reticuloendothelial Marrow RBCs System (RES) Hgb Hgb Fe Globin Heme Precursors Myoglobin Globin Biliverdin + Non-Hgb Heme Heme Proteins Bilirubin Fe + Porphogens Shunt Free Bilirubin – Albumin Complex Pathway Conjugated Urine Bilirubin 68mg 2mg Urobilinogen 70mg Fecal Urobilinogen Stercobilin Pigments 1 Labeling of RBC hemoglobin and fecal stercobilin 0.3 N of haemin N of N of stercobilin N of 15 15 B 0.1 0.2 X X 0.08 X X 0.06 X 0.1 X 0.04 A X X X X X X 0.02 X X X B: Atom % excess excess B: Atom % A: Atom % excess excess A: Atom % 20 40 60 80 100 120 140 160 180 Times ( days) Labeling of red cell hemoglobin and fecal stercobilin in a normal human given 15N orally Sources of bilirubin production in the rat Early Bilirubin Late Bilirubin 15% 65% 0-3 Days 40-80 Days Increased Erythropoiesis Red Cell Non- Senescence Hemoglobin Sources (liver) Sources of bilirubin production in the rat, as adduced from studies of the labeling of plasma bilirubin in Gunn rats and bile bilirubin in normal rats. 2 NADPH NADP Hemin + N N Fe OH NADPH O2 NADP NN N N Fe COO COO NN O2 CO heme-oxygenase complex Fe (II) COO COO OH HO hydroxyheme-oxygenase complex N N OH HO NADPH H NADP NH N N N in H Biliverd OOC COO N N reductase C biliverdin HH OOC COO bilirubin 3 (ligandin) OATP MDR2 A. B. 4 CH2 CH Me β CO (excreted via lungs) Me A B CH2 CH2 CO2H NH N α Fe γ Fe (reutilized) N NH C CH CH CO H H2C CH D 2 2 2 CO H CO H δ 2 2 Me Me CH2 CH2 CH2 CH2 Me CH Me CH2 CH2 Me Me CH CH BCDCH A. A CH2 O N N N N O H H H H BILIRUBIN – IX α (planar structure) D B. A B C BILIRUBIN – IX α (convoluted structure) COOH COOH O O C. OH O O OO HO HO C C OH OH HO CH2 CH CH CH2 2 2 Me Me CH CH2 CH2 Me Me CH CH CH CH2 O N N N N O H H H H BILIRUBIN - IX α DIGLUCURONIDE BILIRUBIN CONJUGATION IN MICROSOMES INVOLVES TWO STEPS, MEDIATED BY ONE BILIRUBIN-UDPGA TRANSFERASE BILIRUBINS: C O H UDPGA H O H UNCONJUGATED C N N O (UCB) O N N H O H H 1 O C C O GA UDPGA O UDP MONO- H H TRANSFERASE C N N O UDPGA GLUCURONIDE O N N H O H H (BMG) O C 2 C O GA O H H C N N O UDP DIGLUCURONIDE O N N H H (BDG) O Conjugation prevents GA O C internal H-bonding by the -COOH groups of Bilirubin 5 OATP MDR2 (=cMOAT) UROBILINOGENS ARE FORMED BY DECONJUGATION AND REDUCTION OF BILIRUBINS BY INTESTINAL BACTERIA CONJUGATED BILIRUBIN A UROBILINOGEN COOGA COOGA COOH COOH M M M M N UNCONJUGATED N N H H N BILIRUBIN H H H H2C CH N H H H H 2 N N H N V M COOH COOH E M O O O M V O M M M E N N Deconju- H H H Reduction gation N H N V M = Methyl M O O + 8H E = Ethyl 2 GA M V V = Vinyl 6 FRACTIONAL DIAZO REACTION OF PLASMA RR SO H 3 Fast Direct + reaction N+ N CONJUGATED BILIRUBIN SO3H DIAZO REAGENT Slow Indirect + reaction N+ N UNCONJUGATED BILIRUBIN 7 TOTAL DIAZO REACTION OF PLASMA RR CONJUGATED SO3H BILIRUBIN + + ACCELERATOR N+ (ALCOHOL, CAFFEINE) N UNCONJUGATED BILIRUBIN TOTAL – DIRECT = INDIRECT Bilirubinuria in Jaundice UNCONJUGATED PLASMA BILIRUBIN (B) CONJUGATED P L A S M A (A=ALBUMIN) U R I NO BILIRUBIN N BILIRUBIN ++ E 8 9 Phototherapy for neonatal jaundice Treatment for Neonatal Jaundice Prevention of kernicterus 10 COOH COOH CH2 CH2 CH2 CH2 Me CH Me CH2 CH2 Me Me CH CH BCDCH A CH2 O N N N N O H H H H Bilirubin IX α COOH COOH CH 2 CH2 CH2 CH2 Me CH2 Me CH2 Me CH Me CH CH CH CH2 O N N N N O H H H H Bilirubin IX β Structure of the α and β isomers of bilirubin IX. In the IXβ isomer (and in the γ and δ isomers, not shown) the propionic acid groups are moved to positions other than those indicated on the central pyrrole rings B and C of bilirubin IXα. h p Sn-PP Liver Co-PP Liver g m / 2.5 16 n i b u r i l i 2.0 b l 12 o m n ( 1.5 e s 8 a n e 1.0 g y x O 4 e 0.5 m e H 0 8 16 24 0 2 4 6 8 10 (hours) (days) Time Effect of Sn-protoporphyrin (Sn-PP) and CO-protoporphyrin (Co-PP) when administered once at a dose of 50 μmol/kg body wt on hepatic heme oxygenase activity in the rat. 11 Bile-Duct RAT PBC Sn-PP 10.0 Ligation (50 ) 18 Control 7.5 16 14 5.0 Sn-PP 12 Plasma Bilirubin mg/dl 2.5 10 -4 0 2 4 0 1 2 3 4 5 67 Time (days) Effect of Sn-protoporphyrin (Sn-PP) (100 μmol/kg body wt) administered at 4d before and on the day of surgery on hyperbilirubinemia in the bile-duct-ligated rat. Effect of Sn-PP (2 x 0.25 μmol/kg body wt) on the levels of serum bilirubin in a patient with primary biliary cirrhosis (PBC). UGT1 gene 5’ 3’ 1J 1I 1H 1G 1F 1E 1D 1C 1B 1A 234 5 mRNA B-UGT1 Phenol UGTs NH2 COOH substrate binding site UDPGA membrane binding site spanning enzyme region 285 amino acids 246 amino acids 12 Unconjugated Hyperbilirubinemia Characteristics Crigler-Najjar Type I Gilbert Syndrome Plasma bilirubin 340-860 μM 50-85 μM (fluctuates) Plasma BSP retention at 45 Normal Usually normal; elevated min in a minority of cases Hepatic bilirubin-UDPGT Undetectable 30-50% of normal activity Effect of Phenobarbital on No effect Reduction plasma bilirubin Pigments in bile Small amounts of unconjugated Increased proportion of bilirubin monoglucuronide Prevalence Rare 2-7% of population Prognosis Kernicterus Benign Animal Model Gunn rat Bolivian Squirrel Monkey Mutation UDPGT null UDPGT promoter A(TA)6TAA Chronic conjugated hyperbilirubinemias Characteristic Dubin-Johnson Syndrome Rotor Syndrome Appearance of liver Grossly black Normal Histology of liver Dark pigment; predominantly in Normal centrilobular areas; otherwise normal Serum bilirubin Elevated, usually between 2 and 5 mg%, Elevated, usually between 2 occasionally as high as 20 mg%; and 5 mg%, occasionally as predominantly direct-reacting high as 20 mg%; predominantly direct- reacting Routine liver function Normal except for bilirubin Normal except for bilirubin tests 45-min plasma BSP Normal or elevated; secondary rise at 90 min Elevated; no secondary rise at retention 90 min Urinary Normal total >80% as coproporphyrin I Elevated total; elevated coproporphyrin proportion of coproporphyrin I but <80% Mode of inheritance Autosomal recessive Autosomal recessive Prevalence Uncommon (1:1300 in Persian Jews) Rare Prognosis Benign Benign Mutation MRP2 13 Jaundice Conjugated bilirubin Unconjugated bilirubin Cholestatic Hemolysis Defect in Hepatocellular Conjugation Intrahepatic Extrahepatic 14 Jaundice Conjugated bilirubin Unconjugated bilirubin Cholestatic Hemolysis Defect in Hepatocellular Conjugation Intrahepatic Extrahepatic 15 Liver Function Tests • Bilirubin • PT (Prothrombin time) •Glucose • Cholesterol • ALT (alanine aminotransferase) • AST (aspartate aminotransferase) • Alkaline phosphatase •GGT (γ-glutamyltranspeptidase) Imaging • Ultrasound •CT scan • Liver-spleen scan • Radionuclide biliary scan • ERCP (endoscopic retrograde cholangiopancreatography) • Transhepatic cholangiography 16 Jaundice ↑ BR Conjugated bilirubin Unconjugated bilirubin ↑ ALT ↑ AP Cholestatic Hemolysis Defect in Hepatocellular Conjugation Nl BD Dilated BD Intrahepatic Extrahepatic 17 Bilirubin Metabolism •Blood •Conjugated & Conjugated •Urine – Urobilinogen •Stool – Stercobilin plus 3 O minus Fe V minus CO α M M D A V COOH COOH N N CH CH δ CH2 2 2 CH2 Fe β Me CH Me CH2 CH2 Me Me CH N N CH CH A BCCH D M C B M 2 O N N N N O H H H H γ CH2 CH2 CH2 CH2 COOH COOH Bilirubin IX α Ferroprotoporphyrin IX (Protoheme) Conversion of protoheme (ferroprotoporphyrin IX) to bilirubin IXα. Cleavage of the protoporphyrin ring occurs selectively at the α-methene bridge. The bridge carbon atom is oxidized to carbon monoxide. 18 BILIRUBIN IS PRODUCED BY OXIDATION OF HEME AND REDUCTION OF THE RESULTANT BILIVERDIN HEME BILIRUBIN IXα M = Methyl Pr Pr H2 E = Ethyl C M M γ M Pr = Propionyl M N N N N H H β Fe δ H N H N N N BILIVERDIN IXα V α M V M Pr Pr O O C M M H V V M M Biliverdin O & Heme 2 N N Reductase + NADPH Oxygenase H NADP H N H N V M NADP+ Fe3+ O O NADPH CO M V 19 cMOAT MDR2 20 21 22.
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