bilirubin and porphyrin metabolism

Abnormal constituents of urine Bile salt and bile pigment: 

Abnormal constituents of urine Bile salt and bile pigment 13.02.12

Warewolf: 

Warewolf

pct: 

pct

Biosynthesis of Heme: 

Biosynthesis of Heme

Defects in Heme Biosynthesis: 

Defects in Heme Biosynthesis Most animals synthesize their own heme Mutations or mis-regulaton of enzymes in heme biosynthesis pathway lead to porphyrias Accumulation of uroporphyrinogen I causes urine to become red teeth to fluoresce under UV light skin to be sensitive to UV light desire to obtain heme with diet Possible biochemical basis for vampire themes in mythology

Bilirubin synthesis: 

Bilirubin synthesis 80% bilirubin originates from senescent RBCs 1-2 х 10*8 RBCs destroyed/hour 6g hb produced in body/day 250-300 mg bilirubin produced/day

Pathway for RBC Scavenging: 

Pathway for RBC Scavenging Liver, Spleen & Bone marrow Hemoglobin Globin Amino acids Amino acid pool Heme Bilirubin Fe 2+ Excreted Phagocytosis & Lysis Through Liver 14

PowerPoint Presentation: 

Bilirubin synthesis

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Fog J, Jellum E. Structure of bilirubin.

SUMMARY OF BILIRUBIN METABOLISM IN LIVER: 

SUMMARY OF BILIRUBIN METABOLISM IN LIVER

BILIRUBIN CONJUGATION: 

BILIRUBIN CONJUGATION Essential for biliary excretion of bilirubin Glucuronic acid – major conjugating sugar in bile Glucosyl,xylosyl conjugates-traces Catalyzed by UDP-glucuronosyltransferase(UGT )

UGT ENZYME SYSTEM: 

UGT ENZYME SYSTEM 2 Major families UGT 1: Major bilirubin conjugating form in human UGT 2: Conjugation of steroids,other endogenous and exogenous substrates Multiple isoforms present One isoform of UGT 2 family: inducible by phenobarbital Significance: UGT 1A locus abnormalities- disorders of bilirubin conjugation phenobarbital used as enzyme inducer in some conditions of hyperbilirubinemia

UGT 1 COMPLEX: 

UGT 1 COMPLEX Chromosome 2q37 Exons 2,3,4,5- used in all isoforms expressed from this locus,so mutations affect all isoforms Exons 1A1-12 : variable ; each exon has different promoter region and differently regulated,mutation affects only the corresponding isoform

PowerPoint Presentation: 

A TATATATATATA TAA A TATATA (TA) TATATA TAA

BILIRUBIN EXCRETION: 

BILIRUBIN EXCRETION The rate limiting step in bilirubin metabolism Excreted across canalicular membrane into bile MRP( Multidrug resistant protein) family – efflux pumps MRP 2- essential for bilirubin excretion Significance: Deficiency of MRP 2: DUBIN JOHNSON SYNDROME MRP 2- downregulated in cholestasis

BILIRUBIN IN INTESTINE: 

BILIRUBIN IN INTESTINE 24

BILIRUBIN HANDLING IN KIDNEY: 

BILIRUBIN HANDLING IN KIDNEY 25

INHERITED DISORDERS OF BILIRUBIN METABOLISM: 

INHERITED DISORDERS OF BILIRUBIN METABOLISM UNCONJUGATED HYPERBILIRUBINEMIA CRIGLER NAJJAR SYN. TYPE 1 CRIGLER NAJJAR SYN. TYPE 2 (ARIAS SYN.) GILBERT SYNDROME CONJUGATED HYPERBILIRUBINEMIA DUBIN JOHNSON SYNDROME ROTOR SYNDROME

GILBERT SYNDROME: 

GILBERT SYNDROME pronounced 'zheel-BAYR', often shortened to GS , also called Gilbert-Meulengrachts syndrome Described by Gilbert in 1901 Most common inherited disorder of bilirubin metabolism Males > females; Prevalence 8-10% Presentation: Bilirubin levels remain < 3mg/dL; may increase during intercurrent illness or stress Jaundice is the only positive finding often Routine lab tests are normal

PowerPoint Presentation: 

Molecular mechanism: A TATATATATATA TAA A TATATA (TA) TATATA TAA Promoter-reporter studies show that an increased TATAA box length reduces UGT1A1 expression Bosma PJ, Roy Chowdhury J, Bakker C, et al. The genetic basis of the reduced expression of bilirubin UDP- glucuronosyltransferase 1 in Gilbert’s syndrome. N Engl J Med 1995; 333:1171. UGT 1A1*28

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DIAGNOSIS: Presumptive diagnosis made if: Mild unconjugated hyperbilirubinemia on several occasions Serum GGT,ALP,fasting and postcibal bile acids normal Confirmation : Estimate relative concentrations of bilirubin monoglucuronide to diglucuronide Genetic analysis

CRIGLER NAJJAR SYNDROME TYPE 1: 

CRIGLER NAJJAR SYNDROME TYPE 1 Described by Crigler and Najjar in 1952. Autosomal recessive inheritance Incidence 0.6-1.0/ million; occurs in all races Characterised by striking unconjugated hyperbilirubinemia 20-45 mg/dL (340-765 µmol/L) Jaundice Appears in neonatal period ; persists for life

MOLECULAR MECHANISM : 

MOLECULAR MECHANISM TYPE 1A : Defect in conjugation of various drugs and xenobiotics in addition to bilirubin Constitutes majority of cases; mutations in exons 2-5 TYPE 1B : Defect limited to bilirubin conjugation Small subset of patients; mutations in exon A1

CLINICAL FEATURES: 

CLINICAL FEATURES Severe unconjugated hyperbilirubinemia at birth Prior to phototherapy: Kernicterus Death in infancy

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With phototherapy: Child may survive infancy Jaundice persists throught life Prone to kernicterus throught life

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LAB FEATURES: High serum bilirubin 18-30 mg, no evidence of hemolysis Other parameters within normal limits Bilirubin not present in urine; bile lacks glucuronides Liver biopsy shows normal histology Molecular diagnostics for gene sequence abnormalities for diagnosis

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TREATMENT : Aims at reducing bilirubin levels Exchange tranfusion: in immediate neonatal period Phototherapy: Main stay of treatment Special blue lamps used;wavelength 450-500 nm

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Phototherpy for infants

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Becomes less effective near puberty Plasmapheresis: Effective in emergencies Orthotopic liver transplantation: Standard treatment for CN-1

CRIGLER NAJJAR SYN.2: 

CRIGLER NAJJAR SYN.2 ARIAS Syndrome Milder variant Autosomal recessive Differs from CN 1 by: Average bilirubin concentrations low Infrequently associated with kenicterus Bile deeply coloured; bilirubin monoglucuronides present UGT1A activity reduced;not absent totally Bilirubin concentration falls by >25% with phenobarbital administration

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Molecular mechanisms: Characterised by aminoacid substitutions – reduce UGT1A1 activity, not abolish it Clinical features: Asymptomatic in most cases Treatment: Similar to CN-1

DUBIN JOHNSON SYNDROME: 

DUBIN JOHNSON SYNDROME First described by DUBIN & JOHNSON in 1954 Characterised by chronic non-hemolytic jaundice with accumulation of conjugated bilirubin in serum Dark pigmented liver- dark liver jaundice Autosomal recessive ; both sex affected Clinical features: Mild icterus Asymptomatic Hyperbilirubinemia during illness, pregnancy

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PATHOGENESIS: Defeciency of MRP 2 protein on canalicular membrane. Tm reduced; storage normal

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LAB FEATURES: S.Bilirubin levels 2-5mg/ Dl Other parameters: normal Liver grossly pigmented..

ROTOR SYNDROME: 

ROTOR SYNDROME First described by ROTOR in 1948 Rare disorder autosomal recessive inheritance Predominantly conjugated hyperbilirubinemia

ctd..: 

ctd.. Shares many features with DJS. Liver not pigmented. Both Tm and storage reduced Abnormality: not known

PowerPoint Presentation: 

?Defect in bilirubin uptake: decreased clearance may also be related to defective uptake Effect of fasting: 2-3 fold increase in s.bilirubin observed on reducing caloric intake to 400 cal. For 48 hours. Limited use in diagnosis

BILIRUBIN- FRIEND OR FOE??: 

BILIRUBIN- FRIEND OR FOE?? Function as natural antioxidants in newborns Attenuates graft rejection in cardiac transplant models Inverse relation between bilirubin and coronary artery disease Inverse relation between bilirubin and colorectal cancer