Bilirubin metabolism and jaundice

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Bilirubin metabolism and jaundice. Pathophysiological importance of bilirubin metabolism. It is the end product of heme degradation. Serum bilirubin level is an important clinical marker of hepatobiliary excretory function. - PowerPoint PPT Presentation

Transcript of Bilirubin metabolism and jaundice

  • Bilirubin metabolism andjaundice

  • Pathophysiological importance of bilirubin metabolism It is the end product of heme degradation.Serum bilirubin level is an important clinical marker of hepatobiliary excretory function.Hepatic uptake, storage, conjugation and excretion of bilirubin are finely balanced. Therefore, enhancement of bilirubin throughput requires coordinated induction of multiple genes, which may be mediated by nuclear receptors.

  • Erythroid Non-erythroidNormal: Senescent erythrocytes Free hemeAbnormal: Hemolysis: Extravascular Intravascular Ineffective erythropoiesis(80%) (20%) Cytochromes Catalase Peroxidase Tryptophane pyrrolase MyoglobinSources of bilirubin

  • Opening of the heme ring and Enzyme-catalyzed formation of bilirubin

  • CNHNHCH2CH2COOHMMVOThe linear structure of bilirubin:Two dipyrroles joined by a central methene bridge

  • CNHMVONHMCH2CH2OOHCH2NHNHCH2CH2COOHMMVOBilirubin contains several polar groups (shown in red):Yet, it is insoluble in water.

  • Conjugation with glucuronic acid makes bilirubin water soluble

  • NHMVONHMCH2OHCH2NHNHCH2CH2COOHMMVOCH2COThe internal hydrogen bonds of bilirubin are disrupted by conjugation of the propionic acidcarboxyl group with glucuronic acid

  • NHMVONHMCH2CH2NHNHCH2CH2COMMVOCH2CO-GlucAGlucA-The internal hydrogen bonds of bilirubin are disrupted by conjugation of the propionic acidcarboxyl group with glucuronic acid

  • Phototherapy changes the configuration of bilirubin making it transiently water soluble

  • Bilirubin throughput: schema of a hepatocyte

  • Bilirubin circulates bound to serum albumin.

  • Bilirubin circulates bound to serum albumin.

    At the sinusoidal surface of hepatocytes, it dissociates from albumin.

  • Bilirubin circulates bound to serum albumin.

    At the sinusoidal surface of hepatocytes, it dissociates from albumin.

  • Bilirubin circulates bound to serum albumin.

    At the sinusoidal surface of hepatocytes, it dissociates from albumin.B

  • Bilirubin circulates bound to serum albumin.

    At the sinusoidal surface of hepatocytes, it dissociates from albumin.B

  • Bilirubin enters through the sinusoidal surface, probably by facilitated diffusion. Uptake is energy independent and bidirectional.BB

  • What is the mechanism of facilitated diffusion of bilirubin? Zucker has proposed that no transporter protein is needed. In a recent report, organic anion transport protein 2 (oatp2) has been implicated in bilirubin uptake. However, oatp2 transports organic anions, such as BSP, it is not sufficient for bilirubin transport.

  • B Inside the hepatocyte, bilirubin binds to cytosolic proteins termed ligandins, which are the same as glutathione-S- transferases (GSTs).BGST binding inhibits the efflux of bilirubin, thereby increasing its net uptake

  • BB

  • B Conjugation of bilirubin with glucuronic acid is catalyzed by UGT1A1, which transfers glucuronic acid from UDP-glucuronic acid to bilirubinUDPGAUDPUGT1A1B Conjugation with glucuronic acid makes bilirubin water-soluble and non-toxic. Glucuronidation is essential for biliary excretion of bilirubin.

  • UDP-glucuronosyltransferases (UGTs)UGTs are ER proteins that convert many internal and exogenous toxins to non-toxic metabolites.UGTs are a family of enzymes concentrated in the liver.One UGT isoform, UGT1A1, conjugates bilirubin and is essential for its excretion. Inherited UGT1A1 deficiency causes jaundice.Substrate UDPGAUGTGlucuronideUDP

  • It is a medical term describes the elevation of bilirubin in blood result in yellow color of skin and sclera.Other symptoms include nausea, vomiting, dark-colored urine andTypes of Jaundice: fatigue.according to the cause of jaundiceit is classified to three main types:

    Pre-hepatic jaundice Hepatic jaundice Post-hepatic (most common type)

  • haemolytic jaundicehepato-cellular jaundiceobstructive jaundice

  • Inherited disorders of bilirubin metabolism causing Unconjugated Hyperbilirubinemia Crigler-Najjar syndrome type 1: Crigler-Najjar syndrome type 2: Gilbert syndrome:Virtually no UGT1A1 activityUGT1A1 activity below 10% UGT1A1 activity ~30%

  • Inherited disorders of bilirubin metabolism causing Unconjugated Hyperbilirubinemia Crigler-Najjar syndrome type 1: Crigler-Najjar syndrome type 2: Gilbert syndrome:Serum bilirubin 18-40 mg/dl:Kernicterus, unless treated vigorouslySerum bilirubin 8-18 mg/dl:Kernicterus is rare Serum bilirubin normal to 5 mg mg/dl (increases during fasting, intercurrent illness, etc.No cerebral toxicity.

  • Inherited disorders of bilirubin metabolism causing Unconjugated Hyperbilirubinemia Crigler-Najjar syndrome type 1: Crigler-Najjar syndrome type 2: Gilbert syndrome:Rareautosomal recessiveRareautosomal recessive Very common, autosomal recessive.

    9% of population homozygous.~4% exhibit clinical jaundice intermittently

  • Inherited disorders of bilirubin metabolism causing Unconjugated Hyperbilirubinemia Crigler-Najjar syndrome type 1: Crigler-Najjar syndrome type 2: Gilbert syndrome:Bilirubin conjugates are almost absent in bileProportion of bilirubin mono- glucuronide is increased in bile normal >10%) Proportion of bilirubin mono- glucuronide is increased in bile normal >10%)

  • Inherited disorders of bilirubin metabolism causing Unconjugated Hyperbilirubinemia Crigler-Najjar syndrome type 1: Crigler-Najjar syndrome type 2: Gilbert syndrome:Phenobarbital treatment: little or no effect.Phenobarbital reduces serum bilirubin is by >25%Serum bilirubin is normalized

  • In 1953, Crigler and Najjar described a mysterious illness that caused jaundice and severe neurological damage

  • Treatment of Crigler-Najjar syndrome type 1Routine phototherapy has extended the life expectancy.During emergency, bilirubin may be removed by plasmapheresis.Tin mesoporphyrin can be used for transient reduction of serum bilirubin levelsAt puberty, phototherapy becomes progressively ineffective.Liver transplantation is the only curative therapy.In one patient, liver cell transplantation reduced serum bilirubin level by 50%.

  • Phototherapy bed

  • CN-1 syndrome-1: permanent brain damage

  • 250-200-150-100- 50- 0-Effect of drugs and hormones on rat liver UGT1A1 activityPercent of basal activityUntreatedPhenobarbitalClofibrateThyroid hormoneRifampinNuclear receptorCARPPARPXRTR

  • Inherited disorders of bilirubin metabolism causing Conjugated + Unconjugated Hyperbilirubinemia Dubin Johnson syndrome Rotor syndromeA disease of canalicular excretion of multiple organic anions, but not bile salts.Hepatic storage disorder

  • Inherited deficiency or abnormality of MRP2 causes Dubin-Johnson syndrome Biliary excretion of many organic anions, but not most bile acids, is deficient in Dubin-Johnson syndrome. Abnormality of biliary excretion causes the retention of a pigment in the liver.

  • However, serum bilirubin is only mildly elevated (3-5 mg/dl), suggesting the existence of alternative pathways for excretion of bilirubin glucuronides.

  • Inherited disorders of bilirubin metabolism causing Mixed (unconjugated and conjugated) hyperbilirubinemia Dubin Johnson syndrome: Rotor syndromeExcretory defect for multiple organic anionsHepatic storage disorder

  • Inherited disorders of bilirubin metabolism causing Mixed (unconjugated and conjugated) hyperbilirubinemia Dubin Johnson syndrome: Rotor syndromeBenign, rare autosomal recessive disorder. 1:1300 in Sephardic JewsBenign, rare, autosomal recessive disorder

  • Inherited disorders of bilirubin metabolism causing Mixed (unconjugated and conjugated) hyperbilirubinemia Dubin Johnson syndrome: Rotor syndromeAccumulation of pigmentsNo pigmentation

  • Inherited disorders of bilirubin metabolism causing Mixed (unconjugated and conjugated) hyperbilirubinemia Dubin Johnson syndrome: Rotor syndromeHighly characteristic urinary porphyrin excretion pattern.Low Urinary porphyrin excretion pattern is similar to that in many cholestatic diseaess.

  • HYPERBILIRUBINEMIAClinical evaluationNormal liver enzymesNormal bile salt levelsAbnormal liver enzymesBilirubin: nearly all indirect-reactingLarge direct-reacting componentHepatitis riskDrugsAlcoholSGPT>alk. phos Pro.-time: not corrected with vitamin K Albumin History suggests obstruction SGPT
  • Summary and implications Bilirubin throughput by the hepatocyte involves four steps: The four steps are finely balanced. Therefore, Reduction at any step may cause hyperbilirubinemia. Enhancement of the throughput requires induction of multiple genes, probably coordinated by nuclear receptors, such as the constitutive androstene receptor (CAR).

    ProcessUptakeStorageConjugationExcretionInvolvedmoleculeUnidentifiedGSTsUGT1A1MRP2

  • Thank you for your attention!

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