The Biochemistry of JaundiceThe Biochemistry of Jaundice

A collaborative effort of Group 3 Section A collaborative effort of Group 3 Section 1C21C2

Members:Members:

Animations by: Gerald FuentesAnimations by: Gerald Fuentes

Formation of BilirubinFormation of Bilirubin

Bilirubin MetabolismBilirubin Metabolism

HemeBiliverdinBilirubinBilirubin DiglucoronideUrobilinogenUrobilinStercobilin

Heme = planar; Others = not anymore

globin globin globin globin

Hemoglobin

heme heme heme heme

I

II

III

IV Fe2+

NADPHC

O2O O2

Heme Oxygenase

O

IIIIIIIV

Biliverdin

NADPH

H

Bilirubin

Processing of BilirubinProcessing of Bilirubin

Excretion of BilirubinExcretion of Bilirubin

3 Steps of Biliverdin Metabolism3 Steps of Biliverdin Metabolism

Hepatic UptakeHepatic Uptake

-Unconjugated bilirubin is presented in the Unconjugated bilirubin is presented in the liver cellliver cell

-The albumin associated with it is dissociatedThe albumin associated with it is dissociated

-Ligandin is delivered to prevent efflux of Ligandin is delivered to prevent efflux of bilirubin back to plasmabilirubin back to plasma

ConjugationConjugation ExcretionExcretion

3 Steps of Biliverdin Metabolism3 Steps of Biliverdin Metabolism

Hepatic UptakeHepatic Uptake

-Unconjugated bilirubin is presented in the Unconjugated bilirubin is presented in the liver cellliver cell

-The albumin associated with it is dissociatedThe albumin associated with it is dissociated

-Ligandin is delivered to prevent efflux of Ligandin is delivered to prevent efflux of bilirubin back to plasmabilirubin back to plasma

ConjugationConjugation

-Unconjugated bilirubin (water insoluble) is Unconjugated bilirubin (water insoluble) is converted to bilirubin diglucoronide (water converted to bilirubin diglucoronide (water soluble)soluble)

-Takes place in the smooth endoplasmic Takes place in the smooth endoplasmic reticulum of the liverreticulum of the liver

-Catalyzed by glucoronyl transferaseCatalyzed by glucoronyl transferase

ExcretionExcretion-Bilirubin which is now water soluble can now Bilirubin which is now water soluble can now be excreted from the liver cell to the biliary be excreted from the liver cell to the biliary system.system.

Conjugation with GlucoronatesConjugation with Glucoronates

BILIRUBIN DIGLUCORONIDE

Role of Blood Proteins in the Role of Blood Proteins in the Metabolism of BilirubinMetabolism of Bilirubin

1. Albumin

Dissolved in Blood

Sparingly soluble in Blood

Blood

Liver

Ligandin

(-) charge

Ligandin

(-) charge

Ligandin Prevents bilirubin from going back to plasma

Different Causes of JaundiceDifferent Causes of Jaundice

Excessive Production of BilirubinExcessive Production of Bilirubin Reduced Hepatocyte UptakeReduced Hepatocyte Uptake Impaired Bilirubin conjugationImpaired Bilirubin conjugation Impaired Bile FlowImpaired Bile Flow

Diagnosis of JaundiceDiagnosis of Jaundice

Urine ExaminationUrine Examination– Qualitative measurement of bilirubinQualitative measurement of bilirubin– Either Ictotest or Dipstick methodEither Ictotest or Dipstick method– Foam Test methodFoam Test method

Normal Urine – foam is absolutely whiteNormal Urine – foam is absolutely white Hyperbilibirunemia – foam is yellowHyperbilibirunemia – foam is yellow

Diagnosis of JaundiceDiagnosis of Jaundice

Stool ExaminationStool Examination Special Blood TestSpecial Blood Test RadiologicalRadiological

Classification of HyperbilirubinemiaClassification of Hyperbilirubinemia

Retention – due to overproduction of Retention – due to overproduction of bilirubinbilirubin

Regurgitation – reflux of bilirubin into bloodRegurgitation – reflux of bilirubin into blood

Acholuric Vs. CholuricAcholuric Vs. Choluric

CHOLURIC – presence of bile derivatives in CHOLURIC – presence of bile derivatives in the urinethe urine– Occurs in regurgitation hyperbilirubinemiaOccurs in regurgitation hyperbilirubinemia– Obstructive typeObstructive type

ACHOLURIC – absence of bile in urineACHOLURIC – absence of bile in urine– Retention hyperbilirubinemiaRetention hyperbilirubinemia– Hemolytic typeHemolytic type

Hemolytic vs. Hepatocellular vs. Hemolytic vs. Hepatocellular vs. ObstructiveObstructive

HemolyticHemolytic HepatocellularHepatocellular ObstructiveObstructive

Urine/Fecal Urine/Fecal UrobilinogenUrobilinogen IncreasedIncreased DecreasedDecreased Absent/ Absent/

fluctuatesfluctuates

BilirubinBilirubin AbsentAbsent PresentPresent PresentPresent

ConjugatedConjugated NoNo YesYes YesYes

Hemolytic JaundiceHemolytic Jaundice

CLINICALCLINICAL Defect in uptake of bilirubin by liver cellsDefect in uptake of bilirubin by liver cells Immature hepatic conjugating systemImmature hepatic conjugating system

BIOCHEMICALBIOCHEMICAL Slight change in liver cellsSlight change in liver cells Severe increase of Alkaline Phospholipase Severe increase of Alkaline Phospholipase

(APL)(APL)

Obstructive JaundiceObstructive Jaundice

CLINICALCLINICAL Presence of tumors, structuresPresence of tumors, structures

BIOCHEMICALBIOCHEMICAL Mild to severe increase of APLMild to severe increase of APL

Hepatocellular JaundiceHepatocellular Jaundice

CLINICALCLINICAL Liver damage (hepatitis, cirrhosis)Liver damage (hepatitis, cirrhosis)

BIOCHEMICALBIOCHEMICAL With marked biochemical change in liver With marked biochemical change in liver

cellscells Marked increase in APLMarked increase in APL

Clinical Conditions Related to Clinical Conditions Related to Increased Unconjugated Increased Unconjugated

HyperbilirubinemiaHyperbilirubinemia

1.1. Gelbert’s SyndromeGelbert’s Syndrome

2.2. Crigler-Najjar Syndrome (Type I)Crigler-Najjar Syndrome (Type I)

3.3. Crigler-Najjar Syndrome (Type II)Crigler-Najjar Syndrome (Type II)

4.4. Neonatal JaundiceNeonatal Jaundice

Clinical Conditions Related to Clinical Conditions Related to Increased Conjugated Increased Conjugated

HyperbilirubinemiaHyperbilirubinemiaDuben-Johnson Duben-Johnson

SyndromeSyndrome Rotor SyndromeRotor Syndrome

Defect Defect (hepatocytes)(hepatocytes) SecretorySecretory TransportTransport

Presence of Presence of PigmentationPigmentation YesYes NoNo

MetabolismMetabolismAbnormal Abnormal Porphyrin Porphyrin

MetabolismMetabolismNoneNone