BILIRUBIN MEABOLISM & JAUNDICE ( Lecture 6).ppt

Billirubin metabolism and jaundice

1. Bilirubin metabolism Bilirubin metabolism
and jaundice and jaundice

2. ObjectivesObjectives
Inherited disorders of bilirubin metabolismInherited disorders of bilirubin metabolism

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

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

5. Inherited disorders of bilirubin metabolism causing Inherited disorders of bilirubin metabolism causing
Unconjugated HyperbilirubinemiaUnconjugated Hyperbilirubinemia
• Crigler-Najjar syndrome Crigler-Najjar syndrome
type 1:type 1:
• Crigler-Najjar syndrome Crigler-Najjar syndrome
type 2:type 2:
• Gilbert syndrome:Gilbert syndrome:
RareRare
autosomal recessiveautosomal recessive
RareRare
autosomal recessive autosomal recessive
Very common, Very common,
autosomal recessive.autosomal recessive.
9% of population homozygous.9% of population homozygous.
~4% exhibit clinical jaundice ~4% exhibit clinical jaundice
intermittentlyintermittently

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

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

8. In 1953, Crigler and Najjar described
“a mysterious illness that caused jaundice
and severe neurological damage”

9. Treatment of Crigler-Najjar syndrome type 1
•Routine 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 levels
•At puberty, phototherapy becomes progressively
ineffective.
•Liver transplantation is the only curative therapy.
•In one patient, liver cell transplantation reduced
serum bilirubin level by 50%.

10. Phototherapy bed

11. CN-1 syndrome-1: permanent brain damageCN-1 syndrome-1: permanent brain damage

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Effect of drugs and hormones on rat liver UGT1A1 activity
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CARCAR PPARPPAR PXRPXR TRTR

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

14. • 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.

15. • However, serum bilirubin is only mildly elevated
(3-5 mg/dl.

16. Inherited disorders of bilirubin metabolism causing Inherited disorders of bilirubin metabolism causing
Mixed (unconjugated and conjugated) Mixed (unconjugated and conjugated)
hyperbilirubinemiahyperbilirubinemia
• Dubin Johnson syndrome:Dubin Johnson syndrome:
• Rotor syndromeRotor syndrome
Excretory defect for Excretory defect for
multiple organic anionsmultiple organic anions
Hepatic storage disorderHepatic storage disorder

17. Inherited disorders of bilirubin metabolism causing Inherited disorders of bilirubin metabolism causing
Mixed (unconjugated and conjugated) Mixed (unconjugated and conjugated)
hyperbilirubinemiahyperbilirubinemia
• Dubin Johnson syndrome:Dubin Johnson syndrome:
• Rotor syndromeRotor syndrome
Benign, rare autosomal Benign, rare autosomal
recessive disorder.recessive disorder.
1:1300 in Sephardic Jews1:1300 in Sephardic Jews
Benign, rare, autosomal Benign, rare, autosomal
recessive disorderrecessive disorder

18. Inherited disorders of bilirubin metabolism causing Inherited disorders of bilirubin metabolism causing
Mixed (unconjugated and conjugated) Mixed (unconjugated and conjugated)
hyperbilirubinemiahyperbilirubinemia
• Dubin Johnson syndrome:Dubin Johnson syndrome:
• Rotor syndromeRotor syndrome
Accumulation of pigmentsAccumulation of pigments
No pigmentationNo pigmentation

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

20. HYPERBILIRUBINEMIAHYPERBILIRUBINEMIA
Clinical evaluationClinical evaluation
Normal liver enzymesNormal liver enzymes
Normal bile salt levelsNormal bile salt levels
Abnormal liver enzymesAbnormal liver enzymes
Bilirubin: nearly allBilirubin: nearly all
indirect-reactingindirect-reacting
Large direct-reactingLarge direct-reacting
componentcomponent
•Hepatitis riskHepatitis risk
•DrugsDrugs
•AlcoholAlcohol
•SGPT>alk. phosSGPT>alk. phos
• Pro.-time: Pro.-time:
not corrected not corrected
with vitamin K with vitamin K
• AlbuminAlbumin
• History suggestsHistory suggests
obstruction obstruction
• SGPT<alk. phosSGPT<alk. phos
• Pro.-time: Pro.-time:
corrected with corrected with
vitamin K vitamin K
• CholesterolCholesterol
• Dubin-JohnsonDubin-Johnson
syndrome syndrome
• Rotor syndromeRotor syndrome
• Hemolysis? Hemolysis?
Splenomegaly, Splenomegaly,
anemia, high LDH, anemia, high LDH,
high retic. count, high retic. count,
low haptoglobin low haptoglobin
• Drugs?Drugs?
Rifampin, Rifampin,
radiographic contrast radiographic contrast
• Inherited disorders ofInherited disorders of
bilirubin conjugation: bilirubin conjugation:
Gilbert syndrome Gilbert syndrome
Crigler syndrome, Crigler syndrome,
types I and II types I and II

HepatocellularHepatocellular
jaundice:jaundice:
• Viral hepatitisViral hepatitis
• Drug hepatitisDrug hepatitis
• Alcoholic hepatitisAlcoholic hepatitis
• End-stage liver End-stage liver
diseasedisease
Cholestatic Cholestatic
jaundice:jaundice:

21. Summary and implicationsSummary and implications
• Bilirubin throughput by the hepatocyte involves
four steps:
Process Uptake StorageConjugationExcretion
Involved
molecule
UnidentifiedGSTs UGT1A1 MRP2
• 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).

22. QuestionsQuestions
1) Enzyme of glucourindation is ( 1) Enzyme of glucourindation is (
UGT1A1/UGD1A1,UGT2A1,UGT2A1).UGT1A1/UGD1A1,UGT2A1,UGT2A1).
2) A type of Jaundice characterized by hepatic obstruction is 2) A type of Jaundice characterized by hepatic obstruction is
( Pre-hepatic, hepatic , post-heaptic).( Pre-hepatic, hepatic , post-heaptic).
3) Black pigmentation of liver is characteristic for ( Rotor 3) Black pigmentation of liver is characteristic for ( Rotor
syndrome , Gilbert syndrome, CNJS1 ,Dubin Johnson syndrome , Gilbert syndrome, CNJS1 ,Dubin Johnson
syndrome). syndrome).

23. Thank you for
your attention!