1. Bilirubin metabolism and jaundice

2. Objectives
Inherited disorders of bilirubin metabolism

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

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

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

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

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

12. Effect of drugs and hormones on rat liver UGT1A1 activity
250-
200-
150-
100-
50- 0-
Percent of basal activity
Thyroid hormone
Clofibrate
Untreated
Rifampin
Phenobarbital
Nuclear
receptor
CAR
PPAR
PXR TR

13. Conjugated + Unconjugated Hyperbilirubinemia
Inherited disorders of bilirubin metabolism causing
Conjugated + Unconjugated Hyperbilirubinemia
Dubin Johnson syndrome
A disease of canalicular excretion of multiple organic anions, but not bile salts.
Rotor syndrome
Hepatic 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. Mixed (unconjugated and conjugated)
Inherited disorders of bilirubin metabolism causing
Mixed (unconjugated and conjugated)
hyperbilirubinemia
Dubin Johnson syndrome:
Excretory defect for multiple organic anions
Rotor syndrome
Hepatic storage disorder

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

18. Mixed (unconjugated and conjugated)
Inherited disorders of bilirubin metabolism causing
Mixed (unconjugated and conjugated)
hyperbilirubinemia
Dubin Johnson syndrome:
Accumulation of pigments
Rotor syndrome
No pigmentation

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

20. HYPERBILIRUBINEMIA Clinical evaluation
Normal liver enzymes
Normal bile salt levels
Clinical evaluation
Abnormal liver enzymes
Bilirubin: nearly all
indirect-reacting
Hepatitis risk
Drugs
Alcohol
SGPT>alk. phos
Pro.-time: not corrected with vitamin K
Albumin
Large direct-reacting
component
History suggests obstruction
SGPT<alk. phos
Pro.-time: corrected with vitamin K
Cholesterol
Hemolysis? Splenomegaly, anemia, high LDH, high retic. count, low haptoglobin
Drugs? Rifampin, radiographic contrast
Inherited disorders of bilirubin conjugation: Gilbert syndrome Crigler syndrome, types I and II
Dubin-Johnson syndrome
Rotor syndrome
Hepatocellular
jaundice:
Viral hepatitis
Drug hepatitis
Alcoholic hepatitis
End-stage liver
disease
Cholestatic
jaundice:

21. Summary and implications
Bilirubin throughput by the hepatocyte involves four steps:
Process
Uptake
Storage
Conjugation
Excretion
Involved
molecule
Unidentified
GSTs
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. Questions
1) Enzyme of glucourindation is ( UGT1A1/UGD1A1,UGT2A1,UGT2A1). 2) A type of Jaundice characterized by hepatic obstruction is ( Pre-hepatic, hepatic , post-heaptic). 3) Black pigmentation of liver is characteristic for ( Rotor syndrome , Gilbert syndrome, CNJS1 ,Dubin Johnson syndrome).

23. Thank you for
your attention!