Bilirubin metabolism and jaundice

Objectives Inherited disorders of bilirubin metabolism

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%

Unconjugated Hyperbilirubinemia Inherited disorders of bilirubin metabolism causing Unconjugated Hyperbilirubinemia Crigler-Najjar syndrome type 1: Serum bilirubin 18-40 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.

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

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%)

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

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

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%.

Phototherapy bed

CN-1 syndrome-1: permanent brain damage

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

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

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.

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

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

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

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.

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:

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).

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).

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