Crigler-Najjar Syndrome

(Hereditary Glucuronyl-Transferase Deficiency)

What sample is needed for the diagnosis of Crigler-Najjar Syndrome?

• The patient’s serum is needed.

What is the Definition of Crigler-Najjar Syndrome?

1. There is a marked congenital deficiency or absence of the glucuronyl-transferase enzyme, which is needed for the conjugation of bilirubin.
2. Crigler-Najjar type 1 has a complete deficiency of the Glucuronyltransferase enzyme.
   • Unconjugated bilirubin is usually 25 to 50 mg/dL.
3. Crigler-Najjar type II has a partial deficiency of the Glucuronyltransferase enzyme.
   • Unconjugated bilirubin is usually 5 to 20 mg/dL.

How will you discuss the pathophysiology of  Crigler-Najjar Syndrome?

1. Crigler-Najjar syndrome is a rare familial autosomal recessive disease.
2. This is rare, but it is a very severe disease; 50% of babies die within one year of birth.
   1. The rest (half) of the patients suffer from severe brain damage.

What is the Mechanism of Crigler-Najjar Syndrome?

1. There is a congenital marked deficiency or absence of the glucuronyl-transferase enzyme (GTE).
2. GTE converts unconjugated bilirubin into bilirubin-glucuronide in the hepatocytes.
   1. The UGT1A1 gene coding has a severe deficiency of the enzyme.
   2. This is caused by gene mutation and deletion.
3. Classification of Crigler-Najjar Syndrome:
4. Type I has no glucuronyltransferase enzyme, leading to neonatal jaundice and kernicterus.
   1. Type 1 has almost no GTE and is a severe disease. There is a homozygous non-functional protein.
   2. There is no enzyme activity in the liver.
5. Type II (Arias syndrome) contains some glucuronyltransferase enzyme activity, usually <10% of the normal, and jaundice appears later.
   1. Type II has a partial or reduced level. The disease is less severe than type 1.
   2. There is <10% of the normal enzyme activity, and survival to adulthood is possible.
6. Now, unconjugated bilirubin (indirect bilirubin) can build up in the body and lead to jaundice.

• The following diagram of bilirubin metabolism provides a good understanding of this disease and the mechanism of Crigler-Najjar syndrome.

What are the Side effects of unconjugated bilirubin (Crigler-Najjar Syndrome)?

1. This unconjugated bilirubin can cause damage to the brain, muscles, and nerves.
2. Crigler-Najjar syndrome has a partial or complete deficiency of the glucuronyl-transferase enzyme.

What are the Signs and Symptoms of Crigler-Najjar syndrome?

1. These patients may have confusion.
2. There is yellowness of the eyes and skin due to raised unconjugated bilirubin.

Crigler-Najjar syndrome type 1:

1. This condition is inherited as an autosomal recessive trait.
2. Jaundice develops in the first few days of birth and is severe by the second week.
   1. Bilirubin may be as high as 25 to 50 mg/dL.
   2. No conjugated bilirubin is present in the serum or urine.
3. These patients may develop kernicterus due to brain damage.
4. Unconjugated hyperbilirubinemia always exceeds 5 mg/dL, and time may exceed 20 mg /dL.
5. Kernicterus, which occurs when bilirubin deposits in the brain, affects the basal ganglia, primarily the lenticular nucleus.
   1. Kernicterus may show hypotonia, deafness, lethargy, oculomotor palsy, and ultimately death.
6. These patients may also have diarrhea, vomiting, fever, seizures, and difficulty swallowing.
   1. Early liver transplantation is the only effective treatment.

What are the Lab findings of Crigler-Najjar syndrome?

1. Fecal urobilinogen is very low.
2. Liver function tests are normal.
3. The BSP test is normal.
4. The liver biopsy is normal.
5. There is no evidence of hemolysis.

What is the outcome of type 1 Crigler-Najjar syndrome?

1. Untreated patients often die of kernicterus before they cross the age of 18 months.
2. Type 1 can be considered when there is unconjugated hyperbilirubinemia of >20 mg/dL after one week of age, there is no evidence of hemolysis, and breast milk jaundice is ruled out.

How will you treat the Crigler-Najjar syndrome type 1?

1. Phlebotomy and plasmapheresis will reduce the unconjugated bilirubin.
2. However, encephalopathy usually develops.
3. Early liver transplantation is the only hope.

How will you treat the type 2 Crigler-Najjar syndrome?

1. This is a rare autosomal dominant disorder.
2. There is a partial deficiency of the glucuronosyltransferase enzyme.
3. Neurological complications are rare.
4. Clinically, there are no signs and symptoms except mild jaundice.
   1. Bilirubin may be 5 to 25 mg/dL.
5. There is roughly 10% of the normal activity of the enzyme.
6. There is a possibility of the child surviving to adulthood.
7. There is a good response to phenobarbitone therapy, and the patient may live longer than expected.
8. With phenobarbitone therapy, bilirubin may be <5 mg/dL.
9. Treatment:
   1. Phenobarbitone therapy may lead to normal life expectancy.

How will you differentiate between type 1 and type 2 Crigler-Najjar syndrome?

How will you diagnose Crigler-Najjar syndrome?

Crigler-Najjar syndrome Type 1:

1. Indirect bilirubin is increased. It appears on the first or second day of life and may be raised to 12 to 45 mg/100 ml.
2. Conjugated bilirubin is absent in the serum.
3. Bilirubin is absent in the urine.
4. Fecalurobilinogen is very low in amount.
5. Liver function tests are normal.
6. The BSP test is normal.
7. The liver biopsy is normal.
8. There is no evidence of hemolysis.
9. These patients die by the age of 18 months due to raised unconjugated bilirubin, leading to kernicterus.
10. Rule out causes of hemolysis in case of persistent unconjugated bilirubinemia of around 20 mg/dL after one week of the infant’s age.

Crigler-Najjar syndrome Type 2:

1. The raised bilirubin level is low in the range of 7 to 20 mg/100 ml.
   1. Unconjugated bilirubin increases with fasting and the removal of fats from the diet.
   2. It may respond to phenobarbitone therapy, and the level may decrease to <5 mg/dL.
2. Liver function tests are normal.
3. The liver biopsy is normal.
4. Fecal urobilinogen is very low.

What is the Treatment of Crigler-Najjar syndrome?

1. These patients need phototherapy throughout their lives (blue LED light). This is difficult because patients need 10 to 12 hours of treatment daily.
2. Phototherapy may not work in some patients after the age of 4 years due to the thickness of the skin.
3. Drugs that may be given are phenobarbital and Vit. E, Vit. C, Coenzyme Q, Actigall, L-carnitine, and Creatine.
4. Blood transfusion exchange or plasma exchange may help to lower the bilirubin level.
5. Calcium may be given to bind the bilirubin in the gut.
6. In type 1, liver transplantation may be done as early as possible, which is the only hope for longer survival.