Crigler-Najjar Syndrome

(Hereditary Glucuronyl-Transferase Deficiency)

Sample for Crigler-Najjar Syndrome

• The serum of the patient is needed.

Definition of Crigler-Najjar Syndrome

• There is a marked congenital deficiency or absence of glucuronyl-transferase enzyme, which is needed for the conjugation of bilirubin.

Pathophysiology of  Crigler-Najjar Syndrome

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

Mechanism of Crigler-Najjar Syndrome:

1. There is a congenital marked deficiency or absence of glucuronyl-transferase enzyme (GTE).
2. GTE converts (conjugated) bilirubin into bilirubin-glucuronide in the hepatocytes.
   1. 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:
   1. Type I has no glucuronyltransferase enzyme leading to neonatal jaundice and kernicterus.
   2. Type II (Arias syndrome) contains some glucuronyltransferase enzyme activity, usually <10% of the normal, and jaundice appears later.
4. Now unconjugated bilirubin (indirect bilirubin) can build up in the body and lead to jaundice.
5. The following diagram showing bilirubin metabolism will give a good concept of this disease to understand the mechanism of Crigler-Najjar syndrome.

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 glucuronyl-transferase enzyme.

Crigler-Najjar syndrome

Crigler-Najjar syndrome classification

1.  Type 1 has an almost absence of GTE and is a severe disease. There is a homozygous non-function protein.
   1. 1. There is no enzyme activity in the liver.
2. Type 2 has a partial or reduced level. The disease is less severe than type 1.
   1. 1. There is <10% of the normal enzyme activity, and survival to adulthood is possible.

Signs and Symptoms of Crigler-Najjar syndrome

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

Type 1 Crigler-Najjar syndrome:

1. Jaundice develops in the first few days of birth and is severed 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.
2. These patients may develop kernicterus due to brain damage.
3. Unconjugated hyperbilirubinemia always exceeds 5 mg/dL, and time may exceed 20 mg /dL.
4. Kernicterus, when there is the deposition of bilirubin in the brain, affects the basal ganglia, mainly the lenticular nucleus.
   1. Kernicterus may show hypotonia, deafness, lethargy, oculomotor palsy, and ultimately death.
5. These patients may also have diarrhea, vomiting, fever, seizures, and difficulty swallowing.
   1. Early liver transplantation is the only effective treatment.
6. Lab findings:
   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.
7. The outcome of type 1:
   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.

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 survival of the child to adulthood.
7. There is a good response to phenobarbitone therapy, and the patient may have more life than expected.
8. With phenobarbitone therapy, bilirubin may be <5 mg/dL.

Difference between type 1 and type 2 Crigler-Najjar syndrome:

Diagnosis of Crigler-Najjar syndrome

1. Type 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.
   1. Conjugated bilirubin is absent in the serum.
   2. Bilirubin is absent in the urine.
   3. Fecalurobilinogen is very low in amount.
   4. Liver function tests are normal.
   5. The BSP test is normal.
   6. The liver biopsy is normal.
   7. There is no evidence of hemolysis.
   8. These patients die by the age of 18 months due to raised unconjugated bilirubin, leading to kernicterus.
   9. Rule out causes of hemolysis in case of persistent unconjugated bilirubinemia of around 20 mg/dL after one week of the infant’s age.
2. Type 2: Raised bilirubin level is low in the range of 7 to 20 mg/100 ml.
   1. 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 <5 mg/dL.
   2. Liver function tests are normal.
   3. The liver biopsy is normal.
   4. Fecal urobilinogen is very low.

Treatment of Crigler-Najjar syndrome

1. These patients need phototherapy throughout their life (blue LED light). This is difficult because patients need 10 to 12 hours of treatment every day.
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.

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