Crigler-Najjar Syndrome

Sample

• Serum of the patient needed.

Pathophysiology

1. Crigler-Najjar syndrome is a rare familial autosomal recessive disease.
2. This is rare but is a very severe disease, 50% of the babies die within one year of birth.
   1. The rest half of the patients suffer from severe brain damage.
3. Mechanism:
   1. There is congenital marked deficiency or absence of glucuronyltransferase enzyme (GTE).
4. GTE converts (conjugated) bilirubin into bilirubin-glucuronide in the hepatocytes.
   1. UGT1A1 gene coding has a severe deficiency of the enzyme.
   2. Type I has no glucuronyltransferase enzyme leading to neonatal jaundice and kernicterus.
   3. Type II (Arias syndrome) some glucuronyltransferase enzyme activity, usually <10% of the normal, and jaundice appears later on.
5. Now unconjugated bilirubin (indirect bilirubin) can build up in the body and lead to jaundice.
6. This is caused by gene mutation and deletion.
7. Side effects of unconjugated bilirubin:
   1. This unconjugated bilirubin can cause damage to the brain, muscles, and nerves.
8. To understand the mechanism of Crigler-Najjar syndrome following diagram of bilirubin metabolism gives a better idea.

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

Signs and Symptoms

1. These patients may have confusion.
2. There is yellowness of eyes and skin due to raised unconjugated bilirubin.
3. In type 1:
   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. These patients may develop kernicterus due to brain damage.
   3. Unconjugated hyperbilirubinemia always exceeds 5 mg/dL and some time may exceed 20 mg /dL.
   4. Kernicterus when there is the deposition of bilirubin in the brain particularly affecting 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 in swallowing.
      1. Early liver transplantation is the only effective treatment.
4. In type 2:
   1. This is a rare autosomal disorder.
   2. Clinically there are no signs and symptoms except mild jaundice.
      1. Bilirubin maybe 5 to 25 mg/dL.
   3. There is roughly 10% of the normal activity of the enzyme.
   4. There is a possibility of survival of the child to adulthood.
   5. There is a good response to phenobarbitone therapy and the patient may have more life than expected.

Diagnosis

1. Type 1: Indirect bilirubin is increased. It appears in the first or second day of life and maybe raised to 12 to 45 mg/100 ml.
   1. Conjugated bilirubin is absent in the serum.
   2. Bilirubin absent in the urine.
2. Type 2: Raised bilirubin level is low in the range of 7 to 20 mg/100 ml.
   1. Liver function tests are normal.
   2. Liver biopsy is normal.
   3. Fecal urobilinogen is very low.

Treatment

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 a thickness of the skin.
3. Drugs that may be given are phenobarbital, Vit.E, Vit.C, Coenzyme Q, Actigall, L-carnitine, and Creatine.
4. Blood transfusion exchange or plasma exchange may be helpful in raising 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 and that is the only hope for longer survival.

 

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