Crigler-Najjar Syndrome

Crigler-Najjar Syndrome (Hereditary Glucuronyl-Transferase Deficiency)
Sample
- Serum of the patient needed.
Pathophysiology
- Crigler-Najjar syndrome is a rare familial autosomal recessive disease.
- This is rare but is a very severe disease, 50% of the babies die within one year of birth.
- The rest half of the patients suffer from severe brain damage.
Mechanism of Crigler-Najjar Syndrome:
- There is a congenital marked deficiency or absence of glucuronyltransferase enzyme (GTE).
- GTE converts (conjugated) bilirubin into bilirubin-glucuronide in the hepatocytes.
- UGT1A1 gene coding has a severe deficiency of the enzyme.
- Type I has no glucuronyltransferase enzyme leading to neonatal jaundice and kernicterus.
- Type II (Arias syndrome) some glucuronyltransferase enzyme activity, usually <10% of the normal, and jaundice appears later on.
- Now unconjugated bilirubin (indirect bilirubin) can build up in the body and lead to jaundice.
- This is caused by gene mutation and deletion.
- To understand the mechanism of Crigler-Najjar syndrome, the following diagram showing bilirubin metabolism will give the good concept of this disease.
Side effects of unconjugated bilirubin (Crigler-Najjar Syndrome):
- This unconjugated bilirubin can cause damage to the brain, muscles, and nerves.
- To understand the mechanism of Crigler-Najjar syndrome following diagram of bilirubin metabolism gives a better idea.
Crigler-Najjar syndrome is of two types:
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- Type 1 has an almost absence of GTE and is a severe disease. There is a homozygous non-function protein.
- There is no enzyme activity in the liver.
- Type 2 has partial or at a reduced level. The disease is less severe than type 1.
- There is <10% of the normal enzyme activity, and survival to adulthood is possible.
- Type 1 has an almost absence of GTE and is a severe disease. There is a homozygous non-function protein.
Signs and Symptoms
- These patients may have confusion.
- There is yellowness of eyes and skin due to raised unconjugated bilirubin.
- In type 1:
- jaundice develops in the first few days of birth and is severed by the second week.
- Bilirubin may be as high as 25 to 50 mg/dL.
- No conjugated bilirubin is present in the serum or urine.
- These patients may develop kernicterus due to brain damage.
- Unconjugated hyperbilirubinemia always exceeds 5 mg/dL and time may exceed 20 mg /dL.
- Kernicterus when there is the deposition of bilirubin in the brain particularly affects the basal ganglia, mainly the lenticular nucleus.
- Kernicterus may show hypotonia, deafness, lethargy, oculomotor palsy, and ultimately death.
- These patients may also have diarrhea, vomiting, fever, seizures, and difficulty in swallowing.
- Early liver transplantation is the only effective treatment.
- Lab findings:
- Fecal urobilinogen is very low.
- Liver function tests are normal.
- BSP test is normal.
- Liver biopsy is normal.
- There is no evidence of hemolysis.
- The outcome of type 1:
- Untreated patients often die of kernicterus before they cross the age of 18 months.
- Type 1 can be considered when there is unconjugated hyperbilirubinemia of >20 mg/dL after one week of age, and there is no evidence of hemolysis, and breast milk jaundice is ruled out.
- In type 2:
- This is a rare autosomal dominant disorder.
- There is a partial deficiency of the glucuronosyltransferase enzyme.
- Neurological complications are rare.
- Clinically there are no signs and symptoms except mild jaundice.
- Bilirubin may be 5 to 25 mg/dL.
- There is roughly 10% of the normal activity of the enzyme.
- There is a possibility of survival of the child to adulthood.
- There is a good response to phenobarbitone therapy and the patient may have more life than expected.
- With phenobarbitone therapy, bilirubin may be <5 mg/dL.
- jaundice develops in the first few days of birth and is severed by the second week.
Difference between type 1 and type 2 Crigler-Najjar syndrome:
Clinical/lab findings | Type 1 | Type 2 |
Incidence | Very rare | Uncommon |
Age at onset | Infancy | Childhood, and adolescent |
Transmission | Autosomal recessive | Autosomal dominant |
Serum bilirubin total | >20 mg/dL | <20 mg/dL |
Type of bilirubin | All unconjugated | All unconjugated |
Kernicterus | Frequent | Absent |
Glucuronytransferase enzyme | Absent | Marked decrease (present) |
Bile | Mostly colorless | Normal color |
Signs and symptoms |
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Stool color | Plae yellow | Normal |
Oral cholecystogram | Normal | Normal |
Phenobarbitone response | No response | There is a positive response |
Status of parents |
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Diagnosis
- Type 1: Indirect bilirubin is increased. It appears in the first or second day of life and may be raised to 12 to 45 mg/100 ml.
- Conjugated bilirubin is absent in the serum.
- Bilirubin is absent in the urine.
- Type 2: Raised bilirubin level is low in the range of 7 to 20 mg/100 ml.
- Liver function tests are normal.
- Liver biopsy is normal.
- Fecal urobilinogen is very low.
Treatment
- These patients need phototherapy throughout their life (blue LED light). This is difficult because patients need 10 to 12 hours of treatment every day.
- Phototherapy may not work in some patients after the age of 4 years due to the thickness of the skin.
- Drugs that may be given are phenobarbital, Vit. E, Vit. C, Coenzyme Q, Actigall, L-carnitine, and Creatine.
- Blood transfusion exchange or plasma exchange may be helpful in raising the bilirubin level.
- Calcium may be given to bind the bilirubin in the gut.
- In type 1 liver transplantation may be done as early as possible and that is the only hope for longer survival.