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Crigler-Najjar Syndrome

November 6, 2023Chemical pathologyLab Tests

Table of Contents

Toggle
  • Crigler-Najjar Syndrome
    • (Hereditary Glucuronyl-Transferase Deficiency)
        • Sample for Crigler-Najjar Syndrome
      • What is the Definition of Crigler-Najjar Syndrome?
      • Pathophysiology of  Crigler-Najjar Syndrome
      • What is the Crigler-Najjar syndrome classification?
      • What are the Signs and Symptoms of Crigler-Najjar syndrome?
      • Crigler-Najjar syndrome type 1:
      • Type 2 Crigler-Najjar syndrome:
      • What is the Diagnosis of Crigler-Najjar syndrome?
      • Crigler-Najjar syndrome Type 1:
      • Crigler-Najjar syndrome Type 2:
      • What is the Treatment of Crigler-Najjar syndrome?
        • How will you describe different types of inherited jaundice?
      • Questions and answers:

Crigler-Najjar Syndrome

(Hereditary Glucuronyl-Transferase Deficiency)

Sample for Crigler-Najjar Syndrome

  • The serum of the patient is needed.

What is the 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.
  • Crigler-Najjar type 1 has a complete deficiency of the Glucuronytrasferase enzyme.
    • Unconjugated bilirubin is usually 25 to 50 mg/dL.
  • Crigler-Najjar type II has a partial deficiency of the Glucuronytrasferase enzyme.
    • Unconjugated bilirubin is usually 5 to 20 mg/dL.

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 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 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.
Crigler Najjar syndrome mechanism

Crigler-Najjar syndrome mechanism

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 glucuronyl-transferase enzyme.
Crigler-Najjar syndrome

Crigler-Najjar syndrome

What is the 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. There is no enzyme activity in the liver.
  2. Type II has a partial or 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.

What are the 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.

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 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.
  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, 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.
  6. These patients may also have diarrhea, vomiting, fever, seizures, and difficulty swallowing.
    1. Early liver transplantation is the only effective treatment.
  7. 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.
  8. 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.
  9. Treatment:
    1. Phlebotomy and plasmapheresis will reduce the unconjugated bilirubin.
    2. However, encephalopathy usually develops.
    3. Early liver transplantation is the only hope.

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.
  9. Treatment:
    1. Phenobarbitone therapy may lead to normal life expectancy.

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
  1. Jaundice
  2. Kernicterus in infants
  3. Kernicterus is also seen in young adults
  1. Mostly asymptomatic
  2. Kernicterus is rare
  3. There is mild jaundice
Stool color Pale yellow Normal
Oral cholecystogram Normal Normal
Phenobarbitone response No response There is a positive response
Status of parents
  1. Normal bilirubin in both parents
  2. Partial defect: there is ∼a 50% defect for glucuronide conjugation in both parents.
  1. One parent shows minimal to severe jaundice.
  2. A defect in glucuronide conjugation is present in one of the parents

What is the Diagnosis of 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 <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 life (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.

How will you describe different types of inherited jaundice?

Clinical parameters Unconjugated Hyperbilirubinemia Conjugated Hyperbilirubinemia
Gilbert’s disease Type 1 Criggler-Najjar Type II Criggler-Najjar syndrome Rotor’s syndrome Dubon-Jhonson syndrome
Inherited mode Autosomal dominant Autosomal recessive Autosomal dominant Autosomal recessive Autosomal recessive
Incidence <7% of the population Very rare Uncommon Rare Uncommon
Age at onset In adolescence In infancy
  1. In childhood
  2. Adolescence
Early adulthood
  1. Childhood
  2. Adolescence
Pathogenesis Glucoronyl transferase  enzyme deficiency (GTE) GTE decreased Marked decrease Impaired conj. bilirubin excretion Impaired cong. bilirubin excretion
Bilirubin level
  1. Mostly indirect
  2. Decreased in fasting
Mainly indirect Mainly indirect
  1. Direct around 60%
  2. 2 to 7  and ≤20
  1. Direct around 60%
  2. 2 to 7 and ≤25
Clinical signs/symptoms
  1. Appear in early adulthood
  2. Mostly found in fasting
  3. Hemolysis is seen in ≤40%
  1. Jaundice
  2. May see kernicterus in infants and young adults
  1. Asymptomatic jaundice
  2. Kernicterus is rarely seen
Asymptomatic jaundice in young adults Asymptomatic jaundice
Effect of phenobarbitone Decreased to normal There is no effect Marked decrease —– —–
BSP (Dye excretion) test May be mildly impaired in <40% of cases It is absent _____ Positive, Initial rapid fall and then rise in 40 to 90 minutes Positive, Slow clearance and no rise
Oral cholecyctography Normal Normal Normal Normal GB usually not visualized
Liver biopsy Normal —- —- No pigments Characteristic pigments
Treatment Not needed There is no treatment Not needed

Questions and answers:

Question 1: What is the difference between type 1 and type 2.
Show answer
In type 1 Crigler-Najjar syndrome, there is the complete absence of the enzyme, and in type 2, there is a partial deficiency.
Question 2: What is kernicterus?
Show answer
Kernicterus seen when the bilirubin level increases more than 12 mg/dL, and it causes damage to the brain.

Possible References Used
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