Crigler–Najjar syndrome

The Crigler -Najjar syndrome is a very rare genetic disease (prevalence < 1:1 000 000 ), which affects the liver especially. It is named after John Fielding Crigler (* 1919) and Victor Assad Najjar (* 1914) named.

• 3.1 Treatment of Type I
• 3.2 treatment of type II

Pathogenesis

As with Crohn's Meulengracht the Crigler -Najjar syndrome is caused by a defect in bilirubin UDP - glucuronosyltransferase, which is responsible for the excretion of bilirubin. The enzyme defect is, however, much more pronounced. There are two types:

• Crigler- Najjar syndrome type I ( CN I ) is inherited as an autosomal recessive trait and is characterized by the complete absence of the enzyme. It comes immediately after birth to a severe jaundice. The prognosis is very poor.

• Crigler- Najjar syndrome type II (CN II, " Arias syndrome " ) is inherited as an autosomal dominant trait and differs from type I in that, due to a " milder " mutation, a residual activity of the enzyme persists, so still a part of bilirubin may be conjugated in the liver and is excreted. Jaundice manifests itself in the first year of life. The prognosis of patients is relatively good.

Pathophysiology of type I

In type 1 Crigler- Najjar syndrome, the enzyme activity is equal to zero or only traces of adhesive available. There are mutations found in exons 2-5 of the UGT1 gene. Depending on the shape and extent of mutation is the glucuronidation of bilirubin, steroid hormones (especially estrogen) and drugs disrupted. Thereby, the concentrations of the unconjugated bilirubin increases excessive (> 20 mg / dl). The other liver function tests (transaminases, gamma -GT, alkaline phosphatase) are normwertig, histology unremarkable. The bile of affected patients is almost colorless. The enzymes of glucuronidation can not induce by the administration of potent enzyme inducers (phenobarbital, rifampin ). Piled bilirubin is metabolized slowly and eliminated in to a small extent on the chair. In urine urobilinogen is not detectable.

Pathophysiology of type II

In contrast to type 1 Crigler- Najjar syndrome is the CN- II, a residual activity of UDP - glucuronyl transferase of about 10 %. The responsible gene defect also affects the UGT1 gene ( over 10 known types of mutation ) and can be similar to the CN -I lead to the Konjugationsstörung of hormones and drugs. The plasma level of unconjugated bilirubin is elevated not so excessively when CN- II (6-20 mg / dl). Through an enzyme inducer, phenobarbital values ​​to 3-5 mg / dl can be achieved. As with the CN- I, the other parameters and liver histology are normal even when CN -II.

Course

The Crigler- Najjar syndrome type 1 manifests itself immediately after birth by an excessive hyperbilirubinemia, the regular way, untreated, leads to a kernicterus with serious neurological damage. Therefore, affected patients die untreated in early childhood.

The Crigler- Najjar syndrome type 2 runs not so destructive. A kernicterus is rare, but the disturbing symptoms of jaundice with yellow skin and copious itching can severely limit the quality of life.

Therapy

The treatment depends on the type and severity of the disease. Especially with a CN- I, the rapid initiation of therapy is extremely important. Phenobarbital, as hepatic enzyme inducer, may reduce bilirubin levels, but is not suitable for long -term therapy. As a causal therapy, a liver transplant or possibly a hepatocyte come into question.

Therapy of type I

Conservative treatment of Crigler- Najjar syndrome type 1 is based on three pillars:

• Consistent daily phototherapy with blue light ( thereby bilirubin water soluble)
• Administration of Tinprotoporphyrin, an inhibitor of heme oxygenase ( weakens bilirubin from )

Through this therapy, the life expectancy can be lengthened and the occurrence of neurological complications may be delayed.

Another treatment option is liver transplantation, to strive for the earliest possible stage. In the experimental phase is allogeneic transplantation of liver cells.

Treatment of type II

The treatment of type II is made by once-daily administration of phenobarbital. Through the induction of enzymatic activity, the concentration of bilirubin in the blood plasma can be reduced to safe levels.