Crigler-Najjar Syndrome

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Classification according to ICD-10
E80.5 Crigler-Najjar Syndrome
ICD-10 online (WHO version 2019)

The Crigler-Najjar syndrome is a very rare genetic disease ( prevalence <1: 1,000,000), which affects the liver concerns. It is named after John Fielding Crigler (1919–2018) and Victor Assad Najjar (1914–2002).

Pathogenesis

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

  • Crigler-Najjar- type I (CN I) is an autosomal - recessive inherited and is characterized by the complete absence of the enzyme. Severe jaundice occurs immediately after birth . The prognosis is very bad.
  • Crigler-Najjar type II (CN II; “ Arias syndrome ”) is inherited in an autosomal dominant manner and differs from type I in that, as a result of a “milder” mutation, there is still some residual activity of the enzyme, so that some of bilirubin can be conjugated in the liver and excreted. The jaundice manifests itself in the 1st year of life. Those affected have a relatively good prognosis.

Type I pathophysiology

In type 1 Crigler-Najjar syndrome, enzyme activity is zero or only traces of it. There are mutations in exons 2-5 of the UGT1 gene. Depending on the form and extent of the mutation, the glucuronidation of bilirubin, steroid hormones (especially estrogen ) and drugs is disturbed. As a result, the concentrations of the unconjugated bilirubin are excessively increased (> 20 mg / dl). The other liver values ​​( transaminases , gamma-GT , alkaline phosphatase ) are normal, the histology normal . The bile of affected patients is almost colorless. The glucuronidation enzymes can not be induced even by the administration of potent enzyme inducers ( phenobarbital , rifampicin ). Accumulated bilirubin is metabolized slowly and too little is eliminated in the stool. In the urine no is Urobilinogen detectable.

Type II pathophysiology

In contrast to Crigler-Najjar syndrome type 1, in CN-II there is a residual activity of UDP-glucuronyl transferase of about 10%. The responsible genetic defect also affects the UGT1 gene (over 10 known mutation forms ) and, similar to CN-I, can also lead to conjugation disorders of hormones and drugs. The plasma level for unconjugated bilirubin is not as excessively increased in CN-II (6–20 mg / dl). Through enzyme induction using phenobarbital, values ​​of 3–5 mg / dl can be achieved. As with the CN-I, the other liver parameters and the histology of the CN-II are normal.

course

Crigler-Najjar syndrome type 1 manifests itself immediately after birth as excessive hyperbilirubinemia, which, if left untreated, usually leads to kernic terus with serious neurological damage. Therefore, if left untreated, affected patients die in early childhood.

Crigler-Najjar syndrome type 2 is not as destructive. Kernicterus is rare, but the disturbing symptoms of jaundice with yellowing of the skin and extensive itching can severely reduce the quality of life.

therapy

The therapy depends on the type and severity of the disease. The rapid initiation of therapy is extremely important, especially with a CN-I. Phenobarbital , as a hepatic enzyme inducer, can lower the bilirubin level, but is not suitable for long-term therapy. Liver transplantation or possibly hepatocyte transplantation can be considered as causal therapy .

Type I therapy

Conservative therapy for Crigler-Najjar syndrome type 1 is based on three pillars:

This therapy can extend life expectancy and delay the occurrence of neurological complications.

Another therapy option , liver transplantation , should be sought as early as possible. The allogeneic transplantation of liver cells is in the experimental phase .

Type II therapy

Type II therapy is carried out by administering phenobarbital once a day . By inducing the enzymatic activity, the bilirubin concentration in the blood plasma can be reduced to harmless levels.

See also

List of syndromes , Meulengracht's disease

Individual evidence

  1. Herold, Gerd: Internal Medicine - A lecture-oriented presentation . Herold Verlag, Cologne 2013. p. 518