Crigler-Najjar disease

Green, R.M., Gollan, J.L. Crigler-Najjar disease type 1 therapeutic approaches to genetic Uver diseases into the next century. Gastroenterology 1997 112 649 -651... 

Sinaasappel, M., Jansen, P.L.M. The differential diagnosis of Crigler-Najjar disease, types 1 and 2, by bile pigment analysis. Gastroenterology 1991 100 783 - 789... 

F. F. Rubaltelli, A. Novello, L. Zancan, et al. Serum and bile bilirubin pigments in the differential diagnosis of Crigler-Najjar disease. Pediatrics 553, (1994). 

Type I Crigler-Najjar syndrome is a rare autosomal recessive disorder. It is characterized by severe congenital jaundice (serum bilirubin usually exceeds 20 mg/dL) due to mutations in the gene encoding bilirubin-UGT activity in hepatic tissues. The disease is often fatal within the first 15 months of life. Children with this condition have been treated with phototherapy, resulting in some reduction in plasma bilirubin levels. Phenobarbital has no effect on the formation of bilirubin glucuronides in patients with type I Crigler-Najjar syndrome. A liver transplant may be curative. 

Finally, there are hereditary causes of non-conjugated, nonhemolytic hyperbilirubinemias. These are Crigler-Najjar types 1 and 2 and Gilbert s syndrome (discussed in the section on Genetic Diseases of Bilirubin Metabolism). 

The other two diseases related to UGT1A1 are Crigler-Najjar (CN) syndrome types I and II. Many different mutations in UGT1A1 have been identified. CN type I patients express a mutated protein that is essentially devoid of activity. These patients therefore are unable to conjugate bilirubin. Until recently, this condition was lethal in childhood however, now these patients can be treated with phototherapy (discussed in the next section on Photobilirubin) and liver transplantation. Patients with CN type II express a mutated protein that retains some activity. These patients generally respond to phenobarbital, which increases the transcription of UGT1A1. Both CN types I and II are recessive disorders and rare. 

Deficiency of UGT leads to ineffective esterification of bihrubin, which in turn results in an unconjugated hyperbUirubinaemia. Reduced bilirubin conjugation, as a result of a decreased or absent UGT activity, is found in a number of acquired conditions and inherited diseases, such as Crigler-Najjar syndrome (types I and II) and Gilbert syndrome. Bilirubin-conjugating activity is also very low in the neonatal liver. 

Labrune, P.H., Myara, A., Francoual, J., Trivin, F., Odievre, M. Cerebellar symproms as the presenting manifestations of bilirubin encephalopathy in children with Crigler-Najjar type I disease. Pediatrics 1992 89 768-770... 

Indications for the transplantation of hepatocytes predominantly involve those liver diseases in which functional failures occur in the liver cells (not in the bile ducts). Permanent transplantation would be indicated, for example, in order to eliminate congenital metabolic disorders of the liver cells. In this case, hepatocytes from the patient could be used, with subsequent elimination of the defect by gene technology, as well as hepatocytes from healthy donors. A few years ago, a therapeutic effect lasting for over one year was achieved for the first time in a girl suffering from the Crigler-Najjar syndrome (I. X Fox et af, 1998). Human hepatocytes are most definitely more suitable than animal liver cells. The latter may well meet the requirements for a provisional substitute, but not for permanent transplantation. 

In Crigler-Najjar syndrome type /activity of hepatic bilirubin UDP-glucuronyltransferase is undetectable and bilirubin conjugates are absent from the serum, bile, and urine, but biliary secretion of sulfobromophthalein and indocyanine green is normal. The disease is apparent shortly after birth, kemicterus develops, and death commonly occurs during the neonatal period. The effectiveness of phototherapy is often transient. The enzyme is not inducible by phenobarbital. This autosomal recessive defect occurs in all races. The Gunn strain of Wister rats has a similar genetic defect and has been used to study the syndrome. 

In Gilbert s disease and in the Crigler-Najjar syndrome the disposal of BSP from plasma is usually normal (B20, MIO), but in the Rotor syndrome, there is BSP retention (R24). In the Dubin-Johnson syndrome, BSP retention is usually increased (B61, D9, Dll, S16). 

Nguyen, N., Bonzo, J. A., Chen, S., Chouinard, S., Kelner, M. J., Hardiman, G., Belanger, A., and Tukey, R. H. (2008). Disruption of the ugtl locus in mice resembles human Crigler-Najjar type I disease. J Biol Chem 283, 7901—7911. 

See also. Crigler-Najjar syndrome, drome, Gilbert s disease... 

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