Current Therapy for Crigler–Najjar Syndrome Type 1: Report of A World Registry

Abstract

which reliable administration of phototherapy cannot This study represents a multicenter survey on the be guaranteed. (HEPATOLOGY 1996;24:311-315.) management of patients with Crigler-Najjar syndrome (CNS) type 1. The aim of the survey was to find guiding principles for physicians in the care of these patients. Fifty-seven patients were included. At the time of incluCrigler-Najjar syndrome (CNS) is characterized by unconsion, 21 patients had received a liver transplant (37%). jugated hyperbilirubinemia since birth.1 CNS type 1 results The average age at transplantation was 9.1 { 6.9 years from a complete deficiency of the enzyme bilirubin UDP-(range, 1-23 years); the age of the patients who had not glucuronosyltransferase (UGT), and CNS type 2 results from been transplanted at the time of inclusion was 6.9 { 6.0 a partial deficiency. Bilirubin UGT is a member of the UGT years (range, 0-23 years). Brain damage had developed family, a group of enzymes encoded by the UGT1 and UGT2 in 15 patients (26%). Five patients died, and 10 are alive genes on human chromosomes 2 and 4. UGTs are located in with some degree of mental or physical handicap. In 2 the endoplasmic reticulum of the hepatocyte. UGT isoforms patients, ages 22 and 23 years, early signs of bilirubin are present in various other organs such as intestine, kidney, encephalopathy could be reversed, in 1 by prompt medi-lungs, and adrenals. 3-5 The after retransplantation, 2 improved neurologically, and first report was in 1952 by Crigler and Najjar.1 Before the 4 remained neurologically impaired. The age of 8 pa-advent of phototherapy, the disease was lethal, with death tients with and 13 without brain damage at or before occurring by the age of 15 months. transplantation was 14.3 { 5.9 and 5.9 { 5.4 years (P In CNS type 1, serum bilirubin values of untreated patients õ .01), respectively. Therapy of CNS type 1 consists of are in excess of 350 mmol/L, and bile contains not more than phototherapy (12 h/d), followed by liver transplantation. traces of bilirubin conjugates. 6,7 Kernicterus is a complication Phototherapy, although initially very effective, is so-that can also develop later in life.1,8,9 CNS type 2 is less secially inconvenient and becomes less efficient in the vere, with serum bilirubin values usually not exceeding 350 older age group, thus also decreasing compliance. Cur-mmol/L. The bile of these patients contains bilirubin monorently, liver transplantation is the only effective ther-and diglucuronides in low concentration.6,7 Their serum biliapy. This survey shows that, in a significant number of rubin responds to phenobarbital treatment with a decrease patients, liver transplantation is performed after some by 30% or more.10 Genetically, both diseases result from muform of brain damage has already occurred. From this, tations in the exons of the UGT1 gene.2 CNS types 1 and one must conclude that liver transplantation should be 2 are autosomal recessive diseases because both alleles are performed at a young age, particularly in situations in aff...

Effective oral treatment of unconjugated hyperbilirubinemia in Gunn rats†

“…Phototherapy becomes less effective with age, probably due to skin alterations, 6,7 a decrease in the surface area to body mass ratio, 8 and a diminishing compliance to the intensive phototherapy regimen, which may take up to 12 hours per day. 6 To prevent irreversible brain damage due to kernicterus, many patients with CriglerNajjar disease type I undergo liver transplantation in their second decade. 9,10 We sought to develop an alternative treatment for unconjugated hyperbilirubinemia based on oral administration and with equal or higher efficacy than phototherapy.…”

“…4,5 Phenobarbital is not effective in Crigler-Najjar disease type I, however, so these patients have to undergo daily phototherapy, which has considerable disadvantages. Phototherapy becomes less effective with age, probably due to skin alterations, 6,7 a decrease in the surface area to body mass ratio, 8 and a diminishing compliance to the intensive phototherapy regimen, which may take up to 12 hours per day. 6 To prevent irreversible brain damage due to kernicterus, many patients with CriglerNajjar disease type I undergo liver transplantation in their second decade.…”

Crigler-Najjar Syndrome Type 2 in a Young Adult

“…A response to phenobarbital is not observed in patients with type 1 disease. 11,12 Our patient showed 50% reduction of total and unconjugated bilirubin after administration of phenobarbital. Another difference between patients with type 1 and 2 disease is the presence of bilirubin glucuronides in bile.…”

Evolución prolongada en síndrome de Crigler-Najjar tipo I

“…E l síndrome de Crigler-Najjar (SCN) es una entidad nosológica infrecuente, con una frecuencia estimada de 0,6 por millón de habitantes 1 . Se describió por primera vez en 1952 por dos pediatras, en 6 niños que desarrollaron ictericia grave en los primeros días de vida, falleciendo por kernicterus antes de los 2 años de edad 2 .…”

“…Existen poco casos de sobrevida en adultos jóvenes. Una encuesta multicéntrica de tratamiento del SNC tipo I, reportó un paciente que murió a los 28 años de edad 1 . Existen escasos reportes de pacientes que alcanzaron la tercera década de vida 7 .…”