Management of hyperbilirubinemia and prevention of kernicterus in 20 patients with Crigler-Najjar disease

Abstract

We summarize the treatment of 20 patients with Crigler-Najjar disease (CND) managed at one center from 1989 to 2005 (200 patient-years). Diagnosis was confirmed by sequencing the UGTA1A gene. Nineteen patients had a severe (type 1) phenotype. Major treatment goals were to maintain the bilirubin to albumin concentration ratio at <0.5 in neonates and <0.7 in older children and adults, to avoid drugs known to displace bilirubin from albumin, and to manage temporary exacerbations of hyperbilirubinemia caused by illness or gallstones. A variety of phototherapy systems provided high irradiance over a large body surface. Mean total bilirubin for the group was 16+/-5 mg/dl and increased with age by approximately 0.8 mg/dl per year. The molar ratio of bilirubin to albumin ranged from 0.17 to 0.75 (mean: 0.44). The overall non-surgical hospitalization rate was 0.12 hospitalizations per patient per year; one-half of these were for neonatal hyperbilirubinemia and the remainder were for infectious illnesses. Ten patients (50%) underwent elective laproscopic cholecystectomy for cholelithiasis. No patient required invasive bilirubin removal or developed bilirubin-induced neurological damage under our care. Visual acuity and color discrimination did not differ between CND patients and age-matched sibling controls. Four patients treated with orthotopic liver transplantation were effectively cured of CND, although one suffered significant transplant-related complications.Conclusions. While patients await liver transplantation for CND, hyperbilirubinemia can be managed safely and effectively to prevent kernicterus. Lessons learned from CND can be applied to screening and therapy of non-hemolytic jaundice in otherwise healthy newborns.

Bilirubin accumulation and Cyp mRNA expression in selected brain regions of jaundiced Gunn rat pups

“…Because of multiple factors affecting UCB binding and Bf, it has not been possible to define a bilirubin/albumin molar ratio (B/A) considered to be safe in protecting against BIND. In humans, at B/A ≥ 0.7 in blood, irreversible neurological damage often occurs, whereas at B/A ≥ 0.6, it is usually reversible (20). In vitro studies suggest that cultured central nervous system cells may suffer UCB toxicity Cerebral cortex, (c) superior collicula, (d) cerebellum, and (e) inferior collicula.…”

“…In both JJ and Jj animals, during the whole postnatal period, the plasma bilirubin/albumin molar ratio (B/A) was below 0.6, the cutoff value for increased risk of bilirubin neurotoxicity (20). In contrast, in hyperbilirubinemic jj rats, the ratio was clearly >1 at d2 and at d9, declining to 0.55 at d17.…”

De Novo Donor-Specific HLA Antibody Formation in Two Patients With Crigler-Najjar Syndrome Type I Following Human Hepatocyte Transplantation With Partial Hepatectomy Preconditioning

“…Patients are at risk of developing severe and irreversible brain injury due to neurotoxicity of unconjugated hyperbilirubinemia. Therapy consists of daily phototherapy for 8–14 h, converting hydrophobic unconjugated bilirubin into water‐soluble isomers 1; however, phototherapy becomes less effective with increasing age and constitutes a substantial impairment of quality of life. Finally, most patients undergo liver transplantation, reducing the risk of brain injury.…”

Recommendations for Pregnancies in Patients with Crigler-Najjar Syndrome

“…Prenatal care and delivery in a tertiary care centre, with facilities for rapid bilirubin and albumin assays and phototherapy for mother and infant 6. Avoidance of drugs that increase unbound, unconjugated bilirubin (Robertson et al 1991;Strauss et al 2006) 7. Neurological testing of the child after birth and during early childhood Features of pregnancies in patients with Crigler-Najjar reported in the literature, PT phototherapy, Phb phenobarbital, CS caesarean sections, NA not available, CB cord blood, D1 blood taken on first day after delivery.…”

“…At present it is impossible to state what concentration of unconjugated bilirubin is non-neurotoxic for the developing foetus, but it seems reasonable to try to keep the maternal (and therefore the foetal) unconjugated bilirubin concentrations below 200 mmol/l and the molar ratio between unconjugated bilirubin and serum albumin below 50% (Gajdos et al 2006;Strauss et al 2006). Current national guidelines state that a bilirubin over 170 mmol/l is an indication for phototherapy in term infants without risk factors for kernicterus and 70 mmol/l in high-risk infants.…”