Gilbert or Crigler-Najjar syndrome? Neonatal severe unconjugated hyperbilirubinemia with P364L UGT1A1 homozygosity.

BACKGROUND: Several mutations of bilirubin uridine diphosphate-glucuronosyltransferase gene (UGT1A1) have been reported in patients with unconjugated hyperbilirubinemia. Few reports are available about the p.Pro364Leu mutation (P364L, c.1091C > T) in homozygous newborns. We describe the clinical, laboratory and therapeutic approach in two Chinese neonates with severe jaundice, homozygous for the P364L mutation. CASE PRESENTATION: Two Chinese breastfed female infants presented prolonged unconjugated hyperbilirubinemia at the age of 1 month. Total bilirubin was higher than 15 mg/dl (D < 1). An exhaustive etiological work-up to detect possible causes of hyperbilirubinemia (notably hemolytic ones) was negative. The promoter and coding regions of UGT1A1 were amplified by polymerase chain reaction (PCR) from genomic DNA isolated from leukocytes. Both patients resulted homozygous for a variant site within the coding region of the gene in the 4 exon, c.1091C > T, p.Pro364Leu. In front of the persistently high level of unconjugated bilirubin, phototherapy was performed without persistent results. A treatment with phenobarbital was then begun and bilirubin level progressively decreased, with a complete and persistent normalization. The therapy was stopped. CONCLUSION: UGT1A1 enzyme activity associated with the P364L mutation has been described as 35.6% of the wild-type enzyme activity. Photo-therapy and phenobarbital can be useful in front of persistently high level of unconjugated bilirubin. Our cases presented high bilirubin values, overlapping between Gilbert syndrome (GS) and Crigler-Najjar syndrome type II (CNS), but the complete normalization of bilirubin makes GS more likely. Homozygous P364L variant can be associated with severe neonatal unconjugated hyperbilirubinemia in Chinese infants, but jaundice can completely resolve in a few months, contrary to what happens in Crigler-Najjar syndrome type II.

Bilirubin Decreases Macrophage Cholesterol Efflux and ATP-Binding Cassette Transporter A1 Protein Expression.

BACKGROUND: Mild but chronically elevated circulating unconjugated bilirubin is associated with reduced total and low-density lipoprotein cholesterol concentration, which is associated with reduced cardiovascular disease risk. We aimed to investigate whether unconjugated bilirubin influences macrophage cholesterol efflux, as a potential mechanism for the altered circulating lipoprotein concentrations observed in hyperbilirubinemic individuals. METHODS AND RESULTS: Cholesterol efflux from THP-1 macrophages was assessed using plasma obtained from normo- and hyperbilirubinemic (Gilbert syndrome) humans (n=60 per group) or (heterozygote/homozygote Gunn) rats (n=20 per group) as an acceptor. Hyperbilirubinemic plasma from patients with Gilbert syndrome and Gunn rats induced significantly reduced cholesterol efflux compared with normobilirubinemic plasma. Unconjugated bilirubin (3-17.1 µmol/L) exogenously added to plasma- or apolipoprotein A1-supplemented media also decreased macrophage cholesterol efflux in a concentration- and time-dependent manner. We also showed reduced protein expression of the ATP-binding cassette transporter A1 (ABCA1), a transmembrane cholesterol transporter involved in apolipoprotein A1-mediated cholesterol efflux, in THP-1 macrophages treated with unconjugated bilirubin and in peripheral blood mononuclear cells obtained from hyperbilirubinemic individuals. Furthermore, we demonstrated that bilirubin accelerates the degradation rate of the ABCA1 protein in THP-1 macrophages. CONCLUSIONS: Cholesterol efflux from THP-1 macrophages is decreased in the presence of plasma obtained from humans and rats with mild hyperbilirubinemia. A direct effect of unconjugated bilirubin on cholesterol efflux was demonstrated and is associated with decreased ABCA1 protein expression. These data improve our knowledge concerning bilirubin's impact on cholesterol transport and represent an important advancement in our understanding of bilirubin's role in cardiovascular disease.

Does moderate unconjugated hyperbilirubinemia in healthy term neonates play a role on their neurodevelopmental status at the age of 18 months?

AIM: Safety of moderate hyperbilirubinemia in healthy term neonates is still a matter of discussion. The purpose of this study was to compare developmental status of 18-month-old children with and without history of neonatal indirect nonhemolytic hyperbilirubinemia. METHODS: In a case-control study, the developmental status of 18-month-old children referred to Azadshar primary health care center in Yazd, Iran, between December 2007 and June 2009 was evaluated via the Persian version of Ages and Stages Questionnaires (ASQ). Children in the case group were healthy term neonates with total serum bilirubin level of 20-25 mg/dl, birth weight of 2500-4000 g and no birth asphyxia who were admitted to hospital and had undergone phototherapy. The control group consisted of children who were healthy term neonates without history of neonatal hyperbilirubinemia. RESULTS: 112 children (56 in each group) were evaluated. Four children in the case group and one in the control group had delay in communication skills. Three in the case group and three in the control group had fine motor delay. Only one child in the case group showed delay in problem solving. Statistically significant differences were not seen in the frequency of developmental delay as well as in the mean scores of all developmental domains in both groups. CONCLUSION: Based on the results of the present study by ASQ, the developmental status at the age of 18 months of healthy term neonates with moderate unconjugated hyperbilirubinemia was not different from the control group.

Intractable neonatal jaundice due to hereditary spherocytosis and Gilbert's syndrome.

In this article the authors present a case of pathological neonatal jaundice resistant to phototherapy in a baby with a family history of Gilbert's syndrome and hereditary spherocytosis. Her presentation was ultimately explained with a diagnosis of both conditions, and required treatment with phenobarbitone. The authors discuss the mechanism by which Gilbert's syndrome results in hyperbilirubinaemia and its similarities with Crigler-Najjar syndrome. The presentation of hereditary spherocystosis in the neonatal period is also explored, as is the mechanism of exaggerated hyperbilirubinaemia when the two conditions co-exist.

Familial unconjugated hyperbilirubinemia syndromes.

Our understanding of the biochemical defects underlying the hepatic forms of congenital, unconjugated hyperbilirubinemias has been greatly enhanced over the past decade. This is mostly due to the availability of pure, labeled bilirubin, the appropriate kinetic analyses, and a better understanding of the mechanisms underlying bilirubin conjugation. Although it is quite obvious that the defect underlying Gilbert's and Crigler-Najjar syndromes is deficient glucuronidation, the molecular explanation may eventually be found in altered composition of the microsomal lipids rather than in a protein defect of glucuronyl transferase. The recognition that Gilbert's syndrome is a quite heterogeneous entity will allow a better understanding of the mode of inheritance of this disorder; its relationship to Crigler-Najjar type II disease also awaits further definition. It is hoped that definition of the molecular defect in Crigler-Najjar type I will lead to better therapeutic modalities, but this remains to be seen.