Jaundice in Older Children and Adolescents

Dear Dr. WSahbeh: Thank you for your interest in our review of jaundice in older children & adolescents. You are quite correct to point out the confusion in the medical literature regarding the genetics of Gilbert disease. Although a familial pattern of inheritance has been well recognized ever since itys original description, many of the biochemical and kinetics studies of bilirubin metabolism among the population of patients classified as having Gilbert disease have demonstrated significant metabolic heterogeneity. Indeed, based on these earlier studies, some experts have postulated that Gilbert syndrome, Crigler-Najjar type 1, and Crigler Najjar type II represent a spectrum of inherited conditions associated either with homogygous or with compound heterozygous states of different alleles within the uridinediphosphoglucuronate glucoronosyl transferases (UGTs) family (1).

With the recent characterization of the UGT1A gene locus, the molecular basis for each of these disorders has now been established (2,3). The mutation responsible for Gilbert syndrome is in the promoter region upstream to exon 1 of the gene encoding bilirubin UGT. The normal sequence of the TATAA element within the promoter has sic tandem repeats (A(TA)6TAA). Patients who have Gilbert syndrome are homozygous for a longer version of the TATAA sequence (A(TA)7TAA), which in turn, causes reduced production of the bilirubin UGT. Thus, its inheritance is most consistent with an autosomal recessive pattern. This defect is different from that in the Crigler Najjar syndromes in which bilirubin -UGT is either absent or produced in an abnormal form with reduced or no activity, due to mutations in structural region of the UGT1A gene.

Approximately 9% of the general population in the Western world are homozygous for the Gilbert type variant promoter, and the gene frequency is approximately 30%. Gilbert syndrome manifests only in people who are homogous for the variant promoter. However, other factors are probably involved in the phenotypic expression of Gilbert's, since not all patients who are homozygous for the variant promoter develop hyperbilirubinemia. Indeed, the Gilbert phenotype is seen in only 4% to 7% of the general population. To confuse matters even more, because of the high gene frequency for the Gilbert type promoter, heterozygote carriers of Crigler Najjar type mutations might also carry an allele of the Gilbert type promoter and have phenotypic hyperbilirubinemia due to compound heterozygosity (3). Perhaps as we continue to unravel the genetics of the hereditary hyperbilirubinemias, we may find that gbenetic heterogeneity with coexistence of a Gilbert-tyupe promoter and mutations in the structural region of the UGT1A gene are the most common inherited cause of intermediate grade gyperbilirubinemia in the North American population.

Richard A. Schreiber, MD

References: 1. Owens IS, Ritter JK. The novel bilirubin/phenol UDP-glucuronosyltransferase UGT1 gene locus: Implications for multiple nonhemolytic familial hyperbilirubinemia phenotypes. Pharmacogenetics.1992;2:93-108 2. Bosma PJ, Chowdhury JR, Bakker C, et al. The genetic basis of the reduced expression of bilirubin uDP-glucoronosyltransferase 1 in Gilbert syndrome. NEJM.1995;333:1171-1175 3. Bosma PJ, Chowdhury JR, Jansen PHM. Genetic inhyeritance of Gilbert's syndrome. Lancet.1995;346:314-315 4. Kadakol A, Sappal BS, Ghosh SS, et al. Interaction of coding region mutations and the Gilbert type promoter abnormality of the UGT1A1 gene causes moderate degrees of unconjugated hyperbilirubinemia and may lead to kernicterus. J Med Gen.2001;38:244-249