Although in
Gilbert's syndrome (GS),
bilirubin glucuronidation is impaired due to an extra TA in the TATA box of the promoter of the gene for
bilirubin UDP-glucuronosyltransferase 1 (UGT1A1), many GS homozygotes lack unconjugated
hyperbilirubinemia. Accordingly, an additional defect in
bilirubin transport might be required for phenotypic expression. Plasma
bilirubin and the early fractional hepatic uptake rate (BSP K(1)) of a low dose of tetrabromosulfophthalein (0.59 micromol/kg) were determined in (1) 15 unrelated patients with unconjugated
hyperbilirubinemia plus 12 random controls; (2) 4 unrelated GS probands and 15 of their first-degree relatives; (3) 7 unrelated patients with
hemolysis due to
beta-Thalassemia minor. Subjects were classified by
DNA sequencing of the promoter region of both UGT1A1 alleles. In group 1, GS homozygotes showed a highly significant negative linear correlation between plasma
bilirubin levels and BSP K(1). BSP K(1) values overlapped considerably between GS and normal subjects, whereas, in group 2, they were clustered within, and sharply segregated among, families. Patients with
hemolysis, despite elevated plasma
bilirubin levels, had mean BSP K(1) values similar to the normal subjects. Within each GS subgroup with defined UGT1A1 mutations, the plasma
bilirubin level is in part determined by the organic
anion uptake rate, assessed by early plasma disappearance of low-dose BSP. The lower BSP uptake in GS is not secondary to the
hyperbilirubinemia, but probably caused by (an) independent, genetically determined defect(s) in hepatic transport mechanism(s), shared by BSP and
bilirubin, that are likely necessary for phenotypic expression of GS.