Hepatic uptake of organic anions affects the plasma bilirubin level in subjects with Gilbert's syndrome mutations in UGT1A1

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 bilirubi n UDP-glucuronosyltransferase 1 (UGT1A1), many GS homozygotes lack unconjug ated hyperbilirubinemia. Accordingly, an additional defect in bilirubin tra nsport might be required for phenotypic expression. Plasma bilirubin and th e early fractional hepatic uptake rate (BSP K-1) of a low dose of tetrabrom osulfophthalein (0.59 mu mol/kg) were determined in (1) 15 unrelated patien ts with unconjugated hyperbilirubinemia plus 12 random controls; (2) 4 unre lated GS probands and 15 of their first-degree relatives; (3) 7 unrelated p atients with hemolysis due to beta -Thalassemia minor. Subjects were classi fied by DNA sequencing of the promoter region of both UGT1A1 alleles. In gr oup 1, GS homozygotes showed a highly significant negative linear correlati on between plasma bilirubin levels and BSP K-1. BSP K-1 values overlapped c onsiderably between GS and normal subjects, whereas, in group 2, they were clustered within, and sharply segregated among, families. Patients with hem olysis, despite elevated plasma bilirubin levels, had mean BSP K-1 values s imilar 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 he patic transport mechanism(s), shared by BSP and bilirubin, that are likely necessary for phenotypic expression of GS.