Persico M, Persico E, Bakker C T, Rigato I, Amoroso A, Torella R, Bosma P J, Tiribelli C, Ostrow J D
Internal Medicine and Hepatology Unit, II, University of Naples, Italy.
Hepatology. 2001 Mar;33(3):627-32. doi: 10.1053/jhep.2001.22499.
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.
尽管在吉尔伯特综合征（GS）中，由于胆红素UDP-葡萄糖醛酸基转移酶1（UGT1A1）基因启动子的TATA框中多了一个TA，导致胆红素葡萄糖醛酸化受损，但许多GS纯合子并无非结合性高胆红素血症。因此，表型表达可能需要胆红素转运方面的额外缺陷。对以下人群测定了血浆胆红素和低剂量四溴酚酞磺酸钠（0.59微摩尔/千克）的早期肝摄取分数率（BSP K(1)）：（1）15例无亲缘关系的非结合性高胆红素血症患者加12名随机对照者；（2）4例无亲缘关系的GS先证者及其15名一级亲属；（3）7例因轻度β地中海贫血导致溶血的无亲缘关系患者。通过对两个UGT1A1等位基因启动子区域进行DNA测序对受试者进行分类。在第1组中，GS纯合子的血浆胆红素水平与BSP K(1)之间呈现高度显著的负线性相关。GS患者与正常受试者的BSP K(1)值有相当大的重叠，而在第2组中，这些值在家族内部聚集，并在家族之间明显分开。溶血患者尽管血浆胆红素水平升高，但其平均BSP K(1)值与正常受试者相似。在每个具有明确UGT1A1突变的GS亚组中，血浆胆红素水平部分由有机阴离子摄取率决定，通过低剂量BSP的早期血浆清除来评估。GS中较低的BSP摄取并非高胆红素血症的继发结果，而可能是由肝脏转运机制中一个（或多个）独立的、基因决定的缺陷所致，BSP和胆红素共享这一缺陷，这可能是GS表型表达所必需的。
