吉尔伯特综合征:高胆红素血症是敌人还是朋友

Gilbert's syndrome:hyperbilirubinemia enemy or friend

吉尔伯特综合征是一种胆红素结合障碍的良性遗传性疾病。主要是由于尿苷二磷酸葡萄糖醛酸转移酶1A1(UGT1A1)基因启动子中的纯合多态性A(TA)7TAA插入启动子UGT1A1*28中,使UGT活性降低至正常值的30%,不能将循环中的脂溶性间接胆红素转化为水溶性的结合胆红素导致高间接胆红素血症。胆红素对红细胞膜磷脂有很强的亲和力,并且可以干扰膜的组成和动力学,使红细胞的脆性增加,容易破裂,存活时间逐渐缩短,但没有明显溶血或铁代谢异常的迹象,红细胞和骨髓形态保持正常。慢性少量的溶血,可能刺激髓外(骨髓形态保持正常)造血活跃,代偿性增加循环中红细胞和血红蛋白的量;高胆红素血症也有可能减弱胃肠动力,增加肠黏膜的跨上皮被动扩散吸收胆红素,使循环胆红素增加1.5~2.0倍,加重或恶化间接胆红素为主的高胆红素血症。由此可见,吉尔伯特综合征患者循环胆红素浓度与红细胞的快速周转和溶血的速度互为因果关系。有趣的是,胆红素还具有显著的抗氧化和抗诱变活性,轻度高胆红素血症潜在的保健作用,包括降低心血管疾病、2型糖尿病(及相关危险因素)、一些癌症的患病率,以及心血管疾病和吉尔伯特综合征相关的全因死亡率。外源性胆红素和胆绿素补充剂可以被肠上皮细胞吸收,并可能增加这些抗氧化剂化合物的循环浓度。通过这些信息,我们希望提高对良性高胆红素血症潜在的有害和有益影响的认识,探索和开发有益的医疗干预措施。

Gilbert’s syndrome is a kind of benign inherited disease of bilirubin binding disorder,mainly due to the homozygous polymorphism A(TA)7TAA in the promoter of the gene for uridine diphosphate-glucuronosyltransferase 1A1(UGT1A1),which is a TA insertion into the promoter,designated as UGT1A1*28,with UGT activity reduction to 30%of the normal value.Therefore,circulating fat-soluble unconjugated bilirubin cannot be converted into water-soluble conjugated bilirubin,leading to unconjugated hyperbilirubinemia.Bilirubin has a strong affinity for erythrocyte phospholipids,which interferes with membrane composition and dynamics,resulting in increased erythrocytes fragility,easy rupture,and gradual shortening of survival time.However,there are no obvious sign of hemolysis or abnormal iron metabolism,erythrocytes and bone marrow morphology.A small amount of chronic hemolysis stimulates extramedullary(normal bone marrow morphology)hematopoiesis,ensuing compensatory increase in circulating erythrocytes and hemoglobin.Hyperbilirubinemia may also weaken gastrointestinal motility,increase passive diffusion and absorption across the intestinal mucosal epithelium by 1.5 to 2 times,thereby aggravating or worsening hyperbilirubinemia mainly with unconjugated bilirubin circulation,which indicates that there is a causal relationship between the circulating bilirubin concentration and rapid erythrocytes turnover and hemolysis rate in patients with Gilbert’s syndrome.Interestingly,bilirubin also has significant antioxidant and anti-mutagenic activities,and the potential health benefits of mild hyperbilirubinemia in Gilbert's syndrome include reduced prevalence of cardiovascular disease,type 2 diabetes mellitus(and related risk factors),certain cancers,and cardiovascular-related and allcause mortality.Exogenous bilirubin and biliverdin supplements in intestinal epithelial cells can be absorbed and may increase circulating concentration of these antioxidant compounds.With this information,we hope to raise awareness of the potentially harmful and beneficial effects of benign hyperbilirubinemia,and explore and develop beneficial medical interventions.