Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, S1-172, University of Amsterdam, Meibergdreef 69, 1105BK, Amsterdam, The Netherlands,
Clin Rev Allergy Immunol. 2015 Jun;48(2-3):243-53. doi: 10.1007/s12016-014-8454-7.
Jaundice results from the systemic accumulation of bilirubin, the final product of the catabolism of haem. Inherited liver disorders of bilirubin metabolism and transport can result in reduced hepatic uptake, conjugation or biliary secretion of bilirubin. In patients with Rotor syndrome, bilirubin (re)uptake is impaired due to the deficiency of two basolateral/sinusoidal hepatocellular membrane proteins, organic anion-transporting polypeptide 1B1 (OATP1B1) and OATP1B3. Dubin-Johnson syndrome is caused by a defect in the ATP-dependent canalicular transporter, multidrug resistance-associated protein 2 (MRP2), which mediates the export of conjugated bilirubin into bile. Both disorders are benign and not progressive and are characterised by elevated serum levels of mainly conjugated bilirubin. Uridine diphospho-glucuronosyl transferase 1A1 (UGT1A1) is responsible for the glucuronidation of bilirubin; deficiency of this enzyme results in unconjugated hyperbilirubinaemia. Gilbert syndrome is the mild and benign form of inherited unconjugated hyperbilirubinaemia and is mostly caused by reduced promoter activity of the UGT1A1 gene. Crigler-Najjar syndrome is the severe inherited form of unconjugated hyperbilirubinaemia due to mutations in the UGT1A1 gene, which can cause kernicterus early in life and can be even lethal when left untreated. Due to major disadvantages of the current standard treatments for Crigler-Najjar syndrome, phototherapy and liver transplantation, new effective therapeutic strategies are under development. Here, we review the clinical features, pathophysiology and genetic background of these inherited disorders of bilirubin metabolism and transport. We also discuss the upcoming treatment option of viral gene therapy for genetic disorders such as Crigler-Najjar syndrome and the possible immunological consequences of this therapy.
黄疸是由于胆红素在体内的系统性积累引起的，胆红素是血红素分解代谢的终产物。胆红素代谢和转运的遗传性肝脏疾病可导致胆红素的肝脏摄取、结合或胆汁分泌减少。在 Rotor 综合征患者中，由于两种基底外侧/窦状肝细胞膜蛋白，即有机阴离子转运多肽 1B1（OATP1B1）和 OATP1B3 的缺乏，胆红素（再）摄取受损。Dubin-Johnson 综合征是由多药耐药相关蛋白 2（MRP2）的缺陷引起的，该蛋白是一种依赖于 ATP 的细胞管转运蛋白，介导结合胆红素向胆汁的输出。这两种疾病都是良性和非进行性的，其特征是血清中主要结合胆红素水平升高。尿苷二磷酸葡萄糖醛酸转移酶 1A1（UGT1A1）负责胆红素的葡萄糖醛酸化；该酶的缺乏导致未结合的高胆红素血症。Gilbert 综合征是遗传性未结合高胆红素血症的轻度良性形式，主要是由于 UGT1A1 基因启动子活性降低引起的。Crigler-Najjar 综合征是由于 UGT1A1 基因突变引起的遗传性未结合高胆红素血症的严重形式，可导致新生儿期核黄疸，并在未经治疗时甚至致命。由于 Crigler-Najjar 综合征的当前标准治疗方法——光疗和肝移植存在重大缺点，因此正在开发新的有效治疗策略。在这里，我们回顾了这些胆红素代谢和转运遗传性疾病的临床特征、病理生理学和遗传背景。我们还讨论了针对 Crigler-Najjar 综合征等遗传疾病的病毒基因治疗的即将到来的治疗选择，以及这种治疗的可能免疫后果。
