Pediatric Gastroenterology and Hepatology, University Medical Centre Groningen, University of Groningen, The Netherlands.
King's College London, United Kingdom.
J Hepatol. 2020 Jul;73(1):84-93. doi: 10.1016/j.jhep.2020.02.007. Epub 2020 Feb 20.
BACKGROUND & AIMS: Mutations in ABCB11 can cause deficiency of the bile salt export pump (BSEP), leading to cholestasis and end-stage liver disease. Owing to the rarity of the disease, the associations between genotype and natural history, or outcomes following surgical biliary diversion (SBD), remain elusive. We aimed to determine these associations by assembling the largest genetically defined cohort of patients with severe BSEP deficiency to date.
This multicentre, retrospective cohort study included 264 patients with homozygous or compound heterozygous pathological ABCB11 mutations. Patients were categorized according to genotypic severity (BSEP1, BSEP2, BSEP3). The predicted residual BSEP transport function decreased with each category.
Genotype severity was strongly associated with native liver survival (NLS, BSEP1 median 20.4 years; BSEP2, 7.0 years; BSEP3, 3.5 years; p <0.001). At 15 years of age, the proportion of patients with hepatocellular carcinoma was 4% in BSEP1, 7% in BSEP2 and 34% in BSEP3 (p = 0.001). SBD was associated with significantly increased NLS (hazard ratio 0.50; 95% CI 0.27-0.94: p = 0.03) in BSEP1 and BSEP2. A serum bile acid concentration below 102 μmol/L or a decrease of at least 75%, each shortly after SBD, reliably predicted NLS of ≥15 years following SBD (each p <0.001).
The genotype of severe BSEP deficiency strongly predicts long-term NLS, the risk of developing hepatocellular carcinoma, and the chance that SBD will increase NLS. Serum bile acid parameters shortly after SBD can predict long-term NLS.
This study presents data from the largest genetically defined cohort of patients with severe bile salt export pump deficiency to date. The genotype of patients with severe bile salt export pump deficiency is associated with clinical outcomes and the success of therapeutic interventions. Therefore, genotypic data should be used to guide personalized clinical care throughout childhood and adulthood in patients with this disease.
ABCB11 基因突变可导致胆汁盐输出泵（BSEP）缺陷，引起胆汁淤积和终末期肝病。由于该疾病罕见，基因型与自然史之间的关联，或外科胆管分流术（SBD）后的结果仍难以确定。我们旨在通过汇集迄今为止最大的遗传性定义的严重 BSEP 缺陷患者队列来确定这些关联。
这项多中心、回顾性队列研究纳入了 264 名纯合子或复合杂合病理性 ABCB11 突变患者。根据基因型严重程度（BSEP1、BSEP2、BSEP3）对患者进行分类。每个分类的预测残留 BSEP 转运功能都会降低。
基因型严重程度与肝内生存（NLS）密切相关（BSEP1 的中位 NLS 为 20.4 年；BSEP2 为 7.0 年；BSEP3 为 3.5 年；p<0.001）。在 15 岁时，BSEP1 患者中肝细胞癌的比例为 4%，BSEP2 为 7%，BSEP3 为 34%（p=0.001）。SBD 与 BSEP1 和 BSEP2 患者显著增加的 NLS 相关（风险比 0.50；95%CI 0.27-0.94：p=0.03）。SBD 后短期内血清胆汁酸浓度低于 102 μmol/L 或至少降低 75%，可可靠预测 SBD 后 NLS 至少 15 年（均 p<0.001）。
严重 BSEP 缺陷的基因型强烈预测长期 NLS、发生肝细胞癌的风险以及 SBD 增加 NLS 的机会。SBD 后短期内的血清胆汁酸参数可预测长期 NLS。
本研究提供了迄今为止最大的遗传性定义的严重胆汁盐输出泵缺陷患者队列的数据。严重胆汁盐输出泵缺陷患者的基因型与临床结果和治疗干预的效果相关。因此，基因型数据应在疾病的整个儿童期和成年期用于指导患者的个体化临床护理。
