Service de Gastroentérologie et Hépatologie Pédiatrique.
Centre de Génétique Humaine.
Hepatology. 2015 Jul;62(1):198-206. doi: 10.1002/hep.27834. Epub 2015 May 12.
We investigated predictors of clinical evolution in progressive familial intrahepatic cholestasis type 2 patients and how they relate to bile salt export pump (BSEP) expression and its (re)targeting. Our retrospective study included 22 children with progressive familial intrahepatic cholestasis type 2. Clinical, biochemical, and histological characteristics were reviewed on admittance and following treatment with either ursodeoxycholic acid alone (10 mg/kg thrice daily, n = 19) or partial biliary diversion (n = 3). Immunostaining of BSEP was performed in 20 patients. Response to treatment was defined as normalization of pruritus, disappearance of jaundice, and alanine aminotransferase (ALT) levels <1.5 times the upper limit of normal. Ten of 22 patients were responders, and paired biopsies were available in six. De novo or retargeted canalicular expression of BSEP occurred in four of these six, two of whom exhibited baseline intracellular expression. Twelve of 22 were nonresponders and exhibited earlier onset of jaundice (<9 months), neonatal cholestasis, and higher ALT levels. An ALT >165 IU/L produced 72% sensitivity and 55% specificity in predicting nonresponse. Seven patients were still responding at last follow-up (median = 20 months, range 5-67 months). Three responders relapsed after 56, 72, and 82 months, respectively. Of nine surviving responders, median relapse-free survival time was 72 months (95% confidence interval 48-96 months) and 5-year relapse-free survival was 75% (95% confidence interval 33-100%). Intracellular BSEP at baseline was seen in six, of whom five were responders. Genetic analysis was performed in 17 of 22, confirming diagnosis in 13 (76%) and in four (24%) in whom only heterozygous mutation was identified.
De novo or retargeted canalicular expression of BSEP occurs in treatment responders; children with late-onset presentation, lower ALT, and intracellular BSEP expression are likely to respond, at least transiently, to nontransplant treatment.
研究进行性家族性肝内胆汁淤积症 2 型（PFIC2）患者临床演变的预测因素及其与胆盐输出泵（BSEP）表达及其（再）靶向的关系。
我们的回顾性研究纳入了 22 例 PFIC2 患儿。入院时和接受熊去氧胆酸（UDCA）单独治疗（10 mg/kg，每日 3 次，n=19）或部分胆汁分流术（n=3）治疗后，回顾性分析了临床、生化和组织学特征。对 20 例患者进行了 BSEP 免疫染色。以瘙痒、黄疸消退和丙氨酸氨基转移酶（ALT）水平<正常上限的 1.5 倍作为治疗反应的定义。22 例患者中 10 例为应答者，其中 6 例获得配对活检。在这 6 例中，有 4 例出现新的或再靶向的胆小管 BSEP 表达，其中 2 例有基线细胞内表达。22 例患者中 12 例为无应答者，其表现为更早出现黄疸（<9 个月）、新生儿胆汁淤积和更高的 ALT 水平。ALT>165 IU/L 对预测无应答的敏感性为 72%，特异性为 55%。7 例患者在最后一次随访时仍有应答（中位随访时间 20 个月，范围 5-67 个月）。3 例应答者分别在 56、72 和 82 个月后复发。9 例存活应答者中，中位无复发生存时间为 72 个月（95%置信区间 48-96 个月），5 年无复发生存率为 75%（95%置信区间 33-100%）。基线时出现细胞内 BSEP 的有 6 例，其中 5 例为应答者。对 22 例中的 17 例进行了基因分析，证实了 13 例（76%）的诊断，4 例（24%）仅发现杂合突变。
新的或再靶向的胆小管 BSEP 表达发生在治疗应答者中；出现晚期发病、较低的 ALT 和细胞内 BSEP 表达的患儿可能对非移植治疗有应答，至少是短暂应答。
