Heubi James E, Bove Kevin E, Setchell Kenneth D R
*Division of Pediatric Gastroenterology, Hepatology and Nutrition †Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
J Pediatr Gastroenterol Nutr. 2017 Sep;65(3):321-326. doi: 10.1097/MPG.0000000000001657.
Patients with bile acid synthesis disorders (BASDs) due to single enzyme defects (SEDs) or Zellweger spectrum disorders (ZSDs) accumulate hepatotoxic atypical bile acids resulting in potentially fatal progressive liver disease. We evaluated the efficacy and safety of oral cholic acid in patients with BASD.
In this phase 3, open-label, single-arm, nonrandomized, noncomparative study conducted over 18 years, patients were administered cholic acid orally 10 to 15 mg · kg · day. The primary efficacy variables were changes from pre- to post-treatment in atypical urinary bile acids, liver chemistries (serum aspartate aminotransferase, alanine aminotransferase), and height and weight. Additional efficacy variables included changes in serum bilirubin and liver histology.
Of the 85 enrolled patients (63 with SED and 22 with ZSD), 79 received at least 1 dose of study medication; 70 patients (50 with SED and 20 with ZSD) were included in the modified intent-to-treat dataset. Cholic acid significantly improved urine bile acid metabolite scores (P < 0.0001) and serum aspartate aminotransferase and alanine aminotransferase (P < 0.0001) in patients with SED and ZSD. Cholic acid also improved height and weight percentiles in both groups, but only the change in weight was significant (P < 0.05). Serum direct bilirubin decreased significantly post-treatment (P < 0.001) in the intent-to-treat population, and liver biopsies showed either stable findings or histologic improvement in all parameters except bridging fibrosis. The overall safety profile of cholic acid was favorable, with no study drug-related serious adverse events or drug-related deaths reported.
Oral cholic acid is a safe, efficacious, and well-tolerated treatment for BASD due to SED and ZSD.
因单酶缺陷（SED）或泽尔韦格谱病（ZSD）导致胆汁酸合成障碍（BASD）的患者会蓄积具有肝毒性的非典型胆汁酸，从而引发可能致命的进行性肝病。我们评估了口服胆酸对BASD患者的疗效和安全性。
在这项为期18年的3期开放标签、单臂、非随机、非对照研究中，患者口服胆酸，剂量为10至15毫克·千克·天。主要疗效变量为治疗前后非典型尿胆汁酸、肝脏生化指标（血清天冬氨酸转氨酶、丙氨酸转氨酶）以及身高和体重的变化。其他疗效变量包括血清胆红素和肝脏组织学的变化。
在85名入组患者中（63名SED患者和22名ZSD患者），79名接受了至少1剂研究药物；70名患者（50名SED患者和20名ZSD患者）被纳入改良意向性治疗数据集。胆酸显著改善了SED和ZSD患者的尿胆汁酸代谢物评分（P<0.0001）以及血清天冬氨酸转氨酶和丙氨酸转氨酶（P<0.0001）。胆酸还改善了两组患者的身高和体重百分位数，但只有体重变化具有统计学意义（P<0.05）。在意向性治疗人群中，治疗后血清直接胆红素显著降低（P<0.001），肝脏活检显示除桥接纤维化外，所有参数的结果均稳定或组织学有所改善。胆酸的总体安全性良好，未报告与研究药物相关的严重不良事件或药物相关死亡。
口服胆酸是治疗因SED和ZSD导致的BASD的一种安全、有效且耐受性良好的疗法。
