In Children With Nonalcoholic Fatty Liver Disease, Cysteamine Bitartrate Delayed Release Improves Liver Enzymes but Does Not Reduce Disease Activity Scores
In Children With Nonalcoholic Fatty Liver Disease, Cysteamine Bitartrate Delayed Release Improves Liver Enzymes but Does Not Reduce Disease Activity Scores
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DOI：
10.1053/j.gastro.2016.08.027
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发表时间：
2016-12-01
期刊：
影响因子：
29.4
通讯作者：
Doo, Edward
中科院分区：
文献类型：
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作者：
Schwimmer, Jeffrey B.;Lavine, Joel E.;Doo, Edward
背景与目的：监管机构尚未批准非酒精性脂肪性肝病(NAFLD)的治疗方法。我们进行了一项随机对照试验，以确定52周的半胱胺重酒石酸盐延迟释放(CBDR)是否降低了NAFLD儿童肝脏疾病的严重程度。方法：我们在10个中心对169名NAFLD活动度评分在4或更高的儿童进行了双盲试验。从2012年6月至2014年1月，患者被随机分配到接受CBDR或安慰剂治疗，每天两次(体重65-80公斤的患者服用300毫克，体重80公斤的患者服用450毫克)，持续52周。意向治疗分析的主要结果是在52周后肝脏组织学有所改善，定义为NAFLD活动评分下降2分或更多而没有恶化纤维化；52周起没有活检标本的患者(CBDR组17例，安慰剂组6例)被认为无反应。我们使用Cochran-Mantel-Haenszel分层分析计算改善的相对风险(RR)。结果：两组之间的主要结果没有显著差异(CBDR组28%的儿童与安慰剂组的22%；RR，1.3；95%可信区间[CI]，0.8-2.1；P=.34)。然而，接受CBDR治疗的儿童在预先指定的次要结果中发生了重大变化：丙氨酸转氨酶(安慰剂组为53+/-88U/L比8+/-77U/L；P=.02)和天冬氨酸转氨酶(安慰剂组为31+/-52比4+/-36U/L；P=.008)的平均水平降低，而且有更大比例的患者小叶炎症减轻(CBDR组为36%比安慰剂组的21%；RR为1.8；95%CI为1.1-2.9；P=.03)。在对体重不超过65公斤的儿童进行的一项特别分析中，服用CBDR的儿童组织学改善的机会是服用CBDR的儿童的4倍(在CBDR组中观察到50%的儿童比在安慰剂组中观察到的13%；RR，4.0；95%CI，1.3-12.3；P=.005)。结论：在一项随机试验中，我们发现，与安慰剂相比，CBDR治疗1年并不会降低儿童NAFLD的总体组织学标志。然而，接受CBDR治疗的儿童血清转氨酶水平和小叶炎症显著降低。
BACKGROUND & AIMS: No treatment for nonalcoholic fatty liver disease (NAFLD) has been approved by regulatory agencies. We performed a randomized controlled trial to determine whether 52 weeks of cysteamine bitartrate delayed release (CBDR) reduces the severity of liver disease in children with NAFLD. METHODS: We performed a double-masked trial of 169 children with NAFLD activity scores of 4 or higher at 10 centers. From June 2012 to January 2014, the patients were assigned randomly to receive CBDR or placebo twice daily (300 mg for patients weighing 65 to 80 kg, and 450 mg for patients weighing >80 kg) for 52 weeks. The primary outcome from the intention-to-treat analysis was improvement in liver histology over 52 weeks, defined as a decrease in the NAFLD activity score of 2 points or more without worsening fibrosis; patients without biopsy specimens from week 52 (17 in the CBDR group and 6 in the placebo group) were considered nonresponders. We calculated the relative risks (RR) of improvement using a stratified Cochran-Mantel-Haenszel analysis. RESULTS: There was no significant difference between groups in the primary outcome (28% of children in the CBDR group vs 22% in the placebo group; RR, 1.3; 95% confidence interval [CI], 0.8-2.1; P = .34). However, children receiving CBDR had significant changes in prespecified secondary outcomes: reduced mean levels of alanine aminotransferase (reduction, 53 +/- 88 U/L vs 8 +/- 77 U/L in the placebo group; P = .02) and aspartate aminotransferase (reduction, 31 +/- 52 vs 4 +/- 36 U/L in the placebo group; P = .008), and a larger proportion had reduced lobular inflammation (36% in the CBDR group vs 21% in the placebo group; RR, 1.8; 95% CI, 1.1-2.9; P = .03). In a post hoc analysis of children weighing 65 kg or less, those taking CBDR had a 4-fold better chance of histologic improvement (observed in 50% of children in the CBDR group vs 13% in the placebo group; RR, 4.0; 95% CI, 1.3-12.3; P = .005). CONCLUSIONS: In a randomized trial, we found that 1 year of CBDR did not reduce overall histologic markers of NAFLD compared with placebo in children. Children receiving CBDR, however, had significant reductions in serum aminotransferase levels and lobular inflammation.