The Natural History of Advanced Fibrosis Due to Nonalcoholic Steatohepatitis: Data From the Simtuzumab Trials
The Natural History of Advanced Fibrosis Due to Nonalcoholic Steatohepatitis: Data From the Simtuzumab Trials
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DOI：
10.1002/hep.30664
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发表时间：
2019-12-01
期刊：
影响因子：
13.5
通讯作者：
Goodman, Zachary
中科院分区：
文献类型：
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作者：
Sanyal, Arun J.;Harrison, Stephen A.;Goodman, Zachary
非酒精性脂肪性肝炎（NASH）的进展特征不完全。我们分析了475例NASH伴桥接纤维化（F3）或代偿性肝硬化（F4）患者的肝组织学、肝静脉压差（HVPG）和血清纤维化标志物的纵向变化数据，这些患者参加了两项2b期安慰剂对照的辛妥珠单抗试验。由于缺乏疗效，试验在96周后终止，因此合并了治疗组的数据。在筛选时以及第48周和第96周采集肝活检和HVPG测量值（仅F4纤维化患者）。评估患者的Ishak纤维化分期、肝胶原含量和α-平滑肌肌动蛋白（通过形态测定法）、NAFLD活动评分（NAS）和纤维化血清标志物。确定与进展为肝硬化（F3纤维化患者）和肝脏相关临床事件（F4纤维化患者）的相关性。22%（48/217）的F3患者进展为肝硬化，19%（50/258）的肝硬化患者发生肝脏相关临床事件。与肝硬化进展显著相关的因素包括肝胶原含量、α-平滑肌肌动蛋白水平和增强型肝纤维化评分的基线值较高和增加较大。类似因素，加上缺乏纤维化分期改善（风险比，9.30; 95%置信区间，1.28-67.37），基线时HVPG较高，HVPG随时间增加较大，与肝硬化患者肝脏相关临床事件风险增加相关。疾病进展与基线时的NAS或校正纤维化分期后治疗期间NAS的变化无关。结论：在NASH导致的晚期纤维化患者中，临床疾病进展的主要决定因素是纤维化及其随时间的变化。
Progression of nonalcoholic steatohepatitis (NASH) is incompletely characterized. We analyzed data on longitudinal changes in liver histology, hepatic venous pressure gradient (HVPG), and serum markers of fibrosis in 475 patients with NASH with bridging fibrosis (F3) or compensated cirrhosis (F4) enrolled in two phase 2b, placebo-controlled trials of simtuzumab. The trials were terminated after 96 weeks because of lack of efficacy, so data from treatment groups were combined. Liver biopsies and HVPG measurements (only for patients with F4 fibrosis) were collected at screening and at weeks 48 and 96. Patients were assessed for Ishak fibrosis stage, hepatic collagen content and alpha-smooth muscle actin (by morphometry), NAFLD Activity Score (NAS), and serum markers of fibrosis. Associations with progression to cirrhosis (in patients with F3 fibrosis) and liver-related clinical events (in patients with F4 fibrosis) were determined. Progression to cirrhosis occurred in 22% (48/217) of F3 patients, and liver-related clinical events occurred in 19% (50/258) of patients with cirrhosis. Factors significantly associated with progression to cirrhosis included higher baseline values of and greater increases in hepatic collagen content, level of alpha-smooth muscle actin, and Enhanced Liver Fibrosis score. Similar factors, plus lack of fibrosis stage improvement (hazard ratio, 9.30; 95% confidence interval, 1.28-67.37), higher HVPG at baseline, and greater increase in HVPG over time, were associated with an increased risk of liver-related clinical events in patients with cirrhosis. Disease progression was not associated with the NAS at baseline or changes in NAS during treatment after adjustment for fibrosis stage. Conclusion: In patients with advanced fibrosis due to NASH, the primary determinant of clinical disease progression is fibrosis and its change over time.