慢性乙型肝炎患者肝脏硬度值下降趋势与肝纤维化逆转结局的关系

Association between the reduction in liver stiffness measurement and the histological outcome of liver fibrosis regression in patients with chronic hepatitis B

目的 分析抗病毒治疗中慢性乙型肝炎患者肝脏硬度值变化趋势与肝纤维化逆转结局的相关性。方法 基于恩替卡韦初治慢性乙型肝炎患者临床随访队列(2013年7月-2015年9月),检测基线和治疗中每半年HBV DNA水平、肝功能、肝脏硬度值。根据更为严格的标准将治疗前后Ishak评分变化分为3组:确定逆转组,Ishak评分下降≥2;不确定组,Ishak评分下降0~1;进展组,Ishak评分升高>1。多组间比较采用单因素方差分析。采用分段线性混合模型拟合不同肝纤维化逆转结局的慢性乙型肝炎患者肝脏硬度值下降趋势,斜率的显著性及不同组间斜率的比较采用t检验。结果 共纳入239例慢性乙型肝炎患者,恩替卡韦治疗1.5年后,18例患者(7.5%)达到肝纤维化组织学确定逆转、196例(82.0%)为不确定、25例(10.5%)为进展。开始抗病毒治疗半年内肝脏硬度值下降率:确定逆转组为-36.3%[95%可信区间(95%CI):-52.8%^-19.7%],不确定组为-23.7%(95%CI:-29.7%^-17.8%),进展组为-12.6%(95%CI:-31.0%~5.9%)。在确定逆转组与不确定组,肝脏硬度值在治疗后的前6个月比治疗6个月后的下降速度更快(P值均<0.05)。结论 抗病毒治疗半年内肝脏硬度值的下降速度与肝纤维化逆转结局相关性较强,治疗半年时肝脏硬度值下降超过30%者发生肝纤维化确定逆转的可能性更大。

Objective To investigate the association between the change in liver stiffness measurement (LSM) and the histological outcome of liver fibrosis in patients with chronic hepatitis B (CHB) during antiviral therapy. Methods In a prospective cohort of CHB patients receiving entecavir-based therapy (from July 2013 to September 2015), HBV DNA, liver function, and LSM were measured at baseline and every 6 months during treatment. According to a more stringent criteria for the change in Ishak score after treatment, the patients were divided into definite regression group (a reduction of ≥2 in Ishak score), indeterminate group (a reduction of 0-1 in Ishak score), and progression group (an increase of >1 in Ishak score). A one-way analysis of variance was used for comparison between multiple groups. The piecewise linear mixed-effects model was used to evaluate the dynamic changes of LSM and its association with the histological outcome of liver fibrosis. The t-test was used for comparison of slope between groups. Results A total of 239 CHB patients were enrolled, and after 1.5 years of entecavir treatment, 18 patients (7.5%) achieved the histological outcome of definite regression of liver fibrosis, 196 (82.0%) achieved indeterminate regression, and 25 (10.5%) experienced progression. The rate of reduction in LSM within the first half year of antiviral therapy was -36.3% in the definite regression group (95% confidence interval [CI]: -52.8% to -19.7%), -23.7% in the indeterminate group (95%CI: -29.7% to -17.8%), and -12.6% (95%CI: -31.0% to 5.9%) in the progression group. In the definite regression group and the indeterminate group, the rate of reduction in LSM in the first 6 months of treatment was significantly higher than that thereafter (both P<0.05). Conclusion The rate of reduction in LSM is associated with the histological outcome of liver fibrosis within the first 6 months of antiviral therapy. The patients with >30% reduction in LSM after the first 6 months of antiviral therapy tend to have a higher probability of definite regression of liver fibrosis.