乙型肝炎病毒相关肝硬化患者肝细胞癌风险评分验证

Verification of the risk score of hepatocellular carcinoma in patients with hepatitis B virus-associated liver cirrhosis

目的评估肝细胞癌预测评分(PAGE-B)和改良肝细胞癌预测评分(mPAGE-B)预测经核苷(酸)类似物(NA)治疗的乙型肝炎病毒(HBV)相关肝硬化患者肝细胞癌发生风险的准确性和实用性。方法回顾性收集2009年6月至2014年12月于福建医科大学附属第一医院肝病中心经NA治疗的707例HBV相关肝硬化患者临床资料并对患者进行随访,分析肝细胞癌发生的危险因素,比较PAGE-B(纳入参数包括血小板计数、年龄、性别)、mPAGE-B(纳入参数包括血小板计数、年龄、性别、白蛋白)、Child-Turcotte-Pugh(CTP)评分和天冬氨酸转氨酶与血小板计数比值指数(APRI)预测5年内肝细胞癌发生的受试者操作特征曲线下面积(AUROC),并对mPAGE-B和PAGE-B进行风险分层分析。采用多因素Cox回归分析、受试者操作特征曲线(ROC)、Mann-WhitneyU检验和Kaplan-Meier法进行统计学分析。结果707例患者年龄为(46.7±12.2)岁,其中男567例(80.2%)、女140例(19.8%);乙型肝炎e抗原阳性率为56.4%(399/707);PAGE-B为(15.90±4.24)分,mPAGE-B为(12.39±3.58)分,CTP评分为(6.88±2.15)分,APRI为1.80分(0.85分,3.79分)。707例患者随访(38.14±20.97)个月,肝细胞癌发病率为8.1%(57/707)。多因素Cox回归分析结果显示,高龄、血小板计数降低和HBV DNA定量降低是肝细胞癌发生的独立危险因素[Wald值=20.44、5.64、9.25,HR(95%置信区间)为1.056(1.031~1.081)、0.994(0.989~0.999)、0.769(0.649~0.911),P<0.001、=0.018、0.002]。PAGE-B、mPAGE-B、CTP评分、APRI预测5年内肝细胞癌发生的AUROC(95%置信区间)分别为0.708(0.639~0.778)、0.724(0.657~0.778)、0.576(0.500~0.652)、0.516(0.443~0.589)。mPAGE-B与PAGE-B预测5年内肝细胞癌发生的AUROC比较,APRI与CTP评分预测5年内肝细胞癌发生的AUROC比较,差异均无统计学意义(均P>0.05)。CTP评分预测5年内肝细胞癌发生的AUROC小于PAGE-B和mPAGE-B,差异均有统计学意义(Z=3.00、3.79,P=0.003、<0.001);APRI预测5年内肝细胞癌发生的AUROC均小于PAGE-B和mPAGE-B,差异均有统计学意义(Z=4.75、5.46,均P<0.001)。经PAGE-B评估为低危(<10分)组、中危(10~17分)组和高危(>17分)组分别为51例(7.2%)、394例(55.7%)和262例(37.1%),肝细胞癌发病率分别为0(0/51)、4.8%(19/394)和14.5%(38/262),年平均发病率分别为0、1.6%和5.5%,肝细胞癌5年累积发病率分别为0、7.3%、31.3%,高危组患者的肝细胞癌5年累积发病率高于中危组和低危组(log-rank检验值=19.27,P<0.001)。经mPAGE-B评估为低危(<9分)组、中危(9~12分)组和高危(>12分)组患者分别为97例(13.7%)、246例(34.8%)和364例(51.5%),肝细胞癌发病率分别为2.1%(2/97)、3.7%(9/246)和12.6%(46/364),年平均发病率分别为0.6%、1.1%和4.7%,肝细胞癌5年累积发病率分别为2.4%、5.1%、26.7%,高危组患者的肝细胞癌5年累积发病率高于中危组和低危组(log-rank检验值=18.64,P<0.001)。结论PAGE-B和mPAGE-B均可预测抗病毒治疗的HBV相关肝硬化患者5年内肝细胞癌的发生风险,筛查出肝细胞癌高风险的肝硬化患者,并指导临床医师应用更积极的筛查策略。

Objective To evaluate the accuracy and practicability of hepatocellular carcinoma prediction score(PAGE-B)and modified hepatocellular carcinoma prediction score(mPAGE-B)in predicting the development of hepatocellular carcinoma in patients with hepatitis B virus(HBV)-associated liver cirrhosis and received nucleos(t)ide analogue(NA)treatment.Methods From June 2009 to December 2014,at Department of Hepatology,the First Affiliated Hospital of Fujian Medical University,the clinical data of 707 patients with HBV-associated liver cirrhosis and received NA treatment were retrospectively collected,and the patients were followed up.The risk factors of development of hepatocellular carcinoma were analyzed.PAGE-B(including platelet count,age,gender),mPAGE-B(including platelet count,age,gender and albumin),Child-Turcotte-Pugh(CTP)score and aspartate aminotransferase to platelet ratio index(APRI)were compared in area under receiver operator characteristic curve(AUROC)for predicting the occurrence of hepatocellular carcinoma within 5 years.Risk stratification analysis was carried out for mPAGE-B and PAGE-B.Multivariate Cox regression analysis,receiver operator characteristic curve,Mann-Whitney U test and Kaplan-Meier method were used for statistical analysis.Results The age of 707 patients was(46.7±12.2)years old,including 567 males(80.2%)and 140 females(19.8%).The positive rate of hepatitis B e antigen was 56.4%(399/707).The scores of PAGE-B,mPAGE-B,CTP and APRI were 15.90±4.24,12.39±3.58,6.88±2.15 and 1.80(0.85,3.79),respectively.The overall follow up time was(38.14±20.97)months and the incidence of hepatocellular carcinoma was 8.1%(57/707).The results of multivariate Cox regression analysis showed that advanced age,low platelet count and quantitative reduction of HBV DNA were independent risk factors of development of hepatocellular carcinoma(Wald=20.44,5.64 and 9.25;HR(95%confidence interval(95%CI)1.056(1.031 to 1.081),0.994(0.989 to 0.999)and 0.769(0.649 to 0.911);P<0.001,=0.018 and 0.002).The AUROCs(95%CI)of PAGE-B,mPAGE-B,CTP score and APRI for predicting the occurrence of hepatocellular carcinoma within 5 years were 0.708(0.639 to 0.778),0.724(0.657 to 0.778),0.576(0.500 to 0.652)and 0.516(0.443 to 0.589),respectively.There were no statistically significant differences in AUROCs for predicting the occurrence of hepatocellular carcinoma within 5 years between mPAGE-B and PAGE-B,between APRI and CTP score(both P>0.05).The AUROC for predicting the occurrence of hepatocellular carcinoma within 5 years of CTP score was less than those of PAGE-B and mPAGE-B,and the differences were statistically significant(Z=3.00 and 3.79;P=0.003,<0.001).The AUROC for predicting the occurrence of hepatocellular carcinoma within 5 years of APRI was less than those of PAGE-B and mPAGE-B,and the differences were statistically significant(Z=4.75 and 5.46,both P<0.001).There were 51 cases(7.2%),394 cases(55.7%)and 262 cases(37.1%)in the low-risk(<10)group,medium-risk(10 to 17)group and high-risk(>17)group as assessed by PAGE-B.The incidence of hepatocellular carcinoma was 0(0/51),4.8%(19/394)and 14.5%(38/262),respectively the annual average incidence of hepatocellular carcinoma was 0,1.6%and 5.5%,respectively,the 5-year cumulative incidence of hepatocellular carcinoma was 0,7.3%and 31.3%,respectively.The 5-year cumulative incidence of hepatocellular carcinoma of high-risk group was higher than those of medium-risk group and low-risk group(log-rank test=19.27,P<0.001).There were 97 cases(13.7%),246 cases(34.8%)and 364 cases(51.5%)in the low-risk group(<9),medium-risk group(9 to 12)and high-risk group(>12)as assessed by mPAGE-B.The incidence of hepatocellular carcinoma was 2.1%(2/97),3.7%(9/246)and 12.6%(46/364),the annual average incidence of hepatocellular carcinoma was 0.6%,1.1%and 4.7%,respectively,the 5-year cumulative incidence of hepatocellular carcinoma was 2.4%,5.1%and 26.7%,respectively.The 5-year cumulative incidence of hepatocellular carcinoma of high-risk group was higher than those of medium-risk group and low-risk group(log-rank test value=18.64,P<0.001).Conclusions Both PAGE-B and mPAGE-B can predict the occurrence of hepatocellular carcinoma within 5 years in patients with HBV-associated liver cirrhosis treated with antiviral therapy,identify liver cirrhotic patients at high risk of development of hepatocellular carcinoma and guide clinicans to use more efficient screening strategies.