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乙型肝炎病毒(HBV)感染仍然是最严重和最普遍的全球性公共卫生问题之一。全世界大约有20亿人曾感染HBV,其中3.5亿人是慢性感染者[1-2]。HBV慢性感染可能导致持续性或间歇性肝脏损伤,这也增加了其发展为肝硬化、肝细胞癌、终末期肝病和死亡的风险[3-4]。慢性乙型肝炎(CHB)治疗的主要目的是最大限度地长期抑制HBV复制,减轻肝细胞炎症坏死及纤维组织增生,从而降低HBV的传染性和致病性[5]。多个指南推荐丙氨酸氨基转移酶(ALT)≥2倍正常上线值(2ULN)或存在显著肝脏病理改变的CHB病人需抗病毒治疗。因此,早期识别肝纤维化的分期,及时合理的抗病毒治疗可以有效地抑制病毒复制,从而防止疾病进展及并发症的发生[6-7]。
目前,肝活检仍然是评估肝组织学的“金标准”[8]。然而,因其疼痛、出血、感染等相关并发症的出现和取样误差、病人依从性差、组织学动态评估有限等局限性的存在,在临床应用中受到一定的限制[9],因此,寻找用于评估肝纤维化的非侵入性方法受到广泛关注。基于常规实验室参数对肝脏组织学的评估主要集中在无创模型,如天门冬氨酸氨基转移酶(AST)与血小板(PLT)的比率指数APRI[10],基于年龄、ALT、AST和PLT的FIB-4指数[11]等。这些非侵入性预测模型在评估肝纤维化方面具有一定的准确性。然而,对ALT≤2(2ULN)且HBeAg阴性的乙型肝炎肝纤维化严重程度评估的报道较少。故本研究对ALT≤2ULN且HBeAg阴性的乙型肝炎肝纤维化病人进行研究,分析与肝纤维化相关的独立危险因素,并建立无创预测模型,从而评估肝纤维化的严重程度,为早期合理的抗病毒治疗提供参考依据。
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295例病人中肝组织纤维化轻度组(S≤1)94例,显著组(S≥2)201例,单因素分析发现,年龄、PT、PLT、GGT、INR、WBC、TBIL、ALB、GLB、ALP组间差异均无统计学意义(P>0.05)。ALT、AST、抗-HBC和HBV-DNA水平显著组均高于轻度组,差异有统计学意义(P < 0.05~P < 0.01)(见表 1)。
项目 轻度组(S≤1) (n=94) 显著组(S≥2) (n=201) t P 年龄/岁 42.2±9.0 43.0±9.4 0.76 >0.05 性别 男 56 128 0.46* >0.05 女 38 73 PT/s 11.3±1.3 11.5±0.7 1.66 >0.05 INR 1.0±0.1 1.0±0.1 0.13 >0.05 WBC/(×109/L) 5.6±1.3 5.9±1.5 1.37 >0.05 PLT/(×109/L) 192.1±55.1 193.1±144.6 0.06 >0.05 TBIL/(μmol/L) 16.2±7.4 16.2±6.4 0.04 >0.05 ALB/(g/L) 44.8±3.2 44.5±3.1 0.86 >0.05 GLB/(g/L) 29.4±4.4 30.3±10.8 0.80 >0.05 GGT/(U/L) 25.5±24.7 28.3±20.9 1.01 >0.05 ALP/(U/L) 81.3±22.6 86.1±25.7 1.54 >0.05 ALT/(U/L) 30.0±16.4 34.6±16.7 2.20 < 0.05 AST/(U/L) 26.8±10.5 31.0±10.6 3.20 < 0.01 抗-HBC/(S/CO) 9.6±1.8 10.6±1.5 5.34 < 0.01 Log10(HBV-DNA)/(IU/mL) 3.3±1.0 3.6±1.0 2.01 < 0.05 *示χ2值 表 1 一般资料的单因素分析(x±s)
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将单因素分析具有统计学意义的变量(ALT、AST、抗-HBC和HBV-DNA)纳入多因素logistic回归分析。因变量赋值为轻度=0,显著=1。结果发现AST和抗-HBC与显著纤维化有关。AST和抗-HBC水平升高可能是ALT≤2ULN且HBeAg阴性的肝纤维化病人的独立危险因素。将筛选出的独立预测指标建立回归模型:Y=0.042×AST+0.435×抗-HBC-4.835(见表 2)。
项目 B SE Waldχ2 OR 95%CI P AST 0.042 0.016 6.99 1.043 1.011~1.076 < 0.01 抗-HBC 0.435 0.096 20.51 1.545 1.280~1.865 < 0.01 常数项 -4.835 1.056 20.97 0.008 — < 0.01 表 2 ALT≤2ULN且HBeAg阴性的CHB病人显著肝纤维化的多因素logistic回归分析
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结果显示,该预测模型的AUC为0.721(95%CI: 0.660~0.782,P < 0.01)。在约登指数最大点处,该无创模型诊断显著肝纤维化的敏感性为60.0%,特异性为74.5%(见图 1)。该模型的AUC值高于各独立预测因素AST(AUC=0.645,95%CI: 0.577~0.714)和抗-HBC(AUC=0.684,95%CI: 0.618~0.749)(P < 0.01)(见表 3)。该无创预测模型对ALT≤2ULN且HBeAg阴性的乙型肝炎显著肝纤维化的诊断性能优于独立预测指标。
项目 AUC 95%CI P AST 0.645 0.577~0.714 < 0.01 抗-HBC 0.684 0.618~0.749 < 0.01 预测模型 0.721 0.660~0.782 < 0.01 表 3 ALT≤2ULN且HBeAg阴性的CHB病人显著肝纤维化独立预测因素与模型的ROC曲线分析
丙氨酸氨基转移酶≤2倍正常上限值且HBeAg阴性乙型肝炎肝纤维化无创预测模型的建立
Construction of a non-invasive model to predict liver fibrosis in HBeAg negative hepatitis B with alanine aminotransferase less than 2 upper limit of normal
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摘要:
目的分析丙氨酸氨基转移酶(ALT)≤2倍正常上限值(2ULN)且HBeAg阴性的慢性乙型肝炎(CHB)肝纤维化的影响因素,并构建无创预测模型,以评估肝纤维化的严重程度。 方法回顾性分析295例ALT≤2ULN且HBeAg阴性的CHB病人的临床资料。所有病人根据肝穿刺病理结果进行肝纤维化分期,以纤维化分期S≥2作为显著肝纤维化的判别标准。其中肝纤维化轻度组(S≤1)94例,显著组(S≥2)201例。通过多因素logistic回归分析,筛选影响肝纤维化的独立预测因素并构建无创模型,最后通过受试者工作特征曲线下对该模型进行验证,以识别肝纤维化的严重程度。 结果多因素logistic回归分析显示,天门冬氨酸氨基转移酶、乙肝核心抗体升高可能是肝纤维化的独立预测因素(P < 0.01)。该模型的AUC为0.721(95%CI:0.660~0.782,P < 0.01),诊断显著肝纤维化的敏感性为60.0%,特异性为74.5%。 结论基于天门冬氨酸氨基转移酶、乙肝核心抗体两项指标构建的无创预测模型对评估CHB肝纤维化的严重程度具有较高的诊断价值。 Abstract:ObjectiveTo evaluate influencing factors of liver fibrosis in HBeAg negative hepatitis B with alanine aminotransferase (ALT) less than 2 upper limit of normal(ULN)and establish the non-invasive prediction model to assess the severity of liver fibrosis. MethodsThe clinical data of 295 patients in HBeAg negative CHB patients with ALT≤2ULN were retrospectively analyzed.The degree of liver fibrosis S≥2 was taken as the discriminant criterion for significant liver fibrosis according to the pathological results of liver puncture.There were 94 cases in the mild group of liver fibrosis (S≤1) and 201 cases in the significant group (S≥2).The independent predictors of liver fibrosis were screened by multivariate logistic regression analysis and non-invasive model was constructed.Finally, the model was evaluated by area under the receiver operating characteristic curve to identify the severity of liver fibrosis. ResultsMultivariate logistic regression analysis showed that aspartate aminotransferase and hepatitis B core antibody were the independent predictors of liver fibrosis (P < 0.01).The AUC of this model was 0.721(95%CI: 0.660-0.782, P < 0.01).The sensitivity and specificity for the diagnosis of significant liver fibrosis were 60.0% and 74.5%. ConclusionsThe non-invasive prediction model based on the two indicators of aspartate aminotransferase and hepatitis B core antibody has high diagnostic value for evaluating the severity of liver fibrosis in CHB. -
表 1 一般资料的单因素分析(x±s)
项目 轻度组(S≤1) (n=94) 显著组(S≥2) (n=201) t P 年龄/岁 42.2±9.0 43.0±9.4 0.76 >0.05 性别 男 56 128 0.46* >0.05 女 38 73 PT/s 11.3±1.3 11.5±0.7 1.66 >0.05 INR 1.0±0.1 1.0±0.1 0.13 >0.05 WBC/(×109/L) 5.6±1.3 5.9±1.5 1.37 >0.05 PLT/(×109/L) 192.1±55.1 193.1±144.6 0.06 >0.05 TBIL/(μmol/L) 16.2±7.4 16.2±6.4 0.04 >0.05 ALB/(g/L) 44.8±3.2 44.5±3.1 0.86 >0.05 GLB/(g/L) 29.4±4.4 30.3±10.8 0.80 >0.05 GGT/(U/L) 25.5±24.7 28.3±20.9 1.01 >0.05 ALP/(U/L) 81.3±22.6 86.1±25.7 1.54 >0.05 ALT/(U/L) 30.0±16.4 34.6±16.7 2.20 < 0.05 AST/(U/L) 26.8±10.5 31.0±10.6 3.20 < 0.01 抗-HBC/(S/CO) 9.6±1.8 10.6±1.5 5.34 < 0.01 Log10(HBV-DNA)/(IU/mL) 3.3±1.0 3.6±1.0 2.01 < 0.05 *示χ2值 表 2 ALT≤2ULN且HBeAg阴性的CHB病人显著肝纤维化的多因素logistic回归分析
项目 B SE Waldχ2 OR 95%CI P AST 0.042 0.016 6.99 1.043 1.011~1.076 < 0.01 抗-HBC 0.435 0.096 20.51 1.545 1.280~1.865 < 0.01 常数项 -4.835 1.056 20.97 0.008 — < 0.01 表 3 ALT≤2ULN且HBeAg阴性的CHB病人显著肝纤维化独立预测因素与模型的ROC曲线分析
项目 AUC 95%CI P AST 0.645 0.577~0.714 < 0.01 抗-HBC 0.684 0.618~0.749 < 0.01 预测模型 0.721 0.660~0.782 < 0.01 -
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