干扰素-λ3水平及白细胞介素28B基因多态性与乙型肝炎病毒相关慢加急性(亚急性)肝衰竭预后的关系

The effect of interferon-λ3 level and interleukin-28B polymorphisms on prognosis of hepatitis B virus acute(subacute)-on-chronic liver failure

目的探讨外周血干扰素-λ3(interferon-λ3,IFN-λ3)水平及白细胞介素28B(interleukin-28B,IL-28B)基因多态性与HBV相关慢加急性(亚急性)肝衰竭预后的关系,并联合其他影响因素以期建立一个早期、敏感、特异性强的HBV相关慢加急性(亚急性)肝衰竭预后模型。方法回顾性队列研究2019年10月至2020年3月在福建医科大学孟超肝胆医院住院诊断为慢加急性(亚急性)肝衰竭乙型病毒性肝炎的患者97例,所有入组患者随访半年,随访终点事件为死亡,根据随访终点患者的生存状态分为死亡组和生存组。检测IFN-λ3水平及IL-28B rs 12979860多态性测序分型。收集患者治疗基线时的血常规、生化、凝血功能等实验室指标,计算治疗基线时的终末期肝病模型(model for end-stage liver disease,MELD)评分,对以上指标进行单因素及多因素分析,建立HBV相关慢加急性(亚急性)肝衰竭预后评估模型。结果随访半年后,死亡组15例,存活组82例,死亡率15.5%。两组年龄、总胆红素、直接胆红素、间接胆红素、总胆固醇、凝血酶原活动度、凝血酶原国际标准化比值、纤维蛋白原、IFN-λ3水平、MELD评分差异有统计学意义(P<0.05)。采用多因素Logistic回归分析及逐步回归法,建立模型。结果显示凝血酶原活动度、IFN-λ3水平为生存预后的独立危险因素。与存活组相比,死亡组凝血酶原活动度及IFN-λ3水平更低。建立新的预后模型方程:Y=0.144+0.054×年龄(岁)+0.005×总胆红素水平(μmol/L)-0.07×凝血酶原活动度(%)-0.002×IFN-λ3(pg/ml)。ROC曲线比较新建立模型、MELD评分和IFN-λ3的诊断价值。结果显示:新的预测模型ROC曲线下面积大于常用的终末期肝病的预测模型MELD评分及IFN-λ3水平。IL-28B rs 12979860多态性测序显示仅1例死亡患者基因型为CT型,其余病例均为CC型,两组基因型频率差异无统计学意义(P>0.05)。结论外周血IFN-λ3水平可以作为判断HBV相关慢加急性(亚急性)肝衰竭患者预后的指标。IFN-λ3水平联合凝血酶原活动度、总胆红素水平及年龄建立的新模型可以更好地预测肝衰竭患者的预后。

Objective To investigate the effect of the interferon-λ3(IFN-λ3)and IL-28B polymorphisms in peripheral blood on the prognosis of hepatitis B acute(subacute)-on-chronic liver failure and try to establish an early,sensitive and specific prognosis model of hepatitis B acute(subacute)-on-chronic liver failure combined with other influencing factors.Method Retrospective cohort study of 97 patients diagnosed with chronic and subacute(subacute)liver failure and viral hepatitis B in Mengchao Hepatobiliary Hospital of Fujian Medical University from October 2019 to March 2020.All the enrolled patients were followed up for half a year,and the end point of follow-up was death.The level of IFN-λ3 and polymorphism of IL-28B rs12979860 were detected.Clinical indicators such as cholesterol,cholinesterase,albumin,total serum bilirubin(TBil),international normalized ratio(INR),plasma thromboplastin antecedent(PTA),and serum creatinine(cr)were collected at baseline treatment,and MELD values at baseline treatment were calculated.Univariate and multiple regression analyses were performed for the above indicators to establish a prognosis assessment model of hepatitis B acute(subacute)-on-chronic liver failure.Result After six months of follow-up,15 cases died and 82 cases survived,with a mortality rate of 15.5%.Age,total bilirubin,direct bilirubin,indirect bilirubin,cholesterol,prothrombin time,PTA,INR,fibrinogen,IFN-λ3 level and MELD score were statistically different between the two groups(P<0.05).The above indexes were included in logistic regression analysis,and the model was established by stepwise regression method.The results showed that PTA and IFN-λ3 level were independent risk factors for survival.PTA and IFN-λ3 levels were lower in the death group than in the survival group.A new prognostic model equation was established:Y=0.144+0.054×age+0.005×TBil(μmol/L)-0.07×PTA(%)-0.002×IFN-λ3(pg/ml).ROC curve comparison:The diagnostic value of the newly established model,MELD score,and IFN-λ3 were compared respectively.The results showed that the area under ROC curve of the new predictive model was larger than the MELD score and IFN-λ3 level.IL-28Brs12979860 polymorphism sequencing:Only one died patient was CT genotype,and the rest were CC genotype,so genotype frequency was not statistically different between the two groups.Conclusion The level of IFN-λ3 can be used as an indicator of prognosis in patients with hepatitis B acute(subacute)-on-chronic liver failure.The new model of IFN-λ3 combined with PTA,total bilirubin level and age can predict the prognosis of patients with liver failure better.