摘要
目的探讨糖皮质激素(GC)治疗早期和中期HBV相关慢加急性(亚急性)肝衰竭(HBV-ACLF)患者时激素受体(GR)及其亚型α、β的表达特征与激素治疗敏感性的关系。方法采用前瞻性、非随机对照研究方法入组2015年9月-2018年6月北京佑安医院住院治疗的33例早、中期HBV-ACLF患者,其中激素组18例在内科综合治疗基础上给予甲基强的松龙静点7 d。采用流式细胞检测仪和逆转录PCR(RT-PCR)检测GR及GR-αmRNA、GR-βmRNA表达情况,观察基线、8 d GR及其亚型表达差异。激素组患者根据10 d时GC疗效分为激素敏感组(13例)和激素不敏感组(5例),分析不同组别GR及其亚型表达的特征与GC治疗敏感性的关系。计量资料2组间比较采用两独立样本t检验,自身前后对照比较采用配对t检验;计数资料2组间比较采用确切概率法检验。28 d生存情况采用Kaplan-Meier生存曲线进行分析,2组间比较采用log-rank检验。结果激素组患者使用激素后8 d时GR-αmRNA表达水平[(0.99±0.48)×10^-2)]较基线[(1.96±0.50)×10^-2)]明显降低(t=6.586,P<0.001)。激素组与非激素组患者第8 d时GR-αmRNA表达[(0.99±0.48)×10^-2vs(1.70±0.66)×10^-2]差异有统计学意义(t=-3.518,P=0.001);激素敏感与不敏感组8 d时比较,激素敏感组GR-αmRNA表达水平[(1.21±0.34)×10^-2]明显高于激素不敏感组[(0.43±0.31)×10^-2](t=4.456,P<0.001);且8 d时激素敏感组GR-αmRNA表达降低幅度明显小于激素不敏感组(t=-2.904,P=0.01)。GR-βmRNA表达水平8 d时激素敏感组[(0.14±0.08)×10^-2]与激素不敏感组[(0.10±0.04)×10^-2]差异无统计学意义(t=1.092,P=0.291)。8 d时激素组患者GR-αmRNA表达降低幅度与基线的比值均值为46%,据此分为≤46%组(10例)和>46%组(8例)。2组GR-αmRNA表达水平降低幅度与基线的比值差异显著(26.99%±25.09%vs 70.09%±16.08%,t=-4.203,P=0.001)。10 d时,TBil降低幅度与基线比值在≤46%组和>46%组间差异显著(P=0.021);10 d时,PTA上升幅度与基线比值在≤46%组和>46%组间差异显著(P=0.048)。结论HBV-ACLF早、中期患者使用GC后GR-αmRNA表达水平明显降低,激素敏感组患者GR-αmRNA水平较基线降低幅度小,且28 d TBil和PTA指标改善优于激素不敏感组,GR-αmRNA动态变化对激素疗效具有一定参考价值。
Objective To investigate the expression features of glucocorticoid receptor(GR)and its subtypesαandβin patients with early-or middle-stage hepatitis B virus-related acute/subacute-on-chronic liver failure(HBV-ACLF)treated by glucocorticoid(GC)and their association with sensitivity to glucocorticoid therapy.Methods A prospective non-randomized controlled trial was performed for 33 patients with early-or middle-stage HBV-ACLF who were hospitalized and treated in Beijing YouAn Hospital from September 2015 to June 2018,and among these patients,18 received intravenous infusion of methylprednisolone for 7 days in addition to comprehensive medical treatment.Flow cytometry and RT-PCR were used to measure the mRNA expression of GR,GR-α,and GR-β,and the expression of GR,GR-α,and GR-βwas observed at baseline and on day 8.According to the response to GC on day 10,the hormone group was further divided into hormone-sensitive group with 13 patients and hormone-insensitive group with 5 patients.The two-independent-samples t test was used for comparison of continuous data between two groups,and the paired t-test was used for comparison within one group before and after treatment;the Fisher’s exact test was used for comparison of categorical data between groups.The Kaplan-Meier survival curve was used to analyze 28-day survival,and the log-rank test was used for comparison between groups.Results The hormone group had a significant reduction in the mRNA expression of GR-αon day 8 after hormone administration[(0.99±0.48)×10^-2 vs(1.96±0.50)×10^-2,t=6.586,P<0.001]There was a significant difference in the mRNA expression of GR-αbetween the hormone group and the non-hormone group on day 8[0.99±0.48)×10^-2 vs(1.70±0.66)×10^-2,t=-3.518,P=0.001]On day 8,the hormone-sensitive group had significantly higher mRNA expression of GR-αthan the hormone-insensitive group[1.21±0.34)×10^-2 vs(0.43±0.31)×10^-2,t=4.456,P<0.001]and the hormone-sensitive group had a significantly greater reduction in the mRNA expression of GR-αcompared with the hormone-insensitive group(t=-2.904,P=0.01).There was no significant difference in the mRNA expression of GR-βon day 8 between the hormone-sensitive group and the hormone-insensitive group[0.14±0.08)×10^-2 vs(0.10±0.04)×10^-2,t=1.092,P=0.291]For the hormone group,the mean ratio of reduction in GR-αmRNA expression to baseline value was 46%on day 8,and according to this,the patients were divided into≤46%group with 10 patients and>46%group with 8 patients.There was a significant difference in the ratio of reduction in GR-αmRNA expression to baseline value between the two groups(26.99%±25.09%vs 70.09%±16.08%,t=-4.203,P=0.001).On day 10,there were significant differences between the≤46%group and the>46%group in the ratio of reduction in total bilirubin(TBil)to baseline value(P=0.021)and the ratio of increase in prothrombin time activity(PTA)to baseline value(P=0.048).Conclusion In patients with early-or middle-stage HBV-ACLF,there is a significant reduction in the mRNA expression of GR-αafter GC treatment.Patients sensitive to hormone have a relatively low degree of reduction in the mRNA expression of GR-α,with better improvements in TBil and PTA on day 28 than those insensitive to hormone.Dynamic change of GR-αmRNA has a certain reference value in predicting the outcome of hormone therapy.
作者
董金玲
贾琳
杨君
于红卫
胡中杰
朱跃科
孟庆华
DONG Jinling;JIA Lin;YANG Jun;YU Hongwei;HU Zhongjie;ZHU Yueke;MENG Qinghua(Department of Severe Liver Disease, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China)
出处
《临床肝胆病杂志》
CAS
北大核心
2020年第6期1252-1257,共6页
Journal of Clinical Hepatology
基金
“艾滋病和病毒性肝炎等重大传染病防治”科技重大专项(2018ZX10302206)
2017年度北京市丰台区卫生与计划生育委员会系统项目(2017-61)。