摘要
目的 分析不同血清ALT不治疗阈值或正常值上限(ULN)判断慢性HBV感染者显著肝组织病理损伤的意义,以期为临床诊治提供指导。方法 选取2015年1月—2023年12月于宁波市第二医院住院接受肝穿刺活检及组织病理学检查、ALT持续≤40 U/L,且HBV DNA阳性(>30 IU/mL)的慢性HBV感染者733例,根据ALT的治疗阈值或ULN分为一组(男性≤35 U/L、女性≤25 U/L)575例、二组(男性≤30 U/L、女性≤19 U/L)430例、三组(男性≤27 U/L、女性≤24 U/L)443例、四组(≤25 U/L)446例、五组(男性>35 U/L、女性>25 U/L)158例、六组(男性>30~≤35 U/L、女性>19~≤25 U/L)145例。通过比较二、五、六组,分析不同ALT水平与肝脏病理损伤的严重程度及显著肝脏病理损伤构成比的关系;通过比较一、二、三、四组,探究不同ALT的ULN或不治疗阈值对肝脏炎症活动度分级(G)和肝纤维化分期(S)以及治疗指征的判断价值。正态分布的计量资料两组间比较采用成组t检验;多组间比较采用单因素方差分析,进一步两两比较采用LSD-t检验或Tambane’s检验。非正态分布的计量资料两组间比较采用Mann-Whitney U检验;多组间比较及进一步两两比较均采用Kruskal-Wallis H检验。计数资料组间比较采用χ^(2)检验或Fisher精确概率法;等级资料采用Ridit分析。以肝脏病理是否符合治疗指征(≥G2和/或≥S2)为因变量,以可能影响因变量且有统计学意义(P<0.05)的相关因素为自变量,行多因素Logistic回归分析(向前步进法)。绘制受试者操作特征曲线(ROC曲线),应用ROC曲线下面积(AUC)并结合敏感度、特异度、阳性预测值、阴性预测值、阳性似然比和阴性似然比评价不同ALT不治疗阈值的诊断价值。结果 733例患者中,≥G2者占35.33%(259例),≥S2者占28.79%(211例),有治疗指征者(≥G2和/或≥S2)占41.75%(306例)。二组、五组、六组患者炎症活动度分级(G0~G4)比较,差异有统计学意义(χ^(2)=22.869,P<0.001);3组间≥G2和≥G3构成比比较,差异均有统计学意义(χ^(2)值分别为21.742、14.921,P值分别为<0.001、0.001)。二组、五组、六组患者肝纤维化分期(S0~S4)比较,差异有统计学意义(χ^(2)=16.565,P<0.001);3组间≥S2、≥S3和S4构成比比较,差异均有统计学意义(χ^(2)值分别为13.264、13.050、6.260,P值分别为0.001、0.001、0.044)。二组、五组、六组无治疗指征和有治疗指征构成比比较,差异有统计学意义(χ^(2)=20.728,P<0.001)。二组、五组、六组间男性构成比(χ^(2)=24.836)、年龄(F=5.710)、ALT水平(F=473.193)、AST水平(F=107.774)、ALT/AST(F=40.167)、GGT水平(H=15.463)、APRI(AST/PLT比率指数)(H=63.024)和LIF-5(肝脏炎症和肝纤维化5项指数)(H=46.397)比较,差异均有统计学意义(P值均<0.05)。一组~四组有治疗指征患者的HBeAg阳性构成比、PLT和HBV DNA水平均低于无治疗指征患者,而年龄、ALT、AST、GGT、APRI、FIB-4(肝纤维化4因子指数)及LIF-5均高于无治疗指征患者,差异均有统计学意义(P值均<0.05)。Logistic回归分析结果显示,一组患者治疗指征的影响因素为年龄(OR=1.044,95%CI:1.025~1.063,P<0.001)、GGT(OR=1.022,95%CI:1.007~1.038,P=0.003)和HBV DNA(OR=0.839,95%CI:0.765~0.919,P<0.001);二组为HBeAg(OR=1.978,95%CI:1.269~3.082,P=0.003)、年龄(OR=1.048,95%CI:1.025~1.071,P<0.001)、GGT(OR=1.016,95%CI:1.001~1.031,P=0.041)和PLT(OR=0.995,95%CI:0.991~1.000,P=0.049);三组为年龄(OR=1.040,95%CI:1.014~1.066,P=0.002)、ALT(OR=1.047,95%CI:1.005~1.092,P=0.029)、HBV DNA(OR=0.817,95%CI:0.736~0.907,P<0.001)和LIF-5(OR=7.382,95%CI:1.151~47.330,P=0.035);四组为年龄(OR=1.054,95%CI:1.031~1.077,P<0.001)、ALT(OR=1.061,95%CI:1.016~1.107,P=0.008)和HBV DNA(OR=0.825,95%CI:0.743~0.917,P<0.001)。一组~四组判断肝组织≥G2、≥S2、治疗指征的AUC均<0.7;一组判断治疗指征的敏感度最低(28.76%),特异度、阳性预测值、阳性似然比、阴性似然比均最高;二组的敏感度及阴性预测值最高,阴性似然比最低;三组与四组各项指标均较为接近。结论 ALT持续低水平慢性HBV感染者肝脏病理损伤的严重程度及显著肝脏病理损伤的构成比随ALT水平的降低而降低,较高的ALT不治疗阈值或ULN有利于诊断需治疗人群(特异度较高),较低的ALT不治疗阈值或ULN有利于诊断不治疗人群(敏感度较高)。
Objective To investigate the significance of different non-treatment thresholds or upper limits of normal(ULN)of alanine aminotransferase(ALT)in evaluating significant liver pathological injury in patients with chronic hepatitis B virus(HBV)infection,and to provide guidance for clinical diagnosis and treatment.Methods This study was conducted among 733 patients with chronic HBV infection who were hospitalized in Ningbo No.2 Hospital from January 2015 to December 2023 and underwent liver biopsy and histopathological examination,and all patients had a persistent ALT level of≤40 U/L and positive HBV DNA(>30 IU/mL).According to the treatment threshold or ULN of ALT,the patients were divided into group 1 with 575 patients(≤35 U/L for male patients,≤25 U/L for female patients),group 2 with 430 patients(≤30 U/L for male patients,≤19 U/L for female patients),group 3 with 443 patients(≤27 U/L for male patients,≤24 U/L for female patients),group 4 with 446 patients(≤25 U/L),group 5 with 158 patients(>35 U/L for male patients,>25 U/L for female patients),and group 6 with 145 patients(>30—≤35 U/L for male patients,>19—≤25 U/L for female patients).Groups 2,5,and 6 were compared to analyze the severity of liver pathological injury in patients with different ALT levels and the constituent ratio of patients with significant liver pathological injury,and groups 1,2,3,and 4 were compared to investigate the value of different ULN or non-treatment thresholds of ALT in determining liver inflammation grade(G),liver fibrosis stage(S),and the treatment indication based on liver pathology.The independent-samples t test was used for comparison of normally distributed continuous data between two groups;a one-way analysis of variance was used for comparison between multiple groups,and the least significant difference t-test or the Tambane’s test was used for further comparison between two groups;the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups,and the Kruskal-Wallis H test was used for comparison between multiple groups and further comparison between two groups;the chi-square test or the Fisher’s exact test was used for comparison of categorical data between groups;a Ridit analysis was used for comparison of ranked data.A multivariate Logistic regression analysis(forward stepwise)was performed with whether liver pathology met the treatment indication(≥G2 and/or≥S2)as the dependent variable and related factors with a significant impact on the dependent variable(P<0.05)as the independent variable.The receiver operating characteristic(ROC)curve was plotted,and the area under the ROC curve(AUC),as well as sensitivity,specificity,positive predictive value,negative predictive value,positive likelihood ratio,and negative likelihood ratio,was used to assess the diagnostic value of different non-treatment thresholds of ALT.Results Among the 733 patients,259(35.33%)had≥G2 liver inflammation,211(28.79%)had≥S2 liver fibrosis,and 306(41.75%)had treatment indication(≥G2 and/or≥S2).There was a significant difference in liver inflammation grade(G0—G4)between groups 2,5,and 6(χ^(2)=22.869,P<0.001),and there were also significant differences in the constituent ratios of patients with≥G2 or≥G3 liver inflammation between the three groups(χ^(2)=21.742 and 14.921,P<0.001 and P=0.001).There was a significant difference in liver fibrosis stage(S0—S4)between groups 2,5,and 6(χ^(2)=16.565,P<0.001),and there were also significant differences in the constituent ratios of patients with≥S2,≥S3 or S4 liver fibrosis between the three groups(χ^(2)=13.264,13.050,and 6.260,P=0.001,0.001,and 0.044).There were significant differences between groups 2,5,and 6 in the constituent ratios of patients with or without treatment indication based on liver pathology(χ^(2)=20.728,P<0.001).There were significant differences between groups 2,5,and 6 in the constituent ratio of male patients(χ^(2)=24.836,P<0.05),age(F=5.710,P<0.05),ALT(F=473.193,P<0.05),aspartate aminotransferase(AST)(F=107.774,P<0.05),ALT/AST ratio(F=40.167,P<0.05),γ-glutamyl transpeptidase(GGT)(H=15.463,P<0.05),aspartate aminotransferase-to-platelet ratio index(APRI)(H=63.024,P<0.05),and LIF-5(5 indicators for liver inflammation and fibrosis)(H=46.397,P<0.05).In groups 1—4,compared with the patients without treatment indication,the patients with treatment indication had a significantly lower constituent ratio of patients with positive HBeAg,significantly lower levels of platelet count(PLT)and HBV DNA,and significantly higher age,ALT,AST,GGT,APRI,FIB-4,and LIF-5(all P<0.05).The Logistic regression analysis showed that age(odds ratio[OR]=1.044,95%confidence interval[CI]:1.025—1.063,P<0.001),GGT(OR=1.022,95%CI:1.007—1.038,P=0.003),and HBV DNA(OR=0.839,95%CI:0.765—0.919,P<0.001)were influencing factors for treatment indication based on liver pathology in group 1;HBeAg(OR=1.978,95%CI:1.269—3.082,P=0.003),age(OR=1.048,95%CI:1.025—1.071,P<0.001),GGT(OR=1.016,95%CI:1.001—1.031,P=0.041),and PLT(OR=0.995,95%CI:0.991—1.000,P=0.049)were influencing factors in group 2;age(OR=1.040,95%CI:1.014—1.066,P=0.002),ALT(OR=1.047,95%CI:1.005—1.092,P=0.029),HBV DNA(OR=0.817,95%CI:0.736—0.907,P<0.001),and LIF-5(OR=7.382,95%CI:1.151—47.330,P=0.035)were influencing factors in group 3;age(OR=1.054,95%CI:1.031—1.077,P<0.001),ALT(OR=1.061,95%CI:1.016—1.107,P=0.008),and HBV DNA(OR=0.825,95%CI:0.743—0.917,P<0.001)were influencing factors in group 4.The diagnostic performance for identifying≥G2 liver inflammation,≥S2 liver fibrosis,and treatment indication in groups 1—4 had an AUC of>0.7;group 1 showed the lowest sensitivity(28.76%)and the highest specificity,positive predictive value,positive likelihood ratio,and negative likelihood ratio in judging treatment indication;group 2 had the highest sensitivity and negative predictive value and the lowest negative likelihood ratio;groups 3 and 4 had similar diagnostic indicators.Conclusion In patients with chronic HBV infection and a persistently low ALT level,the severity of liver histopathological injury and the constituent ratio of significant liver histopathological injury decrease with the reduction in ALT level.A higher non-treatment threshold or ULN of ALT can help to identify the patients requiring treatment(with a higher specificity),while a lower non-treatment threshold or ULN of ALT can help to identify the patients who do not require treatment(with a higher sensitivity).
作者
舒明
蒋素文
胡爱荣
陈琴
王家岚
金梦涵
张豪锦
杨诗琪
范诗阳
SHU Ming;JIANG Suwen;HU Airong;CHEN Qin;WANG Jialan;JIN Menghan;ZHANG Haojin;YANG Shiqi;FAN Shiyang(Liver Diseases Center,Ningbo Institute of Liver Diseases,Ningbo No.2 Hospital,Ningbo,Zhejiang 315010,China;Graduate School of Wenzhou Medical University,Wenzhou,Zhejiang 325035,China;Graduate School of Ningbo University Health Science Center,Ningbo,Zhejiang 315211,China;Graduate School of Shaoxing University School of Medicine,Shaoxing,Zhejiang 312000,China)
出处
《临床肝胆病杂志》
北大核心
2025年第10期2044-2053,共10页
Journal of Clinical Hepatology
基金
国家卫生健康委科学研究基金-浙江省医药卫生重大科技计划项目(WKJ-ZJ-2341)
浙江省临床重点专科建设项目(2024023)
宁波市医疗卫生品牌学科项目(PPXK2024-04)
宁波市公益性科技计划项目(2024S027)。
关键词
乙型肝炎
慢性
丙氨酸转氨酶
阈限值
Hepatitis B,Chronic
Alanine Transaminase
Threshold Limit Values
