抗线粒体抗体与原发性胆汁性胆管炎临床血清学和肝硬化指标的相关性

目的探究首次就诊的抗线粒体抗体(AMA)阳性原发性胆汁性胆管炎(PBC)患者的AMA水平及其与临床指标的相关性。方法通过北京大学人民医院信息系统,收集2013年1月至2016年12月首次检测AMA和(或)M2型抗线粒体抗体(AMA-M2)阳性的1323例患者的临床资料,其中采用间接免疫荧光法183例、免疫印迹法431例、ELISA法709例;分为未诊断PBC组(973例)和新诊断PBC组(350例,其中非肝硬化者268例,肝硬化者82例)。709例采用ELISA法的患者中,未诊断PBC组567例,新诊断PBC组142例(PBC非肝硬化组115例,PBC肝硬化组27例)。183例采用间接免疫荧光法的患者中,未诊断PBC组118例,新诊断PBC组65例;其中AMA滴度为低滴度(1∶40~1∶80)者69例(未诊断PBC组53例,新诊断PBC组16例)、中滴度(1∶160~1∶320)者95例(未诊断PBC组59例,新诊断PBC组36例)、高滴度(≥1∶640)者19例(未诊断PBC组6例,新诊断PBC组13例)。比较各组患者的AMA水平,分析其与PBC临床指标免疫球蛋白(Ig)G、IgM、血小板计数、ALT、AST、GGT、ALP、血清总蛋白、TBil、总胆固醇,以及肝硬化指标天冬氨酸转氨酶与血小板比率指数(APRI)、基于四因子的纤维化指数(Fib-4)的相关性。统计学方法采用Mann-Whitney U检验、Kruskal-Wallis检验和线性回归分析。结果采用ELISA法检测的709例患者的AMA-M2滴度中位值为53 RU/mL,新诊断PBC组的血清AMA和AMA-M2中位水平均高于未诊断PBC组(1∶320比1∶80和180 RU/mL比47 RU/mL),差异均有统计学意义(χ^2=14.111,Z=-7.531,P均<0.01)。未诊断PBC组的AMA-M2值与年龄、IgG、IgM、AST、GGT、ALP、血清总蛋白、总胆固醇水平均呈正相关,均有统计学意义(Rho值=0.114、0.108、0.337、0.089、0.197、0.086、0.121、0.073,P均<0.05);新诊断PBC组的AMA-M2值与年龄、IgM、血清总蛋白、总胆固醇水平均呈正相关,与血小板计数呈负相关,均有统计学意义(Rho值=0.218、0.483、0.230、0.161、-0.183,P均<0.05);PBC非肝硬化组的血清AMA和AMA-M2中位水平均有低于PBC肝硬化组的趋势(1∶160比1∶320和174 RU/mL比495 RU/mL),但差异均无统计学意义(P均>0.05);PBC肝硬化组者组患者的AMA-M2值与IgM水平呈正相关(r=0.38,P=0.039),但与APRI、Fib-4均无明确相关性(P均>0.05)。采用间接免疫荧光法检测的183例患者的AMA滴度中位值为1∶160;未诊断PBC组中AMA低滴度、中滴度和高滴度者的IgM中位水平逐渐升高(分别为1.2、1.7和1.8 g/L),新诊断PBC组中AMA低滴度、中滴度和高滴度者的IgM、GGT、ALP的水平均逐渐升高(中位水平分别为1.5、3.7和4.1 g/L,144、182和317 U/L,137、168和221 U/L),差异均有统计学意义(χ^2=6.260、7.081、8.030、15.226,P均<0.05)。总体中未诊断PBC组男性的血清AMA-M2中位水平低于女性(41 RU/mL比50 RU/mL),差异有统计学意义(Z=-2.945,P=0.003);新诊断PBC组男性的血清AMA-M2中位水平有低于女性的趋势(113 RU/mL比206 RU/mL),但差异无统计学意义(P=0.257)。结论血清AMA水平与诸多临床指标有一定的相关性,并可能与PBC患者的疾病严重程度相关。

Correlation between anti-mitochondrial antibodies and clinical serological and cirrhotic markers of primary biliary cholangitis

Objective To explore the correlation between the level of anti-mitochondrial antibody(AMA)and clinical indicators of first visited primary biliary cholangitis(PBC)patients with positive AMA.Methods From January 2013 to December 2016,the clinical data of 1323 patients with positive AMA and/or AMA-M2 detected for the first time were collected through the Information System of Peking University People′s Hospital.Among them,183 were detected by indirect immunofluorescence assay,431 were measured by immunoblotting,and 709 were determined by enzyme-linked immunosorbent assay(ELISA).Patients were divided into undiagnosed PBC group(non-PBC group,973 cases)and newly diagnosed PBC group(new-PBC group,350 cases including 268 cases of non-liver cirrhosis and 82 cases of liver cirrhosis);among 709 cases detected by ELISA,there were 567 cases in the non-PBC group and 142 cases in the new-PBC group(115 cases of non-liver cirrhosis PBC group and 27 cases of liver cirrhosis PBC group).Among 183 cases determined by indirect immunofluorescence assay,there were 118 cases in the non-PBC group and 65 cases in the new-PBC group.Among them 69 cases with low AMA titer(1∶40—1∶80)(53 cases of non-PBC group and 16 cases of new-PBC group),95 cases with medium titer(1∶160—1∶320)(59 cases of non-PBC group and 36 cases of new-PBC group)and 19 cases with high titer(≥1∶640)(six cases of non-PBC group and 13 cases of new-PBC group).AMA levels among groups were compared,and its correlation with clinical serology and cirrhosis indicators of PBC including immunoglobulin(Ig)G,IgM,platelet,alanine aminotransferase(ALT),aspartate aminotransferase(AST),γ-glutamyltranspeptadase(GGT),alkaline phosphatase(ALP),serum total protein,serum albumin,total bilirubin(TBil),total cholesterol(TC),and aspartate aminotransferase to platelet ratio index(APRI)and fibrosis(Fib-4)was analysed.Mann-Whitney U test,Kruskal-Wallis test,and linear regression analysis were performed for statistical analysis.Results By ELISA method,the median titer of AMA-M2 of 709 patients was 53 RU/mL,the serum AMA and AMA-M2 levels of new-PBC group were both higher than those of non-PBC group(1∶320 vs.1∶80,180 RU/mL vs.47 RU/mL),and the differences were statistically significant(χ^2=14.111,Z=-7.531,both P<0.01).In non-PBC group,the AMA-M2 value was positively correlated with age,serum IgG,IgM,AST,GGT,ALP,serum total protein and TC,all of which were statistically significant(Rho=0.114,0.108,0.337,0.089,0.197,0.086,0.121 and 0.073,all P<0.05).In new-PBC group,AMA-M2 value was positively correlated with age,IgM,serum total protein and TC,however was negatively correlated with platelet count,all of which were statistically significant(Rho=0.218,0.483,0.230,0.161,and-0.183,all P<0.05).The median values of serum AMA and AMA-M2 of PBC without liver cirrhosis group were both tended to be lower than those of PBC with liver cirrhosis(1∶160 vs.1∶320;174 RU/mL vs.495 RU/mL),however the differences were not statistically significant(both P>0.05).AMA-M2 value of patients in PBC with liver cirrhosis group was positively correlated with IgM level(r=0.38,P=0.039),but was not correlated with APRI and Fib-4(all P>0.05).The median of AMA value of 183 patients who underwent indirect immunofluorescence test was 1∶160.In non-PBC group,the IgM levels of patients with low,medium and high AMA titers gradually increased(the median levels were 1.2,1.7 and 1.8 g/L,respectively);in new-PBC group,the levels of IgM,GGT and ALP of patients with low,medium and high AMA titers gradually increased(median IgM levels were 1.5,3.7 and 4.1 g/L,respectively;GGT levels were 144,182 and 317 U/L,respectively;and ALP levels were 137,168 and 221 U/L,respectively),and the differences were statistically significant(χ^2=6.260,7.081,8.030,15.226,all P<0.05).In non-PBC group,the median level of serum AMA-M2 of men was lower than that of women(41 RU/L vs.50 RU/L),and the difference was statistically significant(Z=-2.945,P=0.003).In new-PBC group,the median level of serum AMA-M2 of men tended to be lower than that of women(113 RU/mL vs.206 RU/mL),but the difference was not statistically significant(P=0.257).Conclusion Serum AMA level is correlated with many clinical parameters and may be related with the disease severity in patients with PBC.