慢性乙肝病毒感染者进展为肝癌病程中血清循环免疫复合物的含量变化和意义

摘要

目的 探讨人外周血清循环免疫复合物(CIC)的含量变化与肝癌发生的关系.方法 采用酶联免疫吸附(ELISA)法检测20例临床病理确诊的肝癌和13例肝血管瘤患者术前血清中CIC的含量.采用ELISA法检测45例慢性乙肝病毒(HBV)感染最终进展为肝癌者以及与之匹配的45例慢性HBV感染未进展为肝癌者入组时、随访过程中和随访结束时血清中CIC和抗肝肾微粒体抗体(抗LKM-1)的含量,采用荧光定量PCR法检测这些患者入组时、随访过程中和随访结束时血清HBV-DNA的含量.结果 20例临床手术后病理确诊的肝癌患者术前血清中CIC的含量为(5738±1485)mU/L,显著高于13例肝血管瘤患者[(2410±1080) mU/L;P＜0.001].45例经过长期随访最终进展为肝癌的慢性HBV感染者血清CIC的含量随病程进展而逐渐升高,在肝癌临床诊断时达到最高,与其入组时相比,差异有统计学意义(P＜0.001)；而对照组患者血清CIC的含量未见明显变化(P=0.118).随访方过程中,血清CIC的升高与肝癌累积发病率密切相关(HR =2.77,95％ CI为1.47～5.22).最终进展为肝癌的慢性HBV感染者在入组时、随访进程中和临床确诊为肝癌时的血清抗LKM-1和HBV-DNA含量均显著高于与之相匹配的对照组,并维持在较高水平.最终进展为肝癌的慢性HBV感染者血清CIC的含量与HBV-DNA的含量之间仅在肝癌临床诊断时存在相关性(r=0.344,P=0.026).结论 在慢性HBV感染进程中,血清CIC含量的逐渐升高可能是由慢性HBV感染进展为肝癌的重要转归指标之一.%Objective To investigate the significance of increasing circulating immune complex (CIC) in patients during the progression from chronic hepatitis B to hepatocellular carcinoma (HCC).Methods Serum levels of CIC from 20 hospitalized patients diagnosed by pathology with primary HCC,and 13 with hepatic hemangioma,and from 45 subjects with chronic HBV infection who finally developed into HCC (45 cases),and age- and gender-matched 45 subjects who kept the chronic HBV infection after consecutively followed up for 10-13 years by June of 2009 were quantified by ELISA.The serum levels of anti liver-kidney microsomal ( anti LKM-1 ) antibodies were also measured by ELISA,and that of HBV-DNA were quantified by Taqman probe-based real time PCR in the followed up chronic HBV infection subjects.In the 45 chronic HBV subjects who finally developed into HCC and the 45 controls,serum samples were collected and determinted at 3 time points:the baseline when the subjects were recruited,the middle point during the follow-up,and the end of follow-up.Results The serum level of CIC was significantly higher in the 20 HCC patients than that in the 13 hemangioma cases (P ＜0.001 ).When HCC was diagnosed,the CIC concentration was significantly higher than that in the baselines ( P ＜ 0.001 ) in the 45 chronic HBV subjects who finally developed into HCC after the consecutively follow-up for 5-13 years. Of them, 36patients (80.0％ ) showed progressively increased CIC during the follow-up ( P ＜ 0.001 ).In the controls,the CIC levels were kept relatively stable during the follow-up.Among them,17 patients (37.8％) showed CIC slightly increased ( P =O.046).Kaplan-Meier survival analysis indicated that elevated serum CIC during the follow-up increased cumulative HCC incidence (HR =2.77,95％ CI 1.47-5.22).In addition,the serum levels of anti-LKM-1 and HBV-DNA were also significantly higher in the patients who finally progressed into HCC than that in the controls and maintained at a high level during the follow-up tested at all the 3 time points.Further analysis indicated that the serum level of CIC was correlated with that of serum HBV-DNA only when HCC was diagnosed ( r =0.344,P =0.026).Conclusion Progressive increase of serum CIC level may be one of risk factors reflecting HCC development from chronic HBV infection.