HBx 诱导的抗 URRs 作为肝硬化和 HCC 的早期预警生物标志物的应用。

Application of HBx-induced anti-URGs as early warning biomarker of cirrhosis and HCC.

机构信息

Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai, China.

出版信息

Cancer Biomark. 2011;11(1):29-39. doi: 10.3233/CBM-2012-0261.

DOI:10.3233/CBM-2012-0261

PMID:22820138

Abstract

BACKGROUND

Hepatitis B virus (HBV) carriers are at high risk for the development of hepatocellular carcinoma (HCC), but there are no reliable markers that will identify such high-risk patients. HBV up-regulates the expression of selected genes (URGs) in the liver during chronic infection. These aberrantly expressed proteins trigger corresponding antibodies (anti-URGs) that appear prior to the detection of HCC. This study was undertaken to see if the anti-URGs could be used as early warning biomarker of HBV-induced liver cirrhosis and HCC.

METHODS

A cross sectional study using a total of 625 serum samples from HBV infected and uninfected controls were tested for the anti-URGs using specific ELISAs.

RESULTS

The number and specificity of anti-URGs correlated with the severity of liver disease Anti-URGs were predominantly present among patients with HBV-associated HCC (55.2%) and cirrhosis (60.7%), and at a lower frequency among patients with chronic hepatitis (35.8%), and at still lower frequencies in most asymptomatic carriers (12.3%) with normal ALT, among patients with chronic hepatitis C (38.5%) and blood donors (0.9%). These anti-URGs were rarely detected in sera from those with tumors other than HCC, except among HBV infected patients with cholangioicarcinoma and in some patients with drug induced hepatitis. 3 or more anti-URGs could precede the diagnosis of cirrhosis or HCC 11.8 months on average, and HBV hepatitis patients with 3 or more anti-URGs have much higher risk (5/20 vs 0/30) to develop cirrhosis and HCC than those patients with less anti-URGs. As the early warning biomarker, 3 or more anti-URGs were served as the threshold to separate the cirrhosis and HCC from others with a moderate sensitivity (58.3%) and specificity (80.0%), which was better than other biomarkers (AFP, AFP-L3, GPC3 and GP73) and would improve up to 70.3% when combined with another biomarker.

CONCLUSIONS

The results of this clinical validation study suggest that the anti-URGs might have diagnostic/prognostic utility among patients at high risk for the development of cirrhosis and HCC.

摘要

背景

乙型肝炎病毒（HBV）携带者发生肝细胞癌（HCC）的风险很高，但目前尚无可靠的标志物来识别此类高危患者。HBV 在慢性感染期间上调肝脏中选定基因（URGs）的表达。这些异常表达的蛋白质会触发相应的抗体（抗-URGs），这些抗体在 HCC 检测之前就已经出现。本研究旨在探讨抗-URGs 是否可作为 HBV 诱导的肝硬化和 HCC 的早期预警生物标志物。

方法

采用横断面研究，共检测了 625 份 HBV 感染和未感染对照者的血清样本，使用特异性 ELISA 检测抗-URGs。

结果

抗-URGs 的数量和特异性与肝病的严重程度相关。抗-URGs 主要存在于 HBV 相关 HCC（55.2%）和肝硬化（60.7%）患者中，在慢性乙型肝炎患者（35.8%）中频率较低，在大多数无症状携带者（12.3%）中频率更低，这些携带者 ALT 正常，在慢性丙型肝炎患者（38.5%）和献血者（0.9%）中频率更低。这些抗-URGs 在 HCC 以外的肿瘤患者血清中很少检测到，除了 HBV 感染的胆管癌患者和一些药物性肝炎患者。3 种或更多的抗-URGs 可在肝硬化或 HCC 诊断前平均提前 11.8 个月，而 3 种或更多抗-URGs 的 HBV 肝炎患者发生肝硬化和 HCC 的风险（5/20 比 0/30）比那些抗-URGs 较少的患者高得多。作为早期预警生物标志物，3 种或更多的抗-URGs 作为阈值，可将肝硬化和 HCC 与其他标志物（AFP、AFP-L3、GPC3 和 GP73）具有中等敏感性（58.3%）和特异性（80.0%）区分开来，当与另一种标志物联合使用时，其敏感性可提高至 70.3%。