基于血清代谢组学的ALT低于2倍正常值慢性乙型肝炎抗病毒标志物筛选及功能学研究

多个指南推荐慢乙肝患者ALT≥2×ULN或存在显著肝脏病理改变时需抗病毒治疗。多个研究，包括我们的前期结果显示部分ALT<2×ULN的慢乙肝已存在显著肝脏病理改变。因肝活检是有创检查，限制了该部分患者的早期检出。因此发现能有效反映肝脏病理状态的无创生物标志物，对指导抗病毒治疗有重要的意义。我们前期研究发现不同肝脏病理状态的ALT<2×ULN的慢乙肝各有特异的血清代谢谱，并从中鉴定出4种较特异的代谢物，提示血清代谢物具有成为无创生物标志物的潜能。在此基础上，课题组拟进一步采用基于液相色谱-质谱的代谢组学方法，结合模式识别技术，筛选生物标志物；进而通过临床标本和HBV转基因小鼠体内实验研究验证已入选代谢物的早期诊断价值；最后通过体外实验对标志物代谢通路进行功能研究以阐述发病机制。本课题旨在为 ALT<2×ULN的慢乙肝提供有效的生物标志物，指导临床早期抗病毒治疗，为慢乙肝发病机制提供理论基础。

Several guidelines recommend antiviral therapy for hepatitis B patients with an alanine aminotransferase (ALT) level two folds higher than the upper limit of normal (ULN) range. However, many studies including ours showed that signicant inflammation and fibrosis may present in patients with chronic hepatitis B (CHB) and ALT<2×ULN, suggesting that antiviral treatment should be commenced. At present, liver biopsy is the gold standard for evaluating liver damage,yet it is an invasive and painful procedure, with rare but potential life-threatening complications, limiting its application. New biomarkers which can predict the overall histological severity of liver in CHB patients with ALT<2×ULN are therefore of great importance. We recently analyzed the metabolomic profile of CHB and found four potential serum biomarkers. In the present study, we will develop multivariate models using Liquid chromatography coupled to mass spectrometry（LC/MS）technology providing high metabolomics coverage to differentiate samples from CHB cohort with ALT <2×ULN, and normal health cohort.Based on this model, we will further identify and validate the serum metabolite markers for predicting antiviral treatment in CHB patients with ALT <2×ULN . We will also explore the gene function research based on the metabolic pathways of biomarker in vitro. In summary, this study aims to discover certain non-invasive biomarkers to predict antiviral treatment of CHB with ALT<2×ULN, and to further explore the underlying mechanisms.