中文English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R

Noninvasive diagnostic models for chronic hepatitis B liver fibrosis

DOI: 10.3969/j.issn.1001-5256.2021.10.034
Research funding:

The High-level Health Technicians-reserve Talents Project of Yunnan Province (H-2017071);

The Scientific Research Project for the Department of Education of Yunnan Province (2021J0239)

  • Received Date: 2021-02-23
  • Accepted Date: 2021-03-23
  • Published Date: 2021-10-20
  • Hepatitis B virus (HBV) infection is still a public problem that seriously threatens human health. Evaluation of liver fibrosis progression with an efficient noninvasive model is of great significance for condition assessment, disease management, and prognostic evaluation in patients with chronic HBV infection. This article reviews the noninvasive models commonly used in the diagnosis of liver fibrosis in recent years, summarizes the research background, methods, related studies, and advantages and disadvantages of these models, and analyzes the current research status and possible development trends of liver fibrosis assessment models. Recent studies have shown that although current models are not perfect for Chinese patients with chronic HBV infection as the main predisposing factor for liver fibrosis, the excellent performance of noninvasive models in liver fibrosis assessment provides a reference for the assessment of liver fibrosis in patients with chronic HBV infection and can replace liver biopsy to a certain extent.

     

  • 原发性胆汁性胆管炎(PBC)是一种慢性进行性肝内胆汁淤积的自身免疫性疾病,常见抗线粒体抗体M2亚型(AMA-M2)阳性,血清生化指标ALP或/和GGT等异常升高。PBC是最早确定自身抗体靶抗原的自身免疫性疾病之一,其组织特异性和易于确诊的特点,决定PBC是研究者理解人类免疫调节的一个重要模型。PBC病因至今尚未明确,通常认为是环境因素和遗传因素交互作用的结果。PBC家系的流行病学调查发现PBC患者兄弟姐妹相对风险率(λs)高达10.5,同卵双胞胎PBC发病一致率高达0.63,并且发病年龄较一致,表明遗传因素在PBC的发病进程中起着重要作用[1]。几十年来,PBC遗传学研究经历了小规模的家系研究、候选基因研究、全基因组关联研究(genome-wide association study,GWAS)等阶段。继2017年本研究团队发表汉族人群PBC的GWAS分析结果后,全球主要人种的PBC GWAS分析已基本完成[2-5]。近几年,多种群全基因组Meta分析进一步发现,一些PBC易感的相关位点,尤其是针对X染色体的Meta分析,挖掘出多个新的PBC易感基因,对阐明PBC的发病机制提供了重要线索[6-9]。后期GWAS分析将主要针对PBC的不同临床亚型、药物应答以及对系列GWAS数据的精细挖掘,包括药物开发和转录、蛋白、代谢等多组学整合研究。

    GWAS在全基因组水平上对数十万到数百万个多态位点(SNP)进行分析,是研究复杂疾病和性状遗传易感性的一种有效手段。2009年起,多国学者相继发表了PBC的GWAS研究结果,所有的研究均表明HLA Ⅱ类基因,尤其是DRB1、DQA1、DQB1基因位点与PBC遗传易感性关联最强[2-5]。欧美团队研究[10-12]表明,采用GWA数据推演的等位基因关联信号主要位于DRB1,包括DRB1*08、DRB1*11、DRB1*13和DRB1*14等。不同于欧美人群中DRB1*08∶01与PBC的强关联性,汉族人群基本没有等位基因DRB1*08∶01,而DRB1*08∶03与PBC紧密关联。此外,DPB1*17∶01是中国汉族人群PBC中又一独立关联位点[13-14]。但相比于其他自身免疫性疾病,PBC患者的HLA关联性相对较弱,70%~80%的PBC患者并未携带HLA区域主要的PBC易感基因[14],这也意味着非HLA区域基因可能在PBC的发病过程中发挥重要的作用。迄今为止,共发现了近50个非HLA区域的PBC易感基因位点,多为免疫调节因子和免疫调控信号通路相关的因子,提示HLA基因和非HLA基因协同参与PBC的疾病进程。GWAS研究结果揭示包括JAK-STAT、IL12-IL12R、NF-κB、TLR/TNFα、IL21-IL21R和CCL20-CCR6等多个免疫调节通路与PBC的发病相关。

    GAWS研究结果显示不同种群PBC的易感基因及位点会有所差异。在欧美白人中发现的22个非HLA区域PBC易感基因中分别有10个和5个在中国汉族人和日本人中被证实。值得关注的是,被认为与PBC发病有密切联系的IL12A在欧美白人和中国汉族人群均有很强关联性,但在日本人中并无显著性,而汉族人群与欧美白人IL12A的易感位点并不相同。日本人的两次PBC GWAS研究发现的3个新的PBC易感基因中POU2AF1仅在日本人中有显著性,而TNFSF15和IKZF3在中国汉族人群中被同样证实是PBC的易感基因[2-5, 15]。笔者对中国汉族人群的PBC GWAS研究发现了包括IL21R、IL21、CD58、ARID3A、CD28- CTLA4-ICOS、IL16在内的6个新的PBC易感基因,研究还显示中国汉族人群易感性最强的HLA基因和非HLA基因位点分别位于DRA内含子-1的rs9268644位点和TNFSF15-TNFSF8的rs4979467位点[2]

    由于多数PBC患者出现临床症状较晚,多代家系样本较难收集,因此通过大规模家系样本进行PBC的连锁不平衡分析的难度较大。Wang等[16]近期发表了对30个PBC核心家系的全外显子组测序分析,未发现在GWAS找出的易感基因中存在严重的新生突变(de novo mutation),这一结果表明PBC的遗传易感性主要反映在群体中常见多态位点相互作用,共同影响个体的免疫稳态的失衡。对近50个PBC易感位点或基因的精细定位和功能SNP的鉴定是目前PBC遗传学研究的重点之一。通过对易感基因功能SNP的分析鉴定,确定功能SNP的调控机制,对研究PBC发病机制有重要的提示作用。目前发现的PBC易感基因TNFSF15、IRF5、IRF8、TYK2、MMEL1-TNFRSF14、IL7R、IL12B、TNFAIP3和IKZF3-ORMDL3等的关联SNP,与其他自身免疫性疾病发现的关联SNP是一致的,说明不同自身免疫疾病的易感性存在共性。同时在自身免疫性疾病的共同易感基因中,也存在功能SNP的差异。CD28-CTLA4-ICOS位点的SNP与T2D、RA、PSC、MS和PBC等易感性相关,但在这一区域,PBC的关联SNP与其他疾病的关联SNP没有连锁关系,说明CD28-CTLA4-ICOS位点参与PBC发病的作用机制有其特异性[2]。在目前发现的易感基因中,IL21、IL21R、IL16和ARID3A等不仅表现出种族的特异性,也表现出PBC的疾病特异性,针对这些位点的功能SNP的分析,有助于探讨PBC特异的发病机制。

    尽管GWAS研究发现了大量与PBC相关的基因变异,但是还没有直接证据显示这些基因变异影响PBC的病理进程。由于对复杂的基因调控网络的理解尚不完善,因此也导致对GWAS结果的解读存在一定困难。因此,在未来很长一段时间里,研究者面临的一个重大挑战是如何将免疫遗传学与免疫表型联接,阐明PBC易感性相关的免疫调控分子在其发病及病理进程中的作用。目前基于GWAS研究取得的数据,一些具有PBC典型血清学、生化和组织学特征的基因敲除动物模式如IL12 p35-/-、IL12 p19-/-和dnTGFBRII小鼠模型被建立,并在PBC的免疫病理机制研究方面取得很有价值的成果[13]

    与其他自身免疫疾病相比,PBC表现出疾病的组织特异性,但其临床表症也表现出明显的异质性。PBC患者在发病年龄、起病表症、疾病进程和治疗效果等方面均存在很大的个体差异。目前95%以上的PBC患者AMA- M2阳性,在 < 5%的AMA-M2阴性的PBC中,可能有部分患者是AMA弱阳性,或仅识别目前AMA-M2抗原中被掩盖了的表位,或完全是AMA阴性。对AMA完全阴性的患者,PBC的发病机制与阳性患者可能是完全不同的,但目前要收集到大量的AMA完全阴性的患者进行GWAS分析,有很大的难度,需要从数十万的PBC患者中加以甄别,要完成这样的分析,需要大规模的协作。除AMA-M2外,PBC患者还出现PBC特异的抗核抗体,主要是抗gp210抗体和抗sp100抗体,二者的阳性率分别为30%~40%和20%~35%。抗gp210抗体仅识别gp210的C末端突出到细胞质的部分,目前尚不确定抗gp210抗体是否仅识别单一表位。抗sp100抗体识别多个抗原表位,包括线性和构象表位。Wang等[17]对抗sp100抗体阳性组和阴性组的GWAS队列分析发现,MHC区域的rs1794280和rs492899位点与抗sp100抗体相关联,并鉴定出HLA DRβ1-Asn77/Arg74、DRβ1-Ser37、DPβ1-Lys65是决定抗sp100抗体产生的关键位点,该结果揭示抗sp100抗体具有强烈的遗传倾向,其产生与HLA分子对sp100表位的呈递密切相关,提示分子模拟可能是抗sp100抗体产生的原因。但对抗gp210抗体阳性组和阴性组的GWAS队列分析未发现任何显著的SNP位点。目前抗gp210抗体是如何产生的尚不清楚,但抗gp210抗体阳性患者在临床表征和熊去氧胆酸(UDCA)治疗的应答存在明显的异质性,进一步研究抗gp210抗体的产生机制对PBC的有效治疗有着重要的意义。

    PBC患者在AMA抗体产生、发病年龄、发病表征、无药物干预的疾病进展,UDCA治疗的药物应答等方面存在明显的异质性和个体差异,针对这一系列异质性的GWAS分析有助于了解PBC的发病机制和个性化的治疗。这类研究工作需要建立在大规模临床样品和正确、可靠的临床信息的收集和整理的基础上,目前针对特定PBC亚型的分析已在国内外的部分实验室展开。

    GWAS研究结果揭示了多个与PBC的发病机制密切相关的信号通路,为治疗PBC药物研发提供了新的思路和潜在的靶点。单克隆抗体优特克诺(ustekinumab)的靶向位点是IL12/23 p40亚单位,可作用于IL12/Th1和IL23/Th17通路,但在一项对UDCA治疗生化应答不良的PBC患者应用优特克诺治疗的临床试验中,没有患者在Ⅱ期临床试验中达到预定主要生化应答终点[18]。PBC患者激活的T淋巴细胞靶向针对肝内胆管,用CTLA-4抗体阻断CD80/CD86可能具有治疗作用。阿巴西普(abatacept)是CTLA4分子的细胞外功能区,与人IgG的Fc段结合而成的可溶性融合蛋白,但目前临床试验采用阿巴西普联合UDCA治疗UDCA应答不良的患者,发现阿巴西普联合UDCA治疗并不能改善生化应答和临床疗效[19]。在PBC的易感基因中,与TNFα信号通路相关的有TNFRSF1A、DENND15、TNFAIP2,目前已证实TNFα抑制剂在克罗恩病、溃疡性结肠炎和类风湿性关节炎的治疗中有明显的疗效,但是否对UDCA治疗效果不佳的PBC患者具有疗效尚不明确。利妥昔单抗(rituximab)是B淋巴细胞表面分子CD20的嵌合型抗体,初步临床试验已证实利妥昔单抗可以明显降低UDCA无应答PBC患者体内的自身抗体水平,但对PBC的疗效非常有限[20]。Moritoki等[21]认为可能的原因是患者出现针对利妥昔单抗的抗体(anti-drug antibodies,ADA)和研究中纳入的UDCA疗效不佳(难治型)的PBC患者比例较高。鉴于此,Moritoki等[21]通过小鼠PBC模型发现,抗CD20抗体治疗需要在PBC发病的早期进行,才能广泛抑制PBC的效应通路,但对产生ADA的小鼠,治疗效果有限。Cordell等[9]基于PBC的GWAS数据的分析结合计算机生物学技术的药效分析,建议将多个针对GWAS靶向基因或位点的单克隆抗体或小分子药物作为潜在的PBC治疗药物。期待后期的动物实验和临床测试能够为PBC的治疗提供更多的手段。

    综上所述,尽管PBC的遗传学已取得丰硕的成果,但与多数复杂性疾病遗传学研究面临一样的困境,即不能有效地解析遗传变异如何调控效应蛋白表达,效应蛋白分子又如何对细胞、组织产生影响,进而导致疾病的发生和发展。近年来基于GWAS结果,开发的多个针对PBC治疗单抗药物临床试验结果均不理想,可能是目前困境的具体表现。随着多组学整合研究的深入,单细胞测序和代谢分析等研究手段的发展和普及,必然将PBC的遗传易感性跟分子病理机制紧密联接,为PBC的遗传学研究开拓新的局面。

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