扫描二维码或点击以下链接 查看原文或免费下载PDF http://www.lcgdbzz.org/cn/article/doi/10.3969/j.issn.1001-5256.2021.07.001 慢性HBV感染(CBI)是指HBsAg和/或HBV DNA阳性6个月以上，HBV持续感染引起的慢性肝脏炎症性疾病即慢性乙型肝炎(CHB)，包括HBeAg阳性CHB和HBeAg阴性CHB[1-2]。非酒精性脂肪性肝病(NAFLD)是一组与胰岛素抵抗(IR)和遗传易感密切相关的代谢应激性肝损伤疾病，病理组织学改变与酒精性肝病(ALD)相似，但患者无过量饮酒史，包括非酒精性单纯性脂肪肝(NAFL)伴或不伴轻度小叶内炎症或汇管区炎症、非酒精性脂肪性肝炎(NASH)及其相关肝硬化和肝细胞癌(HCC)[3-7]。2019年Eslam教授、George教授及Sanya教授等国际脂肪肝专家小组建议将NAFLD更名为代谢相关脂肪性肝病(MAFLD)[8]，但尚未被正式采纳，本文仍采用NAFLD命名和定义。CBI和NAFLD是世界范围内慢性肝病常见的两大病因，CHB重叠NAFLD愈加普遍，已成为肝病临床和基础领域关注的热点及难点问题。目前CBI重叠NAFLD(Co-CBI&NAFLD)尚无统一的定义，本文中Co-CBI&NAFLD是指慢性HBV感染前或持续感染中存在或发生不同临床病理类型NAFLD，包括CHB重叠NAFLD(Co-CHB&NAFLD)。本文就Co-CBI&NAFLD的流行病学、自然史、可能的发病机制、病理特征及临床诊疗现状予以述评。 1Co-CBI&NAFLD流行病学 全球约有2.57亿CBI患者，中国CBI患者约7000万，而NAFLD在西方国家患病率超过30%，包括中国在内的亚洲多数国家NAFLD患病率＞25%，据估计，Co-CHB&NAFLD患病率为25%~30%[9-10]。源自韩国的全球最大宗(83 339例)CBI社区人群长期随访研究[11]结果显示，NAFLD发病率为41.7/1000人年，但不同规模研究人群或队列的亚洲CHB患者中NAFLD的患病率报道差异较大，为14%~67%[12-15]，其中韩国51.2%，伊朗42.4%，土耳其34.3%，中国台湾约为43.9%。一项针对北美CHB患者的研究[16]发现，2000年—2005年与2011年—2015年，CHB患者中NAFLD的患病率从1.6%稳步上升至6.8%。源自法国的一个前瞻性队列研究[17]显示21%CHB患者合并NAFLD。中国宓余强教授团队和朱月永教授团队报道了由肝穿刺病理证实的Co-CBI&NAFLD发生率为30.9%~41.7%[18-21]；在中国香港，以受控衰减参数(CAP)＞248 dB/m为标准，CHB患者中NAFLD发病率47.8%(1134/2370)[22]。现有的全球Co-CBI&NAFLD流行病学资料多数为单中心、回顾性队列研究数据，且NAFLD诊断与评价主要基于B型超声、CAP衰减指数等检测手段，肝穿刺病理证实的Co-CBI&NAFLD研究队列相对较少，中国尚缺乏基于多地区、大样本、前瞻性、长期随访CBI人群的NAFLD流行病学资料。 2Co-CBI&NAFLD自然史 Co-CBI&NAFLD自然史尚不清楚。Joo等[11]对来自韩国的单一体检中心的83 339例(HBsAg阳性3926例、HBsAg阴性79 413例)社区成年人群进行了长达12年的前瞻性随访队列研究，Cox回归模型分析显示，484 736.1人年随访期间有20 200例发生NAFLD(NAFLD发病率41.7/1000人年)，调整年龄、性别、随访时间、吸烟、饮酒、定期锻炼、教育水平、体脂指数后，HBsAg阳性与阴性人群校正危险比(aHR)为0.83(95%CI：0.73~0.94)，NAFLD发病率在HBsAg阳性人群较阴性人群低；引入HBV感染和混杂因素(包括IR和代谢因素稳态模型评估)作为时间依赖暴露因素后，HBsAg阳性和NAFLD发生风险降低的关系有所减弱，但仍然存在。源自中国香港的1013例(HBsAg阳性91例、HBsAg阴性922例)社区人群的断面研究[23]中，HBsAg阳性人群中NAFLD患病率为13.5%(95%CI：6.4%~20.6%)，HBsAg阴性人群NAFLD患病率为28.3%(95%CI：25.3%~31.2%)，质子磁共振波谱分析显示平均肝脏TG水平在HBsAg阳性和阴性人群中分别为1.3%和2.1%。但在CBI人群中，血清HBV DNA载量、病毒基因型、e抗原状态与NAFLD发生无相关性。 虽然CBI患者NAFLD发病率较低，但NAFLD和CHB可以共同加重肝损伤，增加肝纤维化和HCC的风险。来自中国香港的270例(合并脂肪肝患者107例、非脂肪肝患者163例)CBI患者(HBsAg阳性超过6个月)的队列研究[24]表明，经过79.9个月的随访，11例(合并脂肪肝患者9例、非脂肪肝患者2例)发生HCC。经过多变量的Cox回归分析发现，并发脂肪肝(HR=7.27，95%CI：1.52~34.76，P=0.013)、年龄、肝硬化、还有APOC3 rs2854116 TC/CC基因型(HR=3.93，95%CI：1.30~11.84，P=0.013)是预测HCC发展的独立因素。另一项来自中国香港的558例NAFLD患者的多中心前瞻性队列研究[25]，经过6.2年随访后，血清抗-HBc阳性的NAFLD患者更易发展为进展期肝纤维化或HCC(6.5% vs 2.2%，P=0.039)。 3Co-CBI&NAFLD的发病机制 Co-CBI&NAFLD的发病机制尚未阐明。HBV感染可能影响肝脏脂质代谢，促进肝细胞内脂质沉积。Kim等[26]通过HepG2细胞系及小鼠模型研究发现，HBx通过增强肝脏X受体和LXR反应元件作用，促进固醇调节原件结合蛋白1(SREBP-1)和脂肪酸合成酶上调，进而增加脂质的胞内沉积。HBx可能通过肝细胞核因子3β(HNF3β)、重组人CCAAT增强子结合蛋白α(C/EBPα)、过氧化物酶体增殖物激活受体α(PPARα)激活肝脏脂肪酸结合蛋白1(FABP1) 启动子，FABP1在细胞内脂肪酸运输和利用中起重要作用，促进肝脏脂质堆积[27]。而NAFLD可能通过破坏HBV复制和增加HBV感染细胞的凋亡来促进HBsAg与HBV DNA的清除[28]。在NAFLD和HepG 2.2.15细胞介导的硬脂酸诱导的脂肪变性HBV转基因小鼠中，TLR4/MyD88信号通路被激活，HBV复制被抑制[29]。 Co-CBI&NAFLD对肝纤维化、肝硬化和HCC促进作用的潜在机制尚不清楚。可能的机制是：(1)NAFLD相关的脂毒性可以通过内质网应激和线粒体呼吸链产生过量的活性氧，导致DNA和其他生物大分子的氧化损伤，这也是Co-CBI&NAFLD进一步发展成HCC的一个关键过程。安威教授团队[30]系列研究显示，线粒体在NAFLD发病中起重要作用，认为NAFLD可视为“线粒体病”范畴。(2)NAFLD介导的HBV感染中炎症损伤和纤维化的加重。譬如，NASH中受损肝细胞释放的危险相关分子模式，以及炎性细胞因子(如IL-1、IL-6、TNFα、CCL2和CCL5)可以导致肝星状细胞的激活和增殖，继而发生肝纤维化或最终的肝硬化[28]。(3)NAFLD中瘦素水平升高和脂联素水平降低，脂源性细胞因子的改变促进肝纤维化的进展[31]。 4Co-CHB&NAFLD的病理学特征及组织学评价 Co-CBI&NAFLD肝组织学改变往往表现为两种肝病的病变混杂，给肝活检组织学评价带来一定困难，但有经验的病理医师通过仔细检查，多数CHB和NAFLD各自的病变特点可以鉴别。NAFLD特征性病变包括肝细胞大泡或大小泡混合型脂变，呈小叶中央区带、汇管区周围、全小叶及无区带型分布；脂变区域可夹杂肝细胞气球样变(ballooning)；可出现脂质肉芽肿、巨型线粒体肝细胞、糖原核肝细胞，而CHB可见毛玻璃样肝细胞；NASH引起的肝小叶内炎症坏死主要呈点灶状坏死，坏死区是以淋巴细胞为主的混合性炎细胞浸润。CHB通常表现为活动性淋巴细胞浸润性界面炎(interface hepatitis)，NASH通常缺乏或轻度混合性炎细胞浸润性界面炎，小叶内及小叶界板处融合性坏死、桥接坏死通常为活动性CHB病变特征，上述病变NASH极少出现。成人型NASH肝纤维化往往见于小叶中央区带肝细胞周和窦周纤维化(chicken-wire fibrosis)，而CHB多以汇管区周围纤维化及桥接纤维化为主要形式。此外，汇管区淋巴细胞聚集性浸润，乃至滤泡样结构形成是CHB病变特点，成人型NASH汇管区炎症通常缺乏。 Co-CHB&NAFLD的组织学评价国内外尚无专门的评分系统，建议选择Ishak评分系统[32]、Metavir评分系统[33]、我国CHB肝组织学评分系统[34]联合NASH-CRN评分系统[35]或FLIP/SAF评分系统[36]，进行病理组织学评价。近年来，魏来教授团队[37]采用二次谐波/双光子激发荧光法对NASH穿刺肝组织切片(无需染色)进行多组织学参数自动定量检测，并建立了qFIBS定量评价模型。Zhuang等[38]利用上述技术对Co-CHB&NAFLD的肝细胞脂变进行了自动定量检测尝试。 5Co-CBI&NAFLD的无创诊断 超声虽然是临床诊断脂肪肝最常用的方法，但其对脂肪肝诊断的敏感性低，特异性也有待提高[39]。CAP能准确区分轻度肝细胞脂变与中-重度肝细胞脂变，近年来对于脂肪肝的诊断价值已被广泛认可[4]。范建高教授团队[40]发现CAP对于脂肪肝的诊断准确性优于超声，但是其与超声相比易高估肝脂肪变程度。陆伦根教授团队[41]多中心队列研究结果显示，FibroTouch对肝脏脂变及纤维化程度有较好的诊断效能，适用于NAFLD患者的临床评估和监测。常见诊断脂肪肝的血清学诊断模型中，脂肪肝指数、肝脂肪变性指数临床诊断效能较佳，但在CHB重叠脂肪肝中研究尚少[3]。 近年来，利用血液中CK-18 M30、成纤维细胞生长因子-21(FGF-21)、IL-1Ra、色素上皮衍生因子(PEDF)、骨保护素(OPG)、miRNAs、活性氧等相关标志物对诊断CHB重叠或合并NASH均呈现出可接受的特异性和敏感性[42-45]，但上述指标在临床上尚未进入准入或普遍应用，且诊断阈值待进一步确定。Co-CHB&NAFLD显著/进展期肝纤维化及肝硬化的预测，GGT/PLT比值(GPR)的AUC似乎高于APRI和FIB-4[46]。瞬时弹性成像技术(TE)在进展期肝纤维化及肝硬化诊断方面优于GPR，使用GRP和TE的两步法检测可进一步优化Co-CHB&NAFLD患者肝硬化的评估效果[47]。Shen等[48]发现中重度肝细胞脂变可增加无显著肝纤维化CHB患者的肝硬度值(LSM)。Xu等[49]发现CAP增加了CHB显著纤维化的假阳性率，其建立的模型公式Fibro-NAFLD可提高LSM对于Co-CHB&NAFLD显著肝纤维化的诊断效能。 6Co-CHB&NAFLD的抗病毒治疗 现有的研究表明，NAFLD与代谢综合征密切相关，代谢综合征是CBI患者晚期纤维化和肝硬化的独立危险因素[50]，然而HBV DNA载量与NAFLD发病率呈负相关[51]。因此，目前对于Co-CHB&NAFLD启动抗病毒治疗的指征仍尚待进一步明确。 根据中国《慢性乙型肝炎防治指南(2019年版)》[1]，无论是否重叠NAFLD，CHB肝硬化均推荐进行抗病毒治疗；而对于非肝硬化的Co-CHB&NAFLD患者，需要综合评估以确定治疗方案。为此，孙剑教授团队提出相关临床管理建议：当Co-CHB&NAFLD患者无其他肝损伤原因ALT＞5×ULN或HBV DNA＞2000 IU/ml时可考虑试验性抗病毒治疗，经治疗HBV DNA阴转后根据ALT下降与否，选择继续抗病毒治疗或按NAFLD管理；当Co-CHB&NAFLD患者ALT为1~5×ULN且HBV DNA≤2000 IU/ml时，先按NAFLD管理3~6个月，再根据ALT水平选择治疗策略。该策略进一步细化了Co-CHB&NAFLD抗病毒治疗的时机、路线图及管理策略，值得临床参考。 对于Co-CHB&NAFLD患者的抗病毒疗效，赵景民教授团队和鲁凤民教授团队对儿童Co-CHB&NAFLD患者开展了相关研究[52]。在抗病毒治疗的第96周，重叠或不重叠NAFLD的CHB患者在HBV DNA低于检测下限的比例、HBeAg阴转及AST和ALT复常方面均无显著差异，但发现NAFLD是HBsAg转阴的独立预测因子(aHR=3.245, 95%CI：1.288~8.176)，Co-CHB&NAFLD儿童患者HBsAg阴转率均高于无NAFLD的CHB儿童患者。有研究[53]显示肝细胞脂变是恩替卡韦治疗失败的独立因素。在伴有肝脂肪变的CHB患者中，HBV DNA清除率较低。还有研究[54]表明Co-CHB&NAFLD患者抗病毒治疗的远期完全病毒学抑制率(HBV DNA＜20~100 IU/ml)和/或生化应答率(女性ALT≤25 U/L，男性ALT≤35 U/L)无明显影响。显然，目前重叠NAFLD对CHB患者抗病毒疗效的影响尚存有争议，需要进行多中心、大样本、随机对照前瞻性临床队列研究，结合临床真实世界研究，以期为Co-CHB&NAFLD抗病毒治疗时机选择、疗效预测、治疗方案优化等提供高等级的循证医学依据。 7总结与展望 Co-CBI&NAFLD两者的相互影响作用尚未明确，现有研究[55-59]显示NAFLD对CHB患者的抗病毒疗效影响不大，单纯CHB组和合并症组的病毒抑制情况区别并不明显，但可能增加HBsAg血清学转换率[60]；Co-CHB&NAFLD较单纯CHB肝纤维化进展呈加快趋势，尤其合并代谢综合征会进一步促进CHB患者肝硬化及HCC的发生；Co-CBI&NAFLD组织学上两者病变并存，各自特征性病变鉴别困难。 未来Co-CBI&NAFLD临床与基础研究有机结合，将明确其疾病演变的各关键环节，阐明其自然史；随着相关新技术的转化与应用，建立高特异性和高灵敏性的无创诊断技术，并确定其诊断阈值，解决Co-CBI&NAFLD重点人群筛查、监测及随访等临床问题；随着高等循证医学证据的增加，Co-CHB&NAFLD抗病毒治疗时机选择、疗效预测及治疗方案优化，尤其是抗病毒与脂肪肝干预综合策略的应用，将显著降低相关终末期肝病的发生率和病死率，相关Co-CBI&NAFLD诊疗指南或共识将会随着证据的积累应运而生；随着Co-CBI&NAFLD相互影响作用机制的逐渐阐明，将为临床疾病管理，乃至新药研发、新型治疗策略的制订提供科学依据。 参考文献： [1]Chinese Society of Infectious Diseases, Chinese Medical Association, Chinese Society of Infectious Diseases, Chinese Medical Association. 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