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乙型肝炎合并脂肪肝的特征和诊治对策

作者:感染病学分会 日期:2018-08-07 浏览量:37

在我国及亚洲其他地区,乙型肝炎病毒(HBV)感染非常常见,慢性乙型肝炎(CHB)仍是导致肝硬化和肝细胞癌的重要病因。随着肥胖、糖尿病患病率的升高,非酒精性脂肪性肝病(NAFLD)发病率逐渐升高。在CHB患者中,合并脂肪肝的患者亦越来越多。CHB和NAFLD已成为我国目前最主要的慢性肝病[1],目前有越来越多的CHB患者合并肝脂肪变[2]。为此,HBV慢性感染对代谢和脂肪肝的影响,以及脂肪肝、代谢因素对CHB患者肝病进展和抗病毒治疗效果的影响已成为当前研究的热点和难点。此外,在CHB合并脂肪肝的患者中,出现血清转氨酶异常以及肝炎活动时,需谨慎鉴别其是否为病毒性肝炎和(或)非酒精性脂肪性肝炎(NASH)相关肝损害,从而采取针对性治疗和随访措施。

1 HBV感染对脂肪肝的影响及原因

在亚洲范围内,肝活检证实的CHB患者中脂肪肝患病率为14%~67%[2]。近十年,随着肥胖的流行,我国CHB患者经肝活检证实的NAFLD患病率不断增高(从2002年的8.2%上升到2011年的31.8%)[3]。目前HBV感染与肝脂肪变之间的关系并不明确。HBV感染患者中脂肪肝的发生与男性、肥胖症、血液糖脂代谢紊乱、甲状腺功能减退以及基因多态性等因素相关[4,5,6,7]。有荟萃分析报道,HBV慢性感染患者肝活检脂肪肝的患病率(均数为29.6%)显著低于慢性丙型肝炎(CHC)患者(50%左右)。多项研究显示,血清HBV DNA水平与脂肪肝的发生呈负相关,提示HBV感染并不增加脂肪肝的发生[4]。Shen等[8]、Wong等[9]和Cheng等[10]研究提示,血清HBsAg携带者和CHB患者B超诊断的脂肪肝患病率显著低于对照组,HBV现症感染与脂肪肝发病风险呈负相关。Wang等[3]研究发现,合并脂肪肝的CHB患者血清HBV DNA水平及肝脏HBsAg免疫组化染色强度显著低于无肝脂肪变的CHB患者,肝脏HBsAg免疫组化染色强度与肝脂肪变程度呈独立负相关。Joo等[11]的前瞻性队列研究显示,HBV现症感染患者脂肪肝的发病率显著低于对照人群。众多研究表明,CHB患者脂肪肝的发生主要与宿主代谢和心血管危险因素相关[12,13]。普通饲料饲养B亚型HBV全基因组转基因模式小鼠并不产生肝脂肪变[14],仅实验研究显示HBx蛋白有促进肝脂肪变形成的作用[15]。因此,HBV感染本身并不导致肝细胞脂肪变,HBV携带者和CHB患者脂肪肝的发生率甚至低于普通人群。

慢性HBV感染有可能是通过改善代谢紊乱,从而导致CHB患者脂肪肝患病率降低。多项研究报道,慢性HBV感染患者高三酰甘油血症和代谢综合征患病率较对照人群显著降低[9,16,17]。Hsu等[18]研究发现,慢性HBV感染患者血清脂联素和内脂素水平增高,而血清三酰甘油和瘦素水平较对照组降低,并且这些脂肪细胞因子的血清水平与HBV DNA水平密切相关。杨蕊旭等[19]通过脂质组学分析发现,肝活检证实的CHB患者血液中多种中性脂质以及与胰岛素抵抗相关的脂质较正常对照人群显著下降,而合并肝脂肪变者与无肝脂肪变的CHB患者血清脂质组学改变迥异,前者与NAFLD患者血清脂质组学改变相近。美国学者对慢性肝病患者进行生活方式调查发现,相较于CHB患者,NAFLD与CHC患者摄入更多的高脂肪、高热量饮食[20];并且,CHB患者较NAFLD和CHC患者日常活动能力评分更好,日常活动受限情况较轻[21],提示饮食和运动习惯相对健康可能与CHB患者代谢综合征和脂肪肝患病率降低有关。

2 脂肪肝及代谢紊乱对CHB进展及预后的影响

多项横向研究显示,肝活检证实的CHB患者肝脂肪变与肝纤维化程度之间无显著相关性[4,22],但是肝活检证实的NASH与CHB患者进展期肝纤维化密切相关[23]。除脂肪肝对CHB的影响,Wong等[24]报道代谢综合征是CHB患者肝硬化发病的独立危险因素,比值比(OR值)随代谢综合征组分的增多而增高。该团队其后的随访研究发现,经过对血清HBV DNA水平和肝脏炎症坏死程度的校正,代谢综合征仍与CHB患者肝纤维化进展相关[25]。并且,代谢综合征、2型糖尿病以及脂肪肝还与CHB患者肝细胞癌、肝内胆管细胞癌发病率增加密切相关[1,2]。脂肪肝、代谢综合征促进CHB患者肝病进展的机制可能涉及高胰岛素血症、NASH相关氧化应激和脂质过氧化等[26]。此外,代谢综合征还与CHB患者肝病和心血管疾病相关病死率增加相关[27]。

3 脂肪肝对CHB患者抗病毒治疗应答的影响

目前就脂肪肝是否对CHB患者抗病毒药物治疗效果有影响尚无定论。临床上合并脂肪肝的CHB患者血清HBV DNA水平通常低于无脂肪肝的患者,并且在HBV转基因小鼠中高脂饮食诱导的脂肪肝可抑制HBV的复制[14]。Hui等[28]的病例对照研究亦发现,重度脂肪肝与血清HBV DNA水平降低独立相关,提示肝脂肪变可影响病毒的复制。Chu等[29]发现在HBV携带者中,出现HBsAg血清转阴的患者脂肪肝的比例较无血清学转阴者高,可能与肝细胞脂肪变导致HBsAg在细胞浆中分布改变以及肝细胞凋亡增多有关。

施军平等团队[30,31,32,33]的研究显示,并存的脂肪肝不影响聚乙二醇干扰素(Peg IFN)治疗CHB患者的病毒学应答效果,但可能会影响患者的生化学应答效果。亦有研究报道,并存的NASH对Peg IFN伴或不伴核苷(酸)类似物治疗CHB患者的病毒学应答和生化学应答均无影响[23]。脂肪肝对核苷(酸)类似物的抗病毒治疗的影响目前仍有争论。Jin等[34]报道,在恩替卡韦治疗CHB患者中,合并脂肪肝的患者HBV DNA转阴率、HBeAg血清学转换率以及丙氨酸转氨酶(ALT)复常率降低;多因素分析提示脂肪肝与恩替卡韦治疗失败独立相关。然而,Zhu等[35]研究显示,脂肪肝不影响恩替卡韦治疗的HBV DNA转阴率和HBeAg血清学转换,但可能影响血清转氨酶的复常。因此,并存的脂肪肝可能并不影响抗病毒药物治疗CHB的病毒学应答,但可能会影响生化学应答。主要的原因应该是并存的脂肪肝特别是脂肪性肝炎并不会因为病毒学应答而缓解,而脂肪肝则是患者血清转氨酶不能完全降至正常范围的原因。

4 CHB患者NAFLD的诊治

B超是普通人群临床诊断脂肪肝的首选措施,CT及普通磁共振检查对脂肪肝的诊断价值并不优于B超。然而,超声受操作者经验及机器性能的影响较大,并且轻度肝脂肪变检出率低(假阴性),而且弥漫性肝纤维化和肝硬化也可呈现脂肪肝的典型声像图(假阳性),更为重要的是CHB患者并存的脂肪肝绝大多数程度较轻(5%~33%)。因此,B超并非CHB患者筛查脂肪肝的可靠方法。振动控制瞬时弹性成像(FibroScan)是一种能够同时定量评估肝脂肪变和肝纤维化的新颖影像学诊断方法。在肝活检证实的CHB患者中,受控衰减参数(CAP)可以敏感检出轻度肝脂肪变,准确区分轻度与中重度肝脂肪变,同时可以敏感诊断进展期肝纤维化和肝硬化[36],CAP对CHB患者肝脏脂肪变的诊断效力高于B超和肝脂肪指数[37]。体质指数>28 kg/m2和皮肤至肝包膜距离>25 mm影响CAP诊断脂肪肝的效能[38],但是肝脂肪变的程度可能并不影响弹性值对CHB患者肝纤维化的判断[39]。

HBV现症感染和NAFLD并存者肝酶异常、肝炎活动的原因包括HBV介导的免疫相关炎症坏死和(或)胰岛素抵抗及酒精滥用介导的脂肪性肝损伤(NASH或酒精性肝炎)[40,41,42,43,44,45,46,47]。Spradling等[41]研究报道,NAFLD和NASH是导致低病毒载量的慢性HBV感染患者血清ALT升高的常见原因。Kumar等[43]报道,在CHB合并脂肪肝患者中,HBV相关ALT升高占48.4%,脂肪肝相关ALT升高仅占24.7%;而在低病毒载量的CHB合并脂肪肝患者中ALT异常主要与NAFLD和酒精滥用有关。对于胰岛素抵抗和酒精滥用相关的脂肪性肝炎和肝酶异常,需要戒酒、减肥和改善胰岛素抵抗,如果此时并无HBV相关肝损伤则可以不抗病毒治疗,至少不建议使用干扰素治疗;而对于HBV相关的慢性肝损伤则需第一时间抗病毒治疗,治疗并存的脂肪肝可以确保在病毒学应答的同时获得生化学应答,从而促进肝病康复,减少肝硬化和肝细胞癌的发生。因此,在HBV现症感染合并脂肪肝时需合理分析血清转氨酶异常及肝炎活动的原因,从而采取个性化的治疗及随访方案。

由于CHB和NASH的肝组织学特征不同,肝活检是明确HBV现症感染合并脂肪肝患者肝损害及其原因的金标准,>5%的肝细胞大泡性脂变、肝细胞气球样变、小叶内炎症及窦周纤维化提示存在NASH[43,44,45,46,47](表1)。HBV携带者和CHB患者NASH的无创诊断是当前研究的热点。Liang等[43]报道,血液细胞角蛋白(CK-18)M30、CAP、空腹血糖和HBV DNA水平联合检测有助于CHB患者NASH的诊断。Zhang等[44]通过血清microRNA谱研究发现,miR-122,-572,-575,-638和-744在CHB及NASH中有不同改变,有助于CHB和NASH的鉴别诊断。Liu等[45]检测CHB和NAFLD患者血清microRNA发现,miR-34a对NASH有较好的诊断效力。Liang等[46]报道,CHB合并NAFLD患者血清CK-18 M30较CHB无NAFLD患者增高。Yang等[47]通过分析CHB和NAFLD患者血清脂质谱发现,单不饱和三酰甘油有助于NAFLD患者以及CHB患者NASH的诊断,提示血清单不饱和三酰甘油无创诊断NASH的效果不受是否存在HBV现症感染的影响。


5 结束语

总之,尽管HBV现症感染不是代谢综合征和脂肪肝的危险因素,但是愈来愈多的CHB患者并发脂肪肝,后者主要与宿主的遗传易感和代谢紊乱密切相关。并存的代谢综合征、2型糖尿病、脂肪肝有可能促进CHB患者肝病进展,增加肝硬化和肝细胞癌的发病率。脂肪肝可能并不影响CHB患者抗病毒药物的病毒学应答率,但脂肪肝是血清HBV DNA转阴患者肝酶持续异常的主要原因。慢性HBV现症感染合并脂肪肝患者出现转氨酶异常和肝炎活动时需谨慎判断其病因,肝活检以及一些无创标志物有助于NASH和CHB的鉴别诊断,临床医师需重视CHB与NASH并存的诊断及防治,从而阻止肝病进展并减少NAFLD相关代谢和心血管并发症的发病率。

志      谢

志谢:肝脏病理专家肖书渊、刘纪民和刘秀丽教授在本文撰写中提出了宝贵意见,在此表示感谢!


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