综 述

随着人们生活方式的改变，非酒精性脂肪性肝病（NAFLD）目前已成为世界范围内最常见的肝脏疾病之一，包括肝脂肪变性、非酒精性脂肪性肝炎(NASH)和肝纤维化，这些疾病可能发展为肝硬化、肝细胞癌（HCC），NASH将成为肝移植的主要适应证^[1]。

由于NAFLD的诊断缺乏统一明确的临床标准，且其发病机制较为复杂，由胰岛素抵抗 (IR) 、脂质紊乱、氧化应激、肠道微生物及遗传等多种因素发挥协同作用导致NAFLD的发生^[2]。目前针对NAFLD的治疗仍以调整生活方式、控制血糖及血脂等危险因素为主，尚无有效治疗药物^[3]，因此，对于NAFLD发病机制的研究具有重要意义。

幽门螺杆菌（HP）是定植于胃壁黏膜上皮细胞的革兰氏阴性致病菌, HP感染与NAFLD的发生具有相关性^[4]，其可能通过诱发胰岛素抵抗、改变脂质谱、促进氧化应激、改变肠道通透性和调控基因表达等作用机制导致NAFLD的发生。因此，本文就HP感染与 NAFLD的相关性及其潜在机制相关研究进展进行综述，以期为NAFLD的诊治提供新思路。

1 HP感染与NAFLD的相关性

诸多研究表明，HP感染与NAFLD的发生存在相关性。

Cindoruk等^[5]在44岁的NASH患者肝脏中首次发现HP 16s重组RNA。研究表明，高脂饮食喂养的小鼠在感染HP后表现出更严重的肝脂肪变性，提示HP可能在NAFLD的发生发展中发挥作用^[6]。

2019年的一项横断面研究发现，HP阳性组的脂肪肝发生率显著高于HP阴性组，且HP感染是NAFLD的独立危险因素，与脂肪变性程度增加相关^[7]。

Yu等^[8]将感染HP的NAFLD患者分为HP根除治疗组和对照组，随访1年后发现，治疗组的代谢指标［如空腹血糖、糖化血红蛋白（HbA1c）、胰岛素抵抗指数（HOMA-IR）、甘油三酯（TG）］、炎症指标［包括白细胞计数、C反应蛋白（CRP）、白细胞介素-6（IL-6）、肿瘤坏死因子α（TNF-α）］显著降低，表明HP感染可能通过影响炎症因子参与NAFLD的发生和发展。

此外，不同严重程度的NAFLD患者HP感染的发生率具有显著性差异，而肝脂肪变性合并NAFLD的发生率在HP阳性和HP阴性患者中亦存在显著差异^[9]。诸多荟萃分析表明，HP感染增加了NAFLD的发生风险，是NAFLD易感患者发病的危险因素^[10-14]。

然而，HP感染与NAFLD的相关性尚存争议。一项孟德尔随机化研究表明，HP感染与NAFLD之间不存在相关性^[15]。日本一项纳入13 737名成年人的横断面研究发现，无论性别如何，HP感染与脂肪肝及NAFLD无关^[16]，另一项研究结论与之相同^[17]。

我国一项回顾性研究通过校正混杂因素后发现，HP感染并非NAFLD的独立危险因素，不同严重程度的NAFLD与HP感染无关^[18]。尽管根除HP可显著降低HP感染合并NAFLD患者的丙氨酸转氨酶水平，但其他代谢指标水平均未变化^[19]。HP感染与NAFLD之间的相关性差异可能与常规超声检查在NAFLD分级诊断方面的局限性和研究样本量不同有关。

2 HP感染导致NAFLD发病的潜在机制

2.1 IR

IR是指胰岛素对脂肪组织、肝脏和骨骼肌等关键靶组织的作用受损，从而引起长期的全身性高胰岛素血症。

研究表明，高胰岛素血症会增加NAFLD的发病风险，其可能机制是高胰岛素血症导致NAFLD患者的肝脏从头脂肪生成增加和脂肪组织脂解抑制受损，促进肝细胞内脂质积聚和极低密度脂蛋白（VLDL）分泌，从而导致肝细胞脂肪变性，而过量的肝内TG又加重了高胰岛素血症和IR^[20-21]。

研究表明，HP感染与IR、血脂紊乱密切相关，HP根除治疗后，血清总胆固醇（TC）、低密度脂蛋白（LDL）、TG、HbA1c、空腹血糖、胰岛素、IR、肝脏脂肪变性指数（HSI）和NAFLD-肝脏脂肪评分（LFS）显著降低，高密度脂蛋白（HDL）显著升高^[22-24]。

Aydemi等^[25]将63例患者分为HP感染组和非HP感染组进行研究，发现两组HOMA-IR具有显著差异，HP感染可能通过促进IR而导致NAFLD的发生。最近一项荟萃分析表明，HP感染可能会导致代谢综合征和IR^[26]。HP感染可能通过以下途径诱导IR，进而导致NAFLD的发生。

2.1.1 炎症因子 

HP感染可引起胃黏膜急慢性炎症，增加TNF-α、CRP和IL-6等炎症因子的表达^[27-28]，可能通过激活多条炎症通路，使机体保持低度慢性炎症，干扰胰岛素的信号转导而诱导IR，参与NAFLD的发生^[25,29]。

TNF-α可通过调节与脂质代谢、炎症因子和肝纤维化相关的关键分子或下调葡萄糖转运体-4（GLUT-4）的表达导致IR，从而在NAFLD的发生中发挥关键作用^[30-31]。CRP作为肝脏产生的一种典型非特异性急性时相蛋白，通过提高核转录因子κB（NF-κB）的活性而干扰胰岛素的信号转导^[32]。

研究发现，IL-6水平与胰岛素敏感性有关，当机体处于IR 状态时，IL-6水平明显升高^[33]。另有研究表明，炎症因子与NAFLD发病风险显著相关^[34]。因此，HP感染可能通过引起慢性炎症或激活上述信号通路促进IR的发生，使肝脏暴露于高水平的炎症因子时加重对肝脏的损伤，从而导致肝细胞坏死、肝纤维化和NAFLD的发生。

2.1.2 脂肪因子和血脂

脂肪组织通过分泌瘦素、脂联素等脂肪因子参与IR，促进NAFLD的发生发展。Abdel-Razik等^[35] 研究发现，HP感染者体内通常表现为高瘦素水平和低脂联素（APN）水平，而APN水平与NAFLD的发生及严重程度密切相关^[36-37]。APN是一种具有抗脂肪变性、抗炎和抗纤维化作用的脂肪因子，其主要机制是与肝脏APN受体结合，激活胰岛素信号通路和AMPK信号通路以增强胰岛素敏感性从而减少肝脏脂质积累^[38]。

而瘦素可通过抑制肝葡萄糖生成和脂肪生成从而发挥抗脂肪变性作用，同时促进胰岛素受体底物-1（IRS-1），即丝氨酸-318磷酸化而干扰胰岛素受体信号转导^[39],在NAFLD后期促进肝脏活性氧（ROS）生成、促炎因子释放以及纤维蛋白生成，发挥促炎和促纤维化作用。这些促炎因子也可调节瘦素的表达，从而维持慢性炎症状态^[40]。

国外一项荟萃分析表明，HP感染可使LDL、TC和TG水平升高、HDL水平降低^[41]。而根除HP可降低血脂异常的发生风险^[42]。此外，Eshraghian等^[43]首次证明了脂联素、瘦素和IR的改变与肝移植者的肝脂肪变性相关。因此，HP感染可能通过影响脂质代谢及胰岛素信号转导而导致NAFLD的发生。

2.1.3 胎球蛋白A

胎球蛋白A主要由肝脏产生，通过抑制胰岛素依赖性受体酪氨酸激酶的自身磷酸化以及IRS-1的丝氨酸磷酸化、抑制IRS减少机体葡萄糖的利用导致IR发生^[44-47]。

动物实验表明，胎球蛋白A将游离脂肪酸(FFAs)与Toll样受体4（TLR4）结合，导致脂肪组织产生炎症反应和IR^[48]。

近期研究表明，胎球蛋白A水平升高与青年人群中NAFLD的发生率和严重程度有关^[49]。HP感染可能通过胎球蛋白A的产生促进IR,且HP阳性组的胎球蛋白A水平显著高于HP阴性组^[50]。因此，HP感染可能通过影响胎球蛋白A水平而诱导IR发生，从而促进NAFLD。

2.2 氧化应激

在生理条件下，ROS和活性氮（RNS）生成与抗氧化水平之间的平衡能够调控细胞功能及细胞间相互作用，而过量的ROS会损害蛋白质和其他生物分子，最终导致细胞死亡^[51]。ROS诱发的氧化应激通过触发肝细胞应激途径导致炎症和纤维化从而参与NAFLD的发生和发展^[52]。

此外，氧化应激可引起肝脏中氧化磷脂（OxPLs）的累积并导致肝细胞线粒体功能障碍,线粒体DNA由氧化受损的肝细胞释放，其对ROS高度敏感,通过激活TRL9引发肝脏炎症，进而诱发NAFLD的发生^[53-54]。近年来的研究表明，感染HP的胃上皮细胞可产生ROS和RNS，其中以活化的中性粒细胞为主，通过氧化应激和细胞凋亡导致肝细胞产生炎症反应、纤维化甚至死亡^[55-56]。

2.3 肠道微生物

肠道菌群包括多种参与代谢、合成和调节功能的微生物，是肠道屏障的第一道防线。肠-肝轴在维持肠道和肝脏的局部稳态中发挥重要作用。研究表明，NAFLD患者的肠道微生物多样性及丰富度均有所改变，对基线时小肠通透性升高的NAFLD患者行粪菌移植后发现其小肠通透性降低^[57-58]，可能机制是肠道菌群失调加重肠道对细菌产物的通透性，导致细菌易位，使肝脏接触毒性物质增多，导致肝脏炎症反应和肝纤维化，进而加重代谢紊乱和NAFLD^[59]。

此外，Heimesaat等^[60]通过检测HP感染组与未感染组小鼠肠道菌群的变化，发现长期感染HP的小鼠肠道远端未感染，而发炎的近端肠道菌群组成发生明显变化。一项益生菌治疗小鼠HP感染的研究表明，治疗后胃肠道菌群多样性增加，抗炎细菌增多，促炎症途径相关基因表达降低^[7,61-63]。

2.4 基因表达调控

研究表明，携带有脂联素基因启动子11391G/A(AA)和细胞外超氧化物歧化酶(EC-SOD)CG+GG基因型的人群属于NAFLD高危人群，而此基因型和HP感染的相互作用促进了NAFLD的发生发展^[64]。

同样，具有谷胱甘肽过氧化物酶-1基因Pro198Leu（PL）、Pro198Leu (LL)、过氧化物酶体增殖物激活受体γ2基因Pro12Ala(PA)和Pro12Ala（AA）的患者在感染HP后促进了NAFLD的发展，因此研究者认为可通过根除HP或调控基因表达预防NAFLD^[65]。

另一项动物实验发现，在感染HP的NAFLD小鼠中，Men1基因或蛋白表达下调，而IL-6 和IL-18表达上调，因此上调Men1基因或蛋白的表达可能会减轻小鼠肝脏损伤程度，或可作为治疗HP感染患者NAFLD的有效靶点^[66]。

3 小结与展望

综上所述，根除HP可进一步降低NAFLD的代谢指标和肝脂肪变性程度，但目前针对 HP根除治疗改善NAFLD伴HP感染患者的血脂、肝功能水平和临床症状的有效性研究较少。由于研究对象、研究设计、疾病诊断标准以及样本量均会影响研究结果，未来仍需多地区、大样本、前瞻性研究，并对HP感染患者进行持续随访，进一步揭示HP感染和NAFLD的相关性以及根除HP对于NAFLD治疗的有效性。

此外，2020年NAFLD被重新命名为代谢相关脂肪性肝病（MAFLD）^[67]。越来越多的学者关注MAFLD在临床实践中的应用，但目前尚无研究使用MAFLD这一术语研究与HP的相关性。因此，建议使用MAFLD诊断标准进行研究，同时比较NAFLD、MAFLD与HP之间的相关性，使非酒精性脂肪性肝病与HP之间的相关性研究更加全面。

因此，HP感染可促进其产生的相关毒素通过门静脉进入肝脏，引发肝脏炎症和肝脂肪变性，从而促进HP及其产生的相关毒素通过门静脉进入肝脏，引发肝脏炎症和肝细胞脂肪变性。

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