一文汇总丨非酒精性脂肪性肝病相关HCC的危险因素与预防策略

南方菩提 2021-05-20

展开全文

据估计，全球四分之一的人口患有非酒精性脂肪性肝病(NAFLD)。在美国、法国和英国，NAFLD已经成为肝细胞癌(HCC)中增长最快的病因。虽然NAFLD相关HCC的发病率低于丙型肝炎等其他病因所致的HCC，但与其他肝病相比，患NAFLD的人更多，所以，有必要采取紧急措施，提高全球意识，应对代谢风险因素，以减轻NAFLD相关HCC的疾病负担。

近日，发表于Nature Reviews的一篇综述，讨论了NAFLD相关HCC的全球流行病学、预测和风险因素，并提出了预防策略。肝胆相照平台特将其中危险因素与预防部分进行摘译，以帮助临床医生对NAFLD相关HCC做出科学管理。

NAFLD相关HCC的危险因素

糖尿病

全球已有多项研究调查了糖尿病与NAFLD相关HCC之间的关系。在梅奥诊所的一项研究中，354例NASH肝硬化患者接受了47个月的随访。在该队列中，30名患者发生HCC¹。糖尿病的存在使NASH相关肝硬化患者HCC风险增加了四倍(HR 4.2，95% CI 1.2-14.2；P=0.02)。

在一项基于欧洲人群的大型研究中，糖尿病被发现是HCC发生的最强独立风险因素，该研究包括136703名NAFLD患者，其中仅有4.7%的患者具有高纤维化评分(Fib-4)²。值得注意的是，糖尿病对HCC风险的影响并非NAFLD独有。来自美国、欧洲和亚洲的多项研究显示，无论肝脏疾病的病因如何，糖尿病患者患HCC的风险均增加^3，4。

Kanwal等学者评估了代谢综合征各组分对非肝硬化NAFLD患者HCC风险的独立和联合影响⁵。研究者评估了美国271906名受试者，其中253名在随访期间发生HCC。分析表明，额外的代谢特征导致风险逐步增加，糖尿病与HCC发展的最高风险相关。综合研究结果表明，无论是NAFLD肝硬化患者还是非NAFLD肝硬化患者，都应定期进行糖尿病或糖尿病前期筛查。

肥胖

肥胖可通过产生促肿瘤细胞因子IL-6和TNF8介导炎症和肝癌发生。

一项对26项前瞻性研究的meta分析显示，肥胖使原发性肝癌的风险增加83%，超重使其风险增加48%⁶。不过，在这些研究中未检查NAFLD状态。

Hassan等学者进行了一项病例对照研究，比较了622名新诊断为HCC的患者和660名按年龄和性别进行匹配的健康对照者⁷。研究人员发现，成年早期肥胖与HCC发展相关(OR 2.6，95% CI 1.4-4.4)。然而，在诊断出NAFLD相关HCC后，肥胖并不影响预后。

在先前提及的Kanwal等人⁵的研究中，无肝硬化且肥胖的患者发生HCC的风险增加了1.3倍，尽管这一发现没有达到统计学意义(HR 1.31，95% CI 0.98–1.74)，而存在糖尿病、高血压和高脂血症时的肥胖将HCC发生风险进一步增加至2.6倍(HR 2.57，95% CI 2.3-2.9)。一项使用器官共享联合网络数据库进行的研究发现，在隐源性肝硬化和酒精性肝硬化患者中，肥胖是HCC的独立危险因素，而在其他病因的肝病患者中则不然⁸。因此，无论是非肝硬化NAFLD患者，还是肝硬化NAFLD患者，肥胖均是其发展为HCC的危险因素。

吸烟

总体来说，吸烟与HCC的风险增加有关⁹。在一项对81项研究进行的荟萃分析中，当前吸烟者HCC发生的综合OR为1.55(95% CI 1.46–1.65)，吸烟史者为1.39(95% CI 1.26–1.52)¹⁰。不过，尚无研究专门验证吸烟与NAFLD相关HCC之间的关联^11、1、2。尽管如此，还是建议NAFLD患者戒烟。

肠道微生物群和胆汁酸代谢

NAFLD与肠上皮细胞间紧密连接的破坏、肠道通透性增加以及肠道细菌和脂多糖的易位有关，从而导致肝脏炎症和纤维化^12-16。肠道微生物群调节胆汁酸池，进而调节法尼醇X受体(FXR)¹⁷。在小鼠模型中，FXR通过保护胆汁酸相关的肝损伤和调节纤维化来帮助预防肝癌的发生^18-20。在一项评估NAFLD相关HCC患者肠道菌群特征的研究中，与NASH肝硬化患者(n=20)相比，NAFLD相关HCC患者(n=21)的粪便钙卫蛋白增加，Akkermansia菌和双歧杆菌种类减少²¹，而Akkermansia菌和双歧杆菌已在小鼠和大鼠模型中被证明可以增强肠道屏障，减少肝脏炎症^22,23。

PNPLA3单核苷酸多态性

PNPLA3 c.444 C>G单核苷酸多态性与人类HCC风险增加有很大关联²⁴。

为了评估PNPLA3 rs738409单核苷酸多态性与HCC之间的关联，Singal等人进行了一项系统综述²⁵，涉及24项研究，9915名肝病患者。结果显示，该多态性与肝硬化患者发生HCC的高风险相关(OR 1.40，95% CI 1.12–1.75)。分组分析显示，NASH相关或酒精相关肝硬化患者的HCC风险增加(OR 1.67，95% CI 1.27–2.21)，而其他病因的肝硬化患者HCC风险并未增加。

在一项对100例NAFLD相关HCC(67%为肝硬化)患者和275例经活检证实为NAFLD的患者进行比较的对照研究中，PNPLA3 rs738409 C>G多态性被证明是HCC发生的独立危险因素(GG纯合子OR 5.05，95% CI 1.47–17.29；P=0.01)²⁶。在对糖尿病、BMI和肝硬化的存在进行调整后，这种显著关联仍然存在。当GG纯合子与英国普通人群(CC纯合子)比较时，效果更为显著(OR 12.19，95% CI 6.89-21.58；P<0.0001)^24,26。

NAFLD相关HCC的预防

控制体重

对于诊断为NAFLD的患者，AASLD、EASL和亚太NAFLD指南建议结合低热量饮食和中等强度运动来维持体重减轻，但未推荐特定的减肥计划^27,28,29。在一项针对293例NASH患者的古巴研究中³⁰，目标体重减轻10%或以上，90%的患者显示出NASH缓解，45%的患者显示出纤维化消退的疗效。

目前，没有直接证据表明体重减轻会导致NAFLD相关HCC发病率降低。然而，仍应鼓励NAFLD患者减肥，对NAFLD相关HCC高风险患者，可考虑正式的减肥计划。减肥手术尚不推荐用于NAFLD相关HCC的预防。

他汀类药物

他汀类药物具有抗炎、抗血管生成和抗增殖作用，可有效对抗炎症驱动的癌症³¹。在一项对10项研究(1,459,417名患者，其中4,298名为HCC患者)进行的系统回顾和荟萃分析中，他汀类药物的使用与HCC风险显著降低相关，尤其是在亚洲人群中³²。在一项对来自退伍军人事务中央癌症登记处的15422名HCC患者的单独分析中，HCC诊断后使用他汀类药物(高剂量和低剂量)与较低的癌症特异性和全因死亡率有关³³。与这些发现相反，一项对22项随机试验的事后分析未显示出他汀类药物对HCC风险的益处³⁴。不过，这些观察性或干预性研究均未在明确定义的NAFLD或NASH人群中进行。因此，目前不常规推荐他汀类药物用于HCC的预防。不过，在NAFLD患者存在血脂异常时，应当考虑使用他汀类药物，以降低心血管风险。

二甲双胍

二甲双胍是一种抗糖尿病药物，在几项荟萃分析中，无论肝病病因如何，使用二甲双胍均可使HCC风险降低约50%^35-37。

在一项回顾性队列研究中，Tseng使用倾向得分匹配法分析比较了21，900名二甲双胍使用者与21，900名从未使用过该药物的个体患HCC的风险。该研究显示，总体危险比为0.5(95% CI 0.45–0.54)³⁸。这些研究均未在定义明确的NAFLD或NAFLD相关HCC人群中进行。基于此，二甲双胍不常规推荐用于HCC预防。不过，在存在NAFLD-NASH的情况下，仍应将二甲双胍作为糖尿病的一线治疗。

阿司匹林

在小鼠模型中，阿司匹林已被证明可以减少T细胞介导的炎症，减缓肝纤维化的发展，并可能减少肝癌瘤体形成³⁹。Sahasrabuddhe及其同事分析了美国国立卫生研究院--美国退休人员协会(NIH-AARP)饮食与健康研究的300,504名参与者的前瞻性数据，发现自我报告的阿司匹林使用者患HCC的风险显著低于非使用者(RR 0.59，95% CI 0.45-0.77)⁴⁰。

在美国进行的两项前瞻性队列研究的汇总分析涉及133,371名报告阿司匹林使用数据的医疗保健专业人员，Simon等人表明，每周定期使用至少650mg阿司匹林与HCC风险降低50%相关(HR 0.51，95% CI 0.34-0.77)⁴¹。根据敏感性分析，阿司匹林在降低HCC风险方面的益处表现出剂量-反应关系，且不受他汀类药物使用的影响。

小结

NAFLD相关HCC在全球多个地区的发病率很高。特别是在美国和中国，NAFLD相关HCC的发病率正在上升。NAFLD和肝硬化患者患HCC的风险最高；其他危险因素包括老年、男性、PNPLA3变异体。糖尿病和肥胖是HCC发生的主要危险因素。

NAFLD患者应调整生活方式，以降低糖尿病、肥胖和后续HCC发生风险。根据目前的证据，化学预防暂不推荐用于HCC的初级预防，但二甲双胍、他汀类药物和阿司匹林可能有一定作用。

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