CGP综述|原发性肝癌的流行病学及其危险因素研究进展

时间:2023-12-06 14:34:01   热度:37.1℃   作者:网络

原发性肝癌(PLC)居世界常见恶性肿瘤的第六位,居恶性肿瘤死亡常见原因的第三位。PLC主要包括肝细胞癌(占75%~85%)和肝内胆管癌(占10%~15%)。2020年全球PLC新发病例约有905677例,死亡病例数高达830180例。世界上PLC发病率最高的地区是亚洲和非洲,其中我国的PLC患者数量约占全球PLC患者的一半。目前,PLC是我国第四位常见恶性肿瘤及第二位恶性肿瘤致死病因,严重威胁人们的生命健康。充分了解PLC的流行病学特点及危险因素,对PLC的防治工作具有重要的意义。本文综述了我国PLC的流行病学特点以及危险因素,以期为我国PLC的防治工作提供参考和借鉴。

01 PLC流行病学

1.1 PLC发病率和死亡率

我国人群PLC的年龄标准化发病率(ASIR)和年龄标准化死亡率(ASMR)分别为17.81/10万和15.29/10万;每年PLC总发病例数和死亡例数约占全球一半,并具有显著的城乡和地区差别。其中,农村地区人口ASIR和ASMR均高于城市人口,尤其是65岁以下的人口中城乡差异更显著。在地域分布上,西部欠发达地区的ASIR和ASMR最高,其次是中部、东部地区,见表1。同时,研究也显示,我国2019年PLC的ASIR比1990年下降了58.5%,这可能与乙型肝炎病毒(HBV)和丙型肝炎病毒(HCV)感染患病率和黄曲霉毒素暴露量的下降有关。

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1.2 PLC人口学特征

PLC的发病率与年龄密切相关。我国PLC的发病率随年龄增长而逐渐增加,<30岁年龄组的发病率较低,≥30岁年龄组的发病率开始快速升高,80~84岁年龄组的发病率达到高峰。此外,我国PLC发病的年龄呈逐年增长趋势,农村和城市地区男性平均发病年龄由2000年的56.53岁和59.67岁增长至2014年的61.20岁和62.66岁,农村和城市女性则由60.60岁和65.50岁延迟到66.07岁和69.87岁。

在全球大多数地区,男性PLC发病率和死亡率均比女性高2~3倍。在我国,男性PLC发病率和死亡率明显高于女性。这可能与男性和女性的危险因素暴露率不同有关。研究发现,吸烟和饮酒的男性病毒性肝炎患病率高于女性。另有研究显示,雌激素/雄激素水平与HBV转录和复制的多少有关,这可能与男性HBV感染患者中炎症导致PLC的发病率高于女性有关。

1.3 PLC人群归因分值(PAF)

PAF被定义为目标人群中可归因于风险因素的癌症负担量。在全球PLC的发病例数中,归因于HBV感染、HCV感染和饮酒的占比分别为33%、21%和30%。我国72.4%的PLC相关死因归于包括HBV感染、HCV感染、吸烟、饮酒、糖尿病(DM)、肥胖等在内的危险因素。HBV感染在我国男性和女性的PLC负担中占比最大;男性吸烟、饮酒和DM的PAF明显高于女性;然而,与男性肥胖PAF相比,女性肥胖PAF更高,见表2。

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此外,不同年龄段的PAF也存在差异。在男性中,HBV引起PLC的PAF在所有年龄段中最大,吸烟和饮酒导致PLC的PAF随年龄增长呈下降趋势。研究发现在女性各年龄组中,HBV引起PLC的PAF也是最大的。男性与女性HCV引起PLC的PAF均随着年龄的增长而升高。在≥60岁的老年人群中,DM、饮酒和吸烟的PAF高于<60岁人群。因此,积极推进HBV疫苗接种、扩大抗病毒治疗、坚持健康的生活方式等是我国PLC一级预防的主要措施。

02 PLC危险因素

PLC常见的危险因素包括慢性HBV、HCV感染、酒精性肝病、代谢性疾病[如非酒精性脂肪性肝病(NAFLD)、DM等]。尽管抗病毒药物可在一定程度上控制乃至根治慢性HBV和HCV感染,但慢性病毒感染仍然是我国PLC的主要病因。此外,随着肥胖、DM人群的增加,代谢综合征(MetS)、NAFLD的流行更加普遍,将进一步导致PLC发病率的上升。

2.1 HBV感染

HBV感染是我国PLC发病的重要危险因素。根据2019年全球疾病负担数据显示,2019年我国HBV感染者约23355000例,HBV相关肝癌新增病例约140000例。HBV感染患者发生PLC的终生风险为10%~25%。HBV还与其他危险因素协同促进PLC的发生。一项荟萃分析显示,男性、饮酒、PLC家族史、DM、未抗病毒治疗以及HBV DNA高复制状态是乙型肝炎肝硬化发生PLC的主要危险因素。因此,在预防和降低PLC的措施方面,HBV疫苗接种是关键。抗病毒治疗也是降低PLC发生风险的有效措施。

2.2 HCV感染

2019年我国约有625000例HCV感染者,HCV相关PLC新增病例约34000例。HCV感染患者一旦进展到肝硬化阶段,PLC的发病率增加为2%~4%。通过抗病毒治疗实现的持续病毒学应答可显著降低HCV相关PLC的发生风险。目前针对HCV相关PLC患者的监测指南中,我国《原发性肝癌的分层筛查与监测指南(2020版)》建议前期已被纳入PLC监测的患者,目前并无停止监测的相关指南,应按原计划继续进行PLC监测。

2.3 吸烟

香烟中含有尼古丁等4000余种有害物质,这些烟草的代谢产物可与DNA结合引发基因突变,增加恶性肿瘤的发生风险。我国一项纳入50万人的前瞻性研究显示,当前吸烟者患PLC的风险比从不吸烟者高28%。研究也显示,戒烟年限与PLC风险呈负相关,戒烟30年的人患PLC的风险与从不吸烟的人相似。

2.4 饮酒

过度饮酒是公认的发生PLC的危险因素。一项荟萃分析表明,酒精相关性肝硬化患者在1年、5年和10年随访时的PLC累积发病率分别为1%、3%和9%。大量饮酒(≥3杯/d)使普通人群的PLC发生风险增加16%。饮酒量越大、饮酒年限越长,PLC的患病风险越高。同时,该研究也显示,控制饮酒和减少饮酒年限有助于预防PLC的发生,特别是>30岁的人群和癌症高发人群应减少酒精的摄入。此外,酒精还和其他危险因素共同促进PLC的发生、发展。一项前瞻性研究显示,饮酒与肥胖可增加PLC的发生风险(HR=3.82)。在酒精相关肝硬化患者中,合并DM比不合并DM患者患PLC的风险高50%。因此,应加强对大量饮酒者的DM筛查,以识别PLC高危患者。

2.5 代谢相关危险因素

2.5.1 DM:

针对不同人群的研究表明,DM与PLC发生风险增加2~3倍相关,男性的相对风险明显高于女性。一项前瞻性研究荟萃分析显示,较长的DM病程与PLC风险的增加有关。此外,DM与NAFLD关系密切。研究显示,DM是NAFLD患者发展为PLC的重要代谢性危险因素。在NAFLD相关肝硬化患者中,DM患者的PLC发生风险较非DM患者升高4.2倍。一项针对85 000例NAFLD合并DM患者进行平均10年随访的研究显示,与没有DM的患者相比,合并DM的患者患PLC的风险高24%(HR=1.24),血糖控制良好的患者与血糖控制欠佳的患者相比,PLC风险降低32%(HR=0.68)。

2.5.2 肥胖:

针对一般人群的荟萃分析显示,肥胖使PLC的风险增加约2倍。美国的队列研究显示,腰围大(定义为男性≥110 cm、女性≥90 cm)的个体罹患PLC的风险增加2倍。除此之外,肥胖还可以增加慢性肝病患者PLC的发生。一项针对慢性HBV患者的中国研究报告称,与非中心性肥胖相比,中心性肥胖(定义为腰围/身高>0.5)与PLC风险增加相关(HR=1.63)。此外,肥胖与NAFLD关系密切,共同促进PLC的发生。

2.5.3 MetS:

MetS是PLC的危险因素,包括腹部肥胖、高甘油三酯血脂、低高密度脂蛋白胆固醇血症、高血压以及高血糖。一项中位随访时间为13.02年的前瞻性研究显示,MetS患者发生PLC的风险是非MetS患者的2.91倍。另一项队列研究显示,在校正年龄、性别和其他合并症后,MetS合并NAFLD的患者发生PLC的风险是对照组(非MetS和非NAFLD患者)的15.33倍。

2.5.4 NAFLD:

随着肥胖和MetS的流行,NALFD导致的PLC发病率呈逐年上升趋势。一项研究发现,NAFLD患者的PLC发病率为0.21/1000人年,显著高于非NAFLD患者(0.02/1 000人年)。每增加一个额外的代谢因素(包括DM、肥胖、血脂异常和高血压),NAFLD患者发生PLC的风险也会增加,其中伴有DM的NAFLD患者进展为PLC的风险是非DM患者的2.77倍,提示临床医生注意对伴有代谢因素的NAFLD患者开展PLC筛查工作。

2.6 其他因素

黄曲霉毒素是一类由黄曲霉、寄生曲霉等真菌产生的致癌物质,其中黄曲霉毒素B1(AFB1)的毒性最大,致癌性最强。一方面,AFBl可诱发急性肝坏死、导致肝硬化或PLC;另一方面,AFBl的代谢产物可通过环氧化物代谢物结合DNA和烷基化碱基,诱导细胞周期紊乱和p53的基因突变,增加PLC的发生风险。自1985年以来,允许水稻代替玉米的政策已经使黄曲霉毒素生物标志物降低了97.4%,这使得我国PLC的发病率有所下降。

蓝藻分泌的微囊藻毒素(MC)是一类天然的具有肝毒性的代谢产物,普遍存在于淡水湖和饮用水中。MC主要通过抑制蛋白磷酸酶1和2A导致中间丝和微丝的过度磷酸化和肝细胞骨架的损伤,从而诱导PLC的发生。

03 小结和展望

目前,HBV和HCV感染仍然是PLC最重要的危险因素。伴随HBV疫苗的接种、对HBV和HCV感染患者有效的抗病毒治疗以及对病毒性肝炎高危人群的筛查,病毒性肝炎的患病率将会有所下降。肥胖、DM、NAFLD以及过量饮酒等因素是PLC发生的重要危险因素。普及并推广健康的生活方式,加大对NAFLD等代谢性疾病的筛查、预防和治疗,完善PLC监测手段并不断精进治疗策略,将有力地提高我国PLC的防治水平,从而在未来全面降低我国PLC的社会、经济和医疗负担。

然而,目前仍有亟需研究和解决的问题:(1)目前缺乏特异性识别早期PLC的生物标志物及监测手段;(2)缺乏PLC高危人群的简便分层识别工具,如可以研发自我监测的APP;(3)缺乏治疗NAFLD的有效方法。希望在不久的将来能解决上述问题,减轻全球PLC负担。

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