文章信息
- 田昊宇, 关琳
- TIAN Haoyu, GUAN Lin
- 非酒精性脂肪性肝病相关肝细胞癌的研究进展
- Progress in non-alcoholic fatty liver disease-related hepatocellular carcinoma
- 中国医科大学学报, 2022, 51(11): 1035-1039, 1047
- Journal of China Medical University, 2022, 51(11): 1035-1039, 1047
-
文章历史
- 收稿日期:2021-09-24
- 网络出版时间:2022-11-04 14:58
2. 中国医科大学 附属第一医院消化内科, 沈阳 110001
2. Department of Gastroenterology, The First Hospital of China Medical University, Shenyang 110001, China
非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD) 是常见的慢性肝脏疾病,全球患病率约为25%[1]。最近研究[2]显示,亚洲地区NAFLD总体患病率为29.62%,其中,我国大陆地区患病率为29.81%。NAFLD是高度异质性疾病,与肥胖症、2型糖尿病和代谢综合征等代谢功能障碍疾病密切相关[1]。由于NAFLD的命名过分强调了酒精这个排他因素,而未能准确反映发病机制,2020年3月,由ESLAM、GEORGE等20个专家组成的国际脂肪肝命名小组发表了将NAFLD更名为代谢相关脂肪性肝病(metabolic associated fatty liver disease,MAFLD) 的国际共识[3]。研究[4]显示,随着人们生活方式和饮食结构的改变,肝细胞癌(hepatocellular carcinoma,HCC) 的流行病学特征也发生了变化,目前NAFLD逐渐成为HCC的主要病因。本文就NAFLD相关HCC的流行病学、发病机制、治疗及预防等方面进行系统综述。
1 NAFLD相关HCC的流行病学自1990年首次报道NAFLD与HCC的相关性以来[5],NAFLD相关HCC的发生率呈明显上升趋势。1项分析了欧洲和北美14个国家的18 031例HCC患者(2005至2012年) 研究发现,10%~12% HCC患者的病因是NAFLD [6]。美国2004至2009年的数据分析[7]发现,NAFLD导致HCC的人群逐年增加,占HCC病因学的14.1%,仅位于丙型肝炎和酒精性肝病之后;这项为期6年的研究显示,NAFLD患者平均年增长率为9%,而慢性丙型病毒性肝炎(hepatitis C virus,HCV) 患者的平均年增长率为13%;6年的随访中NAFLD患者HCC的总发生率为0.3%。也有研究[8]表明,NAFLD发生HCC的风险低于HCV,非酒精性脂肪性肝炎(non-alcoholic steatohepatitis,NASH) 和HCV肝硬化患者5年HCC的发病率分别为11.3%、30.5%。然而与HCV引起的HCC不同,在NASH患者中,HCC可以不经过肝硬化阶段直接发生[9-11]。肝硬化的NASH患者中,HCC估计年发病率为0.5%~2.6%;而非肝硬化NAFLD或NASH患者HCC年发生率为0.01%~0.13% [4],在NASH程度较高或纤维化分级较重的患者中HCC发生率更高[12]。美国需要肝移植的HCC患者中,NAFLD相关HCC患者占比逐年增高。YOUNOSSI等[13]对2 6121例美国列为或接受移植的HCC患者分析结果表明,2002至2017年间,继发于NASH的HCC患者比例从2.1%增至16.2% (P < 0.000 1),而继发于HCV感染(47.9%~60.3%,P = 0.89) 和饮酒(8.3%~14.2%,P = 0.39) HCC患者比例基本保持稳定。
2 NAFLD相关HCC的发病机制 2.1 炎症及细胞因子NAFLD患者往往有超重或肥胖,超重或肥胖能够促进释放各种细胞因子(瘦素、脂联素等),这些细胞因子激活JAK通路导致细胞增殖,同时肿瘤坏死因子-α (tumor necrosis factor-α,TNF-α) 和白细胞介素-6 (interleukin-6,IL-6) 可通过激活STAT3通路促进细胞增殖,进而促进肿瘤的发生。NAFLD患者胰岛素样生长因子(insulin growth factor,IGF) 水平增加,IGF能抑制细胞凋亡和刺激细胞分裂,在肿瘤的浸润转移中发挥促进作用[14]。
2.2 氧化应激与免疫异常氧化应激以及活性氧(reactive oxygen species,ROS) 通过与DNA碱基偶联而诱导基因突变致癌。游离脂肪酸亚油酸可破坏线粒体功能,介导ROS相关的CD4+ T淋巴细胞死亡,减少免疫监视,促进HCC的发生[15]。IgA+ 细胞在NASH中累积可抑制CD8+ T细胞,从而促进HCC的发生[16]。最近研究[17]表明,CD36-Nogo-B-YAP途径重新编程了oxLDL代谢,促进脂噬,导致溶血磷脂酸增强YAP致癌活性,并诱导了NAFLD相关HCC的致癌信号,促进NAFLD相关HCC的发生。
2.3 肠道微生态与胆汁酸代谢NAFLD时肠上皮细胞间紧密连接破坏,引起肠道通透性增加和肠道细菌及脂多糖易位,导致肝脏炎症和纤维化,从而促进HCC发生[18]。肠道微生态可以调节胆汁酸池,从而调节胆汁酸传感器法尼醇X受体(farnesoid X receptor,FXR)。在小鼠模型中,FXR通过保护胆汁酸相关的肝损伤,抑制肝纤维化来预防HCC发生[19]。1项评估NAFLD相关HCC患者肠道微生物谱的研究[20]发现,与NASH肝硬化患者比较,NAFLD相关HCC患者保护性细菌的丰度降低,可能导致肠道和肝脏炎症增加,从而促进HCC的发展。
2.4 基因异常目前,研究较多的与NAFLD相关HCC的基因包括PNPLA3、TM6SF2和MBOAT7。PNPLA3单核苷酸多态性(single nucleotide polymorphisms,SNP) 是NASH患者发生HCC的独立危险因素,特别是PNPLA3rs738409 C > G纯合子与HCC的风险增加密切相关。1项病例对照研究[21]发现,100例NAFLD相关HCC (67%肝硬化) 和275例活检证实的NAFLD患者中,PNPLA3rs738409C > G多态性的存在是HCC发生的独立危险因素(OR = 5.05,95% CI:1.47~17.29;P = 0.01)。相反,TM6SF2 rs58542926基因多态性与欧洲队列中HCC风险增加无关,但这可能与队列比较小有关[22]。在765例意大利NAFLD患者的队列中,MBOAT7 rs641738变异与HCC有很强的相关性,特别是在那些没有晚期纤维化的患者中,但在英国358例无肝硬化的NAFLD患者队列中,MBOAT7 rs641738变异与HCC没有关联[23]。
3 NAFLD相关HCC的危险因素 3.1 年龄、性别和种族研究[4]表明,男性、高龄、种族均是NAFLD相关HCC的危险因素。KANWAL等[12]在1项涉及296 707例NAFLD患者的大型队列研究中发现290例患者发生了HCC。HCC患者中,≥65岁是HCC发展的独立危险因素(HR =1.83,95% CI:1.53~2.18;P < 0.000 1)。男性HCC年发生率高于女性,分别为0.022%、0.004%,原因可能与雌激素可以抑制IL-6产生有关。患有NAFLD的西班牙裔个体中,HCC的年发生率(0.029%) 高于白人(0.021%) 和非裔美国人(0.012%)。
3.2 糖尿病多项病例对照和队列研究[24-25]证实了2型糖尿病与NAFLD所致肝硬化患者发生HCC有显著的关联。1项对354例NASH肝硬化患者进行47个月随访的研究[26]发现,30例患者发生了HCC,糖尿病显著增加NASH肝硬化患者发生HCC的风险(HR=4.2,95%CI:1.2~14.2,P = 0.02)。
3.3 肥胖肥胖可能与HCC的发生、发展有关。SAUNDERS等[27]通过10项队列研究探讨肥胖与HCC的关系,其中有7项发现了积极的关联(RR = 1.4~4.1)。另有HASSAN等[28]的病例对照研究发现成年早期肥胖与HCC的发展有关(OR =2.6,95%CI:1.4~4.4,P = 0.002)。然而,肥胖并不影响NAFLD相关HCC的预后[4]。评估肥胖时不应该仅关注体质量指数(body mass index,BMI),内脏脂肪堆积可能与NAFLD相关HCC密切相关,尤其是在非肥胖人群中。1项欧洲癌症前瞻性调查[29]结果表明,相较于BMI,腰臀比、腹部脂肪沉积更能预测NAFLD相关HCC的发生。
3.4 铁超负荷NASH-肝硬化合并HCC患者中存在铁超负荷,铁负荷增加会诱发基因突变或氧化应激增加,从而导致坏死、炎症和HCC的发生。SORRENTINO等[30]采用半定量方法对153例NASH相关肝硬化患者的肝活检组织进行回顾性检测,其中51例合并HCC (HCC组),102例无HCC (对照组),2组在年龄、性别和疾病分期上基线一致。比较肝细胞铁负荷情况结果表明,与对照组比较,HCC组肝脏铁沉积增加,可见肝脏铁超载可能与NASH相关肝硬化患者HCC的发生发展有关。
3.5 吸烟吸烟通常会增加HCC发生的风险。1项Meta分析[31]显示,未戒烟者HCC发展的合并优势比为1.55 (95%CI:1.46~1.65),已戒烟者为1.39 (95%CI:1.26~1.52)。然而,目前尚无研究明确吸烟与NAFLD相关HCC之间的关系[32],但认为应该建议NAFLD患者停止吸烟。
3.6 饮酒乙醇在胞质中被乙醇脱氢酶氧化成乙醛,乙醛是直接致突变化合物,形成各种蛋白质和DNA加合物,促进DNA修复失败、脂质过氧化和线粒体损伤,促进HCC的发生和发展。另外与饮酒相关的HCC发生有关的关键机制是氧化应激,氧化应激促进ROS产生,ROS是促进NAFLD发生、发展和癌变的重要分子[33]。
4 NAFLD相关HCC的治疗与预后外科治疗是肝癌患者获得长期生存的重要手段,主要包括肝切除术和肝移植术。肝切除术包括楔形切除、节段切除、肝叶切除术和扩展肝切除。切除类型选择取决于病变的数量和位置、是否存在肝硬化以及是否能够保存足够数量的残余肝组织。手术前需要评价肝功能(CTP评分、MELD评分、ALBI分级、ICG实验等) 以及门静脉压力。根据欧洲肝病研究协会指南,极早期HCC (单个肿瘤直径 < 2 cm,无血管侵犯/卫星灶,肝功能分类为Child-Pugh评分A级) 和早期HCC (单个肿瘤直径 > 2 cm或3个结节直径 < 3 cm,肝功能呈代偿期) 患者可以从手术中获益[34]。2018年,YANG等[35]首次在1项大型多中心研究中比较了NAFLD-HCC与慢性乙型病毒性肝炎(hepatitis B virus,HBV) -HCC的肝切除术后资料。结果发现与HBV-HCC比较,NAFLD-HCC组患者年龄较大,2型糖尿病、血脂异常、高BMI增多;NAFLD-HCC患者肿瘤体积较大(分别为7.2 cm和6.2 cm,P < 0.05),肿瘤分化较差(分别为72.9%和82.4%,P < 0.05);诊断HCC时没有肝硬化证据比例较高(分别为69.8%和27.5%)。而2组术中失血量、术中输血发生率、围术期死亡率和并发症的发生率(术后肝衰竭,胆道并发症,败血症,肺、肾、心脏和切口局部并发症) 比较未见显著差异。有研究[36]显示NASH-HCC患者5年生存率为55.2%,而HCV-HCC患者为50.6%;NASH-HCC患者治疗后5年复发率低于HCV-HCC,分别为69.8%和83.1%。WAKAI等[37]比较不同病因HCC患者的手术效果发现,与HCV-HCC和HBV-HCC患者比较,NAFLD-HCC患者的复发率低。
肝移植是HCC根治性治疗手段之一,尤其适用于肝功能失代偿、不适合手术切除及消融治疗的HCC患者。NAFLD-HCC肝脏移植总体生存率与其他病因肝脏移植相似,但肝移植术后NAFLD复发率高达50%,并且有较高的心血管并发症的发病风险[38],肝移植术后仍须有效控制体质量和防治糖脂代谢紊乱,从而最大限度降低肝移植术后并发症发生率[39]。
5 NAFLD相关HCC的监测与预防NAFLD相关HCC发展缓慢,暴露于危险因素越早,恶性肿瘤的发病越早,特别是在遗传易感性背景上的群体。因此,早期识别高危人群并给予积极监测干预可有效减轻患者和社会的负担。首先,应避免危险因素,从儿童开始预防肥胖,改变饮食结构和生活方式。其次,密切监控高危人群(糖尿病、肥胖、老年男性、饮酒以及存在PNPLA3基因变异的个体),积极控制血糖,减轻体质量和戒酒。另外,临床实践中应充分利用无创诊断方法(无创性血清学评分的应用、彩色多普勒超声、Fibroscan或者Fibrotouch、血清肿瘤标志物检测等) 进行早期筛查,若发现报警信号再进一步行CT或者MRI检查[40]。
目前,预防NAFLD-HCC药物主要包括他汀类药物、二甲双胍、阿司匹林等。
他汀类药物具有抗炎、抗血管生成和抗增殖作用,可有效对抗由炎症驱动所导致的癌症[41]。研究[42]表明,他汀类药物与HCC风险显著降低有关,在亚洲人群中尤其明显。他汀类药物还可以改善NAFLD患者血脂异常、降低心血管疾病风险、降低NAFLD相关的死亡率[43-44]。
二甲双胍是降糖药物,可能是通过激活腺苷酸活化蛋白激酶信号通路来减少HCC的发生。1项纳入105 495例2型糖尿病患者的荟萃分析[45]表明,二甲双胍可以使HCC风险降低70%。另1项荟萃分析[46]结果显示,使用二甲双胍的糖尿病患者HCC风险降低了50%,而使用磺脲类药物或胰岛素患者HCC风险增加。此外,二甲双胍改善了HCC治疗的结果。1项针对糖尿病和早期HCC患者接受射频消融治疗的前瞻性研究[47]发现,使用二甲双胍治疗的患者死亡率较低。可见,在NAFLD/NASH存在的情况下,二甲双胍仍是糖尿病首选的治疗方法。
阿司匹林已被证明能减少T细胞介导的炎症,减缓肝纤维化的发展,并能减少小鼠模型中HCC的形成[48]。SIMON等[49]研究表明,每周定期使用至少650 mg阿司匹林与HCC风险降低50%有关(HR= 0.51,95%CI:0.34~0.77),而且这种作用不受他汀类药物的影响。
6 展望NAFLD相关HCC患者通常年龄较大,并伴有多种并发症(糖尿病、超重/肥胖、血脂异常和心脑血管疾病等),极大增加了治疗的难度和医疗负担。NAFLD相关HCC与代谢异常密切相关,是目前面临的重要肝脏健康问题。对于NAFLD患者应进行早期生活方式和饮食运动的指导,对高危人群应进行定期筛查和监测,进而减少NAFLD相关HCC的发生。
[1] |
YOUNOSSI ZM, KOENIG AB, ABDELATIF D, et al. Global epidemiology of nonalcoholic fatty liver disease——Meta-analytic assessment of prevalence, incidence, and outcomes[J]. Hepatology, 2016, 64(1): 73-84. DOI:10.1002/hep.28431 |
[2] |
LI J, ZOU BY, YEO YH, et al. Prevalence, incidence, and outcome of non-alcoholic fatty liver disease in Asia, 1999-2019:a systematic review and meta-analysis[J]. Lancet Gastroenterol Hepatol, 2019, 4(5): 389-398. DOI:10.1016/S2468-1253(19)30039-1 |
[3] |
ESLAM M, NEWSOME PN, SARIN SK, et al. A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement[J]. J Hepatol, 2020, 73(1): 202-209. DOI:10.1016/j.jhep.2020.03.039 |
[4] |
HUANG DQ, EL-SERAG HB, LOOMBA R. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention[J]. Nat Rev Gastroenterol Hepatol, 2021, 18(4): 223-238. DOI:10.1038/s41575-020-00381-6 |
[5] |
POWELL EE, COOKSLEY WG, HANSON R, et al. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years[J]. Hepatology, 1990, 11(1): 74-80. DOI:10.1002/hep.1840110114 |
[6] |
PARK JW, CHEN MS, COLOMBO M, et al. Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE Study[J]. Liver Int, 2015, 35(9): 2155-2166. DOI:10.1111/liv.12818 |
[7] |
YOUNOSSI ZM, OTGONSUREN M, HENRY L, et al. Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009[J]. Hepatology, 2015, 62(6): 1723-1730. DOI:10.1002/hep.28123 |
[8] |
YATSUJI S, HASHIMOTO E, TOBARI M, et al. Clinical features and outcomes of cirrhosis due to non-alcoholic steatohepatitis compared with cirrhosis caused by chronic hepatitis C[J]. J Gastroenterol Hepatol, 2009, 24(2): 248-254. DOI:10.1111/j.1440-1746.2008.05640.x |
[9] |
STINE JG, WENTWORTH BJ, ZIMMET A, et al. Systematic review with meta-analysis: risk of hepatocellular carcinoma in non-alcoholic steatohepatitis without cirrhosis compared to other liver diseases[J]. Aliment Pharmacol Ther, 2018, 48(7): 696-703. DOI:10.1111/apt.14937 |
[10] |
MITTAL S, EL-SERAG HB, SADA YH, et al. Hepatocellular carcinoma in the absence of cirrhosis in United States veterans is associated with nonalcoholic fatty liver disease[J]. Clin Gastroenterol Hepatol, 2016, 14(1): 124-131. e1. DOI:10.1016/j.cgh.2015.07.019 |
[11] |
PARADIS V, ZALINSKI S, CHELBI E, et al. Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis[J]. Hepatology, 2009, 49(3): 851-859. DOI:10.1002/hep.22734 |
[12] |
KANWAL F, KRAMER JR, MAPAKSHI S, et al. Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease[J]. Gastroenterology, 2018, 155(6): 1828-1837. e2. DOI:10.1053/j.gastro.2018.08.024 |
[13] |
YOUNOSSI Z, STEPANOVA M, ONG JP, et al. Nonalcoholic steatohepatitis is the fastest growing cause of hepatocellular carcinoma in liver transplant candidates[J]. Clin Gastroenterol Hepatol, 2019, 17(4): 748-755. e3. DOI:10.1016/j.cgh.2018.05.057 |
[14] |
PARK EJ, LEE JH, YU GY, et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression[J]. Cell, 2010, 140(2): 197-208. DOI:10.1016/j.cell.2009.12.052 |
[15] |
MA C, KESARWALA AH, EGGERT T, et al. NAFLD causes selective CD4 (+) T lymphocyte loss and promotes hepatocarcinogenesis[J]. Nature, 2016, 531(7593): 253-257. DOI:10.1038/nature16969 |
[16] |
SHALAPOUR S, LIN XJ, BASTIAN IN, et al. Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity[J]. Nature, 2017, 551(7680): 340-345. DOI:10.1038/nature24302 |
[17] |
TIAN Y, YANG B, QIU WN, et al. ER-residential Nogo-B accelera- tes NAFLD-associated HCC mediated by metabolic reprogramming of oxLDL lipophagy[J]. Nat Commun, 2019, 10(1): 3391. DOI:10.1038/s41467-019-11274-x |
[18] |
SHARPTON SR, AJMERA V, LOOMBA R. Emerging role of the gut microbiome in nonalcoholic fatty liver disease: from composition to function[J]. Clin Gastroenterol Hepatol, 2019, 17(2): 296-306. DOI:10.1016/j.cgh.2018.08.065 |
[19] |
FICKERT P, FUCHSBICHLER A, MOUSTAFA T, et al. Farnesoid X receptor critically determines the fibrotic response in mice but is expressed to a low extent in human hepatic stellate cells and periductal myofibroblasts[J]. Am J Pathol, 2009, 175(6): 2392-2405. DOI:10.2353/ajpath.2009.090114 |
[20] |
WU WR, LV LX, SHI D, et al. Protective effect of Akkermansia muciniphila against immune-mediated liver injury in a mouse model[J]. Front Microbiol, 2017, 8: 1804. DOI:10.3389/fmicb.2017.01804 |
[21] |
LIU YL, PATMAN GL, LEATHART JBS, et al. Carriage of the PNPLA3 rs738409 C > G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma[J]. J Hepatol, 2014, 61(1): 75-81. DOI:10.1016/j.jhep.2014.02.030 |
[22] |
LIU YL, REEVES HL, BURT AD, et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease[J]. Nat Commun, 2014, 5: 4309. DOI:10.1038/ncomms5309 |
[23] |
DONATI B, DONGIOVANNI P, ROMEO S, et al. MBOAT7 rs641738 variant and hepatocellular carcinoma in non-cirrhotic individuals[J]. Sci Rep, 2017, 7(1): 4492. DOI:10.1038/s41598-017-04991-0 |
[24] |
DAVILA JA, MORGAN RO, SHAIB Y, et al. Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study[J]. Gut, 2005, 54(4): 533-539. DOI:10.1136/gut.2004.052167 |
[25] |
KANWAL F, KRAMER JR, LI L, et al. Effect of metabolic traits on the risk of cirrhosis and hepatocellular cancer in nonalcoholic fatty liver disease[J]. Hepatology, 2020, 71(3): 808-819. DOI:10.1002/hep.31014 |
[26] |
YANG JD, AHMED F, MARA KC, et al. Diabetes is associated with increased risk of hepatocellular carcinoma in patients with cirrhosis from nonalcoholic fatty liver disease[J]. Hepatology, 2020, 71(3): 907-916. DOI:10.1002/hep.30858 |
[27] |
SAUNDERS D, SEIDEL D, ALLISON M, et al. Systematic review: the association between obesity and hepatocellular carcinoma - epidemiological evidence[J]. Aliment Pharmacol Ther, 2010, 31(10): 1051-1063. DOI:10.1111/j.1365-2036.2010.04271.x |
[28] |
HASSAN MM, ABDEL-WAHAB R, KASEB A, et al. Obesity early in adulthood increases risk but does not affect outcomes of hepatocellular carcinoma[J]. Gastroenterology, 2015, 149(1): 119-129. DOI:10.1053/j.gastro.2015.03.044 |
[29] |
SCHLESINGER S, ALEKSANDROVA K, PISCHON T, et al. Abdominal obesity, weight gain during adulthood and risk of liver and biliary tract cancer in a European cohort[J]. Int J Cancer, 2013, 132(3): 645-657. DOI:10.1002/ijc.27645 |
[30] |
SORRENTINO P, D'ANGELO S, FERBO U, et al. Liver iron excess in patients with hepatocellular carcinoma developed on non-alcoholic steato-hepatitis[J]. J Hepatol, 2009, 50(2): 351-357. DOI:10.1016/j.jhep.2008.09.011 |
[31] |
PETRICK JL, CAMPBELL PT, KOSHIOL J, et al. Tobacco, alcohol use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: the Liver Cancer Pooling Project[J]. Br J Cancer, 2018, 118(7): 1005-1012. DOI:10.1038/s41416-018-0007-z |
[32] |
ALEXANDER M, LOOMIS AK, VAN DER LEI J, et al. Risks and clinical predictors of cirrhosis and hepatocellular carcinoma diagnoses in adults with diagnosed NAFLD: real-world study of 18 million patients in four European cohorts[J]. BMC Med, 2019, 17(1): 95. DOI:10.1186/s12916-019-1321-x |
[33] |
GOLDAR S, KHANIANI MS, DERAKHSHAN SM, et al. Molecular mechanisms of apoptosis and roles in cancer development and treatment[J]. Asian Pac J Cancer Prev, 2015, 16(6): 2129-2144. DOI:10.7314/apjcp.2015.16.6.2129 |
[34] |
ESTES C, ANSTEE QM, ARIAS-LOSTE MT, et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030[J]. J Hepatol, 2018, 69(4): 896-904. DOI:10.1016/j.jhep.2018.05.036 |
[35] |
YANG T, HU LY, LI ZL, et al. Liver resection for hepatocellular carcinoma in non-alcoholic fatty liver disease: a multicenter propensity matching analysis with HBV-HCC[J]. J Gastrointest Surg, 2020, 24(2): 320-329. DOI:10.1007/s11605-018-04071-2 |
[36] |
HASHIMOTO E, TOKUSHIGE K. Hepatocellular carcinoma in non-alcoholic steatohepatitis: growing evidence of an epidemic?[J]. Hepatol Res, 2012, 42(1): 1-14. DOI:10.1111/j.1872-034X.2011.00872.x |
[37] |
WAKAI T, SHIRAI Y, SAKATA J, et al. Surgical outcomes for hepatocellular carcinoma in nonalcoholic fatty liver disease[J]. J Gastrointest Surg, 2011, 15(8): 1450-1458. DOI:10.1007/s11605-011-1540-8 |
[38] |
PAIS R, BARRITT AS 4th, CALMUS Y, et al. NAFLD and liver transplantation: current burden and expected challenges[J]. J Hepatol, 2016, 65(6): 1245-1257. DOI:10.1016/j.jhep.2016.07.033 |
[39] |
中华医学会肝病学分会脂肪肝和酒精性肝病学组, 中国医师协会脂肪性肝病专家委员会. 酒精性肝病防治指南(2018年更新版)[J]. 实用肝脏病杂志, 2018, 21(2): 170-176. DOI:10.3969/j.issn.1672-5069.2018.02.006 |
[40] |
POYNARD T, MUNTEANU M, LUCKINA E, et al. Liver fibrosis evaluation using real-time shear wave elastography: applicability and diagnostic performance using methods without a gold standard[J]. J Hepatol, 2013, 58(5): 928-935. DOI:10.1016/j.jhep.2012.12.021 |
[41] |
DEMIERRE MF, HIGGINS PDR, GRUBER SB, et al. Statins and cancer prevention[J]. Nat Rev Cancer, 2005, 5(12): 930-942. DOI:10.1038/nrc1751 |
[42] |
SINGH S, SINGH PP, SINGH AG, et al. Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis[J]. Gastroenterology, 2013, 144(2): 323-332. DOI:10.1053/j.gastro.2012.10.005 |
[43] |
REINER Ž. Statins in the primary prevention of cardiovascular disease[J]. Nat Rev Cardiol, 2013, 10(8): 453-464. DOI:10.1038/nrcardio.2013.80 |
[44] |
PASTORI D, PANI A, DI ROCCO A, et al. Statin liver safety in non-alcoholic fatty liver disease: a systematic review and meta-ana- lysis[J]. Br J Clin Pharmacol, 2022, 88(2): 441-451. DOI:10.1111/bcp.14943 |
[45] |
ZHANG ZJ, ZHENG ZJ, SHI R, et al. Metformin for liver cancer prevention in patients with type 2 diabetes: a systematic review and meta-analysis[J]. J Clin Endocrinol Metab, 2012, 97(7): 2347-2353. DOI:10.1210/jc.2012-1267 |
[46] |
SINGH S, SINGH PP, SINGH AG, et al. Anti-diabetic medications and the risk of hepatocellular cancer: a systematic review and meta-analysis[J]. Am J Gastroenterol, 2013, 108(6): 881-891;quiz892. DOI:10.1038/ajg.2013.5 |
[47] |
CHEN TM, LIN CC, HUANG PT, et al. Metformin associated with lower mortality in diabetic patients with early stage hepatocellular carcinoma after radiofrequency ablation[J]. J Gastroenterol Hepatol, 2011, 26(5): 858-865. DOI:10.1111/j.1440-1746.2011.06664.x |
[48] |
SITIA G, AIOLFI R, DI LUCIA P, et al. Antiplatelet therapy prevents hepatocellular carcinoma and improves survival in a mouse model of chronic hepatitis B[J]. Proc Natl Acad Sci USA, 2012, 109(32): E2165-E2172. DOI:10.1073/pnas.1209182109 |
[49] |
SIMON TG, MA YN, LUDVIGSSON JF, et al. Association between aspirin use and risk of hepatocellular carcinoma[J]. JAMA Oncol, 2018, 4(12): 1683-1690. DOI:10.1001/jamaoncol.2018.4154 |