非酒精性脂肪性肝病相关肝细胞癌的研究进展

桂文芳; 朱清静; 杨玲

doi:10.3969/j.issn.1001-5256.2018.12.040

非酒精性脂肪性肝病相关肝细胞癌的研究进展

DOI: 10.3969/j.issn.1001-5256.2018.12.040

1. 华中科技大学同济医学院附属协和医院消化内科
2. 华中科技大学同济医学院附属协和医院超声影像科
3. 武汉市医疗救治中心肝病科

基金项目:

国家自然科学基金(81570530,81370550,30500658)；武汉卫生和计划生育委员会科研课题(WXD18D30)；

详细信息

中图分类号: R575;R735.7
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出版历程
- 出版日期: 2018-12-20

Research advances in nonalcoholic fatty liver disease-related hepatocellular carcinoma

Research funding:

摘要

摘要: 随着肥胖以及其他代谢综合征发病率的增高,目前非酒精性脂肪性肝病(NAFLD)已经成为最常见的慢性肝脏疾病之一。越来越多的研究表明NAFLD是肝细胞癌的危险因素之一,但NAFLD发展成为肝细胞癌的机制尚未完全阐明。近年研究显示肠道微生态失衡、炎症反应、脂肪因子、胰岛素抵抗、高胰岛素血症、脂肪祖细胞以及遗传基因的突变等参与了NAFLD相关肝癌的发生。现阶段针对NAFLD的治疗措施主要有运动饮食干预、胰岛素增敏剂、抗氧化剂、益生菌以及降脂药等,这些治疗方法能否有效预防NAFLD相关肝细胞癌尚不清楚。综述了近年来NAFLD相关肝细胞癌的流行情况、发病机制、预防、监测及筛查。
- 非酒精性脂肪性肝病 /
- 肝肿瘤 /
- 综述
Abstract: With the increase in the incidence rates of obesity and other metabolic syndromes, nonalcoholic fatty liver disease (NAFLD) has become one of the most common chronic liver diseases. More and more studies have shown that NAFLD is one of the risk factors for hepatocellular carcinoma (HCC) , but the mechanism of NAFLD in HCC remains unclear. Recent studies have found that intestinal microflora imbalance, inflammatory response, adipokines, insulin resistance, hyperinsulinemia, adipose progenitor cells, and genetic mutation are involved in the development of NAFLD-related HCC. Major treatment methods for NAFLD include exercise and diet intervention, insulin sensitizer, antioxidants, probiotics, and lipid-lowering drugs. However, it is still unknown whether these methods can effectively prevent NAFLD-related HCC. This article reviews recent advances in the prevalence, pathogenesis, prevention, monitoring, and screening of NAFLD-related HCC.
- nonalcoholic fatty liver disease /
- liver neoplasms /
- review

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参考文献(59)

[1] NEUSCHWANDER-TETRI BA. Non-alcoholic fatty liver disease[J]. BMC Medicine, 2017, 15 (1) :45.

[2] MICHELOTTI GA, MACHADO MV, DIEHL AM. NAFLD, NASH and liver cancer[J]. Nat Rev Gastroenterol Hepatol, 2013, 10 (11) :656-665.

[3] HOLMBERG SD, SPRADLING PR, MOORMAN AC, et al. Hepatitis C in the United States[J]. N Engl J Med, 2013, 368 (20) :1859-1861.

[4] COHEN JC, HORTON JD, HOBBS HH. Human fatty liver disease:Old questions and new insights[J]. Science, 2011, 332 (6037) :1519-1523.

[5] 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.

[6] PISCAGLIA F, SVEGLIATI-BARONI G, BARCHETTI A, et al.Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease:A multicenter prospective study[J]. Hepatology, 2016, 63 (3) :827-838.

[7] SINGAL AG, EL-SERAG HB. Hepatocellular carcinoma from epidemiology to prevention:Translating knowledge into practice[J].Clin Gastroenterol Hepatol, 2015, 13 (12) :2140-2151.

[8] WONG RJ, CHEUNG R, AHMED A. Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U. S.[J]. Hepatology, 2014, 59 (6) :2188-2195.

[9] TURNBAUGH PJ, LEY RE, MAHOWALD MA, et al. An obesity-associated gut microbiome with increased capacity for energy harvest[J]. Nature, 2006, 444 (7122) :1027-1031.

[10] WU WKK, ZHANG L, CHAN MTV. Autophagy, NAFLD and NAFLD-related HCC[J]. Adv Exp Med Biol, 2018, 1061:127-138.

[11] ZHU L, BAKER SS, GILL C, et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients:A connection between endogenous alcohol and NASH[J]. Hepatology, 2013, 57 (2) :601-609.

[12] MIE L, VALENZA V, LA TORRE G, et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease[J]. Hepatology, 2009, 49 (6) :1877-1887.

[13] SZABO G, CSAK T. Inflammasomes in liver diseases[J]. J Hepatol, 2012, 57 (3) :642-654.

[14] JIAO N, BAKER SS, CHAPA-RODRIGUEZ A, et al. Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD[J]. Gut, 2018, 67 (10) :1881-1891.

[15] JIA W, XIE G, JIA W. Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis[J]. Nat Rev Gastroenterol Hepatol, 2018, 15 (2) :111-128.

[16] MA C, HAN M, HEINRICH B, et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells[J]. Science, 2018, 360 (6391) :eaan5931.

[17] PURI P, DAITA K, JOYCE A, et al. The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids[J]. Hepatology, 2017.[Epub ahead of print]

[18] KALHAN SC, GUO LN, EDMISON J, et al. Plasma metabolomic profile in nonalcoholic fatty liver disease[J]. Metabolism, 2011, 60 (3) :404-413.

[19] XIE G, WANG X, LIU P, et al. Distinctly altered gut microbiota in the progression of liver disease[J]. Oncotarget, 2016, 7 (15) :19355-19366.

[20] LOO TM, KAMACHI F, WATANABE Y, et al. Gut microbiota promotes obesity-associated liver cancer through PGE2-mediated suppression of antitumor immunity[J]. Cancer Discov, 2017, 7 (5) :522-538.

[21] WEISBERG SP, MCCANN D, DESAI M, et al. Obesity is associated with macrophage accumulation in adipose tissue[J]. J Clin Invest, 2003, 112 (12) :1796-1808.

[22] GOMES AL, TEIJEIRO A, BUREN S, et al. Metabolic inflammation-associated IL-17A causes non-alcoholic steatohepatitis and hepatocellular carcinoma[J]. Cancer Cell, 2016, 30 (1) :161-175.

[23] PIKARSKY E, PORAT RM, STEIN I, et al. NF-kappaB functions as a tumour promoter in inflammation-associated cancer[J].Nature, 2004, 431 (7007) :461-466.

[24] PARK EJ, LEE JH, YU GY, et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6and TNF expression[J]. Cell, 2010, 140 (2) :197-208.

[25] ARAB JP, ARRESE M, TRAUNER M. Recent insights into the pathogenesis of nonalcoholic fatty liver disease[J]. Annu Rev Pathol, 2018, 13:321-350.

[26] van der WINDT DJ, SUD V, ZHANG H, et al. Neutrophil extracellular traps promote inflammation and development of hepatocellular carcinoma in non-alcoholic steatohepatitis[J]. Hepatology, 2018.[Epub ahead of print]

[27] WAN S, ZHAO E, KRYCZEK I, et al. Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells[J]. Gastroenterology, 2014, 147 (6) :1393-1404.

[28] QIAN BZ, LI J, ZHANG H, et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis[J]. Nature, 2011, 475 (7355) :222-225.

[29] FLECKEN T, SAROBE P. Tim-3 expression in tumour-associated macrophages:A new player in HCC progression[J]. Gut, 2015, 64 (10) :1502-1503.

[30] DONG P, MA L, LIU L, et al. CD86 (+) /CD206 (+) , Diametrically polarized tumor-associated macrophages, predict hepatocellular carcinoma patient prognosis[J]. Int J Mol Sci, 2016, 17 (3) :320.

[31] MINAMI K, HIWATASHI K, UENO S, et al. Prognostic significance of CD68, CD163 and Folate receptor-beta positive macrophages in hepatocellular carcinoma[J]. Exp Ther Med, 2018, 15 (5) :4465-4476.

[32] 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.

[33] SHALAPOUR S, LIN XJ, BASTIAN IN, et al. Inflammation-induced Ig A+cells dismantle anti-liver cancer immunity[J]. Nature, 2017, 551 (7680) :340-345.

[34] WOLF MJ, ADILI A, PIOTROWITZ K, et al. Metabolic activation of intrahepatic CD8+T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes[J].Cancer Cell, 2014, 26 (4) :549-564.

[35] SAXENA NK, SHARMA D, DING X, et al. Concomitant activation of the JAK/STAT, PI3K/AKT, and ERK signaling is involved in leptin-mediated promotion of invasion and migration of hepatocellular carcinoma cells[J]. Cancer Res, 2007, 67 (6) :2497-2507.

[36] KITADE M, YOSHIJI H, KOJIMA H, et al. Leptin-mediated neovascularization is a prerequisite for progression of nonalcoholic steatohepatitis in rats[J]. Hepatology, 2006, 44 (4) :983-991.

[37] SHARMA D, WANG J, FU PP, et al. Adiponectin antagonizes the oncogenic actions of leptin in hepatocellular carcinogenesis[J].Hepatology, 2010, 52 (5) :1713-1722.

[38] HUI X, GU P, ZHANG J, et al. Adiponectin enhances cold-induced browning of subcutaneous adipose tissue via promoting M2macrophage proliferation[J]. Cell Metab, 2015, 22 (2) :279-290.

[39] CAI D, YUAN M, FRANTZ DF, et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NFkappaB[J]. Nat Med, 2005, 11 (2) :183-190.

[40] 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.

[41] ENGELMAN JA. Targeting PI3K signalling in cancer:opportunities, challenges and limitations[J]. Nat Rev Cancer, 2009, 9 (8) :550-562.

[42] SCHUBBERT S, SHANNON K, BOLLAG G. Hyperactive ras in developmental disorders and cancer[J]. Nat Rev Cancer, 2007, 7 (4) :295-308.

[43] SHAN J, SHEN J, LIU L, et al. Nanog regulates self-renewal of cancer stem cells through the insulin-like growth factor pathway in human hepatocellular carcinoma[J]. Hepatology, 2012, 56 (3) :1004-1014.

[44] DEVHARE PB, RAY RB. Extracellular vesicles:Novel mediator for cell to cell communications in liver pathogenesis[J]. Mol Aspects Med, 2018, 60:115-122.

[45] WANG B, MAJUMDER S, NUOVO G, et al. Role of microRNA-155 at early stages of hepatocarcinogenesis induced by choline-deficient and amino acid-defined diet in C57BL/6 mice[J]. Hepatology, 2009, 50 (4) :1152-1161.

[46] CONTI AD, ORTEGA JF, TRYNDYAK V, et al. MicroRNA deregulation in nonalcoholic steatohepatitis-associated liver carcinogenesis[J].Oncotarget, 2017, 8 (51) :88517-88528.

[47] LEE S, ZHANG C, LIU Z, et al. Network analyses identify liverspecific targets for treating liver diseases[J]. Mol Syst Biol, 2017, 13 (8) :938.

[48] SALAMEH H, HANAYNEH MA, MASADEH M, et al. PNPLA3 as a genetic determinant of risk for and severity of non-alcoholic fatty liver disease spectrum[J]. J Clin Transl Hepatol, 2016, 4 (3) :175-191.

[49] KHLAIPHUENGSIN A, KIATBUMRUNG R, PAYUNGPORN S, et al. Association of PNPLA3 polymorphism with hepatocellular carcinoma development and prognosis in viral and non-viral chronic liver diseases[J]. Asian Pac J Cancer Prev, 2016, 16 (18) :8377-8382.

[50] ANSTEE QM, SETH D, DAY CP. Genetic factors that affect risk of alcoholic and nonalcoholic fatty liver disease[J]. Gastroenterology, 2016, 150 (8) :1728-1744. e7.

[51] SHEN J, TSOI H, LIANG Q, et al. Oncogenic mutations and dysregulated pathways in obesity-associated hepatocellular carcinoma[J]. Oncogene, 2016, 35 (49) :6271-6280.

[52] ZHAO F. Dysregulated epigenetic modifications in the pathogenesis of NAFLD-HCC[J]. Adv Exp Med Biol, 2018, 1061:79-93.

[53] LI QB, ZHUO QB, CHEN L, et al. Research advances in treatment of non-alcoholic fatty liver disease[J]. J Clin Hepatol, 2015, 31 (7) :1135-1139. (in Chinese) 李强, 卓其斌, 陈良, 等.非酒精性脂肪性肝病的治疗进展[J].临床肝胆病杂志, 2015, 31 (7) :1135-1139.

[54] JING J, YU JF, ZHANG TF. Curative effect of Yerba Mate improving phlegm and blood stasis, and blood lipid level of NAFLD[J].Clin J Med Offic, 2017, 45 (7) :683-684. (in Chinese) 井静, 于京芳, 张铁峰.马黛茶改善非酒精性脂肪性肝病痰瘀互结证血脂水平疗效分析[J].临床军医杂志, 2017, 45 (7) :683-684.

[55] BURZA MA, PIRAZZI C, MAGLIO C, et al. PNPLA3 I148M (rs738409) genetic variant is associated with hepatocellular carcinoma in obese individuals[J]. Dig Liver Dis, 2012, 44 (12) :1037-1041.

[56] SINGAL AG, YOPP AC, GUPTA S, et al. Failure rates in the hepatocellular carcinoma surveillance process[J]. Cancer Prev Res (Phila) , 2012, 5 (9) :1124-1130.

[57] SANTI V, TREVISANI F, GRAMENZI A, et al. Semiannual surveillance is superior to annual surveillance for the detection of early hepatocellular carcinoma and patient survival[J]. J Hepatol, 2010, 53 (2) :291-297.

[58] CAUCHY F, MEBARKI M, ALBUQUERQUE M, et al. Anti-angiogenic effect of metformin in human liver carcinogenesis related to metabolic syndrome[J]. Gut, 2015, 64 (9) :1498-500.

[59] EL-SERAG HB, JOHNSON ML, HACHEM C, et al. Statins are associated with a reduced risk of hepatocellular carcinoma in a large cohort of patients with diabetes[J]. Gastroenterology, 2009, 136 (5) :1601-1608.

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