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2017年亚太地区肝病年会非酒精性脂肪性肝病研究报道

2017-04-01刘晓琳范建高

实用肝脏病杂志 2017年3期
关键词:脂肪性酒精性肝病

刘晓琳,范建高

·会议专题介绍·

2017年亚太地区肝病年会非酒精性脂肪性肝病研究报道

刘晓琳,范建高

非酒精性脂肪性肝病;发病机制;流行病学;无创诊断

第26届亚太地区肝病年会(APASL)于2017年2月15~19日在中国上海成功召开,会议聚焦了亚太各国的专家教授和青年学者在肝病领域的最新研究进展。下面将对在此次会议上有关非酒精性脂肪性肝病(NAFLD)领域的最新研究进展做一专题报道。

1 临床特征

近年来,亚太地区NAFLD的患病率不断升高。牛俊奇团队在对吉林省3636例成人的队列研究中发现,6年间男性和女性NAFLD患病率分别由23.4%和17.5%增高至43.7%和42.6%[1]。Alam et al研究发现孟加拉国NAFLD患病率(34.3%)显著高于慢性乙型肝炎(CHB,4.9%)和慢性丙型肝炎(CHC,0.2%)[2]。我们报道来自大陆和香港的1326例经肝活检证实的CHB和/或NAFLD队列研究,基线时CHB合并脂肪肝患者肥胖、高脂血症、高血压、糖尿病的患病率显著高于单纯性CHB患者,在6.4±3.5年的随访期间前者HCC和肝病死亡风险显著增高[3]。

鉴于我国绝大多数NAFLD患者的病程尚不够长,鲜见NAFLD相关肝硬化特别是HCC的研究报道[4]。日本Kang et al分析1135例肝硬化患者的病因发现,CHB和CHC在不断下降,而NAFLD和酒精性肝病(ALD)导致的肝硬化则显著升高[5]。韩国Kim报道NAFLD患者发生HCC风险显著升高(HR:16.73,95%CI:2.09~133.85),进展期肝纤维化是NAFLD患者肝脏及肝外恶性肿瘤的危险因素,男性患者结直肠腺癌风险升高(HR:2.01,95%CI:1.10~3.68),女性患者发生乳腺癌风险升高(HR 1.92,95%CI:1.15~3.20)[6]。韩国Ahn报道,尽管NAFLD、ALD和CHB相关HCC患者生存期相似,但NAFLD相关HCC更常发生于老年人和女性[7]。

NAFLD不仅导致肝内疾病进展,而且可以引起肝外器官损害。巴基斯坦Sheikh et al研究发现,高脂饮食在引起肝脏损伤的同时还可以破坏大鼠的心脏、肾脏、脾脏和骨骼肌的超微结构[8,9]。本研究团队报道肥胖和脂肪肝是慢性肾脏疾病和肺腺癌的独立危险因素[10,11]。

2 诊断

至今,诊断NASH的金标准仍是肝活检组织学检查。印度Sarin团队比较NAFLD活动性积分(NAS)和肝脂肪变炎症活动纤维化积分(SAF)对1000例肝活检确诊的NAFLD患者的诊断价值,结果发现87.3%(214/245)的经NAS积分诊断为临界性NASH患者被SAF积分确诊为NASH,并且显著肝纤维化独立于两个评分系统准确预测肝损伤[12]。

NAFLD的无创诊断主要聚焦在血清学预测模型和影像学检查新技术方面。我们团队在中国汉族人外周血白细胞基因组甲基化芯片的研究中发现,白细胞ACSL4(cg15536552)和CPT1C(cg21604803)低甲基化可能是NASH的生物标记物[13]。PPARGC1A rs8192678等位基因突变、TM6SF2 rs58542926突变独立于PNPLA3 rs738409是大陆汉族人和台北儿童NAFLD的危险因素[14,15]。因为CHB合并NAFLD的发生率逐年升高,因此在CHB患者中预测NAFLD和NASH的发生同样重要。我们团队推出了一项综合了血清miR-192和miR-16水平以及受控衰减参数(CAP)的组合考评指标可以很好地预测CHB患者发生NAFLD的风险。另有来自天津的研究报道了一个可用于无创性诊断CHB合并NAFLD患者发生NASH的模型,包括血清CK18(M30)水平、空腹血糖和CAP[16,17]。同时,我们团队还发现NAFLD和CHB患者血清脂质组学谱存在显著差异,具有低碳原子数和双键的三酰甘油与NASH组织病理学特征显著相关,可作为诊断NASH的生物标记物[18]。

基于瞬时弹性成像技术(TE)的FibroScan和FibroTouch可通过实施CAP和肝脏硬度测定(LSM)来定量评估肝脏脂肪含量和纤维化程度。一项来自19个研究单位包括了3830例患者的荟萃分析提示,CAP诊断脂肪变大于S0期和S1期的AUROC分别可达到0.823(95%CI:0.809~0.837)和0.865(95%CI:0.850~0.880),其最佳截断点分别为248(95%CI: 237~261)和268(95%CI:257~284)[19]。有研究提示CAP诊断肝脂肪变的效力优于肝脂肪变指数和超声检查[20]。鲁凤民团队比较了APRI、FIB-4和LSM三种方法对NAFLD患者肝纤维化的诊断价值,结果证实LSM在各期肝纤维化的诊断价值都优于另外两种指标[21]。新加坡的Woo et al发现使用ALT≥正常上限值3倍诊断进展期肝纤维化,71%患者将会被漏诊。所以,应该应用LSM进行肝纤维化的评估[22]。施军平团队发现磁共振氢谱(H-MRS)检查不仅可以对NAFLD患者进行肝脏甘油三酯含量的测定,还可以准确地评估NAFLD患者肝内铁含量[23]。另一项来自中国杭州的研究发现H-MRS诊断NAFLD患者≥S1、S2、S3级肝脏脂肪变的AUROC分别高达0.934、0.935和0.97,并且HBV感染不影响H-MRS对肝脏甘油三酯定量的准确性[24]。

3 发病机制

近年来,肠道菌群已被证实在NAFLD的发生发展中扮演重要角色,它可以通过分泌内毒素、合成内生性乙醇以及调节肠道免疫稳态来影响疾病的进展。我们对22例健康人和25例NAFLD患者的粪便研究发现,两者具有不同的菌群构成:NAFLD患者志贺氏杆菌比例增高,而普雷沃氏菌降低[25]。香港徐爱民团队发现敲除脂质运载蛋白2可改善NASH小鼠肠道菌群失衡,提示该蛋白在NAFLD发病中发挥着重要作用[26]。山东青岛宣世英等研究发现TM6SF2 E167K和PNP LA3 I148M基因多态性可通过上调SREBP-1c和FASN表达,协同调控脂质代谢[27]。厉有名团队研究发现P53-AMPK-自噬通路在NAFLD发病中被激活,并参与了肝脏脂质沉积[28]。王安江研究发现IL-25可以通过诱导M1型巨噬细胞死亡和巨噬细胞向M2型极化减轻HFD诱导的肝脏脂肪变[29]。日本的Kakazu团队提出棕榈酸诱导的NASH细胞模型可以通过IRE1α依赖途径释放富含神经酰胺的胞外囊泡,该囊泡可趋化巨噬细胞在肝内聚集,引发肝内炎症。我们在该细胞模型也证实了north信号通路在NAFLD炎症的发生中起到重要作用[30,31]。南月敏团队发现miR-130-5p可通过调控TGF-β/Smad信号通路抑制NASH小鼠肝星状细胞的激活和增殖[32]。赵景民和来自韩国的研究团队分别发现了NAFLD患者血清CXCL16可以促进肝星状细胞的激活和增殖,脂肪酸诱导的NASH细胞模型释放的外泌体也同样可以激活肝星状细胞,预示着它们在NAFLD由肝脏脂肪变向肝纤维化进展的过程中起重要作用[33,34]。

4 治疗

目前,饮食和运动疗法仍然是NAFLD诊疗指南推荐的一线治疗方法,但来自印度的Singh团队研究显示中等强度而不是轻度的运动可以改善NAFLD患者的体质指数(BMI)、甘油三酯、转氨酶以及HOMA-IR[35]。近年来,肠道菌群移植已被证实可以改善NAFLD疾病进展:我们和李兰娟团队都通过动物实验证实了粪菌移植和给予丁酸梭菌B1可显著改善HFD和MCD诱导的NASH小鼠肝脏酶学和组织病理学指标,同时粪菌移植还能通过调节T细胞分化纠正NASH动物的免疫失衡状态[36,37]。我们团队还发现丁酸钠可以显著改善NASH小鼠肝脏组织病理学损伤,增加肝脏对GLP-1的敏感性,可作为胰高血糖素样肽1(GLP-1)激动剂而应用于临床[38]。来自法国和苏州的研究团队都证实了GLP-1激动剂不仅可以显著减轻肥胖动物体质量,降低血清甘油三酯和胆固醇水平,还可以显著改善NASH小鼠肝组织炎症程度[39,40]。与此同时,可作用于多环节和多靶点的中药疗法在NAFLD治疗领域的研究也日益增多[41]。冯琴研究发现祛湿化瘀汤可以修复NAFLD动物肠黏膜屏障损伤、降低血清内毒素水平、抑制炎症信号通路,改善NAFLD大鼠的肠道菌群失衡[42]。徐娇雅等学者研究发现降脂颗粒可以抑制NLRP3炎症小体的激活,调控JNK/c-Jun信号通路,显著改善MCD诱导的NASH小鼠肝组织脂肪变和肝损伤[43]。姚宁研究证实,与单纯的生活方式转变疗法相比,消脂化纤汤联合生活方式转变可以显著缓解NASH合并显著肝纤维化患者肝纤维化程度,降低血清甘油三酯水平和改善胰岛素抵抗[44]。

[1]Wu J,Xu H,Wang C,et al.The 6-year changes of epidemiology of non-alcoholic fatty liver disease among general population of northeastern in China.Hepatol Int,2017,11:S562.

[2]Alam S,Chowdhury MAB,Azam G,et al.Prevalence of fatty liverinBangladesh:anationwidepopulationbasedstudy. Hepatol Int,2017,11:S553.

[3]Fan J,Chen G,Ji D,et al.Prevalence of metabolic syndrome andlong-termdiseaseprogressioninchronichepatitisB patients with comorbid nonalcoholic fatty liver disease.Hepatol Int,2017,11:S11.

[4]梁乾飞,赵彩彦.非酒精性脂肪性肝病与肝细胞癌发生.实用肝脏病杂志,2016,19(1):113-116.

[5]Kang JH,Matsui T,Yamamoto Y,et al.Changing etiology of liver cirrhosis during the last 18 years in Sapporo,Japan:upcoming trend in the near future in Asia Hepatol Int,2017,11:S62.

[6]Kim GA,Lee HC,An J,et al.Risk of cancer in patients with nonalcoholic fatty liver disease:a hospital-based cohort study. Hepatol Int 2017,11:S62.

[7]Ahn SY,Shin HS,Kim SS,et al.Clinical nature and outcome of hepatocellular carcinoma in nonalcoholic fatty liver disease. Hepatol Int,2017,11:S256.

[8]Batool T,Akhtar T,Sheikh N.Fatty diet induced change in hepatic genes expression,serum low molecular weight proteinsandtissuearchitectureofheartandkidney.HepatolInt,2017,11:S625.

[9]AsgharA,Akhtar T,SheikhN.Histopathological changes in spleen and skeletal muscles,hepatic genes expression(IFN-α,IFN-b and IFN-c)and serum high molecular weight proteins variations influenced by fatty diet.Hepatol Int,2017,11:S625.

[10]Zeng J,Sun C,Fan J.Association between noinvasive diagnosed hepatic steatosis and chronic kidney disease in health check-up Chinese adults.Hepatol Int,2017,11:S252.

[11]朱婵艳,瞿冀琛,曹海霞,等.非酒精性脂肪性肝病与原发性支气管肺腺癌发生的相关性研究.实用肝脏病杂志,2016,19(6): 683-686.

[12]Rastogi A,Agarwal A,Sm S,et al.Role of histological scoring systems(NAS-CRN&SAF)in assessment of liver injury in NAFLD-a large cohort comparative study.Hepatol Int,2017,11: S122.

[13]Zhang R,Pan Q,Chen G,et al.Genome-wide analysis of DNA methylation in human peripheral leukocytes identifies potential biomarkersofnonalcoholicfattyliverdisease.HepatolInt,2017,11:S969.

[14]ZhangR,PanQ,ChenG,etal.AcommonPPARGC1A polymorphism rs8192678is associatedwithhistological liver damage independently of PNPLA3 rs738409 in Chinese Han population with nonalcoholic fatty liver disease.Hepatol Int,2017,11:S970.

[15]Lin YC,Chang PF,Ni YH.The association between TM6SF2 variant and nonalcoholic fatty liver disease in obese children and adolescents.Hepatol Int,2017,11:S58.

[16]Liu Xl,Zhang RN,Pan Q,et al.A predictive model for hepatic steatosis of chronic hepatitis B patients in China.Hepatol Int,2017,11:S773.

[17]Liang J,Wang F,Liu F,et al.A noninvasive score model for prediction of nonalcoholic steatohepatitis in patients with chronic hepatitis B and nonalcoholic fatty liver disease.Hepatol Int,2017,11:S58.

[18]Yang R,Hu C,Sun C,et al.Distinct serum triacylglycerol characters of nonalcoholic fatty liver disease and chronic hepatitis B by lipidomics approach.Hepatol Int,2017,11:S120.

[19]KarlasT,PetroffD,SassoM,etal.Individualpatientdata meta-analysisofcontrolledattenuationparameter(CAP)technology for assessing steatosis.J Hepatol,2016[ahead of print].

[20]Liang X,Wei L,Ping L,et al.A comparison of hepatic steatosis index,controlled attenuation parameter,and ultrasound as noninvasive diagnostic tools for hepatic steatosis in patients with biopsy-proven chronic hepatitis B.Hepatol Int,2017,11:S934.

[21]Ning J,Yao M,Zhao J,et al.Diagnostic accuracy and practicability of serological fibrosis tests and liver stiffness measurement in non-alcoholic fatty liver disease.Hepatol Int,2017,11:S915.

[22]Woo SJ,Kwok R,Peter F,et al.The accuracy of alanine aminotransferase(ALT)33 upper limit of normal(ULN)in predicting severe non-alcoholic fatty liver disease(NAFLD).Hepatol Int,2017,11:S255.

[23]Qu H,Wang L,Jin P,et al.The value of 1H-MRS in noninvasive quantification of liver iron content in fatty liver disease. Hepatol Int,2017,11:S256.

[24]Wang L,QuJ,Zhuang J,et al.Effectof HBV onhepatic triglyceride content quantification by 1H-MRS in patiens with non-alcoholic fatty liver disease.Hepatol Int,2017,11:S253.

[25]Shen F,Zheng RD,Sun X,et al.Gut microbiota structure in patients withnon-alcoholicfattyliver disease.Hepatol Int,2017,11:S252.

[26]Ye D,Xu Y,Chau HT,et al.Lipocalin-2 promotes metabolic inflammation in the liver through mediating gut-liver axis.Hepatol Int,2017,11:S18.

[27]Chen L,Du S,Lu L,et al.The synergistic effects of TM6SF2 E167KAndPNPLA3I148Mpolymorphismsonlipid metabolism.Hepatol Int,2017,11:S121.

[28]Zeng H,Yu C,Xu C,et al.The p53-AMPK-autophagy axis takes part in lipid accumulation in hepatocytes.Hepatol Int,2017,11:S963.

[29]Zheng XL,Li BM,Zhu X,et al.IL-25 protects against high-fat diet-induced hepatic steatosis in mice by directly promoting macrophages differentiation into M2 Kupffer cells.Hepatol Int,2017,11:S943.

[30]Ding W,Fan J.Palmitic acid induced the expressions of related signalmoleculesatNotchsignalingpathwayin non-alcoholic fatty liver disease.Hepatol Int,2017,11:S950.

[31]Kakazu E,Mauer A,Malh H.Lipotoxicity induces releasing ceramide-rich proinflammatory extracellular vesicles from hepatocytesinanIRE1alpha-dependentmanner.HepatolInt,2017,11:S122.

[32]Wang Y,Du J,Niu X,et al.MiR-130a-3p attenuates activation and induces apoptosis of hepatic stellate cells in nonalcoholic fibrosingsteatohepatitisviadirectlytargetingTGFBR1and TGFBR2.Hepatol Int,2017,11:S119.

[33]Jiang L,Zhao J.CXCL16-mediated steatosis promotes hepatic stellatecellactivationinnonalchoholicfattyliverdisease. Hepatol Int,2017,11:S946.

[34]Lee YS,Yeon JE,Yoo YJ,et al.Exosome derived from palmitic acid-treated hepatocytes activates hepatic stellate cells.Hepatol Int,2017,11:S954.

[35]Nath P,Panigrahi MK,Sahu MK,et al.Effect of exercise on non-alcoholic fatty liver disease:a comparison of moderate and low intensity exercise.Hepatol Int,2017,11:S251.

[36]Zhou D,Pan Q,Chen Y,et al.Both clostridium butyricum B1 and total fecal microbiota transplantation can attenuate high-fatdiet induced steatohepatitis of mice via immunoregulation.Hepatol Int,2017,11:S948.

[37]Ye J,Wu W,Li L.Supplementation of sodium butyrate reshapes the gut microbiota of mice with non-alcoholic steatohepatitis(NASH).Hepatol Int,2017,11:S16.

[38]Zhou D,Pan Q,Yang R,et al.Sodium butyrate increases GLP-1 sensitivity in NAFLD via its HDAC2 inhibition to enhance liver GLP-1R expression.Hepatol Int,2017,11:S944.

[39]Briand F,Quinsat M,Burr N,et al.Both ezetimibe and liraglutide improve liver inflammationina3-weeknon alcoholic steatohepatitis mouse model.Hepatol Int,2017,11:S119.

[40]Lu W,Wang C,Luo X,et al.PB-718,a dual GLP-1/ glucagon receptor agonist demonstrates superior weight loss effect and ameliorates nonalcoholic steatohepatitis(NASH)in animal models.Hepatol Int,2017,11:S958.

[41]巫协宁.非酒精性脂肪性肝病全程治疗策略的探讨和建议.实用肝脏病杂志,2016,19(2):132-134.

[42]Feng Q,Liu W,Baker SS,et al.Multi-targeting therapeutic mechanisms of the Chinese herbal medicine QHD in the treatment of NAFLD.Hepatol Int,2017,11:S977.

[43]Xu J,Song H,Liu Y,et al.Jiangzhi granules ameliorate hepatic injury through regulating the activity of inflammasome in MCD diet-induced NASH mice.Hepatol Int,2017,11:S977.

[44]Wang X,Yao N.Effect of herb formula Xiao Zhi Hua Xian Tang againstnon-alcoholicsteatohepatitiswithadvancedfibrosis:a preliminary clinical study.Hepatol Int,2017,11:S939.

(收稿:2017-03-13)

(本文编辑:陈从新)

Nonalcoholic fatty liver disease in APASL conference in 2017

Liu Xiaolin,Fan Jiangao.Department of Gastroenterology, Xinhua Hospital,Jiaotong University School of Medicine,Shanghai 200092

Nonalcoholic fatty liver disease;Pathogenesis;Epidemiology;Non-invasive diagnosis

10.3969/j.issn.1672-5069.2017.03.039

200092上海市上海交通大学医学院附属新华医院消化内科

刘晓琳,女,27岁,博士研究生。E-mail:LXL55@ foxmail.com

范建高,E-mail:fattyliver2004@126.com

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