Understanding mechanisms of the pathogenesis of nonalcoholic fatty liver disease

A central issue in the understanding of the pathogenesis of nonalcoholic fatty liver disease is the problem of the underlying mechanisms which are not fully understood.In the setting of excessive central adiposity,insulin resistance is the major underlying cause of fat accumulation in hepatocytes.Because of the difficulties with human trials,several animal models have been developed for this purpose mainly characterized as follows:genetically disturbed or murine fatty liver,methionine-choline deficient diet fed or murine steatohepatitis,and high-fat or sucrose diet fed models.Although these animal models have provided useful information,none of them accurately reflect genetic,metabolic and biochemical characteristics of the human disease.

Pathogenesis of non-alcoholic fatty liver disease in children and adolescence: From “two hit theory” to “multiple hit model”

Nonalcoholic fatty liver disease(NAFLD) has become the dominant form of chronic liver disease in children and adolescents with the increasing prevalence of obesity worldwide. NAFLD represents a wide spectrum of conditions, ranging from fatty liver-which generally follows a benign, non-progressive clinical course-to non-alcoholic steatohepatitis, a subset of NAFLD that may progress to cirrhosis and end-stage liver disease or liver carcinoma. The underlying pathophysiological mechanism of "pediatric" NAFLD remains unclear, although it is strongly associated with obesity and insulin resistance. In this review we provide a general overview on the current understanding of NAFLD in children and adolescents, which underpins practice, enabling early diagnosis and appropriate therapeutic intervention for this life-threatening liver disease.

Nonalcoholic fatty liver disease: Evolving paradigms

In the last years new evidence has accumulated on nonalcoholic fatty liver disease(NAFLD)challenging the paradigms that had been holding the scene over the previous 30 years.NAFLD has such an epidemic prevalence as to make it impossible to screen general population looking for NAFLD cases.Conversely,focusing on those cohorts of individuals exposed to the highest risk of NAFLD could be a more rational approach.NAFLD,which can be diagnosed with either non-invasive strategies or through liver biopsy,is a pathogenically complex and clinically heterogeneous disease.The existence of metabolic as opposed to genetic-associated disease,notably including"lean NAFLD"has recently been recognized.Moreover,NAFLD is a systemic condition,featuring metabolic,cardiovascular and(hepatic/extrahepatic)cancer risk.Among the clinico-laboratory features of NAFLD we discuss hyperuricemia,insulin resistance,atherosclerosis,gallstones,psoriasis and selected endocrine derangements.NAFLD is a precursor of type 2 diabetes(T2D)and metabolic syndrome and progressive liver disease develops in T2D patients in whom the course of disease is worsened by NAFLD.Finally,lifestyle changes and drug treatment options to be implemented in the individual patient are also critically discussed.In conclusion,this review emphasizes the new concepts on clinical and pathogenic heterogeneity of NAFLD,a systemic disorder with a multifactorial pathogenesis and protean clinical manifestations.It is highly prevalent in certain cohorts of individuals who are thus potentially amenable to selective screening strategies,intensive follow-up schedules for early identification of liver-related and extrahepatic complications and in whom earlier and more aggressive treatment schedules should be carried out whenever possible.

Nonalcoholic fatty liver disease:A comprehensive review of a growing epidemic

Nonalcoholic fatty liver disease(NAFLD)is quickly becoming one of the most prominent causes of liver disease worldwide.The increasing incidence of NAFLD is tied to the obesity epidemic and the subsequent metabolic derangements brought along with it.Current efforts to elucidate the mechanism and causes of the disease have answered some questions,but much remains unknown about NAFLD.The aim of this article is to discuss the current knowledge regarding the pathogenesis of the disease,as well as the current and future diagnostic,preventative,and therapeutic options available to clinicians for the management of NAFLD.

Untargeted metabolomics characteristics of nonobese nonalcoholic fatty liver disease induced by high-temperature-processed feed in Sprague-Dawley rats

BACKGROUND Nonalcoholic fatty liver disease(NAFLD)has become one of the most common chronic liver diseases in the world.In our early clinical data and questionnaire analysis of NAFLD,it was found that the body mass index of some patients did not meet the diagnostic criteria for overweight or obesity.The consumption of high-temperature-processed foods such as fried food,hot pot and barbecue is closely related to the occurrence of nonobese NAFLD.Reducing the intake of this kind of food can reduce disease severity and improve prognosis.AIM To explore the untargeted metabolomics characteristics of nonobese nonalcoholic fatty liver disease in Sprague-Dawley rats induced by high-temperatureprocessed feed.METHODS Fifty-four male Sprague-Dawley rats were divided into three groups:The control group received a standard diet;the nonfried soybeans(NDFS)group received 60%NDFS and 40%basic feed and the dry-fried soybeans(DFS)group received 60%DFS and 40%basic feed.Six rats were sacrificed at week 4,8,and 12 in each group.The food intake,body weight,Lee’s index,liver index,serological index and hepatic histopathology were assessed.Untargeted metabolomics characteristics were used to analyze the changes in liver metabolites of rats at week 12.Correlations between metabolites and pathology scores between the DFS and control groups and between the DFS and NDFS groups were analyzed.We selected some of the metabolites,both within the pathway and outside of the pathway,to explain preliminarily the difference in liver pathology in the three groups of rats.RESULTS There were no statistically significant differences in the food intake,body weight,Lee's index or serological index between the DFS group and the control group(P>0.05).At week 8 and week 12,the steatosis scores in the DFS group were significantly higher than those in the other two groups(P<0.05).At week 12,the liver index of the DFS group was the lowest(NDFS group vs DFS group,P<0.05).The fibrosis score in the DFS group was significantly higher than those in the other two groups(P<0.05).The correlation analysis of the liver pathology score and differential metabolites in the DFS and NDFS groups showed that there were 10 strongly correlated substances:Five positively correlated substances and five negatively correlated substances.The positively correlated substances included taurochenodeoxycholate-3-sulfate,acetylcarnitine,20a,22bdihydroxycholesterol,13E-tetranor-16-carboxy-LTE4 and taurocholic acid.The negatively correlated substances included choline,cholesterane-3,7,12,25-tetrol-3-glucuronide,nicotinamide adenine dinucleotide phosphate,lysoPC[16:1(9Z)]and glycerol 3-phosphate.The correlation analysis of the liver pathology score and differential metabolites in the DFS and control groups showed that there were 13 strongly correlated substances:Four positively correlated substances and 9 negatively correlated substances.The positively correlated substances included 4-hydroxy-6-eicosanone,3-phosphoglyceric acid,13-hydroxy-9-methoxy-10-oxo-11-octadecenoic acid and taurochenodeoxycholate-3-sulfate.The negatively correlated substances included lysoPC[16:1(9Z)],S-(9-hydroxy-PGA1)-glutathione,lysoPC[20:5(5Z,8Z,11Z,14Z,17Z)],SM(d18:1/14:0),nicotinamide adenine dinucleotide phosphate,5,10-methylene-THF,folinic acid,N-lactoylglycine and 6-hydroxy-5-methoxyindole glucuronide.CONCLUSION We successfully induced liver damage in rats by using a specially prepared hightemperature-processed feed and explored the untargeted metabolomics characteristics.

从“六郁”论代谢相关脂肪性肝病的理论与临床实践

代谢相关脂肪性肝病已成为全球第一大肝病,包括单纯性脂肪变性,脂肪性肝炎,纤维化/肝硬化与肝癌,常与代谢综合征相关。其病理复杂,国内尚无新药上市。既往中医认识或从食,或从痰湿,或从湿热,或从肝郁脾虚等论治,但细致分析其疾病的病理过程与中医“六郁”理论相吻合。本文简要介绍了六郁致病理论的源流、导致脂肪肝的“六郁”病变特点,辨治要点与临床实践等,以期通过对代谢相关脂肪肝中医病机的深入认识,促进临床治疗进展。

代谢相关脂肪性肝病的发病机制与中医病机

代谢相关脂肪性肝病(MAFLD)是目前全球最常见的肝脏疾病。MAFLD不仅本身易进展为肝炎、肝纤维化和肝硬化等不良结局,还常常伴发共患病,如糖尿病、高血压、高血脂、高尿酸血症及心脑血管疾病。病因治疗是疾病治疗的基石,由于MAFLD具有复杂性和不良转归,因此,探索MAFLD的发病机制,并据此开发有效的防治方案和新药等具有重大意义。本文将从遗传因素,饮食不节和氧化应激,脾胃湿热和胰岛素抵抗,湿热邪气和有机酸代谢,肠道微生态几个方面对MAFLD的发病机制进行综述。

脂肪酸代谢异常促进非酒精性脂肪肝发生发展的分子机制研究进展

非酒精性脂肪肝(NAFLD)是一种脂肪在肝脏中积累的慢性肝病,并伴有肥胖和胰岛素抵抗等形式的代谢功能障碍,已成为我国最常见的肝脏疾病。肝脏的脂肪酸代谢是由脂肪酸的摄取和输出,脂肪酸从头合成和脂肪酸β-氧化利用共同调节的。本文综述了NAFLD肝脏脂肪酸异常代谢的分子机制,重点介绍了肝脏脂质稳态失衡的几条主要途径。在NAFLD,脂肪酸获取和消耗的平衡被打破,肝脂肪酸摄取和脂肪酸从头合成增加,线粒体功能受损,过氧化物酶体和细胞色素脂肪酸氧化增加,VLDL输出增加,而补偿性增强的脂肪酸氧化与输出不足以使脂肪酸水平恢复正常,肝脏脂肪酸积累开始。肝细胞内脂肪酸稳态的失调致有毒脂质产生,进一步诱发氧化应激和脂毒性,促进细胞器功能损伤、细胞凋亡和疾病进展。

非酒精性脂肪性肝病中医治疗研究进展

非酒精性脂肪性肝病(NAFLD)通常表现为没有过度饮酒史,并排除其他明确的肝病,是一种在临床普遍存在的代谢综合征。该疾病的发生主要归因于饮食结构和生活方式等因素,饮食不当、缺乏运动、肥胖、糖尿病、高血压等多种因素易引起肝细胞内脂肪堆积从而导致肝脏损伤,发为本病。现代医学尚未研制出特效药物,治疗上目前主要以保肝调脂降酶及防治并发症为主,而中医提倡整体观念,强调辨证论治,以达到为患者提供更加全面的治疗方案,具有全方位、多靶点、安全性高等优点,能够有效防治NAFLD。本文通过查阅近年来的相关文献和研究成果,介绍中医治疗进展,为临床治疗或进一步研究提供参考依据。

miR-654-3p、CHI3L1与不同中医证型慢性乙型肝炎合并非酒精性脂肪性肝病患者肝纤维化的关系

目的:探讨miR-654-3p、血清壳多糖酶3样蛋白1(CHI3L1)与不同中医证型慢性乙肝(CHB)合并非酒精性脂肪性肝病(NAFLD)患者肝纤维化的关系。方法:纳入2019年5月~2022年5月期间收治于本院的156例CHB合并NAFLD患者作为研究对象,根据中医证型将患者分为肝郁脾虚证组(n=52)、湿热内结证组(n=52)及瘀血阻络证组(n=52)。另选择同期健康体检者50例作为对照组。检测并比较各组肝功能指标[丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)]、肝纤维指标[Ⅲ型胶原蛋白(PC-Ⅲ)、小层粘连蛋白(LN)、IV胶原(IV-C)]、miR-654-3p及CHI3L1水平。采用Pearson相关性分析miR-654-3p、CHI3L1与不同中医证型CHB合并NAFLD患者肝纤维化的关系。结果:肝郁脾虚证组、湿热内结证组及瘀血阻络证组ALT、AST水平均高于对照组,且肝郁脾虚证组>瘀血阻络证组>湿热内结证组(P<0.05);肝郁脾虚证组、湿热内结证组及瘀血阻络证组PC-Ⅲ、LN、IV-C、miR-654-3p及CHI3L1水平均高于对照组,且瘀血阻络证组>湿热内结证组>肝郁脾虚证组(P<0.05)。Pearson相关性分析结果显示,miR-654-3p、CHI3L1与PC-Ⅲ、LN、IV-C均呈正相关(P<0.05)。结论:在不同中医证型CHB合并NAFLD患者中,miR-654-3p及CHI3L1水平均上调,二者与肝纤维化指标PC-Ⅲ、LN、IV-C均呈正相关,可为评估此类患者病情提供参考。

基于计划行为理论的中青年肥胖性非酒精性脂肪性肝病患者中医健康管理行为意向的结构方程模型分析

背景中青年肥胖性非酒精性脂肪性肝病(NAFLD)的发病率逐年升高,但中医健康管理的实践效果不尽如人意,依然存在积极性不高、依从性较差、中医资源利用率较低等问题。健康管理的主体是患者,而结合计划行为理论(TPB)进行患者的疾病意识和中医健康管理认知研究尚不多见。目的基于TPB探讨中青年肥胖性NAFLD患者参与中医健康管理的影响因素。方法选取2016年10-12月在湖北省中医院肝病研究型门诊进行体检并被纳入肝病研究型门诊超重/肥胖人群生物样本库建档的志愿者,发放调查问卷552份,收回552份,有效问卷432份,有效回收率为78.26%。采用深度访谈和文献法收集问卷指标池,通过专家咨询和课题组多轮修订后形成初始问卷,经预调查后反复修正调整,形成了正式问卷《中青年肥胖性非酒精性脂肪性肝病患者中医健康管理行为意向调查表》。采用探索性因子分析寻找潜在因子,构建中青年肥胖性NAFLD患者中医健康管理行为意向的结构方程模型,进行验证性因子分析。结果探索性因子分析在65个测量指标体系中找出主观规范、自我效能、负性态度、身体健康感知、感知行为控制、中医健康管理意向及实际行为7个潜在因子;验证性因子分析验证了上述7个潜在因子的相互关系,结构方程模型拟合评价较好〔比较拟合指数(CFI)=0.949,本特勒-波内特规范拟合指数(NFI)=0.977,Tucker-Lewis指数(TLI)=0.932,拟合优度指数(GFI)=0.868,χ^2/df=2.436,近似均方根残差(RMSEA)=0.065〕;假设检验结果显示:主观规范、感知行为控制与中医健康管理意向具有正相关性(路径系数分别为0.144、0.098,P<0.001),负性态度、身体健康感知与中医健康管理意向具有负相关性(路径系数分别为-0.097、-0.168,P<0.001),自我效能与中医健康管理意向不具有相关性(路径系数为-0.023,P=0.471);主观规范、自我效能、身体健康感知与实际行为不具有相关性(路径系数分别为-0.038、0、0.095,P值分别为0.457、0.991、0.083),感知行为控制与实际行为具有正相关性(路径系数为0.093,P<0.001),负性态度与实际行为具有负相关性(路径系数为-0.110,P<0.001);中医健康管理意向与实际行为不具有相关性(路径系数为-0.091,P=0.074)。结论基于TPB的模型构建适用于解释中青年肥胖性NAFLD患者中医健康管理意愿;主观规范、负性态度、身体健康感知、感知行为控制这些因素可以影响中医健康管理意向,中医健康管理意向与实际行为的发生还存在距离。建立NAFLD中医健康管理模式时,应优化中医资源,保证质量,尤其要加强资源的可用性和可行性建设。同时,规范中医信息,提高患者对NAFLD的认知,具有重要意义。进一步分析患者的个性和行为模式,有利于制定个性化的中医健康管理计划。

非酒精性脂肪性肝病蛋白质组学研究进展

非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)是一种常见慢性肝脏疾病,其发病率呈逐年上升趋势,但发病机制尚未明确,诊疗手段仍不完善.蛋白质组学(proteomics)的出现使NAFLD研究有了进一步的发展,相关研究已达21个.目前,蛋白质组学技术可以研究疾病相关的分子改变,从而寻找新的生物标志物和治疗靶标.在此,对蛋白质组学在NAFLD诊断及分期、发病机制和其他相关领域研究进展作一个较为全面的综述.首先,对研究中遇到的研究对象、样本种类、实验方法和标志物特征选择进行经验性总结.其次,除了介绍如何运用蛋白质组学研究病因、危险因素和重要分子在NAFLD发病机制中的作用,还介绍NAFLD发病机制的亚细胞蛋白质组学、修饰蛋白质组学以及蛋白质组学与转录组学相结合的研究实例.此外,对差异蛋白质的分析策略和价值作了重点阐述,收集到一些有望成为NAFLD治疗靶标的候选分子.最后,结合新技术展望研究新空间,以期能够有助于推动蛋白质组学在寻找新的疾病标志物、探索疾病分子机制和治疗靶标中开辟新的途径.

非酒精性脂肪性肝病中医治疗研究进展--中医药治疗非酒精性脂肪性肝病研究述评

部分患者无明显临床症状。故当从病机出发探讨非酒精性脂肪性肝病fnon—alcoholicfattyliverdisease，NAFLD）的中医病名，如“肝癖”．NAFLD的发病与饮食、劳逸及精神因素等有关，但目前对不同病因之间的区别缺乏深入研究．痰瘀互结、痹阻肝络是NAFLD的病机共性，但不同阶段之间的具体病机存在差异，目前对此研究不足．NAFLD的治疗有辨证论治、专法专药，以及辨病辨证相结合等，但均缺乏严谨有效的评价体系，对患者生存质量也不够重视．实验研究集中体现在证候及单味药物治疗机制的研究上，但存在造模方式未体现中医特色，以及中药安全性和中药复方机制研究不足的问题．

宜昌市职业人群非酒精性脂肪性肝病流行病学调查及其与代谢综合征相关性研究

目的调查研究宜昌市职业人群中非酒精性脂肪肝（NAFLD）患病率及其与代谢综合征（MS）的关系,对本市职业人群NAFLD患病规律进行分析。方法抽样调查宜昌市城区15个单位职业人群共6 450人（男3 284人,女3 166人）,年龄20~70岁,对其进行体格和肝区超声检查,并抽取空腹血进行葡萄糖、三酰甘油、高密度脂蛋白胆固醇、尿酸、CRP等检测,对结果进行统计分析。结果宜昌市职业人群NAFLD的患病率为21.71%,男性为28.68%,女性为14.47%（P〈0.01）。60岁以前各年龄段男性患病率明显高于女性,女性患病率与年龄呈正相关,60岁后达31.31%。NAFLD组中,MS相关组分中患病率最高的为肥胖（69.98%）、高TG血症（61.10%）。结论宜昌市职业人群中60以下男性、60岁以上女性为NAFLD患病高风险人群,该群体应作为定期监测、预防和干预的重点。MS人群中NAFLD患病率显著增高,其最重要相关因素为肥胖、高TG血症。

丹芍疏肝颗粒对不同中医证型非酒精性脂肪肝临床疗效研究

目的:研究丹芍疏肝颗粒对不同中医证型非酒精性脂肪肝临床疗效。方法:120例非酒精性脂肪肝患者随机分为两组,其中90例丹芍疏肝颗粒组根据中医辨证分型分为肝郁脾虚、痰湿阻滞组,痰阻血瘀、湿郁化热组和湿郁血瘀、肝阴不足组,每组30例,给予丹芍疏肝颗粒口服,30例罗格列酮组组给予罗格列酮口服,3个月后予以证候积分、血脂、肝功能、血糖空腹胰岛素B超检查以评定疗效。结果:试验组和对照组B超显示脂肪肝严重程度改变的总有效率分别为92.2%、80.0%,组间比较无显著性差异(P>0.05);试验组与对照组治疗后证候评分、TC、TG、FINS、HOMA-IR有明显改善(P<0.05);试验组治疗后ALT、AST、GGT显著降低(P<0.05),丹芍疏肝颗粒组各中医证型之间无显著性差异。结论:丹芍疏肝颗粒对非酒精性脂肪肝各中医证型均有较好的临床疗效,明显改善非酒精性脂肪肝患者的临床症状,降低非酒精性脂肪肝严重程度,改善脂质代谢和胰岛素抵抗,保护肝功能。

长沙地区1386例NAFLD患者中医体质分布特征及其与生活方式的相关性研究

目的探索长沙地区非酒精性脂肪肝(nonalcoholic fatty liver disease,NAFLD)中医体质分布特征及其与生活方式的相关性。方法采取多阶段整群随机抽样的方法对来自于长沙地区工薪阶层的体检人群进行中医体质类型的抽样调查。结果1.NAFLD的中医体质分布如下:(1)第一体质构成比:平和质42.9%、痰湿质17.1%、湿热质10.2%、阳虚质9.9%、气虚质6.2%、阴虚质6.0%、气郁质4.5%、血瘀质1.9%、特禀质1.3%;(2)不同性别、年龄NAFLD患者的中医体质构成比不一(P<0.01);2.NAFLD主要中医体质与生活方式存在相关性:(1)痰湿质中保护因素:睡眠较好(Exp(β)=0.432,P=0.023);危险因素:很少运动(Exp(β)=2.524,P<0.01);(2)湿热质中保护因素:偶吸烟(Exp(β)=0.326,P=0.003)、不饮酒(Exp(β)=0.266,P<0.01)、偶饮酒(Exp(β)=0.487,P=0.011)、清淡饮食(Exp(β)=0.105,P=0.002);(3)阳虚质中保护因素:睡眠较好(Exp(β)=0.318,P=0.01);危险因素:很少运动(Exp(β)=4.378,P<0.01)。结论 1.长沙地区NAFLD患者中医体质分布以平和质、痰湿质、湿热质、阳虚质为主,存在兼夹体质;不同性别、年龄的NAFLD患者中医体质分布不同。2.NAFLD中医体质与饮食、烟酒、睡眠、运动关系密切,其中很少运动是体质最重要的影响因素。(1)痰湿质以偏咸及肉荤饮食、常饮酒、常失眠、很少运动为主;其中睡眠较好为保护因素,很少运动为危险因素;(2)湿热质以辛辣饮食、嗜烟酒、很少运动为主;其中少烟酒、清淡饮食为保护因素;(3)阳虚质以清淡饮食、常失眠为主;其中很少运动为危险因素,睡眠较好为保护因素。

2016年美国肝病年会非酒精性脂肪性肝病深度报道

非酒精性脂肪性肝病（NAFLD）的疾病谱有单纯性脂肪肝（SFL）、非酒精性脂肪性肝炎（NASH）及其相关肝硬化和肝细胞癌。随着人们生活方式的改变以及肥胖和糖尿病全球化的流行，NAFLD患病率迅速增长。

糖尿病合并非酒精性脂肪肝的证治探讨

作者参阅古今文献,总结多年临床经验,提出糖尿病合并非酒精性脂肪肝的病机特点为"肝郁脾虚、湿热内阻,痰瘀互结",其中脾气亏虚是其病理基础,肝气郁滞是其重要环节,湿热、痰瘀互结是其致病因素并贯彻始终。治疗当以健脾疏肝、清热祛湿、化痰活血为主,健脾益气治其本,调达肝气保证气机通畅,清热祛湿、化痰活血治其标。通过标本兼治可使脏腑得养,肢体得充,病情缓解,诸症转愈。

小陷胸汤化裁治疗非酒精性脂肪肝临床研究

目的观察小陷胸汤化裁治疗非酒精性脂肪肝的临床疗效。方法将患者57例随机分为两组,治疗组予以小陷胸汤化裁,对照组给服血脂康。两组均治疗90d。结果两组患者肝功能及血脂方面治疗后均有明显改善,而以治疗组改善为优,治疗组B超结果亦有明显改善。结论小陷胸汤具有明显的保肝、降脂的作用。

基于数据挖掘探讨非酒精性脂肪肝证型、证素的分布规律

目的:总结非酒精性脂肪肝(NAFLD)的中医证型、证素在临床中的常见规律,为临床辨证治疗NAFLD提供思路和参考依据。方法:检索中国知网、维普、万方等数据库近5年与临床证型、证素的相关文献,将符合要求的文献进行分析,并进行中医理论分析。结果:NAFLD的主要证型为肝郁脾虚、湿热内蕴、痰瘀互结、痰湿内阻、肝郁气滞、脾虚湿蕴、湿浊内停、肝肾亏虚。NAFLD的病位证素为肝、脾、肾,病性证素为湿、气虚、气滞、痰、热、血瘀、阴虚。结论:NAFLD的证型分布呈虚实夹杂的特点,其中以实证为主,病变部位主要在肝、脾、肾,湿、气虚、气滞、痰、热是NAFLD发病的关键。