非酒精性脂肪肝的研究进展

非酒精性脂肪肝（NAFLD）是一种无过量饮酒史，但病理学改变类似酒精性脂肪性肝病（AFLD），以肝细胞脂肪变性和脂质贮积为特征的临床病理综合征。其疾病谱包括单纯性脂肪肝、脂肪性肝炎（NASH）、脂肪性肝纤维化和脂肪性肝硬化四个从轻到重的病理阶段。     

性激素在非酒精性脂肪性肝病发病机制中的作用

非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)是一类由遗传-环境-代谢应激相关因素所致的,以弥漫性肝细胞大泡性脂肪变性和肝小叶内炎症为主要特征的临床病理综合征.近年来,随着研究深入,发现NAFLD不仅与肝脏脂质代谢紊乱、胰岛素抵抗(insulin resistance,IR)、氧化应激、内毒素血症等相关,其发生还存在明显性别差异,推测其可能与不同性别间性激素水平、肝脂代谢差异以及糖脂代谢酶表达及活性差异等多种因素相关[1].现结合近年来国内外最新文献,就性激素在NAFLD患者中的变化及其对NAFLD发病的影响和作用机制作一简要综述. 一、NAFLD流行病学与性别差异 Hepatology于2011年发表了澳大利亚一项最新研究结果,1170例青少年中,NAFLD发病率为12.8％,其中男女比例约为1:1.6[2].该结论与多项国内外研究结果显示的男性脂肪肝患病率高于女性相悖,分析其原因可能与不同研究人口基础特征、ALT水平及不同性别人群肥胖比例差异等相关[3].有关NAFLD性别差异的研究结果显示,整体人群中,男性NAFLD患者高于女性,但青春期前及50岁以后女性发病率明显高过男性,说明女性激素可能对生育期女性脂肪肝的发生起保护作用.     

Treatment of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is the most common cause for elevated liver enzymes in the developed nations. Beyond prevention programs which are of particular interest because of the increasing number of overweight children, treatment should be focussed on the most important risk factors, obesity and insulin resistance. As a consequence of elucidating the pathomechanisms of NAFLD, the number of potential therapeutic options increased. However, many studies investigating the therapeutic effect show shortcomings in at least one of the following points: lack of a serial liver biopsy, short term of treatment and limited number of included patients. The second generation insulin sensitizer piogiitazone and rosiglitazone show the most promising improvements in NAFLD, but weight gain and potential hepatotoxicity calls for attention. In conclusion, a general recommendation for the application of specific drugs cannot be given. Besides controlled clinical trials, weight reduction and physical activity to improve insulin sensitivity in obese patients should be the priority objective.     

Histopathology of nonalcoholic fatty liver disease

Histological analysis of liver biopsies remains a standard against which other methods of assessment for the presence and amount of hepatic injury due to nonalcoholic fatty liver disease(NAFLD) are measured.Histological evaluation remains the sole method of distinguishing steatosis from advanced forms of NAFLD,i.e.nonalcoholic steatohepatitis(NASH) and fibrosis.Included in the lesions of NAFLD are steatosis,lobular and portal inflammation,hepatocyte injury in the forms of ballooning and apoptosis,and fibros...     

脂联素在非酒精性脂肪肝中的作用及机制

脂联素是由脂肪细胞分泌的胰岛素敏感性脂肪因子,其对非酒精性脂肪肝病(NAFLD)有多种有益作用.在循环中脂联素有3种低聚亚型,包括三聚体、六聚体及高分子量低聚复合物.脂联素通过与靶器官上脂联素受体结合来发挥效应,其保肝作用已经在临床和实验室研究中证明.脂联素的下降是NAFLD及肝脏功能损害的独立危险因素.在动物实验中,通过药物或基因疗法使循环中的脂联素增高可导致肝肿大、脂肪变、坏死炎症及其相关肝脏疾病.脂联素敲除的小鼠,会发生肝脂肪变和线粒体功能损害,这致使小鼠易于遭受脂肪肝病的二次打击.本文旨在综述近年来对于脂联素在NAFLD中的保肝作用及机制的研究成果.     

缺氧对非酒精性脂肪性肝病发病的影响*

非酒精性脂肪性肝病（NAFLD）患者存在系统性和肝脏局部缺氧。对于呼吸睡眠暂停综合征与脂肪性肝病的研究显示机体缺氧程度与胰岛素抵抗、肝脏脂肪变、炎症和纤维化程度相关。动物实验和分子生物学研究显示缺氧及其缺氧诱导因子能促进肝细胞脂肪堆积,加速肝脏炎症、纤维化,甚至肿瘤的发生和发展。     

Role of endoplasmic reticulum stress in the pathogenesis of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD)has emerged as a common public health problem in recent decades.However,the underlying mechanisms leading to the development of NAFLD are not fully understood.The endoplasmic reticulum(ER)stress response has recently been proposed to play a crucial role in both the development of steatosis and progression to nonalcoholic steatohepatitis.ER stress is activated to regulate protein synthesis and restore homeostatic equilibrium when the cell is stressed due to the accumulation of unfolded or misfolded proteins.However,delayed or insufficient responses to ER stress may turn physiological mechanisms into pathological consequences,including fat accumulation,insulin resistance,inflammation,and apoptosis,all of which play important roles in the pathogenesis of NAFLD.Therefore,understanding the role of ER stress in the pathogenesis of NAFLD has become a topic of intense investigation.This review highlights the recent findings linking ER stress signaling pathways to the pathogenesis of NAFLD.     

肝细胞因子与非酒精性脂肪性肝病

非酒精性脂肪性肝病(NAFLD)是目前最常见的慢性肝病,其特点是肝脏内脂肪大量堆积(脂肪变性).肝细胞因子指由肝脏分泌的具有自分泌、旁分泌或内分泌活性的蛋白质,主要功能为调节脂质和葡萄糖代谢.研究发现,在发生肝脏脂肪变性时,许多肝细胞因子的表达会发生变化,包括成纤维细胞生长因子21、性激素结合球蛋白、adropin、血...     

Transition of an acronym from nonalcoholic fatty liver disease to metabolic dysfunction-associated fatty liver disease

Nonalcoholic fatty liver disease(NAFLD) is a global public health concern owing to its substantial contribution to chronic liver diseases. The disease is closely linked to metabolic syndrome(MS), suggesting a common biological pathway and shared disease mechanism for both ailments. Previous studies revealed a close relationship of NAFLD with the components of MS including abdominal obesity,dyslipidemia, hypertension, and hyperglycemia. Hence, a group of experts recently renamed NAFLD as metabolic dysfunction-associated fatty liver disease(MAFLD) in order to encompass a more appropriate pathogenesis of the disease.NAFLD was first named to describe a condition similar to alcoholic hepatitis in absence of significant alcohol consumption. However, knowledge pertaining to the etiopathogenesis of the disease has evolved over the past four decades. Recent evidence endorses NAFLD as a terminology of exclusion and suggests that it may often leads to misdiagnosis or inappropriate management of patients, particularly in clinical practice. On the other hand, the new definition is useful in addressing hepatic steatosis with metabolic dysfunction, which ultimately covers most of the patients with such illness. Therefore, it seems to be helpful in improving clinical diagnosis and managing high-risk patients with fatty liver disease. However, it is imperative to validate the new terminology at the population level to ensure a holistic approach to reduce the global burden of this heterogeneous disease condition.     

肠道屏障功能在非酒精性脂肪性肝病发病机制中的作用

非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)是一种常见的慢性肝脏疾病,且发病率有逐年上升的趋势.关于其发病的具体机制的研究从未停止.自马歇尔(Marshall)于1998年正式提出了"肠-肝轴"的概念,肠道屏障功能在NAFLD发病机制中的作用逐渐成为关注的重点.肠道屏障功能的4大方面机械屏障、化学屏障、生物屏障、免疫屏障相互密切联系,并且与NAFLD之间的关系也密不可分.本文对近年来关于肠道屏障功能与NAFLD的发生和发展的相关性研究结果进行综述,旨在探讨在NAFLD的发病机制中肠道屏障功能所起到的作用.     

Histopathology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD), a hepatic manifestation of metabolic syndrome, is the most common chronic liver disease, and the prevalence is rapidly increasing worldwide. Nonalcoholic steatohepatitis (NASH), the severe form of NAFLD, can progress to liver cirrhosis and hepatocellular carcinoma (HCC). Although noninvasive clinical scores and image-based diagnosis for NAFLD have improved, histopathological evaluation of biopsy specimens remains the gold standard for diagnosing NAFLD/NASH. Steatosis, lobular inflammation, and hepatocellular ballooning are all necessary components for the diagnosis of NASH; fibrosis is also typically observed. Other histopathological abnormalities commonly observed in NASH include hepatocellular glycogenated nuclei, lipogranulomas, and acidophil bodies. The characteristics of pediatric NAFLD/NASH differ from adult NAFLD/NASH. Specifically, steatosis and portal inflammation are more severe in pediatric NAFLD, while intralobular inflammation and perisinusoidal fibrosis are milder. Although interobserver agreement for evaluating the extent of steatosis and fibrosis is high, agreement is low for intralobular and portal inflammation. A recently reported histological variant of HCC, steatohepatitic HCC (SH-HCC), shows features that resemble non-neoplastic steatohepatitis, and is thought to be strongly associated with underlying NASH. In this report, we review the histopathological features of NAFLD/NASH.     

IL-18对大鼠非酒精性脂肪肝病形成的作用

目的: 分析在高脂饮食诱发大鼠非酒精性脂肪肝病(NAFLD)形成过程中胰岛素抵抗(IR)与IL-18之间的相关性,并探讨IL-18对大鼠NAFLD形成的作用.方法: 将48只♂SD大鼠随机分为正常饮食组(NG)及高脂饮食组(FG),各24只,喂养至第2、4、6、8周末时,2组各随机抽取6只,抽取门静脉血测空腹血糖(FBS)、空腹胰岛素(FINS),计算空腹胰岛素抵抗指数(FIRI);检测血清及肝组织匀浆IL-18浓度;光镜检查肝组织切片以评价肝脏脂肪变性程度.结果: FG第4周末开始出现IR,血清及肝组织匀浆IL-18均随喂养时间的延长逐渐升高,各期均高于NG,肝组织匀浆IL-18在第2、4、6、8周末均与同期NG比较均有统计学差异均P<0.05),而血清IL-18是第4、6、8周末与同期NG比较均有统计学差异(均P<0.05). FINS、FIRI、血清及肝组织匀浆IL-18均与肝脂肪变性呈正相关( r = 0.951,0.971,0.950,0.937,均P<0.05). 血清IL-18与FINS、FIRI及肝组织匀浆IL-18与FINS、FIRI均成正相关( r = 0.951,0.933,0.929,0.913,均P<0.05).结论: IR在高脂饮食诱发的NAFLD的发生发展中有重要作用,IL-18与IR形成有关,并与NAFLD的形成相关联.     

肠道益生菌对非酒精性脂肪肝的影响

目的探讨肠道菌群与非酒精性脂肪肝(NAFLD)的关系。方法对53例服用肠道益生菌的NAFLD患者和56例对照组患者进行服药前后肝脏的超声检查,抽血查血肌酐、尿素氮、总胆固醇、三酰甘油、空腹血糖,并同时对年龄和体质量指数(BMI)进行统计。结果服药前两组各项指标比较,差异无统计学意义(P0.05)。服药后肠道益生菌组和对照组比较,脂肪肝消退数明显增加,差异有统计学意义(P0.05)。服药前后两组比较,肠道益生菌组服药后较服药前脂肪肝消退数明显增加,差异有统计学意义(P0.01);而对照组各项指标比较,差异均无统计学意义(P0.05)。两组服药前后各种观察指标差值的比较,脂肪肝消退、中度脂肪肝减少数、总胆固醇、三酰甘油和尿素氮下降在肠道益生菌组差异有统计学意义(P0.05、P0.01)。结论口服益生菌可以降低NAFLD的发生,益生菌可能具有预防和治疗NAFLD的作用。     

壳聚糖治疗大鼠非酒精性脂肪性肝病的初步实验研究

目的探索不同剂量壳聚糖治疗非酒精性脂肪性肝病的效果。方法60只大鼠随机分为空白对照组（10只）、脂肪肝模型组（20只）和3个不同剂量壳聚糖治疗组（各10只）。脂肪肝模型组和治疗组先用高脂饲料（含88％普通饲料＋10％猪油＋2％胆固醇）喂养12周。壳聚糖治疗组在13～20周每日经灌胃给予相对分子质量为127100壳聚糖溶液1次。三组的剂量分别为每公斤体质量0．094g、0．188g和0．375g。20周时处死动物,分别取肝组织切片观察脂肪变、炎症和纤维化情况,血清行生化指标检测。结果模型组动物均形成F4级脂肪变、G1～G2炎症和S1～S2纤维化。模型组动物ALT、AST、ALP、TC和LDL均较空白对照组显著升高。TG增高和HDL降低差异无统计学意义。与模型组相比,壳聚糖治疗各组大鼠肝脂肪变和炎症差异无统计学意义;但治疗组肝纤维化有明显好转。大剂量壳聚糖治疗组中60％大鼠肝纤维化减轻到S0期,无S2期。壳聚糖治疗组的生化指标也有一定程度的好转,但未恢复到空白对照组水平。结论大剂量壳聚糖（每日0．375g／kg）对改善大鼠肝组织的脂肪肝和纤维化有明显效果,对生化指标改善也有一定效果。     

非酒精性脂肪性肝病的相关危险因素研究进展

非酒精性脂肪性肝病(NAFLD)是指一群组织病理异常,其发病以胰岛素抵抗为基础,并与肥胖、高脂血症、Ⅱ型糖尿病、原发性高血压等密切相关。疾病早期症状隐匿,如不及时控制可诱发肝硬化及慢性肝病。NAFLD治疗策略有限,因此探讨脂肪肝相关危险因素对降低NAFLD发病及延缓其病程进展具有重要意义。     

Ghrelin-ghrelin O-acyltransferase system in the pathogenesis of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD) is currently considered as the most common liver disease in Western countries,and is rapidly becoming a serious threat to public health worldwide.However,the underlying mechanisms leading to the development of NAFLD are still not fully understood.The ghrelin-ghrelin O-acyltransferase(GOAT) system has recently been found to play a crucial role in both the development of steatosis and its progression to nonalcoholic steatohepatitis.Ghrelin,the natural ligand of the growth hormone secretagogue receptor,is a 28-amino acid peptide possessing a unique acylation on the serine in position 3 catalyzed by GOAT.The ghrelin-GOAT system is involved in insulin resistance,lipid metabolism dysfunction,and inflammation,all of which play important roles in the pathogenesis of NAFLD.A better understanding of ghrelin-GOAT system biology led to the identification of its potential roles in NAFLD.Molecular targets modulating ghrelin-GOAT levels and the biologic effects are being studied,which provide a new insight into the pathogenesis of NAFLD.This review probes into the possible relationship between the ghrelin-GOAT system and NAFLD,and considers the potential mechanisms by which the ghrelin-GOAT system brings about insulin resistance and other aspects concerning NAFLD.     

Animal models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) is a condition in which excess fat accumulates in the liver of a patient without a history of alcohol abuse. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can progress to liver cirrhosis and hepatocellular carcinoma. NAFLD is regarded as a hepatic manifestation of metabolic syndrome and incidence has been increasing worldwide in line with the increased prevalence of obesity, type 2 diabetes, and hyperlipemia. Animal models of NAFLD/NASH give crucial information, not only in elucidating pathogenesis of NAFLD/NASH but also in examining therapeutic effects of various agents. An ideal model of NAFLD/NASH should correctly reflect both hepatic histopathology and pathophysiology of human NAFLD/NASH. Animal models of NAFLD/NASH are divided into genetic, dietary, and combination models. In this paper, we review commonly used animal models of NAFLD/NASH referring to their advantages and disadvantages.     

非酒精性脂肪性肝病动物模型研究进展*

目的 非酒精性脂肪性肝病(NAFLD)发病率逐年增加,并可能发展成为终末期肝病。目前,仍缺乏针对该病的治疗药物,建立动物模型研究很有必要。尽管已有多种不同种类的疾病模型,但仍没有一种能真正反映人类整个疾病谱的代表性的NAFLD模型。本文对目前应用的NAFLD模型进行了综述,重点介绍动物模型、2D细胞模型和3D肝脏模型及其优缺点。     

Clinical differences between alcoholic liver disease and nonalcoholic fatty liver disease

Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are serious health problems worldwide. These two diseases have similar pathological spectra, ranging from simple hepatic steatosis to steatohepatitis, liver cirrhosis, and hepatocellular carcinoma. Although most subjects with excessive alcohol or food intake experience simple hepatic steatosis, a small percentage of individuals will develop progressive liver disease. Notably, both ALD and NAFLD are frequently accompanied by extrahepatic complications, including cardiovascular disease and malignancy. The survival of patients with ALD and NAFLD depends on various disease-associated conditions. This review delineates the clinical characteristics and outcomes of patients with ALD and NAFLD by comparing their epidemiology, the factors associated with disease susceptibility and progression, and the predictors and characteristics of outcomes. A comprehensive understanding of the characteristics and outcomes of ALD and NAFLD is imperative in the management of these chronic liver diseases.     

非酒精性脂肪性肝病研究进展

非酒精性脂肪性肝病(NAFLD)的相关研究进展日益显示出肝脏脂肪沉积在促发胰岛素抵抗和糖脂代谢异常方面的重要地位.作为一个代谢性疾病的早期可逆性干预治疗靶位,NAFLD越来越受到国内外内分泌代谢和消化领域专家的重视,对其研究也不断深入拓展.本综述结合NAFLD的最新研究进展,从代谢的角度阐述对NAFLD的新认识和新概念,介绍我国最新NAFLD诊疗共识的特点以及国内外在NAFLD诊断和治疗方面取得的最新成果.在此基础上,预测NAFLD研究领域的进一步探索发展方向.