Novel therapeutic targets for nonalcoholic fatty liver disease

Introduction: Nonalcoholic fatty liver disease (NAFLD) is a serious public health problem. It is now estimated to affect 30% of adults and about 10% of children in the U.S. Hispanics are disproportionably affected with not only higher rates of NAFLD but also more severe disease. Treatment options are currently limited.

Areas covered: In this review, we will focus on a series of novel findings related to the pathobiology of liver damage in nonalcoholic steatohepatitis (NASH) that are attractive targets for development of novel therapeutic strategies for human NASH. In particular, we will discuss four different areas due to their novelty and growing importance including microparticles, the inflammasomes, gut-liver axis and dietary lipids.

Expert opinion: There is an urgent need to develop novel safe and effective therapies for the growing NAFLD epidemic. The data discussed in this article provide strong rational to think out of the box when considering novel therapeutic targets for patients with NAFLD.     

非肥胖型与肥胖型非酒精性脂肪性肝病进展性肝纤维化临床特点分析

目的:探究非肥胖型与肥胖型非酒精性脂肪性肝病(NAFLD)进展性肝纤维化患者的临床特点.方法:选取2019年9月至2020年6月在我院肝病门诊诊断为NAFLD进展性肝纤维化的患者91例,并按BMI分为非肥胖型组18例和肥胖型组73例,另选取同期健康体检者35例为对照组.比较3组一般资料与实验室检查结果.结果:与非肥胖型...     

低碳水化合物饮食对非酒精性脂肪肝肥胖患者的影响

目的评估低碳水化合物饮食对非酒精性脂肪肝肥胖患者体重和代谢综合征的影响。方法在3个月内对16例成年非酒精性脂肪肝肥胖患者,予以低碳水化合物饮食指导进行减重干预(碳水化合物占总供能比20%~40%,蛋白质占30%~60%,脂肪占20%~30%)。在干预前后分别检测16例参与者体重、体成分、血压等,空腹抽血测定丙氨酸氨基转移酶、天门冬氨酸氨基转移酶、三酰甘油、总胆固醇、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇、尿素、肌酐、尿酸和血糖等。结果16例患者采用3个月内的低碳水化合物减重干预后体重、身体质量指数、体脂肪、体脂肪百分比、内脏脂肪面积、腰围、腰臀比等,与干预前比较差异均有统计学意义(P<0.05)。但是,骨骼肌含量也呈现一定程度地下降。患者减重干预后舒张压、空腹葡萄糖、丙氨酸氨基转移酶、天门冬氨酸氨基转移酶、胆固醇、三酰甘油、低密度脂蛋白胆固醇及尿酸水平均有所改善(P<0.05);而收缩压、高密度脂蛋白胆固醇,尤其是尿素和肌酐的改善并不显著(P>0.05),说明减重过程中采用的特殊饮食模式未对肾功能产生不良影响。结论低碳水化合物饮食可以在短期内减轻非酒精性脂肪肝肥胖患者的体重并改善代谢综合征相关指标。     

他莫昔芬诱发非酒精性脂肪性肝病的研究进展

他莫昔芬是一种广泛应用于治疗激素敏感型乳腺癌的抗雌激素类药物。临床研究和动物实验已经证实他莫昔芬可以诱发非酒精性脂肪性肝病(NALFD)。目前认为他莫昔芬诱发NALFD的机制主要包括脂肪酸的合成、脂肪酸的β氧化、三酰甘油转运异常以及雌激素拮抗作用。对他莫昔芬诱发NAFLD及其发病机制的研究现状进行了综述。     

天然免疫与非酒精性脂肪肝病

肝脏中大量的巨噬细胞、自然杀伤细胞(natural killer,NK)、自然杀伤T细胞(natural killer T cell,NKT)等构成了天然免疫系统.这一系统细胞功能紊乱,发生Th-1极化,使促炎症因子产生增多,促进了非酒精性脂肪性肝炎(nonalcoholic steatohepatitis,NASH)的形成;肝脏持续的暴露于这些炎症因子,可以促进多种促纤维化因子产生,但Th-2细胞因子分泌的不足, 使NASH进一步发展为肝硬化的现象却相对比较少见.本文就肝脏天然免疫系统在非酒精性脂肪肝病(nonalcoholic fatty liver disease, NAFLD)中的调节机制作一综述.     

非酒精性脂肪肝与代谢综合征的临床相关性分析

目的：探讨非酒精性脂肪肝（NAFLD）与代谢综合征（MS）相关指标变化的关系,并进行临床相关性研究。方法：选择本院诊断的NAFLD患者共122例作为研究对象,检测其酶学、代谢指标及并发症情况。结果：与单纯NAFLD组比较,NAFLD合并MS组患者的BMl、TG、收缩压、舒张压、空腹血糖明显增高,差异具有统计学意义（P〈0．05）;血清总胆固醇（TC）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）及血尿酸差异无统计学意义（P〉0．05）;两组并发症之间差异具有统计学意义（P〉0．05）。结论：NAFLD合并MS患者的代谢指标异常及并发症发生率高,临床医师应重视,并给与患者合理的建议。     

Pharmacological management of nonalcoholic fatty liver disease in type 2 diabetes

Introduction: The prevalence of nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes (T2D) is high and it is associated with poor prognosis. Hepatic steatosis results as a consequence of excessive hepatic lipid accumulation which correlates with insulin resistance and lipotoxicity, with subsequent oxidative stress, inflammation, apoptosis and fibrosis.

Areas covered: This article presents the main pathophysiologic mechanisms and currently available drugs evaluated for their therapeutic effects on NAFLD/nonalcoholic steatohepatitis (NASH) and drugs under development that target relevant pathogenetic pathways. However, to date there is no particular drug approved for treatment of NAFLD in patients with T2D.

Expert commentary: Early recognition and intervention are essential to ameliorate disease progression. Specific recommendations are still needed for NAFLD/NASH screening and diagnosis and therapeutic algorithm in patients with T2D. Lifestyle optimization with significant weight loss is a key intervention in patients with NAFLD and T2D. Pioglitazone, liraglutide, vitamin E, OCA and pentoxifylline have proven some histological improvements in NASH and omega 3-PUFAs were shown to decrease liver fat, but no specific recommendation can be made for treatment of NASH. Perhaps a combination of agents that target different pathogenic pathways are needed to better control disease progression, but more robust evidence for these agents is still needed.     

Nonalcoholic fatty liver disease: a review

Nonalcoholic fatty liver disease is an umbrella term that includes steatosis, nonalcoholic steatohepatitis and advanced fibrosis or cirrhosis. The terminology, although cumbersome, was intended to differentiate these disorders from alcohol-related liver disorders, as they are histologically similar. The term was first used by Ludwig in 1980, but has received a tremendous amount of attention in the past several years as a result of a better understanding of the scope of the problem [1]. Although the pathogenesis has not been fully elucidated, there is a tremendous amount of research ongoing in this arena, both clinical and basic, to determine how the course of the disease can be altered. This text reviews the epidemiology of the disease, leading theories of pathogenesis, and treatment options.     

非酒精性脂肪性肝病患者肝组织脂联素表达及其意义

目的探讨肝组织脂联素表达在非酒精性脂肪性肝病（NAFLD）发病机制中的作用及地位,为NAFLD的预防及治疗提供新的思路。方法47例NAFLD患者及20例正常对照均测量身高、体重,计算体重指数（BMI）;分别应用ELISA方法测定血清脂联素（adiponectin）浓度、血清肿瘤坏死因子-α（TNF-α）浓度;采用稳态模式评估法,计算胰岛素抵抗指数（HOMA-IR）;对肝组织进行HE、Masson染色及脂联素免疫组化染色,对脂联素表达量进行半定量分析。结果非酒精性脂肪性肝炎（NASH）组肝组织脂联素表达较对照组及单纯性脂肪肝组显著减少（P〈0.05）,与血清脂联素浓度呈显著正相关（P〈0.01）,与血清TNF-α浓度、ALT、HOMA-IR及肝组织炎症、纤维化程度呈负相关（P〈0.01）,而与脂变程度不相关（P〉0.05）。多元线性逐步回归分析显示,肝组织脂联素表达是肝组织炎症及纤维化发生的保护因素。结论肝组织脂联素表达在NAFLD患者肝组织炎症及纤维化发生发展中起保护性作用。     

脂必泰对非酒精性脂肪肝病大鼠模型疗效评价

目的:观察脂必泰胶囊对非酒精性脂肪性肝病(NAFLD)大鼠肝组织病理、纤维化指标及炎症的影响。方法:采用高脂饲料和10%果糖诱导NAFLD大鼠模型,并随机分为模型组,脂必泰低、高剂量组(100,200 mg·kg^-1),二甲双胍组(200 mg·kg^-1),水飞蓟宾组(100 mg·kg^-1),另设正常组,造模成功后连续给药9周。肝脏称重后并计算肝脏指数,对肝组织进行HE、油红和Masson染色;检测各组大鼠血清ALT、AST、CHOL、TG、HDL-C、LDL-C,肝纤维化指标透明质酸酶(HA),层粘连蛋白(LN),IV型胶原(IV-C)和Ⅲ型前胶原(PC-Ⅲ)水平;炎症指标(IL-2、IL-6、IL-8、IL-10、IL-18、TNF-α)。结果:与模型组比较,HE、油红和Masson染色示脂必泰组肝脏病变和肝纤维化显著减轻;ALT、AST、TG、CHOL、LDL-C、肝脏脏器系数及HA、LN、IV-C、PC-Ⅲ、IL-6、IL-8、IL-10、IL-18、TNF-α明显降低,HDL-C明显升高(P<0.05)。二甲双胍组和水飞蓟宾组对NAFLD大鼠血清肝功能指标、肝纤维化指标及炎性细胞因子的改善与脂必泰一致,脂必泰高剂量组对多项指标的作用效果优于水飞蓟宾组。结论:脂必泰胶囊可降低NAFLD大鼠血脂水平,减少炎性细胞因子释放,减轻炎性反应,改善大鼠的肝脏功能和肝纤维化,对NAFLD大鼠具有良好治疗作用。     

2型糖尿病伴非酒精性脂肪肝的危险因素分析

目的 探讨2型糖尿病（T2DM）伴非酒精性脂肪肝（NAFLD）患者的相关危险因素.方法 选取T2DM患者122例,根据肝脏彩超检查分为T2DM伴NAFLD组和T2DM不伴NAFLD组.对其腰围、腰臀比（WHR）、BMI、肝功能、血脂、胰岛素抵抗指数（HOMA-IR）进行比较分析.结果 与单纯T2DM组相比,T2DM伴NAFLD组的腰围、WHR、BMI、TC、TG、LDL-C、ALT、HOMA-IR升高（P＜0.05）.多元逐步回归分析显示,TG、腰围、BMI、HOMAIR是NAFLD的独立危险因素.结论 T2DM伴NAFLD患者存在多种代谢异常,其中肥胖、TG、胰岛素抵抗对其影响最大.     

老年非酒精性脂肪肝与载脂蛋白B的相关性分析

目的分析中老年人非酒精性脂肪肝（NAFLD）与载脂蛋白B（ApoB）的相关性。方法我院体检中心411例中老年人（〉50岁）经B超筛查分为NAFLD组和对照组。两组人群均记录相关病史,测量身高、体质量、腰围、臀围、血压,采血检测空腹血糖、血脂等生化指标,并检测75g葡萄糖负荷后2h血糖,计算体质量指数（BMI）、腰臀比（WHR）;采用多元Logistic回归分析NAFLD与ApoB的相关性。结果 1）NAFLD组BMI、WHR、收缩压（SBP）、舒张压（DBP）、ALT、AST、UA、UN、Cr、FBG、P2hBG、TG、ApoB水平明显高于对照组（P〈0.05）,高血压、糖尿病及代谢综合征的检出率也明显高于对照组（P〈0.001）;而HDL-C、ApoA水平低于对照组（P〈0.05）。2）多元线性回归分析显示,NAFLD与ApoB呈独立正相关（r=0.321,P〈0.05）。结论中老年人群体检发现NAFLD后应据情干预血脂,以预防动脉粥样硬化和心脑血管事件发生。     

阿托伐他汀对非酒精性脂肪性肝病大鼠脂肪细胞因子的影响

目的:探讨阿托伐他汀对高脂饮食诱导的非酒精性脂肪性肝病(NAFLD)大鼠脂肪细胞因子脂联素、内脂素、抵抗素的影响.方法:采用高脂饮食10周建立NAFLD大鼠模型,同时以阿托伐他汀进行干预;生化法检测肝组织甘油三酯(TG)和胆固醇(CHOL)含量,HE染色光镜观察肝组织脂肪变和炎症程度,计算NAFLD活动度积分(NAS);ELISA法检测脂联素、内脂素和抵抗素水平,实时荧光定量PCR检测肝组织脂联素、内脂素、抵抗素基因的mRNA表达.结果:模型组大鼠肝组织NAFLD活动度积分和TG、CHOL含量较正常组明显增高(P＜0.01),脂联素血清含量及肝组织mRNA表达较正常组明显降低(P＜0.01),而内脂素、抵抗素血清含量及肝组织mR-NA表达均较正常组显著增强(P＜0.01);应用阿托伐他汀干预后,肝组织病理学改善,肝脏TG、CHOL含量较模型组明显降低(P＜0.05),脂联素血清含量及肝组织mRNA表达水平较模型组增高(P＜0.05),内脂素、抵抗素血清含量及肝组织mRNA表达则均较模型组显著下降(P＜0.05).结论:高脂饮食诱导的NAFLD存在脂联素、内脂素、抵抗素等炎症因子分泌的紊乱,阿托伐他汀可能通过降低脂质在肝脏沉积,上调脂联素,抑制内脂素、抵抗素的过表达,从而抑制肝细胞炎症,防止NAFLD的进展.     

阻塞性睡眠呼吸暂停与非酒精性脂肪性肝病的关系研究

目的：探讨阻塞性睡眠呼吸暂停（ OSA）与非酒精性脂肪性肝病（ NAFLD）的关系。方法141例进行多导睡眠监测的患者为研究对象,根据监测结果分为阻塞性睡眠呼吸暂停低通气综合征（ OSAHS）组和非OSAHS组,均进行肝脏B超检查。比较两组间一般临床资料和实验室检查结果、呼吸暂停低通气指数（ AHI）指数与NAFLD发病率关系以及最低血氧饱和度（ LSaO2）与肝酶指标的相关性并分析原因。结果诊断为OSAHS者83例,其他58例纳入非OSAHS组。 OSAHS组的性别、年龄、血压、血脂、糖尿病、体质指数（ BMI ）和天冬氨酸氨基转移酶（ AST ）,与非OSAHS组比较差异无统计学意义（ P＞0.05）,但丙氨酸氨基转移酶（ALT）、稳态模型胰岛素抵抗（HOMA-IR）指数和NAFLD发病率较非OSAHS组显著增高（P＜0.01）。 AHI指数增加与NAFLD发病率相关。在OSAHS组中,LSaO2与ALT呈负相关,而与AST无相关性。结论 OSA患者易于发生NAFLD,可能与胰岛素抵抗和夜间间歇性低氧有关。     

中药蛤蚧治疗非酒精性脂肪肝小鼠的临床观察

目的：研究蛤蚧治疗非酒精性脂肪肝（ NAFLD）模型小鼠的临床效果。方法选取95只清洁剂雄性昆明小鼠建立NAFLD研究模型,抽签随机分为正常组和模型组,正常组25只给予普通饲料喂养,模型组70只给予高脂饲料喂养,持续喂养6周建立NAFLD模型。模型建立后将模型组中60只抽签随机分为对照组和观察组各30只,两组均给予等渗盐水灌注治疗,观察组加用蛤蚧进行喂养,观察两组血清丙氨酸氨基转移酶（ ALT）、天冬氨酸氨基转移酶（ AST）活性以及血脂总胆固醇（ TC）、三酰甘油（ TG）、高密度脂蛋白胆固醇（ HDL?C）、低密度脂蛋白胆固醇（ LDL?C）变化。结果实验小鼠模型成功建立,血脂指标与组织切片与对照组比较,差异具有统计学意义。治疗后观察组ALT（33．54±4．23）IU／L、AST（205．73±20．84）IU／L较对照组（38．75±5．81）IU／L、（221．68±21．25）IU／L明显较低,具有统计学意义（P＜0．05）。血脂指标TC（2．82±0．26）mmol／L、TG（1．87±0．36）mmol／L、LDL?C（0．34±0．08）mmol／L较对照组（3．23±0．32）mmol／L、（2．24±0．38）mmol／L、（0．48±0．11）mmol／L明显较低,HDL?C（1．06±0．35）mmol／L较对照组（0．73±0．42）mmol／L明显较高,均具有统计学意义（P＜0．05）。结论蛤蚧能有效降低AST、ALT活性。     

脂肪细胞因子与非酒精性脂肪肝病

非酒精性脂肪肝病是发病率仅次于病毒性肝炎的常见肝病,是隐原性肝硬化的主要危险因素之一。多种脂肪细胞因子参与了脂肪肝的病理过程。本文就脂联素、瘦素、抵抗素、内脏脂肪素、Apelin、肠凝集素、网膜素等7种脂肪细胞因子与非酒精性脂肪肝的关系研究进展作一综述。     

防风通圣颗粒联合硫普罗宁治疗非乙醇性脂肪肝临床观察

目的观察防风通圣颗粒联合硫普罗宁治疗非乙醇性脂肪肝的近期临床疗效。方法72例非乙醇性脂肪肝患者随机平行分为对照组和观察组,各36例。对照组给予硫普罗宁注射液静脉滴注,口服复合维生素B片;观察组给予硫普罗宁注射液静滴,内服防风通圣颗粒。两组均连续用药8周。观察两组的疗效及治疗前后症状及体征、肝功能、血脂、B超肝脏脂肪沉积情况。结果对照组显效率27．8％,总有效率69．4％;观察组分别为55．6％和91．7％。两组比较,差异具有统计学意义（P〈0．05）。观察组降酶（ALT、AST）、降血脂（TG、TCH、HDL）,改善B超肝脏脂肪沉积,以及改善症状和体征均明显优于对照组（P〈0．05或P〈0．01）。结论防风通圣颗粒联合硫普罗宁治疗非乙醇性脂肪肝具有较好的近期临床疗效。     

Promising therapies for treatment of nonalcoholic steatohepatitis

Introduction: Non-alcoholic fatty liver disease (NAFLD) has become the most common etiology for abnormal aminotransferase levels and chronic liver disease. Its growing prevalence is largely linked to the presence of metabolic syndrome, particularly diabetes and insulin resistance. It is estimated that 60–80% of the type 2 diabetic population has NAFLD. NAFLD encompasses a range of conditions ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). A subset of patients with hepatic steatosis progress to NASH, while 15–20% of patients with NASH develop cirrhosis. This progression is thought to be multifactorial, and there are currently no FDA-approved medications for the treatment of NASH.

Areas covered: We review drugs currently in Phase II and III clinical trials for treatment of NAFLD and NASH, including their mechanisms of action, relationship to the pathophysiology of NASH, and rationale for their development.

Expert opinion: The treatment of NASH is complex and necessitates targeting a number of different pathways. Combination therapy, preferably tailored toward the disease stage and severity, will be needed to achieve maximum therapeutic effect. With multiple agents currently being developed, there may soon be an ability to effectively slow or even reverse the disease process in many NAFLD/NASH patients.     

老年非酒精性脂肪肝与糖代谢异常的相关性分析

目的 分析中老年人群非酒精性脂肪肝（NAFLD）与糖代谢异常的相关性及发生糖代谢异常的相关危险因素.方法 体检中心423例既往无糖尿病病史的中老年人群（＞50岁）,通过B超筛查分为非酒精性脂肪肝组（NAFLD）和对照组.两组人群均记录相关病史,测量身高、体质量、腰围、臀围、血压,采血检测空腹血糖、血脂等生化指标,并检测75 g葡萄糖负荷后2h血糖,计算体质量指数（BMI）、腰臀比（WHR）;采用Logistic回归分析NAFLD与糖代谢异常的相关性.结果 NAFLD组的BMI、WHR、收缩压（SBP）、舒张压（DBP）、ALT、AST、UA、FBG、P2hBG、TG、TC水平明显高于非NAFLD组（P＜0.05）,而HDL-C水平低于对照组（P＜0.05）;高血压、脂代谢异常、糖代谢异常及代谢综合征的检出率也明显高于对照组（P＜0.001）.Logistic回归分析显示,NAFLD与糖代谢异常呈独立正相关（OR=1.86,95％CI为1.51～2.28,P＜0.001）,TG、ALT、WHR也与糖代谢异常独立相关.结论 中老年人群NAFLD与糖代谢异常表现独立正相关;而TG、WHR与糖代谢异常发生密切相关.