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。     

吡格列酮对合并代谢综合征的非酒精性脂肪性肝病患者血清TNF-α、IL-6的影响及意义

目的:研究吡格列酮对合并代谢综合征(MS)的非酒精性脂肪性肝病(NAFLD)患者血清肿瘤坏死因子α(TNF-α)和白细胞介素6(IL-6)水平的影响及其意义。方法:连续收集2012年1月-2013年6月在长江航运总医院治疗的合并MS的NAFLD患者。患者分别接受非药物治疗(中等程度热量限制和中等量有氧运动)或吡格列酮(30 mg·d^-1)联合非药物治疗6个月。比较治疗后2组病例的TNF-α、IL-6、NAFLD/MS相关指标和疗效的差异,并分析TNF-α、IL-6与胰岛素抵抗指数(HOMA-IR)、疗效之间的关系。结果:共收集合并MS的HAFLD患者64例,每组各32例。非药物组治疗后6个月仅体重指数和空腹胰岛素显著性降低(P<0.05),吡格列酮联合非药物组治疗后TNF-α、IL-6水平及NAFLD/MS指标均显著改善(P<0.05)。联合治疗组的总有效率显著优于非药物组(81.3% vs 21.9%)。患者治疗前后血清TNF-α和IL-6水平差值与HOMA-IR差值显著性正相关(分别为r=0.676,P<0.001;r=0.498,P<0.001);HOMA-IR差值与疗效级别亦呈显著性正相关(r=0.608,P<0.001)。结论:吡格列酮可有效降低合并MS的NAFLD患者血清TNF-α、IL-6水平。TNF-α、IL-6可能通过影响胰岛素敏感性参与病变治疗过程。     

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.     

The uric acid metabolism pathway as a therapeutic target in hyperuricemia related to metabolic syndrome

Introduction: Uric acid (UA) increase is considered an important risk factor for the development of cardiovascular disease (CVD) favoring oxidative stress and endothelial dysfunction and is also involved in metabolic syndrome (MS) pathophysiology.

Areas covered: Insulin has a physiological action on renal tubules, causing a reduction in UA clearance, what could explain the hyperuricemia found in MS. On the other hand, it was also hypothesized a causal role of UA in fructose-induced MS. Moreover, it has been suggested that higher UA levels predict the development of MS. MS subjects present a redox imbalance and UA participates in this process. UA can contribute to oxidative stress present in MS; however, it has also an important role in the antioxidant defense system. Although UA may have a protective effect due to its antioxidant properties, it is clear that the dominant effect of UA in MS is deleterious. All-cause mortality and CVD have been shown to be increased with higher UA levels.

Expert opinion: It is extremely important to prescribe drugs which concomitantly decrease hyperuricemia and improve co-morbidities associated with hyperuricemia. Long-term studies to verify the consequences of decreasing UA concentration below current recommendations in asymptomatic patients are needed.     

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。     

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.     

Current pharmacotherapy for treating pediatric nonalcoholic fatty liver disease

Introduction: In the past decade, nonalcoholic fatty liver disease (NAFLD) had rapidly become one of the most common liver diseases. If efficient therapeutic strategies will not reduce the prevalence of NAFLD in children soon, serious deleterious effects on the quality of life of these patients in adulthood are expected. Lifestyle modification is the current first-line therapy for pediatric NAFLD, even though it is difficult to obtain and to maintain. Therefore, lifestyle changes are usually ineffective and long-lasting improvement of the NAFLD-associated liver damage is rarely observed. As guidelines for the management of NAFLD in children are still lacking, the identification of effective treatments represents a challenge for pediatric hepatologists in the near future.

Areas covered: Here, we review the existing therapeutic approaches for treating NAFLD in children and overview all ongoing clinical trials for new promising drugs in pediatric setting.

Expert opinion: Considering the multifactorial pathogenesis and the wide spectrum of histological and clinical features of NAFLD, we believe that a drug mix, containing agents that are effective against the principal pathogenetic factors, associated with lifestyle modification, could represent the winning choice of treatment for pediatric NAFLD.     

非酒精性脂肪性肝病药物治疗进展及认识

非酒精性脂肪性肝病(NAFLD)是西方国家慢性肝病的首要病因。当代人们不良生活习惯增多,NAFLD的全球发病率逐年增高,我国也有相应增高。临床治疗NAFLD的药物包括降脂药、减肥药、胰岛素增敏剂和抗氧化剂等。本文综述NAFLD的药物治疗进展及认识。     

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.     

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。     

SREBPs的调节及在非酒精性脂肪肝形成机制中的研究进展

非酒精性脂肪肝(NAFL)是以肝细胞脂肪变性和脂肪沉积为病理特征,但无过量饮酒史的临床综合征,目前NAFL在国内外的发病率正呈明显上升趋势。固醇调节元件结合蛋白(SREBPs)是调控胆固醇、脂肪酸和甘油三酯及脂肪细胞分化过程的关键转录调控因子,现将它的调节以及在NAFL形成中的作用作一综述。     

Managing the combination of nonalcoholic fatty liver disease and metabolic syndrome

Introduction: Metabolic syndrome (MetS) and nonalcoholic fatty liver disease (NAFLD) are part of the same metabolic defect, both having insulin resistance as the main pathogenic mechanism and sharing similar outcomes (i.e., cardiovascular and liver-related mortality). The prevalence of NAFLD is expected to rise, owing to the increasing worldwide prevalence of obesity and MetS; therefore, the identification of factors responsible for disease progression is essential to devise therapeutic strategies.

Areas covered: The available and potential future treatments for NAFLD in combination with MetS are reviewed in this paper, following an extensive literature search and personal experience.

Expert opinion: All NAFLD patients should be evaluated for their metabolic, cardiovascular and liver-related risk. Weight loss through lifestyle intervention remains the most comprehensive and safe treatment of NAFLD and associated MetS; however, > 50% of patients fail to achieve target weight loss. Pharmacologic treatment seems to be important for these patients and for NAFLD cases with more advanced liver disease. It temporarily reverses metabolic alterations, but liver disease progresses after the treatment is stopped. Although current treatments are unsatisfactory, new drugs have been proposed and a few innovative compounds are in the pipeline of pharmaceutical companies. Before pharmacologic treatment can be routinely recommended for NAFLD, long-term randomized trials are needed, along with assessments of the safety and benefits of drugs on proper histological outcomes or validated surrogate markers. The intensive control of individual features of MetS remains mandatory.     

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。     

尿酸在非酒精性脂肪性肝病形成的作用

非酒精性脂肪性肝病（nonalcoholic fatty liver disease, NAFLD）作为世界上最常见的慢性肝病之一,一直是研究的热点。NAFLD与肥胖及相关代谢紊乱密切相关。高尿酸血症或高血清尿酸水平是发生在肥胖者身上常见的代谢异常。流行病学研究证实了血清尿酸水平与非酒精性脂肪肝显著相关,而黄嘌呤氧化酶（xanthine oxidase, XO）是控制尿酸合成的关键酶。本文着重对尿酸及控制其合成的限速酶XO在NAFLD形成中的作用进行综述;阐述了尿酸与代谢综合症（metabolic syndrome, MS）相关疾病之间的关系,如胰岛素抵抗、糖尿病和高血脂;最后介绍了XO抑制剂在各种疾病治疗中的应用。     

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。     

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...     

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。     

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。