非酒精性脂肪性肝病的综合治疗

非酒精性脂肪性肝病(NAFLD)是代谢综合征在肝脏的表现,其疾病谱包括非酒精性单纯性脂肪肝、非酒精性脂肪性肝炎(NASH)和肝硬化.其治疗应为综合性下预,包括通过调整生活方式、药物及手术治疗等方法改善胰岛素抵抗,减少易致肝脏损伤的因素,必要时可应用保肝抗炎药物,终末期NAFLD患者需行肝移植术.     

Current therapies for nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease in adults and children in many regions of the world. Although a relatively benign condition in some, for others the disease will progress to cirrhosis and end-stage liver disease with associated complications including hepatocellular cancer. Pharmaceutical therapies have had mixed results and none are accepted as standard therapy. Depending on the metric used to assess response (biochemical or histological), there are some therapies which may afford benefit. Others, however, have caused less than desirable adverse effects. Unfortunately, no particular treatment has emerged as safe and highly effective. The cornerstones of management of this problematic condition should include exercise and efforts at weight reduction through dietary changes and increased physical activity. Weight reduction does indeed seem to be beneficial in this setting, as evidenced by studies including those evaluating the effect of bariatric surgery. Less is known, however, about the effort of exercise in and of itself as a treatment strategy, even in the absence of a reduction in body weight. In this paper, we review the literature pertaining to the current state of NAFLD management with an emphasis on pharmacotherapy.     

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.     

减肥药用于非酒精性脂肪性肝病治疗的评价

非酒精性脂肪性肝病(NAFLD)是一种临床综合征,其肝组织学改变与酒精性肝病相类似但患者并无过量饮酒史.NAFLD患者通常合并肥胖症,而肥胖又可加重NAFLD的病情,甚至导致肝功能衰竭等终末期肝病.NAFLD患者肝细胞内过量脂肪沉积可能涉及多种机制,部分临床研究及动物试验显示,肥胖可致内脏脂肪组织功能失调、异常细胞因子表达及内源性大麻素系统相关的免疫紊乱等.近来研究提示,减轻体重有益于NAFLD的治疗.本文主要介绍并评价减肥药在NAFLD治疗中的作用,包括奥利司他、西布曲明及利莫那班等.     

保肝抗炎药物在非酒精性脂肪性肝病治疗中的作用

非酒精性脂肪性肝病(NAFLD)的早期干预已获得大多数学者认同.保肝抗炎药物包括多烯磷脂酰胆碱、维生素E、水飞蓟素、熊去氧胆酸、甘草酸制剂和己酮可可碱等,是NAFLD综合治疗的重要组成部分.本文重点综述保肝抗炎药物的适用人群及常用药物的选用.多项临床研究提示,保肝抗炎药物町改善NAFLD患者的临床症状和血清氨基转移酶水平,但大多数保肝抗炎药物对肝脏纤维化进程的改善依据尚不足.     

罗格列酮治疗非酒精性脂肪肝的临床效果观

目的观察罗格列酮治疗非酒精性脂肪肝（NAFLD）的临床效果。方法将100例NAFLD患者完全随机的方法分为观察组和对照组,各50例。观察组口服罗格列酮4 mg,1次/d;对照组口服二甲双胍片0.5 g,3次/d;2组疗程均为6个月。观察2组治疗前后体重指数、肝功能［丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）、谷氨酰转肽酶（GGT）］、血脂（总胆固醇、三酰甘油）、胰岛素抵抗指数（HOMA IR）及空腹胰岛素（FINS）水平的变化。结果观察组总有效率为84.0%（42/50）,对照组总有效率为66.0%（33/50）,2组比较差异有统计学意义（P＜0.05）。观察组治疗后体重指数、肝功能（ALT、AST、GGT）、血脂（总胆固醇、三酰甘油）、HOMA IR及FINS水平较治疗前明显改善［（22±7）kg/m2比（28±9）kg/m2;（36±7）U/L比（116±9）U/L,（29±7）U/L比（97±8）U/L,（27±6）U/L比（75±8）U/L;（4.0±1.1）mmol/L比（5.0±1.3）mmol/L,（1.3±0.7）mmol/L比（2.6±1.3）mmol/L;（9±4）mU/L比 （13±9）mU/L,（1.6±1.1）×103比（2.6±1.2）×103］（P＜0.05）,与对照组治疗后［分别为（25±7）kg/m2,（71±9）U/L,（66±3）U/L,（62±6）U/L,（3.6±1.7）mmol/L,（1.8±0.7）mmol/L,（11±3）mU/L,（2.1±1.4）×103］比较,差异均有统计学意义（均P＜0.05）。结论罗格列酮能够治疗NAFLD,通过改善靶组织对胰岛素的敏感性,改善NAFLD的胰岛素抵抗,调节血脂,从而减轻NAFLD的肝损害,疗效优于二甲双胍。     

Advances in the understanding and treatment of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a well recognised form of chronic liver disease that has recently gained greater recognition. Originally described in the late 1950s, NAFLD is currently considered the leading cause of abnormal liver enzyme levels in the US, closely paralleling the increase in obesity and diabetes mellitus. NAFLD has a worldwide distribution, affecting both adults and children, and typically is seen in association with obesity, diabetes, hypertension and hypertriglyceridaemia. Most patients are asymptomatic and usually present with mild elevations in aminotransferases. The natural history of NAFLD is not clearly defined but progression to cirrhosis and end-stage liver disease is well recognised in some patients. The accumulation of hepatic steatosis is thought to occur initially, primarily through hepatic and peripheral insulin resistance, which leads to altered glucose and free fatty acid metabolism. The progression from simple fatty liver to more severe forms of NAFLD (nonalcoholic steatohepatitis and cirrhosis) is much less clear but evidence suggests that oxidative stress may preferentially enhance proinflammatory cytokines, which leads to cellular adaptations and dysfunction followed by development of inflammation, necrosis and fibrosis. Therapeutic modalities remain limited and are largely focused on correcting the underlying insulin resistance or reducing oxidative stress. However, at the present time, there are several limitations to the current potential therapies, mainly because of the lack of large-scale, prospective, randomised studies, as well as clearly defined histological endpoints. Ultimately, the future for potential therapeutic modalities to treat this disease are quite promising, but further research is needed to clearly demonstrate which therapy or therapies will be effective at eliminating fatty liver disease and its potential complications.     

Herbal drug discovery for the treatment of nonalcoholic fatty liver disease

Few medications are available for meeting the increasing disease burden of nonalcoholic fatty liver disease (NAFLD) and its progressive stage, nonalcoholic steatohepatitis (NASH). Traditional herbal medicines (THM) have been used for centuries to treat indigenous people with various symptoms but without clarified modern-defined disease types and mechanisms. In modern times, NAFLD was defined as a common chronic disease leading to more studies to understand NAFLD/NASH pathology and progression. THM have garnered increased attention for providing therapeutic candidates for treating NAFLD. In this review, a new model called “multiple organs-multiple hits” is proposed to explain mechanisms of NASH progression. Against this proposed model, the effects and mechanisms of the frequently-studied THM-yielded single anti-NAFLD drug candidates and multiple herb medicines are reviewed, among which silymarin and berberine are already under U.S. FDA-sanctioned phase 4 clinical studies. Furthermore, experimental designs for anti-NAFLD drug discovery from THM in treating NAFLD are discussed. The opportunities and challenges of reverse pharmacology and reverse pharmacokinetic concepts-guided strategies for THM modernization and its global recognition to treat NAFLD are highlighted. Increasing mechanistic evidence is being generated to support the beneficial role of THM in treating NAFLD and anti-NAFLD drug discovery.     

非酒精性脂肪性肝病的药物治疗

<正>由于缺少有组织学终点以及远期并发症和死亡转归的随机对照研究,药物对非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)的治疗效     

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。     

胰岛素增敏剂在非酒精性脂肪性肝病中的应用

近年我国非酒精性脂肪性肝病(NAFLD)的患病率逐渐增高,胰岛素抵抗在NAFLD发病机制中具有重要作用,胰岛素增敏剂如噻唑烷二酮类药物和二甲双胍等逐渐成为NAFLD治疗药物的研究重点.本文综述近年NAFLD的临床治疗研究,评价胰岛素增敏剂在NAFLD治疗中的作用.     

脂肝康治疗非酒精性脂肪肝的疗效观察

目的评估脂肝康治疗非酒精性脂肪肝的效果.方法选择158例非酒精性脂肪肝病人,随机分为对照组和治疗组,对照组采用水飞蓟素、熊去氧胆酸治疗,治疗组采用脂肝康治疗,治疗3月后观察肝功能(重点观察总胆红素、谷丙转氨酶、谷草转氨酶、γ-谷酰胺转肽酶,血脂(TC,TG)并进行疗效判断.结果治疗组与对照组在改善临床症状、肝功能和血脂方面差异无显著性.结论脂肝康可用于治疗非酒精性脂肪肝.     

复方中药治疗非酒精性脂肪性肝病的实验研究

目的观察复方中药治疗非酒精性脂肪性肝病的疗效和作用机制。方法运用高脂饲料饮食制备非酒精性脂肪性肝病动物模型,治疗组药物灌胃,采用酶法测定血及肝组织中总胆固醇(TC)、甘油三酯(TG)、游离脂肪酸(FFA)及血中丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)的含量,观察肝组织学变化。采用反转录-聚合酶链反应(RT-PCR)测定酰基辅酶A氧化酶(AOX)的表达。结果中药高剂量组血及肝中TC、TG、FFA含量较模型组有明显降低(P<0.05);中药高剂量组ALT、AST较模型组有明显降低(P<0.05);中药治疗组肝组织脂肪变及炎症计分较模型组有明显降低(P<0.05);AOX的表达中药组和吉非贝齐组较模型组明显升高(P<0.05)。结论中药治疗非酒精性脂肪性肝病有明显疗效,可能通过激活过氧化物酶体增生物激活受体-α(PPAR-α)使AOX表达上调而改善脂肪变。     

GI epidemiology: nonalcoholic fatty liver disease

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a common diagnosis in clinical practice. Insulin resistance and oxidative stress play an important role in NAFLD development and progression. AIM: To review the data available on the epidemiology and natural history of NAFLD as well as the risk factors for its development and the areas where future research is necessary. RESULTS /CONCLUSIONS: NAFLD may affect individuals of any age range and race/ethnicity. NAFLD affects one in three adults and one in ten children/adolescents in the United States. Mortality in patients with NAFLD is significantly higher than in the general population of same age and gender with liver-related complications being a common cause of death. Liver-related morbidity and mortality in NAFLD occurs when the disease has progressed to advanced fibrosis and cirrhosis. Further studies are necessary to determine the impact of NAFLD on health-related quality of life and resources utilization, and to the extent to which preventing the development of the metabolic syndrome would prevent NAFLD development and reduce liver-related morbidity and mortality. Lifestyle intervention may improve NAFLD, but medications that increase insulin sensitivity and the antioxidant defenses in the liver deserve evaluation in carefully controlled trials.     

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.     

Therapeutic strategies in nonalcoholic fatty liver disorders

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in developing countries. Many of the risk factors are well defined, but the underlying pathogenesis is not well understood. The demographics of the condition mirror those of the metabolic syndrome, with obesity and insulin resistance being the most commonly associated conditions. At present, therapy is aimed at correcting the risk factors, but there are no proven therapies at this point.     

Current best treatment for non-alcoholic fatty liver disease

Treatment of patients with non-alcoholic fatty liver disease (NAFLD) has typically been focused on the management of associated conditions such as obesity, diabetes mellitus and hyperlipidaemia. NAFLD associated with obesity may be resolved by weight reduction, although the benefits of weight loss have been inconsistent. Improving insulin sensitivity with lifestyle modifications or medications usually improves glucose and lipid levels in patients with diabetes and hyperlipidaemia. Improving insulin sensitivity is expected to improve the liver disease but in many diabetic/hyperlipidaemic patients with NAFLD, the appropriate control of glucose and lipid levels is not always accompanied by improvement of the liver condition. Results of pilot studies evaluating ursodeoxycholic acid, gemfibrozil, betaine, N-acetylcysteine, αtocopherol, metformin and thiazolidinedione derivatives suggest that these medications may be of potential benefit. This article reviews the treatment modalities currently available for patients with NAFLD, including emerging data from clinical trials evaluating promising medications as well as possibilities for the future.     

Current best treatment for non-alcoholic fatty liver disease

Treatment of patients with non-alcoholic fatty liver disease (NAFLD) has typically been focused on the management of associated conditions such as obesity, diabetes mellitus and hyperlipidaemia. NAFLD associated with obesity may be resolved by weight reduction, although the benefits of weight loss have been inconsistent. Improving insulin sensitivity with lifestyle modifications or medications usually improves glucose and lipid levels in patients with diabetes and hyperlipidaemia. Improving insulin sensitivity is expected to improve the liver disease but in many diabetic/hyperlipidaemic patients with NAFLD, the appropriate control of glucose and lipid levels is not always accompanied by improvement of the liver condition. Results of pilot studies evaluating ursodeoxycholic acid, gemfibrozil, betaine, N-acetylcysteine, alphatocopherol, metformin and thiazolidinedione derivatives suggest that these medications may be of potential benefit. This article reviews the treatment modalities currently available for patients with NAFLD, including emerging data from clinical trials evaluating promising medications as well as possibilities for the future.     

甘草酸二铵脂质复合物对大鼠非酒精性脂肪肝的治疗效果研究

目的:研究甘草酸二铵脂质复合物(甘平,DGLL)对大鼠非酒精性脂肪肝(NAFLD)的治疗作用。方法:以高脂饲料喂养方式建立大鼠非酒精性脂肪肝模型,证实造模成功后随机分为空白对照组、模型组、多烯磷脂酰胆碱组和甘平高中低(900、300、100mg/kg)剂量组。给药4周后,处死所有动物,检测血脂、氧化应激、肝功能、胰岛素相关等指标,并观察肝脏组织病理学变化。结果:甘平能显著降低NAFLD大鼠的转氨酶(ALT、AST)活力、丙二醛(MDA)含量、TNF-α水平、空腹血糖(FBG)、空腹胰岛素(FINS)水平和空腹胰岛素抵抗指数(HOMA-IR),升高超氧化物歧化酶(SOD)活力,改善NAFLD大鼠的总胆固醇(TC)、甘油三酯(TG)水平。结论:甘平可以用来治疗大鼠NAFLD,其机制可能与抗氧化作用及改善胰岛素抵抗有关。