Probiotics as a complementary therapeutic approach in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD) is currently recognized as one of the most common causes of chronic liver disease. It involves a spectrum of conditionsthat include pure steatosis without inflammation, steatohepatitis, fibrosis and cirrhosis. The key factor in the pathophysiology of NAFLD is insulin resistance that determines lipid accumulation in the hepatocytes and, thus, oxidative stress, which is followed by inflammatory response. However, NAFLD pathogenesis is still largely unknown and has been extensively investigated. Although life style modification with the aim of losing weight has been advocated to treat this disorder, its effectiveness is limited; additionally, there is no specific pharmacologic treatment until nowadays. Recent evidence suggests that the gut microbiota may play a role in the development of insulin resistance, hepatic steatosis, necroinflammation and fibrosis. Differences in gut microbiota between NAFLD patients and lean individuals as well as presence of small intestinal bacterial overgrowth in NAFLD subjects have been demonstrated. Furthermore, some data indicate that the immunoregulatory effects of probiotics may be beneficial in NAFLD treatment as they modulate the intestinal microbiota; improve epithelial barrier function and strengthen the intestinal wall decreasing its permeability; reduce bacterial translocation and endotoxemia; improve intestinal inflammation; and reduce oxidative and inflammatory liver damage. In this article, we review the clinical trials on the use of probiotics in the treatment of NAFLD and discuss the effects of these agents and their efficacy as an emerging therapeutic resource to treat NAFLD patients.     

Pediatric nonalcoholic fatty liver disease: a multidisciplinary approach

Nonalcoholic fatty liver disease (NAFLD) is a multifactorial condition, ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) with or without fibrosis. NAFLD affects both adults and children who present with particular risk factors, including obesity, sedentary lifestyle and/or a predisposing genetic background. The escalation of the prevalence of NAFLD in children worldwide is a worrying phenomenon because this disease is closely associated with the development of both cirrhosis and cardiometabolic syndrome in adulthood. The etiopathogenesis of primary NAFLD in children is unknown; however, considerable knowledge about the mechanisms of liver damage that occur during disease progression has been gathered over the past 30 years. Understanding the pathogenetic mechanisms, together with the histological pattern, provide the basis to characterize potential early predictors of the disease, suitable noninvasive diagnostic tools and design novel specific treatments and possible management strategies. Despite a few clinical trials on the use of antioxidants combined with lifestyle intervention for NAFLD that showed encouraging results, to date, no treatment guidelines exist for children with NAFLD. In this Review, we provide an overview of current concepts in epidemiology, histological features, etiopathogenesis, diagnosis and treatment of NAFLD in children and adolescents.     

非酒精性脂肪性肝病的药物治疗

非酒精性脂肪性肝病(以下简称脂肪肝)的病因和发病机制较复杂,迄今尚未完全明了,因此,目前临床上缺乏针对脂肪肝治疗的有效药物。脂肪肝的治疗,多数学者认为重点在于去除病因,治疗原发疾病;调整饮食,修整不良行为,合理运动,辅以一定的药物治疗。根据脂肪肝发生发展的不同阶段,相关的发病机制以及突出的临床表现和异常的实验室结果酌情进行药物选择。 胰岛素抵抗、游离脂肪酸增加引发的糖脂代谢紊乱是脂肪肝形成的第一次打击。改善胰岛素抵抗,糖脂代谢异常,可望阻止肝细胞从脂肪变性向脂肪性肝炎发展。二氯醋酸二异丙胺     

非酒精性脂肪肝的药物治疗

非酒精性脂肪肝目前尚无疗效理想的治疗药物，希望能够做到的仅仅是改善胰岛素抵抗，维护机体内环境脂质代谢、能量代谢和抗氧化物的平衡，促使机体保持在适应性反应阶段，延缓、阻止脂肪性肝病的病情进展。     

自噬在非酒精性脂肪性肝病中的变化及作用

自噬是一种溶酶体依赖性降解途径,已有大量研究报道,自噬参与了非酒精性脂肪性肝病(NAFLD)的发生及发展.在NAFLD早期,自噬增强,并可以通过抑制引起NAFLD的“二次打击”延缓NAFLD的进展.在NAFLD晚期,由于自噬相关基因(Atg)7降解、哺乳动物雷帕霉素靶蛋白通路过度激活、高胰岛素血症、自噬-溶酶体蛋白水解功能减弱、自噬体膜及溶酶体膜脂质构成改变、肝细胞内钙离子水平增加引起自噬减弱,加重了NAFLD.     

非酒精性脂肪性肝病的治疗现状

非酒精性脂肪性肝病(Nonalcoholic fatty liver disease,NAFLD)是一类肝组织学改变与酒精性肝病相类似,但无过量饮酒史的临床病理综合征。NAFLD的发病率逐年升高,主要包括单纯性脂肪肝、脂肪性肝炎(nonalcoholic steatohepatitis,NASH)、脂肪性肝硬化三种病理类型,NAFLD的防治可阻止慢性肝病的进展,改善NAFLD患者的预后。 一、去除病因及诱因,治疗原发基础疾病     

Dietary approach in the treatment of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD) has been identified as one of the most prevalent chronic liver disease in adults and children populations. NAFLD is usually associated with the metabolic syndrome(MS), which is chiefly related to insulin resistance and its consequences. Insulin resistance has a crucial role in the pathogenesis of hepatic steatosis and potentially nonalcoholic steatohepatitis(NASH). Because of the contemporary epidemics of MS and obesity, the burden of NAFLD is also expected to rise. Unhealthy diets, such as the so-called western diet, are enriched in fructose, trans-fatty acids and saturated fat and seem to be associated with the development of NAFLD. In human studies, certain dietary sugars, particularly fructose, are used as a substrate for lipogenesis leading to hepatic fatty infiltration, inflammation, and possibly fibrosis. Other investigations have shown that fat consumption especially cholesterol and trans/saturated fatty acids are also steatogenic and seem to increase visceral adiposity. The identification of specific dietary components that favor the development of NASH could be important for the management of this disorder. This review focuses on the effects of different dietary approaches to prevent and treat NAFLD emphasizing the macronutrients and energy composition.     

非酒精性脂肪性肝病的靶向治疗研究进展

非酒精性脂肪性肝病（NAFLD）是最常见的进行性疾病,临床上目前尚无疗效确切的治疗药物。介绍了脂肪酸-胆酸偶合物（FABACs）和熊去氧胆酸-溶血磷脂酰乙醇胺偶合物（UDCA-LPE）两种新型的具有NAFLD防治作用的肝靶向药物的研究进展。FABACs通过调节脂代谢,特异性的降低高脂饲料所致NAFLD的肝脏脂肪升高,预防NAFLD的形成;而且对已形成的NAFLD也有治疗作用;Ⅱ期临床研究结果显示其起效快、安全性好。UDCA-LPE在降低NAFLD的肝脏脂肪的同时,能够抑制线粒体损伤和凋亡,促进肝细胞再生,对NAFLD发展过程中的相关炎症具有显著的抑制作用。因此,FABACs和UDCA-LPE对防治NAFLD具有良好的应用前景。     

Weight loss as a treatment for nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease that can progress to cirrhosis and hepatocellular carcinoma. NAFLD has been associated with obesity and other features of the metabolic syndrome, including insulin resistance, impaired glucose tolerance, and dyslipidemia. As a result, and with a lack of other effective treatments, weight loss achieved through lifestyle modifications (diet and exercise) has been promoted as the standard treatment. However, there is very little empiric evidence to support the effectiveness of weight loss for NAFLD. This article reviews the current literature on the effects of weight loss achieved through lifestyle modification or medications on NAFLD. To date, there have been no randomized controlled trials of weight loss interventions on hepatic pathology. Only three published trials (N = 89 subjects), which include a comparison group, have been published. These studies suggest improvement in liver enzymes and/or hepatic pathology; however, direct between group comparisons are lacking. Four small, nonrandomized studies (N = 59 subjects) have evaluated the effect of weight loss achieved with medications (4 of orlistat, 1 of sibutramine) on NAFLD. These suggest some improvement in liver enzymes and histopathology. Finally, a brief review of observational studies on the association between NAFLD pathology or liver enzymes and diet composition suggests a possible role for the manipulation of macronutrients and/or micronutrients in NAFLD treatment. In summary, there is little empiric evidence to support the role of weight loss achieved through lifestyle modification or medication in the treatment of NAFLD. Rigorously conducted, randomized controlled trials are needed in this area.     

自拟中药治疗非酒精性脂肪性肝病患者血清炎症反应指标水平的变化*

目的 探讨应用自拟中药辅助治疗非酒精性脂肪性肝病（NAFLD）患者对血清肝损伤、炎症反应和糖脂代谢指标的影响。方法 2015年1月~2017年1月诊治的NAFLD患者100例,采用office软件提供的数字表随机将患者分为观察组50例和对照组50例,给予对照组饮食和运动指导,观察组在常规指导的基础上加上自拟中药辅助治疗8 w。常规检测血生化指标,包括空腹血糖（FBG）和空腹胰岛素（FINS）,计算胰岛素抵抗指数（HOMA-IR）,采用ELISA法检测血清总抗氧化能力（T-AOC）、超氧化物歧化酶（SOD）、丙二醛（MDA）和一氧化氮（NO）水平。结果 在治疗结束时,观察组血清ALT、AST和GGT水平分别为（65.1±7.8） U/L、（69.4±8.5） U/L和（95.4±12.3） U/L,显著低于对照组[分别为（94.1±12.3） U/L、（99.3±8.6） U/L和（141.9±15.7） U/L,P<0.05];观察组血清T-AOC、SOD、NO和MDA水平分别为（38.1±5.1） U/ml、（89.1±12.1） μg/ml、（20.1±1.8） mg/L和（8.4±1.1） ng/ml,与对照组的（25.1±3.2） U/ml、（62.1±6.9） μg/ml、（13.1±1.2） mg/L和（12.0±1.2） ng/ml比,差异显著（P<0.05）; 观察组FBG、HOMA-IR、TC和TG分别为（6.1±1.2） mmol/L、（5.8±0.9）、（2.2±0.1） mmol/L和（0.4±0.1）mmol/L,均显著低于对照组【分别为（6.8±2.3） mmol/L、（6.4±1.9）、（2.7±0.3） mmol/L和（0.7±0.3） mmol/L,P<0.05]。结论 应用自拟中药治疗非酒精性脂肪性肝病患者,短期内能降低血清肝酶活性,调节糖脂代谢,其远期作用还有待观察。     

Current biochemical studies of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis suggest a new therapeutic approach

The study population in this report by Lin et al. was ob/ob mice that have an inherited genetic deficiency of the appetite-suppressing hormone leptin. These mice develop hyperinsulinemia, insulin resistance, and fatty livers. Compared with their lean littermates and wild-type C57BL-6 mice, ob/ob mice have hepatomegaly. In this study, the authors compared three different groups of adult mice (aged 8-10 wk), including male ob/ob C57BL-6 mice, their lean littermates, and wild-type C57BL-6 mice of the same age and sex.The primary purpose of this study was to test the efficacy of metformin for treatment of fatty liver disease in obese, ob/ob mice that develop hyperinsulinemia or insulin resistance and fatty livers. Metformin therapy was found to eliminate fatty liver disease in this model. The potential mechanisms of the action of metformin were the inhibition of hepatic tumor necrosis factor (TNF)alpha and several TNF-inducible responses, which are likely to promote hepatic steatosis and necrosis.In these experiments, ob/ob mice were divided into three treatment groups. Group 1 consisted of eight mice that were treated with metformin and permitted to consume a nutritiously replete liquid mouse diet ad libitum. Mice in group 2 (n = 8) did not receive metformin but were pair-fed the same volume of liquid diet that the mice in the metformin-treated group had consumed on the previous day. Obese ob/ob mice in group 3 (n = 4) and lean mice received no metformin, as with the mice in group 2, but were permitted to consume the liquid diet ad libitum. Liquid diet was given to facilitate accurate daily comparison of food intake among the various treatment groups. All mice were weighed at the beginning of the study and weekly thereafter until killed and then sera, fat, and liver tissues were collected. Tissues were either fixed in buffered formalin and processed from the deceased mice for histology or snap frozen in liquid nitrogen and stored until RNA and proteins were isolated.The feeding protocol was repeated with a second group of 18 ob/ob mice. After 4 wk, hepatocytes were obtained by in situ liver perfusion with collagenase and assayed for cellular adenosine triphosphate (ATP) content. In each experiment, hepatocytes isolated from 3 mice from each treatment group were suspended in a medium and pooled for subsequent analysis to evaluate cell viability, determine the number of obtained cells, and to assay cellular ATP content. These experiments were repeated using another 3 mice from each treatment group, so that analysis of hepatocytes took place from six ob/ob mice in each feeding group.Hepatic steatosis was decreased significantly only in the metformin-treated group. The authors found that metformin's beneficial effect on the fatty liver disease of mice was not due to its ability to constrain hyperphagia, nor due to decreased caloric ingestion, because the daily caloric intakes of the metformin-treated mice and the pair-fed control mice were virtually identical. These caloric intakes were consistently approximately 20% less than that of another obese control group that was permitted to consume diet ad libitum. The authors also observed no significant effect of metformin on serum glucose concentration from fed, ob/ob mice. Metformin is known to reduce hyperinsulinemia by about 40% in both of these obese hyperinsulinemic and insulin-resistant rodent strains. In conclusion, Lin et al. documented that metformin improves fatty liver disease and reverses hepatomegaly, steatosis, and aminotransferase abnormalities in mice. In addition, the authors suggest that metformin might inhibit dieting-induced redistribution of lipid from the liver to adipose tissue depots. In summary, this study identifies a potential treatment for fatty liver disease in humans.     

Leptin in nonalcoholic fatty liver disease

Background: Non-alcoholic fatty liver disease (NAFLD) is a prevalent condition associated with obesity and insulin resistance (IR). Leptin plays a key role in the control of energy balance, and insulin sensitivity. In this study, we aimed to examine whether serum leptin levels correlate with insulin resistance, oxidative stress parameters and the severity of histological changes in NAFLD. Methods: Fifty-two patients (M/F: 28/24) with no alcohol intake and biopsy-proven diagnosis of NAFLD were studied. Serum leptin levels were measured by radioimmunoassay. HOMA (homeostasis model assessment) IR index was calculated. Comparisons between the patients with NAFLD and non-alcoholic steatohepatitis (NASH) were performed using the Student’s t test. Multivariate regression analysis and the area under the receiver operating characteristic (ROC) curve were used to identify the independent predictors for NASH. Results: We found no association between serum leptin, fasting insulin levels, and oxidative stress parameters. ROC curve and multiple regression analysis revealed no association between the severity of histological changes and serum leptin levels. During six months followed-up period only NASH group with elevated leptin levels had significant reductions of ALT and AST values (p = 0.03, and 0.005, respectively). Conclusion: Our findings show a preventive effect of leptin against progressive liver injury in NAFLD.     

限食疗法对非酒精性脂肪性肝病的治疗作用

作为一种代谢性疾病,非酒精性脂肪性肝病的治疗主要是生活方式干预.限食疗法作为生活方式干预的一种,已被证实可减轻患者的体重、减少肝脏内脂肪含量、减轻胰岛素抵抗,改善其他代谢异常.而且,有研究认为,不同方式的限食对该病的治疗效果存在差异,低脂及低碳水化合物限食对其治疗效果优于低热量限食,这值得进一步研究探索.     

Biomarkers in nonalcoholic fatty liver disease

BACKGROUND:

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver condition characterized by insulin resistance, type 2 diabetes and fat accumulation in the liver that may cause hepatic inflammation and progressive scarring leading to nonalcoholic steatohepatitis (NASH) and irreversible liver damage (cirrhosis). As a result, there has been increased recognition of the need to assess and closely monitor individuals for risk factors of components of NAFLD and NASH, as well as the severity of these conditions using biomarkers.

AIM:

To review the biomarkers used to diagnose and define the severity of NAFLD and NASH.

METHODS:

A comprehensive PubMed and Google Scholar literature search was performed using the terms “non-alcoholic fatty liver disease”, “non-alcoholic steatohepatitis”, as well as the name of each biomarker known to be used. Articles indexed between 2004 and 2014 were used. Each author read the publications separately and the results were discussed.

RESULTS:

Biomarkers offer a potential prognostic or diagnostic indicator for disease manifestation, progression or both. Serum biomarkers, including total cholesterol, triglycerides, insulin resistance and C-peptide, have been used for many years. Emerging biomarkers, such as apolipoprotein A1, apolipoprotein B, leptin, adiponectin, free fatty acids, ghrelin and tumour necrosis factor-alpha, have been proposed as tools that could provide valuable complementary information to that obtained from traditional biomarkers. Moreover, markers of cell death and mitochondrial dysfunction (cytokeratins) represent powerful predictors of risk. For biomarkers to be clinically useful in accurately diagnosing and treating disorders, age-specific reference intervals that account for differences in sex and ethnic origin are a necessity.

CONCLUSIONS:

The present review attempts to provide a comprehensive analysis of the emerging risk biomarkers of NAFLD and NASH, and to use the clinical significance and analytical considerations of each biomarker pointing out sentinel features of disease progression.     

Mitochondria in nonalcoholic fatty liver disease

Nonalcoholic fatty liver (NAFL) is associated with fundamental issues of fat metabolism and insulin resistance. These abnormalities have been linked to impairment of ATP homeostasis, and a growing body of literature has reported mitochondrial abnormalities in various forms of hepatic steatosis. The changes are evident as structural abnormalities, including greatly increased size and the development of crystalline inclusions, and are usually regarded as pathologic, reflecting either a protective or degenerative response to injury. Although the relationships between structural changes,decreased mitochondrial function, and disease states are becoming clearer, the molecular basis for the perturbations is not well understood.Oxidative damage is the most likely causative process and may result in alterations of mitochondrial DNA (mtDNA), stimulated apoptotic pathways, and increased propensity for necrosis.Overall mitochondrial health likely depends on multiple factors including the integrity of the mtDNA, the composition of cellular lipids, lipoprotein trafficking, the balance of pro- and antioxidant factors, and the metabolic demands placed on the liver. Mitochondrial dysfunction may play a role in numerous clinical conditions associated with NAFL, such as hepatocellular carcinoma, lipodystrophy,age-related insulin resistance, gut dysmotility, cryptogenic cirrhosis, a mild form of gaze palsy, and possibly other more severe neurodegenerative diseases. The prominent role of mitochondrial dysfunction in NAFL provides a new and exciting paradigm in which to view this disorder, its complications, and potential dietary and pharmacologic intervention.