Metformin in the treatment of non-alcoholic fatty liver disease: safety,efficacy and mechanism

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease etiology worldwide. It encompasses a spectrum ranging from simple steatosis to non-alcoholic steatohepatitis. Although the physiopathology of NAFLD is partly known. Insulin-resistance plays a central role in the development and progression of NAFLD. Several studies have indicated that metformin, as an insulin sensitizer, effectively improves NAFLD and its related metabolic status. Metformin was effective in reducing enzyme levels in the short period, but very limited and controversial information are available on liver histology. Larger randomized controlled trials of sufficient duration using clearly defined histological endpoints are needed to fully assess the efficacy of this drug in modifying the natural history of NAFLD.     

非酒精性脂肪性肝病的研究进展

非酒精性脂肪性肝病经历由非酒精性单纯性脂肪肝发展至非酒精性脂肪性肝炎和肝硬化或原发性肝癌的缓慢过程,并与心血管病的发生关系密切.本文针对非酒精性脂肪性肝病的流行病学、发病机制、诊断和治疗等的研究进展进行综述.     

活血化痰方对非酒精性脂肪肝大鼠炎性因子的影响

[目的]观察活血化痰方对非酒精性脂肪肝（NAFLD）大鼠炎性因子的影响。[方法]将30只大鼠随机分为正常对照组、模型组和活血化痰方组。检测各组大鼠血清中白细胞介素（IL）-6、IL-10及肿瘤坏死因子-α（TNF-α）的水平。[结果]与正常对照组比较,模型组血清中IL-6、TNF-α水平增高,血清中IL-10含量降低;与模型组相比,活血化痰方组血清中IL-6、TNF-α水平显著降低,血清中IL-10含量显著升高。[结论]活血化痰方可能通过降低血清中IL-6、TNF-α水平,提高血清中IL-10含量,调节体内炎性因子的变化,从而使NAFLD渐愈。     

Increased lipid peroxidation in patients with non-alcoholic fatty liver disease and chronic hepatitis C as measured by the plasma level of 8-isoprostane

BACKGROUND: Oxidative stress plays an important role in the pathogenesis of chronic liver diseases. The plasma level of 8-isoprostane, a product of lipid peroxidation, is a marker of oxidative stress in vivo. The aim of the present study was to clarify whether the degree of lipid peroxidation, as measured by the plasma level of 8-isoprostane, influences the progression of chronic liver diseases and hepatocarcinogenesis. METHODS: Plasma 8-isoprostane levels were investigated in 14 patients with non-alcoholic fatty liver disease (NAFLD), 75 with chronic hepatitis C (CH-C), 14 with cured CH-C, 14 with HCV-positive hepatocellular carcinoma (HCC-C) and 38 healthy volunteers. 8-Isoprostane was measured by enzyme immunoassay after affinity column purification. RESULTS: Plasma 8-isoprostane was significantly elevated in NAFLD (11.9 [3.8-56.8] pg/mL), CH-C (10.1 [4.2-134.5] pg/mL) as compared to controls (6.3 [3.6-11.1] pg/mL). Plasma 8-isoprostane values were positively correlated with body mass index in NAFLD (P < 0.05) and with total cholesterol in cured CH-C (P < 0.01). 8-Isoprostane levels were not significantly related to sex, age, biochemical data or iron metabolism markers in all liver diseases. In addition, after the administration of peg-interferon, the values of 8-isoprostane improved in almost all patients, reaching values of healthy subjects. CONCLUSIONS: 8-Isoprostane values are elevated in patients with NAFLD and CH-C as compared to healthy controls. Oxidative stress caused by increased lipid peroxidation is involved in the pathogenesis of NAFLD and CH-C.     

非酒精性脂肪性肝病的诊断和治疗进展

随着非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD)流行率的上升以及对其危害的全面认识,其诊断和治疗发展迅速。本文介绍了新的NAFLD病理学评分系统和病理学检查指征;在无创性诊断方面概述了肝脏脂肪变性、肝脏炎症和纤维化无创性诊断的现有方法及最新进展,以及疾病进展风险因素;在治疗方面,描述了饮食控制要点,并介绍了抗阻运动联合有氧运动和避免静坐的三联运动方式;在药物治疗方面,介绍了维生素E和吡格列酮2个重点药物的优缺点。最后,简述了以疾病分级为基础的检测和治疗策略。     

Validation of the Fatty Liver Index for identifying non-alcoholic fatty liver disease in a Kenyan population

Background and Aim

Fatty Liver Index (FLI) is a simple clinical scoring system estimating non-alcoholic fatty liver disease (NAFLD). It is validated in European-descent and Asian populations, but not in sub-Saharan Africans. The aim of this study is to evaluate the validity of the FLI for predicting NAFLD in a population from Kenya.

Methods

Participants were recruited from a community-based study conducted in Kenya. NAFLD was diagnosed using hepatic ultrasonography. Clinical, anthropometrical, biochemical and lifestyle data were obtained. The accuracy and cut-off point of the FLI to detect NAFLD were evaluated by area under the receiver operator characteristic curve and the maximum Youden index analysis.

Results

A total of 640 participants (94 with NAFLD) were included. Mean age was 37.4 ± 0.4 years and 58.7% were women. Mean body mass index (BMI) was 22.3 ± 0.2 kg/m² and waist circumference (WC) 79.1 ± 0.4 cm. A total of 15 (2.3%) participants were diagnosed with type 2 diabetes and 65 (10.2%) with obesity (BMI ≥ 30 kg/m²). AUROC of FLI for predicting NAFLD was 0.80 (95% CI 0.74–0.85), which was significantly higher compared to individual components gamma-glutamyl transferase and triglycerides (p < 0.05), but not compared to anthropometric parameters BMI (AUROC of 0.83, 95% CI 0.79–0.88) and WC (AUROC of 0.81, 95% CI 0.76–0.87).

Conclusions

FLI is a simple valid scoring system to use in rural and urban Kenyan adults. However, this index might not be superior to BMI or WC to predict NAFLD, and those measurements might therefore be more appropriate in limited settings.     

Protein glutathionylation increases in the liver of patients with non-alcoholic fatty liver disease

Background and Aim:  Oxidative stress is an important pathophysiological mechanism in non-alcoholic steatohepatitis, where hepatocyte apoptosis is significantly increased correlating with disease severity. Protein glutathionylation occurs as a response to oxidative stress, where an increased concentration of oxidized glutathione modifies post-translational proteins by thiol disulfide exchange. In this study, we analyzed the protein glutathionylation in non-alcoholic fatty liver disease (NAFLD) and evaluated a potential association between glutathionylation, fibrosis, and vitamin E treatment.
Methods:  Protein glutathionylation was studied in the livers of 36 children (mean age 12.5 years, range 4–16 years) subdivided into three groups according to their NAFLD activity score (NAS) by Western blot analysis and immunohistochemistry, using a specific monoclonal antibody. In addition, we identified the hepatocyte ultrastructures involved in glutathionylation by immunogold electron microscopy.
Results:  Our findings showed that protein glutathionylation increases in the livers of patients with NAFLD and it is correlated with steatohepatitis and liver fibrosis. Its increase appears mainly in nuclei and cytosol of hepatocytes, and it is reversed by antioxidant therapy with reduced fibrosis.
Conclusion:  Protein glutathionylation significantly increases in livers with NAFLD, strongly suggesting that oxidative injury plays a crucial role in this disease. Furthermore, the marked increase of protein glutathionylation, in correlation with collagen VI immunoreactivity, suggests a link between the redox status of hepatic protein thiols and fibrosis.     

An update on non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in Asia

Introduction: Non-alcoholic fatty liver disease (NAFLD) has become the most overwhelming liver disease in Asia. In consideration of its increasing medical and economic impact on Asian people, it is time for us to review the update data in Asian countries and formulate strategies to cope with this emerging health problem in Asia. Moreover, growing data indicates that NAFLD may be a systemic disease, not just confined to liver-specific morbidity and mortality, but also associated with several extra-hepatic manifestations, such as cardiovascular diseases, chronic renal diseases, and malignancy. As the co-occurrence of NAFLD and viral hepatitis is common in Asia, issues related to the impact of NAFLD on the clinical outcomes and management of viral hepatitis remain to be elucidated.

Areas covered: In this article, a narrative review was conducted, searching for literature from PubMed, Ovid MEDLINE, and the Cochrane Library database till August 2016. Studies relevant to the emerging data of NAFLD in Asia, including the diagnosis, risk factors, the assessment and management of Asian NAFLD patients were examined and discussed.

Expert commentary: Collaboration in Asian countries to develop an effective and practical measurement to assess the severity of NAFLD is urgently required.     

Zebrafish facilitate non-alcoholic fatty liver disease research: Tools,models and applications

Non-alcoholic fatty liver disease (NAFLD) has become an increasingly epidemic metabolic disease worldwide. NAFLD can gradually deteriorate from simple liver steatosis, inflammation and fibrosis to liver cirrhosis and/or hepatocellular carcinoma. Zebrafish are vertebrate animal models that are genetically and metabolically conserved with mammals and have unique advantages such as high fecundity, rapid development ex utero and optical transparency. These features have rendered zebrafish an emerging model system for liver diseases and metabolic diseases favoured by many researchers in recent years. In the present review, we summarize a series of tools for zebrafish NAFLD research and the models established through different dietary feeding, hepatotoxic chemical treatments and genetic manipulations via transgenic or genome editing technologies. We also discuss how zebrafish models facilitate NAFLD studies by providing novel insights into NAFLD pathogenesis, toxicology research, and drug evaluation and discovery.     

非酒精性脂肪性肝病患者血清中循环microRNAs表达水平及意义

目的研究microRNAs(miRNAs)在非酒精性脂肪性肝病(NAFLD)患者血清中的表达水平和意义。方法选择NAFLD患者78例(NAFLD组)和非NAFLD人群58例(对照组)。采集入组人群血清,提取总RNA,应用qRT-PCR方法对血清中miR-21、miR34a、miR-122及miR-451表达水平进行检测;分析miRNAs血清表达水平与脂肪变性程度之间的关系。结果两组人群血清中miR-145(P=3.290)和miR21(P=1.570)表达水平无显著变化;miR-451(P=0.0309)、miRNA-122(P=0.0083)和miR-34a(P=0.0032)表达水平显著升高。NAFLD组患者根据肝脏脂肪变性程度分为轻度(46例)和重度(32例),miRNA-122(P=0.0062)和miRNA-34a(P=0.0044)的表达水平随脂肪变性程度的增加而显著升高。结论 NAFLD患者较健康人群血清miR-21、miR-34a、miR-122及miR-451表达水平升高,特别是miR-34a和miR-122可以作为NAFLD诊断的一个生物学标志分子。     

Association between low thigh fat and non-alcoholic fatty liver disease

Background and Aim:  Some people have a fatty liver despite having low visceral fat and a low body mass index (BMI). We investigated whether fat distribution, especially thigh subcutaneous fat and thigh intramuscular fat, is associated with non-alcoholic fatty liver disease (NAFLD).
Methods:  The patients consisted of 408 men and women. NAFLD was defined by an ultrasound scan and excluded other liver diseases. Visceral, subcutaneous abdominal, intramuscular, and subcutaneous thigh adipose tissue was measured by computed tomography.
Results:  The frequency of NAFLD decreased over a quartile of thigh fat independently of BMI in the female patients. Additional adjustments for age and visceral fat area did not change the results. This finding was not observed in the male patients. To investigate the relationship between each fat distribution and NAFLD, we performed a logistic regression analysis. Fat distribution was divided into four groups: visceral fat, abdominal subcutaneous fat, thigh subcutaneous fat, and thigh intramuscular fat. All four fat components were chosen as variables for the regression model. Age, BMI, and the homeostasis model assessment (HOMA) index were then adjusted successively. A larger subcutaneous fat area was negatively associated with NAFLD after adjustment for visceral fat and abdominal subcutaneous fat areas in women, but not in men. It did not change even after age adjustment, BMI, and the HOMA index.
Conclusion:  Low femoral subcutaneous fat amounts were shown to be independently associated with fatty liver disease in women. These results show the importance of accurate measurements of other regional body compositions as well as visceral fat amounts when investigating NAFLD.     

MicroRNA在非酒精性脂肪性肝病发病过程中作用的研究进展

微小RNA(microRNA,miRNA)是一种小的非编码RNA,参与机体的生理和病理反应。非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD)是以弥漫性肝细胞大泡性脂肪变性为主要特征的临床病理综合征。近年来,有报道称miRNA在肝脏炎症、纤维化和硬化中发挥了一定的作用,尤其是在NAFLD发生发展过程中,miRNA表达特点、致病机制、临床诊治中的意义等方面引起了较大关注,故本文对此进行综述。