Pathogenesis and management issues for non-alcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) has, although it is a very common disorder, only relatively recently gained broader interest among physicians and scientists.Fatty liver has been documented in up to 10 to 15percent of normal individuals and 70 to 80 percent of obese individuals. Although the pathophysiology of NAFLD is still subject to intensive research, several players and mechanisms have been suggested based on the substantial evidence. Excessive hepatocyte triglyceride accumulation resulting from insulin resistance is the first step in the proposed 'two hit' model of the pathogenesis of NAFLD. Oxidative stress resulting from mitochondrial fatty acids oxidation, NF-κB-dependent inflammatory cytokine expression and adipocytokines are all considered to be the potential factors causing second hits which lead to hepatocyte injury, inflammation and fibrosis. Although it was initially believed that NAFLD is a completely benign disorder, histologic follow-up studies have showed that fibrosis progression occurs in about a third of patients. A small number of patients with NAFLD eventually ends up with end-stage liver disease and even hepatocellular carcinoma. Although liver biopsy is currently the only way to confirm the NAFLD diagnosis and distinguish between fatty liver alone and NASH, no guidelines or firm recommendations can still be made as for when and in whom it is necessary. Increased physical activity, gradual weight reduction and in selected cases bariatric surgery remain the mainstay of NAFLD therapy. Studies with pharmacologic agents are showing promising results, but available data are still insufficient to make specific recommendations; their use therefore remains highly individual.     

A pilot trial of fenofibrate for the treatment of non-alcoholic fatty liver disease

BACKGROUND: Dyslipidaemia and insulin resistance are two important risk factors for non-alcoholic fatty liver disease. Both factors can improve with fenofibrate. AIMS: To evaluate the effect of fenofibrate on the clinical, analytical and histological evolution of patients with non-alcoholic fatty liver disease. SUBJECTS AND METHODS: Sixteen consecutive patients with biopsy-confirmed non-alcoholic fatty liver disease were treated with 200mg/day of fenofibrate for 48 weeks. A clinical and biochemical follow-up was done every 3 months. A new liver biopsy was performed in all patients at the end of therapy. RESULTS: All patients completed 48 weeks of therapy with fenofibrate, without adverse events. At the end of the study, a significant decrease in triglyceride, glucose, alkaline phosphatase and gamma-glutamyl transpeptidase and an increase of apolipoprotein A1 levels were found. Insulin levels and insulin resistance showed a trend to decrease. Moreover, a reduction in the proportion of patients with abnormal aminotransferase levels (>45IU/L) was observed (alanine aminotransferase: 93.7% vs. 62.5%, p=0.02; aspartate aminotransferase: 50% vs. 18.7%, p=0.02). The body mass index did not show any significant change, but the proportion of patients with metabolic syndrome decreased significantly (43.7% vs. 18.7%, p=0.04). A control biopsy after treatment revealed a decrease in the grade of hepatocellular ballooning degeneration (p=0.03), but the grade of steatosis, lobular inflammation, fibrosis or non-alcoholic fatty liver disease activity score did not change significantly. CONCLUSIONS: In patients with non-alcoholic fatty liver disease, treatment with fenofibrate is safe and improves metabolic syndrome, glucose and liver tests. However, its effects on liver histology are minimal.     

非酒精性脂肪性肝病与代谢综合征的相关性研究

目的分析非酒精性脂肪性肝病（NAFLD）与代谢综合征（MS）的关系。方法10357例在我院体检的普通人群入选本研究,检测人体学参数、生化指标及肝脏彩超,分析该人群NAFLD和MS的患病率,探讨MS组分与NAFLD的关系。结果10357例体检者中NAFLD的患病率为31．1％,MS患病率为23．6％,NAFLD合并MS患病率为15．5％。经年龄标化后NAFLD和MS患病率男性仍明显高于女性。将全部受试者按BM1分组后,各组间NAFLD、MS及NAFLD合并MS患病率差异均有统计学意义（P〈0．01）。选择同期体检无NAFLD的个体（非NAFLD组）,经性别、年龄、BMI与NAFLD组相匹配后,NAFLD组MS患病率明显高于非NAFLD组（59．8％VS5．2％,P〈0．01）。多因素Logistic回归分析表明：NAFI。D危险因素的前五位为TG、BMI、FPG、LDL-C和吸烟。结论即使排除BMI因素的影响,NAFLD患者MS的患病率仍然明显增高。NAFLD危险因素由高到低依次为TG、BMI、FPG、LDL-C、吸烟、TC、性别、血压、SUA及ALT。HDL-C为NAFLD保护性因素。     

脂肪因子与非酒精性脂肪肝

非酒精性脂肪性肝病的发病机制目前尚不十分清楚,脂代谢异常(尤其是TG)与胰岛素抵抗(IR)可能是其病因的关键环节,瘦素、脂联素、抵抗素、肿瘤坏死因子等多种脂肪因子在非酒精性脂肪肝的形成、炎性改变及纤维化的过程中发挥了重要作用.     

Liver transplantation for nonalcoholic fatty liver disease:New challenges and new opportunities

Nonalcoholic fatty liver disease(NAFLD)is becoming rapidly one of the most common indications for orthotopic liver transplantation in the world.Development of graft steatosis is a significant problem during the posttransplant course,which may happen as a recurrence of pre-existing disease or de novo NAFLD.There are different risk factors that might play a role in development of graft steatosis including post-transplant metabolic syndrome,immune-suppressive medications,genetics and others.There are few studies that assessed the effects of NAFLD on graft and patient survival;most of them were limited by the duration of follow up or by the number of patients.With this review article we will try to shed light on post-liver transplantation NAFLD,significance of the disease,how it develops,risk factors,clinical course and treatment options.     

Non-alcoholic fatty liver disease and liver transplantation:Outcomes and advances

Non-alcoholic fatty liver disease(NAFLD)is one of the most prevalent causes of chronic liver disease worldwide.In the last decade it has become the third most common indication for liver transplantation in the United States.Increasing prevalence of NAFLD in the general population also poses a risk to organ donation,as allograft steatosis can be associated with non-function of the graft.Post-transplant survival is comparable between NAFLD and non-NAFLD causes of liver disease,although long term outcomes beyond 10 year are lacking.NAFLD can recur in the allograft frequently although thus far post transplant survival has not been impacted.De novo NAFLD can also occur in the allograft of patients transplanted for non-NAFLD liver disease.Predictors for NAFLD post-transplant recurrence include obesity,hyperlipidemia and diabetes as well as steroid dose after liver transplantation.A polymorphism in PNPLA3 that mediates triglyceride hydrolysis and is linked to pre-transplant risk of obesity and NAFLD has also been linked to post transplant NAFLD risk.Although immunosuppression side effects potentiate obesity and the metabolic syndrome,studies of immunosuppression modulation and trials of specific immunosuppression regimens post-transplant are lacking in this patient population.Based on pre-transplant data,sustained weight loss through diet and exercise is the most effective therapy for NAFLD.Other agents occasionally utilized in NAFLD prior to transplantation include vitamin E and insulin-sensitizing agents.Studies of these therapies are lacking in the post-transplant population.A multimodality and multidisciplinary approach to treatment should be utilized in management of post-transplant NAFLD.     

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。     

Metabolic associated fatty liver disease: Addressing a new era in liver transplantation

Metabolic associated fatty liver disease (MAFLD), previously termed non-alcoholic fatty liver disease, is the leading global cause of liver disease and is fast becoming the most common indication for liver transplantation. The recent change in nomenclature to MAFLD refocuses the conceptualisation of this disease entity to its metabolic underpinnings and may help to spur a paradigm shift in the approach to its management, including in the setting of liver transplantation. Patients with MAFLD present significant challenges in the pre-, peri- and post-transplant settings, largely due to the presence of medical comorbidities that include obesity, metabolic syndrome and cardiovascular risk factors. As the community prevalence of MAFLD increases concurrently with the obesity epidemic, donor liver steatosis is also a current and future concern. This review outlines current epidemiology, nomenclature, management issues and outcomes of liver transplantation in patients with MAFLD.     

抵抗素与非酒精性脂肪性肝病

抵抗素是存在于血浆中的富含半胱氨酸的分泌性蛋白,属于抵抗素样分子家族,又称脂肪组织特异性分泌因子.其与胰岛素抵抗及炎症等关系密切.非酒精性脂肪性肝病(NAFLD)代表了一组以甘油三酯在肝内过度贮积而引起的临床病理综合征,目前认为其属于代谢综合征的范畴,胰岛素抵抗及炎症因子的参与是其发病的重要环节.深入研究抵抗素与胰岛素抵抗及炎症的关系将有助于进一步了解NAFLD的发病机制,为寻求合理的治疗方案提供理论依据.     

Iron and non-alcoholic fatty liver disease

The mechanisms that promote liver injury in non-alcoholic fatty liver disease(NAFLD) are yet to be thoroughly elucidated. As such, effective treatment strategies are lacking and novel therapeutic targets are required. Iron has been widely implicated in the pathogenesis of NAFLD and represents a potential target for treatment. Relationships between serum ferritin concentration and NAFLD are noted in a majority of studies, although serum ferritin is an imprecise measure of iron loading. Numerous mechanisms for a pathogenic role of hepatic iron in NAFLD have been demonstrated in animal and cell culture models. However, the human data linking hepatic iron to liver injury in NAFLD is less clear, with seemingly conflicting evidence, supporting either an effect of iron in hepatocytes or within reticulo-endothelial cells. Adipose tissue has emerged as a key site at which iron may have a pathogenic role in NAFLD. Evidence for this comes indirectly from studies that have evaluated the role of adipose tissue iron with respect to insulin resistance. Adding further complexity, multiple strands of evidence support an effect of NAFLD itself on iron metabolism. In this review, we summarise the human and basic science data that has evaluated the role of iron in NAFLD pathogenesis.     

解读非酒精性脂肪性肝病诊治指南

随着肥胖与糖尿病患者的日趋增多,脂肪性肝病(FLD)目前已成为全球性的重要肝病。临床上FLD分为酒精性肝病(ALD)与非酒精性脂肪性肝病(NAFLD);研究表明,NAFLD与肥胖、代谢综合征、2型糖尿病和心血管疾病密切相关。2006年和2010年中华医学会相继制定了中国NAFLD诊疗指南,较全面和广泛地反映了目前NAFLD的临床诊疗现状,与国际上颁布的一些诊治指南相比存在差异。本文就NAFLD诊治指南及相关问题进行解读。     

MicroRNAs as controlled systems and controllers in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is a multi-faceted condition including simple steatosis alone or associated with inflammation and ballooning (non-alcoholic steatohepatitis) and eventually fibrosis. The NAFLD incidence has increased over the last twenty years becoming the most frequent chronic liver disease in industrialized countries. Obesity, visceral adiposity, insulin resistance, and many other disorders that characterize metabolic syndrome are the major predisposing risk factors for NAFLD. Furthermore, different factors, including genetic background, epigenetic mechanisms and environmental factors, such as diet and physical exercise, contribute to NAFLD development and progression. Several lines of evidence demonstrate that specific microRNAs expression profiles are strongly associated with several pathological conditions including NAFLD. In NAFLD, microRNA deregulation in response to intrinsic genetic or epigenetic factors or environmental factors contributes to metabolic dysfunction. In this review we focused on microRNAs role both as controlled and controllers molecules in NAFLD development and/or their eventual value as non-invasive biomarkers of disease.     

非酒精性脂肪性肝病与代谢综合征

非酒精性脂肪性肝病(NAFLD)是一种包括从单纯的肝脂肪变性到非酒精性脂肪性肝炎,以致最终发展为肝硬化的一组肝脏慢性广谱性临床病理综合征。近年来大量研究表明,NAFLD与代谢综合征(MS)的各个组分密切伴随,甚至有学者将其作为MS的组分之一,并发现胰岛素抵抗在NAFLD发病机制中起关键作用。迄今对NAFLD的发病机制还了解甚少,目前广泛接受的一个理论是“二次打击”假说。脂肪酸和甘油三酯在肝脏沉积造成的“第一次打击”之后,肝细胞对氧化应激和炎症因子作用导致的“第二次打击”的敏感性增加而引起肝损害。本文主要目的是对NAFLD的临床病理特点、与胰岛素抵抗及MS的关系以及可能的分子机制进行综述,同时也介绍了目前预防和治疗NAFLD的策略。     

Influence of gut bacteria on development and progression of non-alcoholic fatty liver disease

The intestine of the human contains a dynamic population of microbes that have a symbiotic relationship with the host. In addition, there is an effect of the intestinal microbiota on metabolism and digestion. Non-alcoholic fatty liver disease (NAFLD) is a common cause worldwide of hepatic pathology and is thought to be the hepatic manifestation of the metabolic syndrome. In this review we examine the effect of the human microbiome on the components and pathogenesis of the metabolic syndrome. We are now on the threshold of therapeutic interventions on the human microbiome in order to effect human disease including NAFLD.     

成人非酒精性脂肪肝与代谢综合征相关性分析

目的分析成人非酒精性脂肪肝病（NAFLD）和代谢综合征（MS）的关系。方法对2007年6月～10月广元市北街社区3180例20岁以上居民进行体格检查及肝脏B超检查,并检测空腹血糖（FBG）、血脂和丙氨酸氨基转氨酶（ALT）。结果（1）NAFLD患病率为13．5％,MS患病率为16．5％,丽病共患率为9．5％。（2）MS、中心性肥胖、血压升高、FBG升高、高甘油三酯（TG）、高密度脂蛋白（HLD—C）降低,各组NAFLD患病风险是对照组的12．7～24．1倍。（3）以NAFLD取代诊断MS的5个组分中的任何一个后,与原诊断定义相比有较高的一致性。结论该社区中1／8以上人群患有NAFLD或MS,且NAFLD与MS密切相关,NAFLD可能是MS的重要组成成分。     

Pathogenesis and therapeutic approaches for non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease affects approximately one-third of the population worldwide, and its incidence continues to increase with the increasing prevalence of other metabolic disorders such as type 2 diabetes. As non-alcoholic fatty liver disease can progress to liver cirrhosis, its treatment is attracting greater attention. The pathogenesis of non-alcoholic fatty liver disease is closely associated with insulin resistance and dyslipidemia, especially hypertriglyceridemia. Increased serum levels of free fatty acid and glucose can cause oxidative stress in the liver and peripheral tissue, leading to ectopic fat accumulation, especially in the liver. In this review, we summarize the mechanism underlying the progression of hepatic steatosis to steatohepatitis and cirrhosis. We also discuss established drugs that are already being used to treat non-alcoholic fatty liver disease, in addition to newly discovered agents, with respect to their mechanisms of drug action, focusing mainly on hepatic insulin resistance. As well, we review clinical data that demonstrate the efficacy of these drugs, together with improvements in biochemical or histological parameters.     

Risk factors for hepatic steatosis in adults with cystic fibrosis: Similarities to non-alcoholic fatty liver disease

AIM To investigate the clinical, biochemical and imaging characteristics of adult cystic fibrosis(CF) patients with hepatic steatosis as compared to normal CF controls.METHODS We performed a retrospective review of adult CF patients in an academic outpatient setting during 2016. Baseline characteristics, genetic mutation analysis as well as laboratory values were collected. Abdominal imaging(ultrasound, computed tomography, magnetic resonance) was used to determine presence of hepatic steatosis. We compare patients with hepatic steatosis to normal controls.RESULTS Data was collected on 114 patients meeting inclusion criteria. Seventeen patients(14.9%) were found to have hepatic steatosis on imaging. Being overweight(BMI 25)(P = 0.019) and having a higher pp FEV1(75 vs 53, P = 0.037) were significantly associated with hepatic steatosis. Patients with hepatic steatosis had a significantly higher median alanine aminotransferase level(27 vs 19, P = 0.048). None of the hepatic steatosis patients had frank CF liver disease, cirrhosis or portal hypertension. We found no significant association with pancreatic insufficiency or CF related diabetes.CONCLUSION Hepatic steatosis appears to be a clinically and phenotypically distinct entity from CF liver disease. The lack of association with malnourishment and the significant association with higher BMI and higher pp FEV1 demonstrate similarities with non-alcoholic fatty liver disease. Long term prospective studies are needed to ascertain whether CF hepatic steatosis progresses to fibrosis and cirrhosis.     

老年人非酒精性脂肪肝病与代谢综合征的相关研究

目的调查老年体检人员非酒精性脂肪肝病（NAFLD）和代谢综合征（MS）及其相关疾病的情况。方法从参与本院体检的405名60岁及以上的老年人中选取313例（男224例,女89例）,平均76．08±7．53岁,检测身高、体重、腰围、体质指数（BMI）、空腹血糖、总胆固醇、甘油三脂、高密度脂蛋白及多普勒超声,并对结果分析。结果老年男、女性MS患病率分别为14．3％和20．2％,男、女NAFLD患病率为40．2％、36．0％。在MS各种组合中,男、女性均以肥胖、高血压、高血脂组合比例最高,占40％以上,NAFLD患病率在肥胖、高血压、高血脂、血糖异常组合中高达100％。NAFLD病人中的脑梗死、糖尿病、高血压比例较高,NAFLD病人的空腹血糖、甘油三酯、BMI、腰围也、显著高于非NAFLD,但血清胆固醇差异无统计学意义。NAFLD和MS相关（r=0．374,P〉0．01）。结论60岁及以上老年人的NAFLD和MS患病率均较高,NAFLD作为MS的一个组成部分应及早干预治疗。     

Characteristics of hepatocellular carcinoma in cirrhotic and non-cirrhotic non-alcoholic fatty liver disease

AIM: To determine characteristics and prognosticpredictors of patients with hepatocellular carcinoma(HCC) in association with non-alcoholic fatty liver disease(NAFLD).METHODS: We reviewed the records of all patients with NAFLD associated HCC between 2000 and 2012. Data collected included demographics; histology; presence or absence of cirrhosis, size and number of HCC, alpha-fetoprotein, body mass index(BMI), and the presence of diabetes, hypertension, or dyslipidaemia.RESULTS: Fifty-four patients with NAFLD associated HCC were identified. Mean age was 64 years with 87% male. Fifteen percent(8/54) were not cirrhotic. 11%, 24% and 50% had a BMI of 25 kg/m2, 25-29 kg/m2 and ≥ 30 kg/m2 respectively. Fifty-nine percent were diabetic, 44% hypertensive and 26% hyperlipidaemic. Thirty-four percent of the patients had ≤ 1 of these risk factors. Non-cirrhotics had a significantly larger mean tumour diameter at diagnosis than cirrhotics(P = 0.041). Multivariate analysis did not identify any other patient characteristics that predicted the size or number of HCC.CONCLUSION: HCC can develop in NAFLD without cirrhosis. At diagnosis such tumours are larger than those in cirrhotics, conferring a poorer prognosis.