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.     

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.     

Current pharmacological treatment of nonalcoholic fatty liver

Nonalcoholic fatty liver disease (NAFLD) is a frequent and potentially progressive chronic liver disease that occurs in subjects who do not abuse alcohol. NAFLD is often associated with obesity, metabolic syndrome and insulin resistance and its more aggressive form, nonalcoholic steatohepatitis (NASH) is a major cause of cryptogenic cirrhosis. NAFLD/NASH are commonly detected because of elevated serum aminotransferase levels, ultrasonographic fatty liver and, at liver histology, steatosis, inflammation, and occasionally fibrosis that may progress to cirrhosis. No established treatment exists for this potentially serious disorder. Current management of NAFLD/NASH is largely conservative and includes diet regimen, aerobic exercise, and interventions towards the associated metabolic abnormalities. The main concern is therefore to decrease liver steatosis and its progression toward steatohepatitis and fibrosis, and the risk of "cryptogenic" cirrhosis. Among the most promising medications, weight reducing drugs, insulin sensitizers and lipid-lowering agents, antioxidants, bile salts, co-factors increasing the mitochondrial transport of fatty acids are being considered. Among them, thiazolidinediones are the most promising drug family that act by activating PPARgamma nuclear receptors and by regulating both microsomal and peroxisomal lipid oxidative pathways. Pharmacological treatment of obesity and probiotics should be considered as potential therapeutic options. In this review, after summarizing the general background on fatty liver, the most current and attractive pharmacological approaches to the problem of NAFLD/NASH are discussed.     

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.     

肠道菌群与非酒精性脂肪性肝病

非酒精性脂肪性肝病（non-alcoholic fatty liver disease, NAFLD）在全球范围内越来越常见,造成极大的疾病负担,故对其发生、发展及防治措施进行研究变得十分迫切。近年来,肠道菌群被认为是机体的一个重要的“特殊器官”,它参与机体的代谢并与相关疾病的发生、发展相关,与NAFLD的关系亦密切,值得深入探索,以期能寻找到防治NAFLD的新措施。     

ω-3多不饱和脂肪酸治疗非酒精性脂肪性肝病的研究进展

非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)是由多种危险因素,如营养过剩、胰岛素抵抗(insulin resistance,IR)及相关代谢紊乱等诱导的慢性肝损伤,是代谢综合征在肝脏的病理表现。其病程的进展表现为非酒精性单纯性脂肪肝(nonalcoholic simple fatty liver,NAFL)、非酒精性脂肪性肝炎(nonalcoholic steatohepatitis,NASH)、脂肪性肝纤维化和脂肪性肝硬化。NAFLD患病率逐年升高,已成为我国最常见的慢性肝病之一。NAFLD的治疗主要为增加运动、健康饮食等基础治疗,药物治疗尚未达成共识。ω-3多不饱和脂肪酸(ω-3 polyunsattrated fatty acids,ω-3PUFAs)具有调节血脂的功能。NAFLD患者ω-3PUFAs水平较低,增加饮食中的ω-3PUFAs可以延缓病情进展,改善肝脏脂代谢的失衡和肝细胞的炎性损伤。本文主要就ω-3PUFAs对NAFLD治疗的研究进展作一综述。     

Variations in ATP-binding cassette transporter regulation during the progression of human nonalcoholic fatty liver disease

Transporters located on the sinusoidal and canalicular membranes of hepatocytes regulate the efflux of drugs and metabolites into blood and bile, respectively. Changes in the expression or function of these transporters during liver disease may lead to a greater risk of adverse drug reactions. Nonalcoholic fatty liver disease (NAFLD) is a progressive condition encompassing the relatively benign steatosis and the more severe, inflammatory state of nonalcoholic steatohepatitis (NASH). Here, we present an analysis of the effect of NAFLD progression on the major ATP-binding cassette (ABC) efflux transport proteins ABCC1-6, ABCB1, and ABCG2. Human liver samples diagnosed as normal, steatotic, NASH (fatty), and NASH (not fatty) were analyzed. Increasing trends in mRNA expression of ABCC1, ABCC4-5, ABCB1, and ABCG2 were found with NAFLD progression, whereas protein levels of all transporters exhibited increasing trends with disease progression. Immunohistochemical staining of ABCC3, ABCB1, and ABCG2 revealed no alterations in cellular localization during NAFLD progression. ABCC2 staining revealed an alternative mechanism of regulation in NASH in which the transporter appears to be internalized away from the canalicular membrane. This correlated with a preferential shift in the molecular mass of ABCC2 from 200 to 180 kDa in NASH, which has been shown to be associated with a loss of glycosylation and internalization of the protein. These data demonstrate increased expression of multiple efflux transporters as well as altered cellular localization of ABCC2 in NASH, which may have profound effects on the ability of patients with NASH to eliminate drugs in an appropriate manner.     

Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults

Aliment Pharmacol Ther 2011; 34: 274–285

Summary

Background Non‐alcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease, and its worldwide prevalence continues to increase with the growing obesity epidemic. This study assesses the epidemiology of NAFLD in adults based on clinical literature published over the past 30 years. Aim To review epidemiology and natural history of non‐alcoholic fatty liver disease and non‐alcoholic steatohepatitis in adults based on clinical literature published over the past 30 years. Methods An in‐depth search of PubMed (1980–2010) was based on five search terms: ‘non‐alcoholic fatty liver disease’ OR ‘non‐alcoholic steatohepatitis’ OR ‘fatty liver’ OR ‘steatosis’ AND ‘incidence’ [MeSH Terms] OR ‘prevalence’ [MeSH Terms] OR ‘natural history’. Studies of paediatric cohorts were excluded. Articles were categorised by topic and summarised, noting generalisations concerning their content. Results Four study categories included NAFLD incidence, prevalence, risk factors and natural history. Studies related to NAFLD prevalence and incidence indicate that the diagnosis is heterogeneous and relies on a variety of assessment tools, including liver biopsy, radiological tests such as ultrasonography, and blood testing such as liver enzymes. The prevalence of NAFLD is highest in populations with pre‐existing metabolic conditions such as obesity and type II diabetes. Many studies investigating the natural history of NAFLD verify the progression from NASH to advanced fibrosis and hepatocellular carcinoma. Conclusions Non‐alcoholic fatty liver disease is the most common cause of elevated liver enzymes. Within the NAFLD spectrum, only NASH progresses to cirrhosis and hepatocellular carcinoma. With the growing epidemic of obesity, the prevalence and impact of NAFLD continues to increase, making NASH potentially the most common cause of advanced liver disease in coming decades.     

The treatment of NAFLD

Nonalcoholic fatty liver disease (NAFLD) is becoming an increasing cause of chronic liver damage. The decision of start a medical treatment is based on the documented risk of progression to cirrhosis and liver cancer, when steatohepatitis (NASH) occurs. The therapy of this syndrome requires, as obviously, some considerations on the natural history of the condition, on the efficacy and safety of various therapeutic options, as well as on the costs. Treatment of patients with NAFLD has typically been focused on the management of associated conditions such as obesity, diabetes mellitus and hyperlipemia. Weight loss improves insulin sensitivity, and NASH may resolve with weight reduction. Insulin resistance seems to be the common denominator in many cases of NAFLD. Two classes of drugs have been shown to correct insulin resistance: biguanides (e.g., metformin) and thiazolidinediones (e.g., rosiglitazone and pioglitazone). The last two decades have witnessed a considerable progress in the understanding of the mechanisms respon-sible for the fibrogenic progression of chronic liver diseases. Several drugs believed to be hepatoprotective or antifibrotic agent as UDCA, betaine, vitamin E, lecithin, beta-carotene and selenium have been used in patients with NASH. Silybin is the main component of silymarin that is absorbed when linked whith a phytosome. This substance reduces in rats the lipid-peroxidation and the activaction of hepatic stellate cells. In humans, some non controlled data show that silybin is able to reduce insulin resistance, liver steatosis and plasma markers of liver fibrosis.     

Efficacy of phospholipidated curcumin in nonalcoholic fatty liver disease: a clinical study

Curcumin is a safe and dietary phytochemical that can improve different pathophysiologic features of non-alcoholic fatty liver disease (NAFLD). Here, we investigated the efficacy of phospholipidated curcumin supplementation in NAFLD patients. In this single-arm study, 36 patients were recruited. Each patient received three capsules a day (each containing 500?mg of phospholipidated curcumin [overall content of curcuminoids per capsule: 100?mg]) for a period of 8 weeks. The results indicated that phospholipidated curcumin supplementation reduced NAFLD severity and ameliorated ultrasonographic and biochemical measures (including liver transaminases and lipid profile) associated with disease progression.     

The relationship between the contents of 13 amino acids in brain tissues and the progression of NAFLD via C57BL/6 model mice

Non-alcoholic fatty liver disease (NAFLD) is the steatosis of liver parenchyma unrelated to alcoholism, autoimmunity, and viral infection. It is also a metabolism-related syndrome, which has an unseparated relationship with adipose tissue dysfunction and obesity. Hepatic encephalopathy (HE) is one of the severe complications of chronic liver disease and one of the end-stage syndromes of liver disease. Some researchers have suggested that NAFLD, like other forms of liver injury, may be related to the metabolic disorder of branched-chain amino acids (BCAAs), which have been approved to be associated with HE influencing ammonia and energy metabolism. However, several studies have revealed the relationship among amino acids in serum, HE, and chronic liver disease; there are few studies on the contents of amino acids in brain tissues of an animal model with NAFLD. In the present research, we established a NAFLD mouse model with C57BL/6 mice and determined the contents of 13 amino acids in brain tissues of model mice by HPLC-FLD derivatization method using ortho-phthalaldehyde (OPA) to explore the relationship between the contents of amino acids in brain tissues and the progression of NAFLD. Moreover, the study showed that the changes of amino acid contents in the brain of the C57BL/6 mice were associated with the advancement of NAFLD, and this change might be related to the mechanism of HE.     

Review article: nonalcoholic fatty liver disease and hepatitis C virus--partners in crime

Background Both nonalcoholic fatty liver disease (NAFLD) and chronic hepatitis C (CHC) are frequent causes of chronic liver disease. In recent years, there have been significant revelations as regards the relationship between NAFLD and CHC. Aim To conduct a systematic, evidence‐based review of the epidemiology, pathophysiology and potential treatments of coexistent NAFLD and CHC. Methods The terms such as hepatitis C, fatty liver, NAFLD, nonalcoholic steatohepatitis and steatosis were searched on PubMed up to January 2008. References from selected articles and pertinent abstracts were also included. Results Hepatic steatosis affects up to 80% of patients with CHC and is dependent on both viral and host factors. While insulin resistance (IR) is associated with hepatic steatosis and hepatitis C virus, genotype‐specific pathogenic mechanisms have been identified and are currently the focus of intense investigation in the literature. Clinical implications of concurrent NAFLD, CHC and IR include increased disease progression, elevated risk of hepatocellular carcinoma, and decreased response to antiviral therapy. Conclusions NAFLD and IR are common in patients with CHC virus infection. IR is a driving force in the development of hepatic steatosis. Because of the clinical implications of hepatic steatosis and IR in the setting of CHC, further studies evaluating treatments, which may increase response to antiviral therapy, are needed.     

Di(2-ethylhexyl) phthalate exacerbates non-alcoholic fatty liver in rats and its potential mechanisms

Di(2-ethylhexyl) phthalate (DEHP) may be responsible for inducing alterations similar to those encountered in nonalcoholic fatty liver disease (NAFLD). The aim of the present study was to investigate the detrimental effects and possible mechanisms of DEHP on fatty liver rats directly through triggering the disorder of liver lipid metabolism or indirectly by hepatotoxic effect. Considering these effects, DEHP may play a significant role in the pathogenesis of NAFLD. In this study, high-fat diet was used to induce NAFLD in rats for eight weeks. DEHP treated groups received (0.05, 5, 500 mg/kg daily, respectively) dose by gavage during the whole experiment period. Our results indicated that the detrimental effects of DEHP on high-fat diet induced NAFLDs were mediated via increasing lipid accumulation in the liver and causing lipid peroxidation and inflammation.     

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.     

非酒精性脂肪肝病和心力衰竭:临床证据和病理生理学机制

非酒精性脂肪性肝病( NAFLD)和心力衰竭(心衰)是两大重要的公共健康问题。 NAFLD增加心血管疾病(冠状动脉疾病、心房颤动、高血压、心肌病、心衰)风险间接或直接与心衰关联。 NAFLD通过胰岛素抵抗、肾素 -血管紧张素 -醛固酮系统和交感神经系统的激活、全身炎症、氧化应激、肠道菌群失调和扩张的异位脂肪等病理生理学机制促进心脏重塑和心衰的发生和进展。该研究总结了 NAFLD与心衰关联的临床证据和病理生理学机制,及这两种疾病可能的管理和治疗。     

41例学龄儿童非酒精性脂肪性肝病代谢综合征分析

目的：研究学龄儿童非酒精性脂肪性肝病（NAFLD）患儿中代谢综合征（MS）的发病情况,探讨学龄儿童非酒精性脂肪性肝病的MS关系。方法：选取在本院就诊的NAFLD患儿41例作为NAFLD组,同期住院的的60例单纯性肥胖患儿作为对照组,检测体质量、身高、血压、腹围、血生化、空腹血糖及肝脏彩色多普勒超声检查,分析两组代谢综合征发生率及生化改变。结果：NAFLD组和对照组比较,除TG外NAFLD组ALT、AST、ALT/AST及TC均较对照组升高,而NAFLD组HDL-c低于对照组;NAFLD组MS发生率为41.46%,高于对照组的21.67%,两者比较差异有统计学意义（χ2=4.57,P=0.03）。结论：肥胖儿童若合并NAFLD,则其发生MS的风险明显增加。NAFLD的早期应当积极地改变生活方式、减轻体重、调节血脂、控制血糖,使肝脏损害早期逆转,防止或减缓其进一步发展。     

肝脏非实质细胞在非酒精性脂肪性肝炎中的作用研究进展

非酒精性脂肪性肝病是全球最流行的肝脏疾病,其疾病谱包含非酒精性脂肪肝、非酒精性脂肪性肝炎、与非酒精性脂肪性肝炎相关的纤维化、肝硬化和肝细胞癌。非酒精性脂肪性肝炎是非酒精性脂肪性肝病进展性的肝脏病理表征,临床上需要药物治疗或其他治疗方式干预,但目前全球尚无针对非酒精性脂肪性肝炎的药物获批上市。非酒精性脂肪性肝炎发病机制复杂,涉及多种细胞内、细胞间的交互作用以及复杂的分子信号通路。非酒精性脂肪性肝炎治疗是一个尚未被满足的巨大临床需求。综述了肝脏中几种主要的非实质细胞在非酒精性脂肪性肝炎发病中的重要作用,同时探讨了非酒精性脂肪性肝炎药物开发靶点与不同细胞之间的相关性。     

Expert opinion on current therapies for nonalcoholic fatty liver disease

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming one of most common liver diseases in industrialized countries owing to the increasing prevalence of obesity and being overweight. Until now, loss of weight and physical activity have represented the cornerstone of treatment, but they are very difficult to achieve and to maintain. Therefore, new treatments based on pathogenetic mechanisms leading to NAFLD are under evaluation to establish an effective pharmacological therapy for this disorder. AREAS COVERED: An overview of current therapeutic interventions to treat NAFLD is given. This review provides evidence of the efficacy of natural and pharmacological agents used so far in the treatment of both adult and pediatric NAFLD, on the basis of clinical trials published in the last 10 years. EXPERT OPINION: In the last 10 years, many pharmacological agents on the basis of the pathogenetic mechanism of NAFLD have been attempted, but so far guidelines for the management of NAFLD are lacking. We believe that the advance in the understanding of pathogenesis and factors involved in the progression of the disease may disclose the way to defining new, solid, therapeutic strategies. A multidisciplinary approach considering the risk factors and comorbidities of fatty liver will represent in the future a successful therapeutic strategy for NAFLD.     

Acanthopanax senticosus reverses fatty liver disease and hyperglycemia in ob/ob mice

Non-alcoholic fatty liver disease (NAFLD) is common in obesity. However, weight reduction alone does not prevent the progression of NAFLD to end-stage disease associated with the development of cirrhosis and liver disease. In a previous experiment, 50% ethanol extract of Acanthopanax senticosus stem bark (ASSB) was found to reduce body weight and insulin resistance in high fat diet-induced hyperglycemic and hyperlipidemic ICR mice. To evaluate the anti-steatosis action of ASSB, insulin-resistant ob/ob mice with fatty livers were treated with ASSB ethanol extract for an 8 week-period. ASSB ethanol extract reversed the hepatomegaly, as evident in reduction of % liver weight/body weight ratio. ASSB ethanol extract also specifically lowered circulating glucose and lipids, and enhanced insulin action in the liver. These changes culminated in inhibition of triglyceride synthesis in non-adipose tissues including liver and skeletal muscle. Gene expression studies confirmed reductions in glucose 6-phosphatase and lipogenic enzymes in the liver. These results demonstrate that ASSB ethanol extract is an effective treatment for insulin resistance and hepatic steatosis in ob/ob mice by decreasing hepatic lipid synthesis.     

Efficacy and safety of fluoxetine monotherapy in bipolar depression: a systematic review

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in Western countries with up to 30% of the population affected. Since NAFLD is associated with an increased risk of cardiovascular (CV) disease, these patients should be stratified for CV risk factors, including atherogenic dyslipidemia, and managed accordingly. Lifestyle modifications represent an effective treatment for NAFLD, since most patients are overweight or obese. Also, promising, but not conclusive, results are available for current pharmacologic treatment. Drugs potentially effective against NAFLD include insulin sensitisers as well as fibrates and omega-3 polyunsaturated fatty acids, while there is reluctance to use statins in patients with suspected or established chronic liver disease. Several other therapeutic options are potentially available, and more data are expected from new peroxisome proliferator-activated receptor agonists and incretin-based therapies.