Pharmacological management of nonalcoholic fatty liver disease in type 2 diabetes

Introduction: The prevalence of nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes (T2D) is high and it is associated with poor prognosis. Hepatic steatosis results as a consequence of excessive hepatic lipid accumulation which correlates with insulin resistance and lipotoxicity, with subsequent oxidative stress, inflammation, apoptosis and fibrosis.

Areas covered: This article presents the main pathophysiologic mechanisms and currently available drugs evaluated for their therapeutic effects on NAFLD/nonalcoholic steatohepatitis (NASH) and drugs under development that target relevant pathogenetic pathways. However, to date there is no particular drug approved for treatment of NAFLD in patients with T2D.

Expert commentary: Early recognition and intervention are essential to ameliorate disease progression. Specific recommendations are still needed for NAFLD/NASH screening and diagnosis and therapeutic algorithm in patients with T2D. Lifestyle optimization with significant weight loss is a key intervention in patients with NAFLD and T2D. Pioglitazone, liraglutide, vitamin E, OCA and pentoxifylline have proven some histological improvements in NASH and omega 3-PUFAs were shown to decrease liver fat, but no specific recommendation can be made for treatment of NASH. Perhaps a combination of agents that target different pathogenic pathways are needed to better control disease progression, but more robust evidence for these agents is still needed.     

非酒精性脂肪性肝病无创诊断研究进展

非酒精性脂肪性肝病是全球最常见的慢性肝病。据估计,全球约25%的成年人患有非酒精性脂肪性肝病,且患病率逐年增加。非酒精性脂肪性肝病的疾病谱涵盖非酒精性脂肪肝、非酒精性脂肪性肝炎、非酒精性脂肪性肝炎相关纤维化、肝硬化和肝细胞癌。肝活检作为非酒精性脂肪性肝病诊断和分期的“金标准”,因有创性、取样变异和评价不一致等局限性限制了其广泛应用。随着进展为非酒精性脂肪性肝炎的患者数量增加,特别是疾病严重程度较重的病人增多,临床上迫切需要有效治疗药物,也迫切需要开发无创标志物来筛查、诊断、监测患者和判断疗效。对非酒精性脂肪性肝病的无创诊断研究进展进行综述,包括对脂肪变的评估、非酒精性脂肪性肝炎的诊断和纤维化的评估。     

Present and emerging pharmacotherapies for non-alcoholic steatohepatitis in adults

Introduction: Multiple parallel factors are implicated in the pathogenesis and progression of non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH). Currently recommended therapies for NASH include vitamin E and pioglitazone, besides dietary and lifestyle changes.

Areas covered: This review focuses on the clinical development of several emerging drugs for the treatment of NASH and the impact of these drugs on current treatment standards.

Expert opinion: Four drug classes (FXR agonists, CCR2/CCR5 antagonists, ASK1 inhibitors, and PPARα/δ agonists) have moved into phase 3 trials for their investigation as NASH treatments. Results from phase 2 trials of other therapeutic agents with other pharmacological actions are also expected. The importance of combinational therapies with synergistic benefits engaging different targets, is now understood. Furthermore, studies have determined that the Mediterranean diet is beneficial for patients with NAFLD, while the traditional Okinawan diet is also considered useful. In the future, it will be important to establish new biomarkers to assess NAFLD activity, furthermore non-invasive diagnostic methods will promote the development of new drugs for NASH.     

Emerging and future therapies for nonalcoholic steatohepatitis in adults

Introduction: Nonalcoholic steatohepatitis (NASH) is a disease of increasing prevalence with morbidity and mortality closely related to cardiovascular disease, malignancies and cirrhosis. Despite the need for pharmacological treatment and intense research in the field, there is currently no approved agent for NASH.

Areas covered: There are medications shown to improve hepatic steatosis, including thiazolidinediones, vitamin E and pentoxifylline. However, hepatic fibrosis, the hard prognostic end-point for NASH, has shown little improvement with pharmaceutical intervention. Long-term use of thiazolidinediones has provided a marginal effect on fibrosis, whereas obeticholic acid, a farnesoid X receptor, showed to improve fibrosis, but further data are needed. There are currently many novel agents under investigation, including glucagon-like peptide-1 analogs, sodium glucose co-transporters and peroxisome proliferator-activated receptor-γ selective modulators, whose preliminary results have been promising.

Expert opinion: Given the multifactorial pathogenesis of NASH, it is rational to consider multiple treatments rather than monotherapy as a more promising approach. Although, it remains to be shown, targeting more than one pathogenetic ‘hit’ of the disease may provide more efficacious management. Furthermore, the establishment of a noninvasive index for long-term follow-up of NASH patients will facilitate treatment guidance by reducing the need for multiple liver biopsies.     

Novel therapeutic targets for nonalcoholic fatty liver disease

Introduction: Nonalcoholic fatty liver disease (NAFLD) is a serious public health problem. It is now estimated to affect 30% of adults and about 10% of children in the U.S. Hispanics are disproportionably affected with not only higher rates of NAFLD but also more severe disease. Treatment options are currently limited.

Areas covered: In this review, we will focus on a series of novel findings related to the pathobiology of liver damage in nonalcoholic steatohepatitis (NASH) that are attractive targets for development of novel therapeutic strategies for human NASH. In particular, we will discuss four different areas due to their novelty and growing importance including microparticles, the inflammasomes, gut-liver axis and dietary lipids.

Expert opinion: There is an urgent need to develop novel safe and effective therapies for the growing NAFLD epidemic. The data discussed in this article provide strong rational to think out of the box when considering novel therapeutic targets for patients with NAFLD.     

Are statins ‘IDEAL’ for non-alcoholic fatty liver disease?

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and cause of elevated serum liver enzyme activities in the developed world1. Obesity, diabetes mellitus (DM), and dyslipidaemia, common components of the metabolic syndrome (MetS), are frequently associated with NAFLD; 75–100% of patients with MetS or DM have NAFLD2. NAFLD is characterized by hepatic triglyceride (TG) infiltration in the absence of alcohol abuse or chronic liver disease1. NAFLD includes a spectrum of conditions varying from steatosis to steatosis with inflammation [steatohepatitis (NASH)], necrosis, fibrosis or cirrhosis that rarely progresses to hepatocellular carcinoma3. NAFLD and NASH are the hepatic manifestations of MetS and are associated with increased cardiovascular disease (CVD) risk4. Most NAFLD/NASH patients die from CVD rather than from liver disease4,5. There is no universally accepted treatment for NAFLD1-5.     

Non-alcoholic fatty liver disease (NAFLD) – pathogenesis,classification, and effect on drug metabolizing enzymes and transporters

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disorders. It is defined by the presence of steatosis in more than 5% of hepatocytes with little or no alcohol consumption. Insulin resistance, the metabolic syndrome or type 2 diabetes and genetic variants of PNPLA3 or TM6SF2 seem to play a role in the pathogenesis of NAFLD. The pathological progression of NAFLD follows tentatively a “three-hit” process namely steatosis, lipotoxicity and inflammation. The presence of steatosis, oxidative stress and inflammatory mediators like TNF-α and IL-6 has been implicated in the alterations of nuclear factors such as CAR, PXR, PPAR-α in NAFLD. These factors may result in altered expression and activity of drug metabolizing enzymes (DMEs) or transporters.

Existing evidence suggests that the effect of NAFLD on CYP3A4, CYP2E1 and MRP3 is more consistent across rodent and human studies. CYP3A4 activity is down-regulated in NASH whereas the activity of CYP2E1 and the efflux transporter MRP3 is up-regulated. However, it is not clear how the majority of CYPs, UGTs, SULTs and transporters are influenced by NAFLD either in vivo or in vitro. The alterations associated with NAFLD could be a potential source of drug variability in patients and could have serious implications for the safety and efficacy of xenobiotics. In this review, we summarize the effects of NAFLD on the regulation, expression and activity of major DMEs and transporters. We also discuss the potential mechanisms underlying these alterations.     

Changes in drug transport and metabolism and their clinical implications in non-alcoholic fatty liver disease

Introduction: The incidence of non-alcoholic fatty liver disease (NAFLD) is rising, especially in Western countries. Drug treatment in patients with NAFLD is common since it is linked to other conditions like diabetes, obesity, and cardiovascular disease. Consequently, changes in drug metabolism may have serious clinical implications.

Areas covered: A literature search for studies in animal models or patients with obesity, fatty liver, non-alcoholic steatohepatitis (NASH) or NASH cirrhosis published before November 2016 was performed. After discussing epidemiology and animal models for NAFLD, we summarized both basic as well as clinical studies investigating changes in drug transport and metabolism in NAFLD. Important drug groups were assessed separately with emphasis on clinical implications for drug treatment in patients with NAFLD.

Expert opinion: Given the frequency of NAFLD even today, a high degree of drug treatment in NAFLD patients appears safe and well-tolerated despite considerable changes in hepatic uptake, distribution, metabolism and transport of drugs in these patients. NASH causes changes in biliary excretion, systemic concentrations, and renal handling of drugs leading to alterations in drug efficacy or toxicity under specific circumstances. Future clinical drug studies should focus on this special patient population in order to avoid serious adverse events in NAFLD patients.     

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.     

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。     

Treatment of non-alcoholic fatty liver disease with focus on emerging drugs

Introduction: Non-alcoholic fatty liver disease (NAFLD) is becoming one of the most common causes of chronic liver disease worldwide. The economic and social cost of disease is very high and there is a need for effective treatments.

Areas covered: The available and potential future treatments for NAFLD are reviewed.

Expert opinion: Weight loss remains the cornerstone of treatment of hepatic steatosis, but difficult to pursue. A pragmatic approach relies on generic recommendations for weight loss and physical activity in the whole population and limiting interventions to subject at risk of disease progression, but the type of preferred treatment remains a matter of debate. The large number and mechanistic diversity of drugs that have so far been investigated bear testimony to the lack of a specific, effective agent. Insulin resistance remains the pivotal alteration responsible for liver disease and its progression and insulin sensitizers are regarded as the treatment of choice. Several ongoing studies are testing the effectiveness of new approaches on histological outcomes and new metabolic pathways are under scrutiny.     

Treatment options for nonalcoholic steatohepatitis - a safety evaluation

Introduction: There is an urgent as yet unmet need to develop highly effective and safe therapeutics for nonalcoholic fatty liver disease (NAFLD). The remarkable progress in understanding NAFLD pathogenesis allowed the identification of injury pathways which may be recruited as therapy targets.

Areas covered: This article reviews the safety and tolerability data of the NAFLD therapies and explains the mechanistic basis for each of the established and investigational drugs. Treatment targets include: weight loss, anti-metabolic agents such as lipid lowering and anti-diabetic drugs, inflammation, fibrosis and others such as targeting gut microbiota, immune modulation and apoptosis.

Expert opinion: Current therapies continue to remain suboptimal. Weight loss is effective but hard to achieve. Traditional and endoscopic bariatric procedures are promising although more randomized trials are needed and the long-term safety remains to be established. Clinical trials have demonstrated the efficacy of several drugs for the treatment of NASH. Of these, there remains some uncertainty about the long-term safety of vitamin E. Pioglitazone is associated with osteopenia, fluid retention and weight gain. Obeticholic acid causes pruritus in a substantial proportion of subjects and elafibranor has been associated with transient rises in creatinine. Several exciting therapies are under development and results of clinical and post-marketing trials will help elucidate their safety.     

Magnetic resonance imaging and transient elastography in the management of Nonalcoholic Fatty Liver Disease (NAFLD)

Introduction: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and cirrhosis worldwide and the second most common cause of liver transplantation in major medical centers. Because liver steatosis and fibrosis severity are related to disease morbidity and mortality, the extent of disease, and disease progression, they need to be assessed and monitored. In addition, innovation with new drug developments requires disease staging and monitoring in both phase 2 and 3 clinical trials. Currently, disease assessment in both clinical practice and research is mostly performed by liver biopsy, an invasive, procedure with risks. Noninvasive, highly accurate tests are needed that could be used in clinical trials as surrogate endpoints and in clinical practice for monitoring patients.

Area Covered: We discuss noninvasive tests, transient elastography (TE) with controlled attenuation parameter (CAP), magnetic resonance imaging (MRI), and MR elastography (MRE), summarize the available evidence of their usefulness for assessing steatosis and fibrosis. Therefore they could be used as clinical trials outcomes and in disease monitoring in clinical practice.

Expert Commentary: TE with CAP, MRI and MRE are highly accurate noninvasive diagnostic tools for quantifying hepatic steatosis and fibrosis. Therefore they could be used as clinical trials outcomes and in disease monitoring in clinical practice.     

非酒精性脂肪性肝炎诊断研究进展

非酒精性脂肪性肝病是一种慢性非传染性疾病。近年来其患病率和发病率不断增高,发病年龄也出现低年龄化趋势,该疾病已取代慢性乙型肝炎成为第一大慢性肝脏疾病。重点综述非酒精性脂肪性肝病中的非酒精性脂肪性肝炎的诊断研究进展,介绍非酒精性脂肪性肝炎的临床病史、病理学诊断、非侵入方法诊断,为临床诊断提供参考。     

PPAR agonists reduce steatosis in oleic acid-overloaded HepaRG cells

Although non-alcoholic fatty liver disease (NAFLD) is currently the most common form of chronic liver disease there is no pharmacological agent approved for its treatment. Since peroxisome proliferator-activated receptors (PPARs) are closely associated with hepatic lipid metabolism, they seem to play important roles in NAFLD. However, the effects of PPAR agonists on steatosis that is a common pathology associated with NAFLD, remain largely controversial. In this study, the effects of various PPAR agonists, i.e. fenofibrate, bezafibrate, troglitazone, rosiglitazone, muraglitazar and tesaglitazar on oleic acid-induced steatotic HepaRG cells were investigated after a single 24-hour or 2-week repeat treatment. Lipid vesicles stained by Oil-Red O and triglycerides accumulation caused by oleic acid overload, were decreased, by up to 50%, while fatty acid oxidation was induced after 2-week co-treatment with PPAR agonists. The greatest effects on reduction of steatosis were obtained with the dual PPARα/γ agonist muraglitazar. Such improvement of steatosis was associated with up-regulation of genes related to fatty acid oxidation activity and down-regulation of many genes involved in lipogenesis. Moreover, modulation of expression of some nuclear receptor genes, such as FXR, LXRα and CAR, which are potent actors in the control of lipogenesis, was observed and might explain repression of de novo lipogenesis.     

Personalized therapy when tackling nonalcoholic fatty liver disease: a focus on sex,genes, and drugs

Introduction: Nonalcoholic fatty liver disease (NAFLD) is the most frequent liver disease in the world. It describes a term for a group of hepatic diseases including steatosis, fibrosis, and cirrhosis that can finally lead to hepatocellular carcinoma. There are many factors influencing NAFLD initiation and progression, such as obesity, dyslipidemia, insulin resistance, genetic factors, and hormonal changes. However, there is also lean-NAFLD which is not associated with obesity. NAFLD is considered to be a sexually dimorphic disease. In most cases, men have a higher prevalence for the disease compared to premenopausal women.

Areas covered: In this review, we first summarize the NAFLD disease epidemiology, pathology, and diagnosis. We describe NAFLD progression with the focus on sexual and genetic differences for disease development and pharmacological treatment. Personalized treatment for multifactorial NAFLD is discussed in consideration of different factors, including genetics, gender and sex.

Expert opinion: The livers of female and male NAFLD patients have different metabolic capacities which influence the metabolism of all drugs applied to such patients. This aspect is not yet sufficiently taken into account. The liver computational models might quicken the pace toward assessing personalized disease progression and treatment options.     

非酒精性脂肪性肝病的治疗进展

目前全球非酒精性脂肪性肝病的发病率增加,并与代谢综合征,尤其是肥胖及糖尿病密切相关.越来越多的证据表明,胰岛素抵抗是代谢综合征患者发生脂肪性肝炎的关键病因,其可增加脂肪变性及肝脏游离脂肪酸聚集,刺激氧化应激反应,促进脂质过氧化及炎症细胞因子产生.非酒精性脂肪性肝病的治疗以改善代谢综合征为主,尚缺乏已验证的疗效理想的治疗药物.近年来随着对其发病机制的深入理解,一些尚处于动物试验及前期临床研究的新药值得关注.     

The pharmacological management of NAFLD in children and adolescents

Introduction: Non-alcoholic fatty liver disease (NAFLD) represents a spectrum, including ‘simple’ steatosis, non-alcoholic steatohepatitis (NASH), and fibrosis. Increasing prevalence of NAFLD has followed the international rise in obesity and lifestyle modification is the mainstay therapy for children. To date, pharmacological trials have had varying efficacy but a large number of new agents are in early phase trials for adults.

Areas covered: This review explores the effect of current and potential future paediatric NAFLD treatments in terms of histological and biochemical endpoints. The potential for the extension of adult treatments to children is discussed, as well as what limits the use of certain agents in children.

Expert commentary: No drugs have yet to be licenced for NAFLD. Trial heterogeneity makes comparison of drugs between studies challenging. FXR agonists are yet to be trialled in children but may represent a safe and potentially efficacious therapy. Future treatments would likely encompass a multimodal approach that may include bariatric surgery.