NAFLD：不断演变的景观

StephenW

www.natap.org
Editorial
NAFLD: The evolving landscapeJnl of Hepatology Jan 2018 - Jacob George1,⇑, Quentin Anstee2,3, Vlad Ratziu4, Arun Sanyal5
1Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and the University of Sydney, Sydney, NSW, Australia;
2Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; 3Liver Unit,
Newcastle Upon Tyne Hospitals NHS Trust, Freeman Hospital, Newcastle upon Tyne, United Kingdom; 4Hospital Pitié-Salpêtrière,
Institute of Cardiometabolism and Nutrition, Sorbonne Universités, Paris, France; 5Div. of Gastroenterology, Hepatology and Nutrition,
Dept. of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, United States






Non-alcoholic fatty liver disease (NAFLD) comprising non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), together with their complications of cirrhosis, liver failure and liver cancer will be the predominant liver disease for the conceivable future. Traditionally, viral hepatitis has been the focus of basic and clinical research, and the bread and butter for clinicians in the field. However, with the advent of therapies that suppress hepatitis B virus replication and the shift in standard of care for the treatment of hepatitis C to highly effective direct acting antivirals, the focus of clinical practice and research has altered. For hepatitis C, the goal has moved to elimination strategies and the massive treatment scale up required to achieve this outcome. For hepatitis B, lifelong antiviral therapy for those that require it, as well as cancer surveillance for at-risk groups, has established a relatively easy to follow management algorithm, as we transition to global hepatitis B eradication through immunisation and development of strategies to achieve a functional cure.
While these achievements are a highlight for the speciality, NAFLD has now replaced viral hepatitis as the mainstay of clinical hepatology. Not only does NAFLD and its many variations comprise an ever-increasing number and proportion of referrals to specialists, but it also represents a challenge for primary care physicians managing the early and intermediate stages of the disease. In this respect, disease due to fatty liver is a relative late comer to the limelight in Hepatology, compared to the consequences of the same systemic metabolic derangements to other organ systems including type 2 diabetes, cardiovascular and cerebrovascular disease, and chronic kidney disease.
As we move towards a world where the glimmer of viral hepatitis elimination is becoming a possibility and NAFLD related disease increases, it is appropriate that the Journal commissioned this supplement. Together with my co-editors and the Senior Editors, we focus on four main themes of relevance to both clinicians and researchers. While the topics selected for in-depth review are by no means exhaustive, they cover the broad themes of disease models, pathogenesis, clinical diagnosis and clinical controversies. These were selected from a range of over 20 topics suggested to the Editors, cognizant of recent reviews on various aspects of NAFLD published recently in the Journal. These include articles in areas as diverse as basic pathobiology (2015),[url=]1[/url] the acid sphingomyelinase-ceramide system in steatohepatitis (2015)[url=]2[/url] and the metabolic interplay between white, beige and brown adipocytes with the liver (2016),[url=]3[/url] to MRI/MRE-based assessment of hepatic steatosis and fibrosis (2016),[url=]4[/url] clinical aspects including lifestyle intervention strategies (2017),[url=]5[/url] emerging pharmacotherapies (2015)[url=]6[/url] and liver transplantation for NAFLD (2016).[url=]7[/url] Looking back, the field has moved ahead rapidly, particularly in reaching a critical threshold for understanding the basic pathophysiology of this disease. Coupled with increased interest in developing non-invasive biomarkers that reflect disease stage and grade, there has been an explosion of interest both in academia and more importantly from Pharma for developing new therapies.
To reflect this growing interest in all aspects of NAFLD, the Editor in Chief and Senior Editors commissioned this set of up-to-date reviews on key aspects of NAFLD. The complexities and controversies surrounding the biological rationale for various clinical trial endpoints, histologic and biomarker endpoints, trial enrollment and trial design in the context of NASH, as well as an updated list of phase II and III trials currently being undertaken, is reviewed in-depth by Harrison and colleagues[url=]8[/url] and Ratziu.[url=]9[/url] At the other end of the spectrum, everyone accepts, and current guidelines recommend lifestyle intervention with diet modulation and physical activity as first line management for NAFLD/NASH. Unfortunately, while large scale trials in cardiovascular and metabolic diseases demonstrate clear benefits, practicing physicians are either skeptical of its efficacy in clinical practice or are not sufficiently resourced to provide effective interventions. In this context, the review by Simpson and colleagues[url=]10[/url] is timely, bringing advances in concepts from nutritional science to the clinic. They introduce the concept of the Geometric Framework for Nutrition (GFN), a novel overarching theoretical foundation to integrate key aspects of nutritional systems (nutrients, foods, diets, appetites and nutritional homeostatic physiology) and to map the relationship between nutrient intakes, physiology and health outcomes. While studies to date in liver disease have not utilised the GFN, they propose that GFN offers a framework for future studies of the causes and treatment of NAFLD.
For the clinician awaiting the approval of new and effective therapies, a key challenge is understanding the spectrum of liver disease in the context of a disrupted systemic metabolic milieu consequent to relative over nutrition and reduced physical activity. From this perspective, type 2 diabetes mellitus, hypertension and cardiovascular disease are the most frequent comorbidities, present in a high proportion of patients with NAFLD. As Lonardo and colleagues[url=]11[/url] conclude, emerging high-quality evidence suggests that the interaction between these metabolic syndrome components and NAFLD is complex and importantly, bi-directional. Thus, evidence from cross sectional and longitudinal studies favours the idea that both the presence of NAFLD and its severity may precede and/or promote the development of metabolic comorbidities. Concomitantly, this relationship is bi-directional with the systemic metabolic milieu impacting both incident and prevalent fatty liver disease. In the same vein, both in terms of bi-directionality and complexity, is the relationship of NAFLD to alcoholic liver disease (ALD). While clinical and small animal research has sought to dichotomise NAFLD and ALD for reasons of scientific purity, this is rarely so at the bedside. As Boyle and colleagues illustrate,[url=]12[/url] both alcohol and metabolic cofactors co-exist, and perhaps do so in a majority of patients. This interaction drives and potentially accelerates the ultimate phenotypic expression of liver disease. In turn, the concept of “dual-aetiology fatty liver disease” they suggest should be considered as a useful and distinct diagnostic category, requiring its own future research agenda.
A final controversy that we cover is the vexed issue as to whether we undertake hepatocellular carcinoma (HCC) surveillance in NAFLD. As Younes and Bugianesi[url=]13[/url] conclude, there is reasonable epidemiological cohort data to recommend surveillance in patients with NASH cirrhosis. However, implementing an effective program at population level in a disease that is largely asymptomatic, perhaps even in the majority of patients with cirrhosis, is a mammoth logistic challenge. At the opposite end of the spectrum, a significant burden of HCC arises in non-cirrhotic NAFLD, where currently the low absolute incidence would suggest that screening is not cost effective until better algorithms are developed to identify and stratify the at-risk population.
The large number of pharmacotherapies currently being trialled for NASH and advanced forms of the disease suggests that at least some of these therapies will become available for clinical use. However, given the costs involved in research and development, the new therapies are likely to be costly, at least in the short term for payers. In the scenario of roll out of the new therapies, the current gold standard of liver biopsy will be an impractical and costly approach to identify patients suitable for treatment. Thus, in parallel with drug development, there has been a push to develop non-invasive tools to stage and grade the severity of metabolic liver disease. Of the tools available, imaging based technologies are perhaps the most advanced for day to day practice, while MRI and MRE techniques have the best performance. The latter are however, still predominantly clinical research tools given cost considerations, as reviewed by Dr. Loomba.[url=]14[/url] Blood-based biomarkers for staging and grading NAFLD are particularly attractive for population level disease screening, providing they have high sensitivity and specificity. The current ‘state of the art’ in the field is reviewed by Vilar-Gomez and Chalasani,[url=]15[/url] including clinical prediction rules, as well as a discussion of what is on the horizon in terms of next generation ‘omic’ technologies.
Compared to diseases with a single aetiology, such as viral hepatitis, alcohol or drug induced liver injury, metabolic liver disease as exemplified by NAFLD is significantly more difficult to reverse. This is particularly so because multiple interacting stimuli lead to the clinical manifestations. The outcome in the broadest possible terms, is a composite of gene × gene, environment × environment and gene × environment interactions. Thus, our present understanding of NAFLD/NASH as a single conglomerate disease is perhaps overly simplistic. There are likely multiple subtypes and drivers of various intensity that operate in any single individual leading to his or her final phenotype. For example, why does one person remain with persistent fatty liver while another progresses, or why does one patient develop a predominant liver phenotype, while the next develops cardiovascular predominant disease? Viewed from this angle, the single therapies currently being trialled may have suboptimal effects compared to combination therapies. Moreover, a single agent may be most effective if it targets the predominant driver of the disease in a particular patient. Clearly answers to these questions can only be garnered through further fundamental research. For NAFLD, this requires preclinical models that reflect pathogenesis in humans as reviewed by Santhekadur and colleagues[url=]16[/url] and a detailed understanding of the drivers of disease progression and regression. The latter is reviewed in all its complexity by Schuppan and colleagues,[url=]17[/url] who highlight the key roles of hepatocyte lipoapoptosis, the cellular composition of the fibrotic milieu and the non-cellular pathological extracellular matrix, which has been shown to have functional modulatory effects. While disease pathogenesis in its totality is beyond the scope of this supplement, lipotoxicity and the gut-liver axis have come to the forefront both as drivers of disease, but also as targets for therapeutic intervention. Mara and Svegliati-Baroni[url=]18[/url] discuss both aspects, focussing on the role of toxic lipid subclasses including free fatty acids, cholesterol, lysophosphatidylcholine and ceramides, and their downstream effects. In the second part of their review, the authors discuss the role of the microbiota, bile acids, nuclear receptors, gut hormones and the system of gut-liver cross talk. Finally, no current review of NAFLD would be complete without an examination of the enormous increases in understanding of how host genetic variation influences disease phenotype. The era of host genomics and its contribution to NAFLD was heralded by the identification of the I148M PNPLA3 variant as the major common genetic determinant of NAFLD. Subsequent genome wide and candidate gene studies have identified and characterised several other variants with moderate effect size, including variants in TM6SF2, MBOAT7 and GCKR. Together with the potential to identify additional variants and other types of genetic variation that contribute to NAFLD through the interrogation of well annotated clinical cohorts, we are at the cusp for developing polygenic risk scores for clinical decision making, as reviewed by Eslam and colleagues.[url=]19[/url]
As stated at the outset, this supplement does not seek to cover in its entirety, the current state of play in the field of NAFLD/NASH. Rather, if we have provided a comprehensive and up-to-date review of the unresolved controversies and clinical research questions in the field, the supplement will have achieved its goal.

StephenW

社论
NAFLD：不断演变的景观

肝脏病学Jnl 2018年1月 - Jacob George1，Que，Quentin Anstee2,3，Vlad Ratziu4，Arun Sanyal5
Westmead医学研究院Westmead医院和澳大利亚新南威尔士悉尼悉尼大学的1Storr肝脏中心;
2纽卡斯尔大学医学院细胞医学研究所，英国泰恩河畔纽卡斯尔; 3肝脏单位，
泰恩河畔纽卡斯尔医院英国泰恩河畔纽卡斯尔Freeman医院的NHS Trust，英国;医院Pitié-Salpêtrière，
法国巴黎索邦大学心脏代谢与营养研究所; 5DIV。胃肠病学，肝病学和营养学，
美国弗吉尼亚州里士满弗吉尼亚联邦大学医学院内科医学系


非酒精性脂肪肝（NAFLD）由非酒精性脂肪肝（NAFL）和非酒精性脂肪性肝炎（NASH）组成，并发症为肝硬化，肝衰竭和肝癌是未来可能发生的主要肝病。传统上，病毒性肝炎一直是基础和临床研究的焦点，也是该领域临床医生的面包和黄油。然而，随着抑制乙型肝炎病毒复制的疗法的出现和将丙型肝炎的治疗标准转变为高效的直接抗病毒药物的出现，临床实践和研究的重点已经改变。对于丙型肝炎，目标已经转移到消除策略，并需要大规模的治疗来达到这个结果。对于乙型肝炎，需要终身抗病毒治疗以及对高危人群进行癌症监测，已经建立了一个相对容易遵循的管理算法，因为我们通过免疫接种和发展策略实现全球乙肝根除功能治愈。

虽然这些成就是该专业的一个亮点，但NAFLD已经取代了病毒性肝炎成为临床肝病的主流。 NAFLD及其许多变化不仅包括对专家转诊的数量和比例不断增加，而且对初级保健医生管理疾病的早期和中期阶段也是一个挑战。在这方面，与其他器官系统（包括2型糖尿病，心血管和脑血管疾病以及慢性肾病）相同的系统性代谢紊乱的后果相比，由脂肪肝引起的疾病是肝炎学相对较晚的出发点。

随着我们走向一个消除病毒性肝炎一线可能性和NAFLD相关疾病增加的世界，“日刊”委托撰写本增刊是合适的。与我的共同编辑和资深编辑一起，我们将重点放在与临床医生和研究人员相关的四个主要主题上。虽然深入审查选择的主题并不是详尽无遗，但涵盖了疾病模型，发病机制，临床诊断和临床争议等广泛的主题。这些是从编辑建议的20多个主题中选出的，认识到近期在“日刊”上发表的有关NAFLD各方面的评论。其中包括基础病理学（2015），酸性鞘磷脂酶 - 神经酰胺系统（2015）2和白色，米色和棕色脂肪细胞与肝脏之间的代谢相互作用（2016），MRI / MRE （2016）评估肝脏脂肪变性和纤维化（2016），包括生活方式干预策略（2017），5种新兴药物治疗（2015）6和肝脏移植在内的4个临床方面。回顾过去，该领域已经迅速前进，尤其是在达到了理解该疾病基本病理生理学的关键阈值之后。加上开发反映疾病阶段和等级的非侵入性生物标志物的兴趣增加，学术界以及更重要的是来自Pharma开发新疗法的兴趣已经激增。

为了反映对NAFLD各方面日益增长的兴趣，总编辑和高级编辑委托撰写了关于NAFLD关键方面的最新评论。包括各种临床试验终点的生物学原理，组织学和生物标志物终点，NASH试验注册和试验设计的复杂性和争议，以及目前正在进行的II期和III期试验的最新清单， Harrison等[8]和Ratziu [9]深入研究。另一方面，每个人都接受，现有的指南建议将生活方式干预与饮食调节和身体活动作为NAFLD / NASH的一线管理。不幸的是，虽然心血管和代谢疾病的大规模试验表现出明显的益处，但是实践医师或者怀疑其在临床实践中的有效性，或者没有足够的资源来提供有效的干预措施。在这种情况下，Simp son及其同事10的回顾是及时的，将营养科学的概念带到临床。他们介绍了营养几何框架（GFN）的概念，这是一个整合营养系统（营养素，食物，饮食，食欲和营养稳态生理学）的关键方面的新颖的理论基础，并绘制营养摄入量，生理和健康状况。迄今为止在肝病的研究尚未使用GFN，他们提出GFN为未来NAFLD的病因和治疗研究提供了一个框架。

对于正在等待新的有效治疗的临床医师来说，一个关键的挑战就是在营养相对过剩和体力活动减少的情况下，在全身代谢环境受到破坏的情况下，了解肝脏疾病谱。从这个角度来看，2型糖尿病，高血压和心血管疾病是最常见的合并症，存在于NAFLD患者中的比例很高。正如Lonardo及其同事11所得出的结论，正在出现的高质量证据表明，这些代谢综合征组分与NAFLD之间的相互作用是复杂且重要的，双向的。因此，来自横断面和纵向研究的证据支持NAFLD和其严重性可能先于和/或促进代谢合并症的发展。同时，这种关系是双向的，系统代谢环境影响事件和流行的脂肪肝疾病。同样，在双向性和复杂性方面，是NAFLD与酒精性肝病（ALD）的关系。尽管临床和小动物研究试图以科学纯度为理由将NAFLD和ALD二分化，但在床边很少这样做。正如博伊尔及其同事所说，酒精和代谢辅因子并存，也可能在大多数患者中共存。这种相互作用驱动并可能加速肝病的最终表型表达。反过来，他们认为“双重病原学脂肪肝疾病”的概念应该被认为是一个有用的和独特的诊断类别，需要自己的未来研究议程。

我们报道的最后一个争议是关于我们是否在NAFLD中进行肝细胞癌（HCC）监测的烦恼。正如Younes和Bugianesi13所总结的那样，有合理的流行病学队列数据建议对NASH肝硬化患者进行监测。然而，在大多数无症状的疾病（甚至在大多数肝硬化患者中）实施人群水平的有效方案是一个巨大的后勤挑战。另一方面，非肝硬化非酒精性脂肪肝发生HCC的重要负担，绝对低发生率意味着筛选不具有成本效益，除非有更好的算法来确定和分层高危人群。

目前正在进行NASH试验的大量药物治疗以及这种疾病的晚期形式表明至少一些这些疗法将可用于临床使用。但是，考虑到研究和开发所涉及的成本，新的治疗方法很可能是昂贵的，至少在付款人的短期内。在推出新疗法的情况下，目前的肝活检金标准将成为确定适合治疗的患者的不切实际和昂贵的方法。因此，在药物开发的同时，推动开发非侵入性工具来评估代谢性肝病的严重程度。在可用的工具中，基于成像的技术可能是日常实践中最先进的技术，而MRI和MRE技术则具有最佳性能。然而，如Loomba博士所回顾的，后者主要是考虑到成本考虑的临床研究工具.14用于分期和分级NAFLD的血液生物标志物对于人群级疾病筛查特别有吸引力，因为它们具有高灵敏度和特异性。 Vilar-Gomez和Chalasani [15]对包括临床预测规则在内的当前“最先进的”技术进行了回顾，并就下一代“组件化”技术展开了讨论。

与单一病因的疾病如病毒性肝炎，酒精或药物引起的肝损伤相比，以NAFLD为代表的代谢性肝病显然更难以逆转。这是特别如此，因为多个相互作用刺激导致临床表现。最广泛的结果是基因×基因，环境×环境和基因×环境的相互作用。因此，我们目前将NAFLD / NASH理解为单一的砾质性疾病可能过于简单。有可能有多种不同强度的亚型和驱动因素在任何单一个体中起作用，导致其最终表型。例如，为什么一个人在持续性脂肪肝的同时又继续发展，或者为什么一个病人发展为主要的肝脏表型，而下一个发展为心血管疾病的主要疾病呢？从这个角度来看，与联合治疗相比，目前正在试验的单一疗法可能具有次优效应。此外，如果单一药物针对特定患者中的主要疾病驱动因素，则其可能是最有效的。显然，只有通过进一步的基础研究才能获得这些问题的答案。对于NAFLD，这需要临床前模型来反映Santhekadur及其同事[16]综述的人类发病机制，并详细了解疾病进展和退化的驱动因素。 Schuppan等[17]强调了肝细胞脂肪凋亡的关键作用，纤维化环境的细胞组成和非细胞性病理性细胞外基质，后者已被证明具有功能调节作用。虽然疾病的发病机制在其整体上超出了这一补充的范围，但是脂毒性和肠 - 肝轴作为疾病的驱动因素已经走到了前列，而且也是治疗干预的目标。 Mara和Svegliati-Baroni18讨论了这两个方面，重点讨论了有毒脂质亚类（包括游离脂肪酸，胆固醇，溶血磷脂酰胆碱和神经酰胺）及其下游效应的作用。在第二部分的综述中，作者讨论了微生物群，胆汁酸，核受体，胃肠激素和肠 - 肝交叉系统的作用。最后，如果不检查对宿主遗传变异如何影响疾病表型的认识的巨大增加，目前没有关于NAFLD的综述是完整的。宿主基因组学的时代及其对NAFLD的贡献被I148M PNPLA3变体鉴定为NAFLD的主要常见遗传决定因素。随后的全基因组和候选基因研究已经鉴定和表征具有中等效应大小的几种其他变体，包括TM6SF2，MBOAT7和GCKR中的变体。加上有可能通过询问充分注释的临床队列来鉴定其他变异和其他类型的遗传变异，这些变异和遗传变异有助于NAFLD，正如Eslam及其同事所审查的那样，我们正在为临床决策制定多基因风险评分。

正如开头所述，这份补充材料并不是要全面涵盖NAFLD / NASH领域的现状。相反，如果我们对这个领域中尚未解决的争议和临床研究问题提供了一个全面和最新的回顾，补充将达到它的目标。

windu

控制体重很重要啊