Correspondence Address correspondence to: Mohammed Eslam, Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead 2145, NSW, Australia. fax: +61-2-96357582.
Jacob George, MD, Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead 2145, NSW, Australia. fax: +61-2-96357582.
Fatty liver associated with metabolic dysfunction is common, affects a quarter of the population, and has no approved drug therapy. Although pharmacotherapies are in development, response rates appear modest. The heterogeneous pathogenesis of metabolic fatty liver diseases and inaccuracies in terminology and definitions necessitate a reappraisal of nomenclature to inform clinical trial design and drug development. A group of experts sought to integrate current understanding of patient heterogeneity captured under the acronym nonalcoholic fatty liver disease (NAFLD) and provide suggestions on terminology that more accurately reflects pathogenesis and can help in patient stratification for management. Experts reached consensus that NAFLD does not reflect current knowledge, and metabolic (dysfunction) associated fatty liver disease “MAFLD” was suggested as a more appropriate overarching term. This opens the door for efforts from the research community to update the nomenclature and subphenotype the disease to accelerate the translational path to new treatments. 与代谢功能障碍相关的脂肪肝很常见，影响四分之一的人口，并且尚未获得批准的药物治疗。尽管药物疗法正在开发中，但反应率似乎并不高。代谢性脂肪肝疾病的异质性发病机制以及术语和定义的不准确性需要重新评估命名法，以便为临床试验设计和药物开发提供信息。一组专家试图整合当前对非酒精性脂肪性肝病 (NAFLD) 首字母缩写词下患者异质性的理解，并提供术语建议，以更准确地反映发病机制，并有助于对患者进行分层管理。专家们一致认为 NAFLD 并不反映当前的知识，并且代谢（功能障碍）相关的脂肪肝疾病“MAFLD”被建议作为更合适的总体术语。这为研究界更新疾病的命名和亚表型以加速新疗法的转化之路打开了大门。
in 1980 to describe fatty liver disease arising in the absence of significant alcohol intake, the nomenclature and criteria for a diagnosis has not been revisited. Yet, this disease has risen in prevalence, with a major impact on clinical and economic burden to society, such that nearly 1 billion people globally are affected.
The estimated annual medical costs directly attributable to NAFLD exceed €35 billion in 4 large European countries (United Kingdom, France, Germany, and Italy) and $100 billion in the United States.
Although reducing disease burden through prevention seems obvious, this has not been achieved. Further, although pharmacotherapies are expected to become available in the near future, none to date has been approved. Thus far, several phase 2b and phase 3 studies either have fallen short of meeting current required histologic endpoints, or have done so with a modest margin. Muted efficacy of various compounds in development are in part a reflection of the imprecise definitions and the lack of precision medicine including consideration of heterogeneity of the disease. 自 Ludwig 及其同事
Despite these alarming data, the nomenclature of the disease and the criteria for diagnosis have not been updated to reflect our expanding knowledge. The heterogeneity of the population with NAFLD with respect to its primary drivers and coexisting disease modifiers, represent an important impediment to the discovery of highly effective drug treatments. The phenotypic manifestation of fatty liver diseases likely reflects the sum of the dynamic and complex systems-level interactions of these drivers; it follows that effective treatment requires that they be targeted with precision, based on a person’s phenotype and genetic background.
However, trial recruitment is currently based on histologic grading and staging, and that is a problem because many pathways lead to the same histologic phenotype, without dissection of the predominant pathogenic pathways.
Thus, a “one size fits all approach” would seem inappropriate when dealing with a very heterogeneous liver disease. 尽管有这些令人震惊的数据，但该疾病的命名和诊断标准尚未更新以反映我们不断扩大的知识。 NAFLD 人群在其主要驱动因素和共存疾病调节因素方面的异质性，是发现高效药物治疗的重要障碍。脂肪肝疾病的表型表现可能反映了这些驱动因素动态且复杂的系统级相互作用的总和；因此，有效的治疗需要根据一个人的表型和遗传背景进行精确的治疗。
From the patient’s perspective, the term “nonalcoholic fatty liver disease” not only trivializes the problem by including terms such as “non,” but is also pejorative, as it introduces words such as “alcoholic,” potentially placing the blame on patients as having caused their condition. It also implies that the treatment must entirely lie in the patient’s hand. This has enormous implications on how industry and policy makers choose to allocate resources for tackling the syndrome, which clearly is a major cause of death. Lessons can be learned from cardiologists, diabetologists, neurologists, and oncologists who have successfully distanced the disease they are trying to treat from the underlying obesity, smoking, alcohol abuse, and drug abuse. Some of these factors have high genetic predisposition. In support of this idea, a meeting organized by the European Liver Patient’s Association with the European Commission in 2018 suggested that a change in nomenclature was one of their key requirements. 从患者的角度来看，“非酒精性脂肪肝”一词不仅通过包含“非”等术语来淡化问题，而且还带有贬义，因为它引入了“酒精”等词，可能将责任归咎于患者造成了他们的状况。这也意味着治疗必须完全掌握在患者手中。这对于行业和政策制定者如何选择分配资源来应对这种综合症有着巨大的影响，这种综合症显然是导致死亡的一个主要原因。我们可以从心脏病学家、糖尿病学家、神经学家和肿瘤学家那里吸取经验教训，他们成功地将他们试图治疗的疾病与潜在的肥胖、吸烟、酗酒和药物滥用区分开来。其中一些因素具有高度遗传倾向。为了支持这一想法，欧洲肝病患者协会与欧盟委员会于 2018 年组织的一次会议表明，命名法的改变是他们的关键要求之一。
As a first step to tackle this challenge, revising the nomenclature and definitions of the disease is critical. Recently, concerns over the inaccuracies of the nomenclature of fatty liver disease have been raised by individual experts.
and in this review, an international panel sought to integrate epidemiological knowledge about disease progression that includes steatosis and steatohepatitis associated with metabolic dysfunction, with information about risk prediction derived from genetic and phenotyping studies. We suggest a new nomenclature based on consensus voting by participants to describe the disease that will allow us to properly subphenotype and stratify patients, via the application of more precise genetic, anthropometric, and metabolic phenotyping approaches. In turn, detailed phenotyping will translate into individualized risk prediction and prevention strategies, and improvements in clinical trial design. 作为应对这一挑战的第一步，修订该疾病的术语和定义至关重要。最近，个别专家对脂肪肝疾病命名不准确提出了担忧。
Following discussions, an initial concept sheet was circulated to the panel of contributors. This revealed widespread agreement and consensus that it was time to revisit the nomenclature of metabolic fatty liver disease as a critical initial step for improved patient subphenotyping, clinical trials design, and ultimately, for personalization of medicine. 经过讨论，初步概念表已分发给贡献者小组。这揭示了广泛的共识和共识，即是时候重新审视代谢性脂肪肝疾病的命名法，作为改善患者亚表型、临床试验设计以及最终实现药物个性化的关键的第一步。
Subsequently, a manuscript was drafted, circulated to the panel, and feedback incorporated over several rounds of revision. To reach consensus on a nomenclature, the Delphi method was adopted in 2 rounds. This method is a recommended iterative process for use in the health care setting as a reliable means to solicit and distil the judgments of experts and to determine consensus via a systematic progression of repeated rounds of voting.
A “closed” electronic survey URL was sent to participants providing a unique link that could be used only once. Survey data were collected and managed using REDCap (Research Electronic Data Capture). In the first round of surveys members suggested 1 or more terms to describe metabolic fatty liver disease. In a second round (based on a summary of the experts’ suggestions), participants were asked to vote on the suggested terminology. To ensure a robust and transparent process, anonymity of the participants was maintained. 随后，起草了一份手稿，分发给专家组，并在几轮修订中纳入反馈。为了就命名法达成共识，德尔菲法分两轮采用。该方法是推荐在医疗保健环境中使用的迭代过程，作为征求和提炼专家判断并通过系统性的重复轮次投票确定共识的可靠手段。
Metabolic Associated Fatty Liver Disease: A Heterogeneous Phenotype 代谢相关脂肪肝：异质表型
We now recognize that metabolic fatty liver disease is a phenotype with complex and disparate causes; the current terminology (NAFLD) represents an umbrella term for the multiple underlying subtypes.
“Not all forms of NAFLD were created equal.” Do metabolic syndrome-related NAFLD and PNPLA3-related NAFLD exert a variable impact on the risk of early carotid atherosclerosis?.
This is evidenced by the wide spectrum of disease severity and natural history, as well as the substantial interpatient variability across the spectrum. Although hepatic steatosis is highly prevalent, only a minority exhibit inflammatory injury at any time; more importantly, an individual can oscillate between steatosis and steatohepatitis even over a short timeframe.
In addition, although there is convincing evidence that liver-related complications (ie, cirrhosis and cancer) are more likely in those with steatohepatitis, progression is far from inevitable.
Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi-national cohort study.
Even among those with steatohepatitis, there appear to be individuals with apparent rapid-fibrosis progression and those with inherently slow-fibrosis progression.
and can even “spontaneously” regress, as has been demonstrated in placebo group participants in treatment trials and by observational dual-biopsy studies in secondary/tertiary care settings.
Rates of and factors associated with placebo response in trials of pharmacotherapies for nonalcoholic steatohepatitis: systematic review and meta-analysis.
Adding to the complexity, it is unknown if the propensity for metabolic fatty liver diseases progression can vary across the life span. For example, given the rapidly escalating prevalence of metabolic fatty liver disease in children and young adolescents, we still do not understand if their natural history follows a different trajectory from those who develop disease in adulthood, middle age, or even old age.
“Not all forms of NAFLD were created equal.” Do metabolic syndrome-related NAFLD and PNPLA3-related NAFLD exert a variable impact on the risk of early carotid atherosclerosis?.
Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi-national cohort study.
Rates of and factors associated with placebo response in trials of pharmacotherapies for nonalcoholic steatohepatitis: systematic review and meta-analysis.
The heterogeneity in clinical presentation and disease course of fatty liver disease is likely influenced by multiple factors, including age, gender, hormonal status, ethnicity, diet, alcohol intake, smoking, genetic predisposition, the microbiota, and metabolic status. Thus, the final outcome will reflect the balance of these diverse inputs, each interacting with the other and modifying the ultimate manifestations and clinical course (Figure 1). It follows that effective treatment will require systematic dissection of the pathways involved and likely multifaceted and personalized treatments.
A brief summary of current knowledge about factors contributing to NAFLD heterogeneity is provided below. 脂肪肝的临床表现和病程的异质性可能受到多种因素的影响，包括年龄、性别、激素状态、种族、饮食、酒精摄入量、吸烟、遗传倾向、微生物群和代谢状态。因此，最终结果将反映这些不同输入的平衡，每个输入彼此相互作用并改变最终的表现和临床过程（图 1）。因此，有效的治疗需要对所涉及的途径进行系统剖析，并可能需要多方面和个性化的治疗。
Figure 1Heterogeneity of MAFLD. The heterogeneity in clinical presentation and course of fatty liver disease is influenced by a multitude of factors, including age, sex, ethnicity, alcohol intake, dietary habits, hormonal status, genetic predisposition, and epigenetic factors, the microbiota, and metabolic status. It is likely that there is a differential impact in the contribution of the various factors in any individual over time and among individuals that then shapes disease phenotype and course. 图 1 MAFLD 的异质性。脂肪肝疾病临床表现和病程的异质性受到多种因素的影响，包括年龄、性别、种族、酒精摄入量、饮食习惯、激素状态、遗传倾向和表观遗传因素、微生物群和代谢状态。随着时间的推移，各种因素对任何个体以及个体之间的贡献可能会产生不同的影响，从而形成疾病的表型和病程。
NAFLD prevalence, the risk of hepatic and extrahepatic complications, and the likelihood of overall and disease-specific mortality increases with advancing age.
Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi-national cohort study.
With aging, substantial changes occur in the liver, including a decline in hepatic blood flow, hepatic volume, and liver function, a reduction in bile acid synthesis and alterations in cholesterol metabolism, as well as a reduction in mitochondrial number with subsequent increases in oxidative respiration.
Furthermore, aging is accompanied by changes in body composition, including a decrease in muscle mass, an increase in abdominal adiposity and ectopic fat deposition, with increases in insulin resistance and prevalence of the metabolic syndrome.
Emerging evidence suggests that sarcopenia is associated with both NAFLD and NAFLD-related advanced fibrosis, even after adjusting for body mass index (BMI) and insulin resistance.
Sarcopenia is associated with significant liver fibrosis independently of obesity and insulin resistance in nonalcoholic fatty liver disease: nationwide surveys (KNHANES 2008–2011).
Presumably, aging also captures greater exposure to the drivers, which result in steatohepatitis and fibrosis. NAFLD 患病率、肝脏和肝外并发症的风险以及总体死亡率和特定疾病死亡率的可能性随着年龄的增长而增加。
Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi-national cohort study.
Sarcopenia is associated with significant liver fibrosis independently of obesity and insulin resistance in nonalcoholic fatty liver disease: nationwide surveys (KNHANES 2008–2011).
there is substantial sexual dimorphism in many aspects of fatty liver disease with regard to risk factors, prevalence, fibrosis pattern, and disease outcomes. Generally, prevalence tends to be lower in women predominantly at earlier disease stages, whereas disease frequency increases in postmenopausal women.
Among postmenopausal women, those not on hormone replacement therapy tend to have higher disease prevalence compared with those on hormone replacement therapy,
Consistently, a longer duration of estrogen deficiency associates with a higher likelihood of fibrosis among postmenopausal women with fatty liver disease.
Although the mechanisms for these effects are not completely understood, sex differences in adiposity, metabolic risk factors, and body fat distribution (which tends to shift toward abdominal obesity after menopause), likely play a role.
A recent study in mice from approximately 100 strains included in the hybrid mouse diversity panel demonstrated that multiple molecular pathways and gene networks implicated in lipid metabolism, insulin-signaling, and inflammation show sexual dimorphism.
Similarly, another study demonstrated sexual differences in liver gene expression of regulators of multiple metabolic pathways using a mice computational model. Notably, some such as peroxisome proliferator-activated receptor PPARα, farnesoid X receptor, and liver X receptor, which are highly gender dependent, are currently being investigated as therapeutic targets for steatohepatitis.
A further study demonstrated gender-related pathways contribute to steatosis and fibrosis in male and female mice (males mainly inflammation and females mainly alterations of redox state), despite similar endpoints.
Clearly, sex and menopausal status influence disease outcomes and require stratification as treatment responses can vary substantially. 尽管这些影响的机制尚不完全清楚，但肥胖、代谢危险因素和身体脂肪分布（绝经后倾向于腹部肥胖）的性别差异可能发挥了作用。
Population-based data show ethnic differences in the prevalence of fatty liver; a recent meta-analysis demonstrated both NAFLD prevalence and risk of nonalcoholic steatohepatitis (NASH) were highest in Hispanic individuals, intermediate in white individuals, and lowest in black individuals; however, fibrosis risk did not differ according to ethnicity.
Racial and ethnic disparities in nonalcoholic fatty liver disease prevalence, severity, and outcomes in the United States: a systematic review and meta-analysis.
The course of disease also appears to be more severe in Asian compared with non-Asian individuals, and they tend to have more lobular inflammation and higher grades of ballooning compared with other ethnicities.
Although data regarding fibrosis are scarce in the preceding studies, Asian individuals tended to have a higher risk of fibrosis, whereas African individuals were at lower risk compared with white individuals; this did not reach significance, perhaps due to sample size limitations.
However, and notably, these biopsy-based studies might suffer from selection bias. For example, a community-based study in Hong Kong suggested that although NAFLD is detected in a quarter of the population, the prevalence of advanced fibrosis is low.
Prevalence of non-alcoholic fatty liver disease and advanced fibrosis in Hong Kong Chinese: a population study using proton-magnetic resonance spectroscopy and transient elastography.
Racial and ethnic disparities in nonalcoholic fatty liver disease prevalence, severity, and outcomes in the United States: a systematic review and meta-analysis.
Prevalence of non-alcoholic fatty liver disease and advanced fibrosis in Hong Kong Chinese: a population study using proton-magnetic resonance spectroscopy and transient elastography.
The reasons for racial disparities in fatty liver risk are not completely understood. Plausible explanations include variations in genetic predisposition, metabolic attributes, cultural and socioeconomic factors, dietary and exercise habits, and access to health care, as well as environmental risks. There are substantial differences in genetic heritage across ethnic groups; variation in the risk allele of the Patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene that is most frequent in Hispanic individuals (49%), followed by non-Hispanic white (23%) and African American individuals (17%) has helped, at least partially, to explain some of this ethnic variability.
Notably, because the effect size of fatty liver–related gene variants supports the existence of differences among races, the relative contribution of specific genetic and and environmental triggers (eg, dietary factors) or modifying risk variants, toward disease pathogenesis is likely variable among ethnic groups (Figure 2). 脂肪肝风险种族差异的原因尚不完全清楚。合理的解释包括遗传倾向、代谢属性、文化和社会经济因素、饮食和运动习惯、获得医疗保健的机会以及环境风险的变化。不同种族的遗传基因存在显着差异；含 Patatin 样磷脂酶结构域的蛋白 3 (PNPLA3) 基因的风险等位基因变异在西班牙裔个体 (49%) 中最常见，其次是非西班牙裔白人 (23%) 和非洲裔美国人 (17%)至少在一定程度上有助于解释这种种族差异。
Figure 2Interindividual variation in the predominant drivers of MAFLD. MAFLD is a complex phenotype shaped by the dynamic interaction of genetic predisposition with environmental factors and components of the metabolic syndrome. The effect size of genetic variants and the predominant drivers can exhibit marked interindividual variation. As an example, disease in patient 1 is driven predominantly by environmental influences with less contribution from genetic predisposition; in patient 2, metabolic syndrome is the predominant driver, whereas disease in patient 3 is driven by genetic factors with a limited contribution from other factors. Identification of the predominant drivers in every patient can help in personalization of medicine. 图 2 MAFLD 主要驱动因素的个体差异。 MAFLD 是一种复杂的表型，由遗传倾向与环境因素和代谢综合征组成部分的动态相互作用形成。遗传变异和主要驱动因素的影响大小可能表现出明显的个体差异。例如，患者 1 的疾病主要是由环境影响引起的，遗传倾向的影响较小；对于患者 2，代谢综合征是主要驱动因素，而患者 3 的疾病则由遗传因素驱动，其他因素的影响有限。识别每个患者的主要驱动因素有助于个性化医疗。
On the other hand, there are marked racial/ethnic socioeconomic disparities that are likely also reflected in differences in multiple disease risk factors. For example, there is a clear difference between European and Asian populations with regard to insulin resistance and body fat distribution, as discussed later. There are also disparities in physical activity; in 2016, a report including 1.9 million participants across 168 countries suggested that women in Latin America, south Asia, and high-income Western countries have the highest prevalence of physical inactivity.
Likewise, data from the NASH Clinical Research Network reported less physical activity, increased carbohydrate consumption, and lower income levels in Hispanic individuals compared with non-Hispanic white patients with NASH.
A role for gut microbiota could also be implicated, as discussed later in this article. 另一方面，存在明显的种族/民族社会经济差异，这也可能反映在多种疾病风险因素的差异上。例如，欧洲和亚洲人群在胰岛素抵抗和身体脂肪分布方面存在明显差异，如下文所述。身体活动方面也存在差异； 2016 年，一份涵盖 168 个国家 190 万名参与者的报告显示，拉丁美洲、南亚和高收入西方国家的女性缺乏身体活动的比例最高。
Since its first description, metabolic has been considered distinct from alcoholic-associated liver disease based on a cutoff of daily alcohol intake of 30 g daily for men and 20 g daily for women. The assumption underlying the cutoff has been that alcohol intake below these thresholds does not induce hepatic steatosis or have deleterious impacts on liver disease progression and outcomes.
GBD 2016 Alcohol Collaborators Alcohol use and burden for 195 countries and territories, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016 (vol 392, pg 1015, 2018).
Some reports suggest that modest alcohol consumption, even after adjustment for previous heavy drinking, is associated with a reduction in vascular complications
Other studies have demonstrated that moderate drinking (2 drinks a day for women and 3 drinks a day for men) is associated with a reduced prevalence of NASH and advanced fibrosis.
In contrast, some studies highlight that even low alcohol intake in those with a fatty liver is associated not only with increased risk of disease progression, but also for advanced liver disease and cancer,
Åberg F, Puukka P, Salomaa V, et al. Risks of light and moderate alcohol use in fatty liver disease–follow-up of population cohorts [published online ahead of print July 19, 2019]. Hepatology https://doi.org/10.1002/hep.30864.
Among patients with nonalcoholic fatty liver disease, modest alcohol use is associated with less improvement in histologic steatosis and steatohepatitis.
GBD 2016 Alcohol Collaborators Alcohol use and burden for 195 countries and territories, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016 (vol 392, pg 1015, 2018).
Åberg F, Puukka P, Salomaa V, et al. Risks of light and moderate alcohol use in fatty liver disease–follow-up of population cohorts [published online ahead of print July 19, 2019]. Hepatology https://doi.org/10.1002/hep.30864.
Among patients with nonalcoholic fatty liver disease, modest alcohol use is associated with less improvement in histologic steatosis and steatohepatitis.
Dietary Intake, Gut Microbiota, and Bile Acids 膳食摄入量、肠道微生物群和胆汁酸
For metabolic homeostasis, the neuroendocrine axis, dietary intake, muscle mass, physical activity, and the enterohepatic circulation, gut microbiota, bile acids, and their related metabolites are intimately implicated in fatty liver pathogenesis (Supplementary Figure 1). The dietary pattern that characterizes the Western diet, including increased fat and fructose consumption that is fueling the increase in obesity and fatty liver, is associated with a wide range of metabolic dysfunction, including insulin resistance and abnormal lipid profile.
In contrast, adoption of a Mediterranean dietary pattern is accompanied with a decrease in liver fat in patients with NAFLD and a decrease in cardiovascular risk.
Gut microbiota are also implicated in regulating bile acids and their metabolites, which in turn regulate glucose, lipid, and choline metabolism, and energy homeostasis.
This leads to increased circulating levels of bacterial products including lipopolysaccharide, as well as other bioactive compounds that may induce intrahepatic activation of proinflammatory cells, hepatic stellate cells, and hepatocytes via stimulation of toll-like receptors (particularly 2, 4, and 9), a sensor for these products.
Toll-like receptor 2 and palmitic acid cooperatively contribute to the development of nonalcoholic steatohepatitis through inflammasome activation in mice.
However, it remains challenging to disentangle the effects of diet and its associated consequences for liver disease, from effects mediated by diet-induced alterations to the microbiome, and to ascertain causality under these same conditions. Notably, a role for human genetic variation and ethnicity in driving differences in microbiomes has recently been suggested.
Toll-like receptor 2 and palmitic acid cooperatively contribute to the development of nonalcoholic steatohepatitis through inflammasome activation in mice.
Whereas obesity can be classified as metabolically healthy obesity and metabolically unhealthy obesity, with the former affecting approximately 45% of obese subjects, there is no consensus on a definition of metabolic health. Various definitions of metabolic syndrome include a combination of different metabolic components.
it has not been included in several definitions of metabolic syndrome. Notably, multiple large-scale cohort studies do not clearly support the notion that metabolically healthy obesity subgroups, at least as currently defined, are protected from cardiometabolic complications compared with those with a stable normal weight who are metabolically healthy.
Transition from metabolic healthy to unhealthy phenotypes and association with cardiovascular disease risk across BMI categories in 90 257 women (the Nurses' Health Study): 30 year follow-up from a prospective cohort study.
Better classification based on molecular or genetic profiling could help dissect with high precision, metabolically favorable and unfavorable subtypes, with distinct metabolism, anthropometry, and patterns of fat deposition, and likely differential responses to drug treatments.
On the other hand, approximately 30% of normal-weight individuals can be classified as metabolically obese normal weight, and they demonstrate an increased propensity for cardiometabolic risk; a fair proportion of patients with a fatty liver are also lean. 尽管肥胖与肝脏脂肪密切相关，但并非所有肥胖患者都会患代谢性脂肪肝。
Transition from metabolic healthy to unhealthy phenotypes and association with cardiovascular disease risk across BMI categories in 90 257 women (the Nurses' Health Study): 30 year follow-up from a prospective cohort study.
Current consensus suggests that the distribution and the overall health of fat, rather than its amount is likely the major determinant of disease risk. For example, higher amounts of visceral relative to peripheral and subcutaneous adipose tissue is associated with greater metabolic risk
Sex, sex hormones (as discussed previously), ethnicity, and genes obviously play important roles in determining the location and health of adipose tissue. There is, for example, strong evidence that ethnicity is implicated in determining fat distribution and health.
Genome-wide and abdominal MRI-imaging data provides evidence that a genetically determined favourable adiposity phenotype is characterized by lower ectopic liver fat and lower risk of type 2 diabetes, heart disease and hypertension.
Genome-wide and abdominal MRI-imaging data provides evidence that a genetically determined favourable adiposity phenotype is characterized by lower ectopic liver fat and lower risk of type 2 diabetes, heart disease and hypertension.
Although lipid accumulation in liver is a hallmark of NAFLD, there is emerging evidence that there is likely a variety of underlying mechanisms and routes for its development. For instance, a recent study has demonstrated that lipid composition in liver is very different in 2 proposed subtypes of NAFLD. In subtype 1, based on insulin resistance, patients tend to have monounsaturated triacylglycerols and free fatty acids enriched with ceramides in liver, whereas subtype 2, based on carrying the PNPLA3 risk genotype at rs738409, have polyunsaturated triacylglycerols.
In another study, regions with steatosis demonstrated distinct lipid composition, predominantly in the form of a loss of arachidonic acid-containing intracellular phospholipids, compared with nonsteatosis liver tissue.
A further report used RNA-sequencing analysis and identified molecular subtypes with distinct gene expression pattern clusters that are implicated in lipid metabolism, interferon signaling, and immune system pathways, according to different histological scores.
In total, these new datasets emphasize that there are likely multiple NAFLD subtypes characterized by unique metabolomic signatures. Based on subtype, it is likely that treatment responses will vary, and hence defining the metabolic landscape of an individual is likely important in clinical trial design. 尽管肝脏中的脂质积累是 NAFLD 的一个标志，但新出现的证据表明，其发展可能存在多种潜在机制和途径。例如，最近的一项研究表明，两种拟议的 NAFLD 亚型的肝脏脂质成分有很大不同。在亚型 1 中，基于胰岛素抵抗，患者肝脏中往往含有富含神经酰胺的单不饱和三酰甘油和游离脂肪酸，而亚型 2 则基于在 rs738409 处携带 PNPLA3 风险基因型，具有多不饱和三酰甘油。
Currently, lean NAFLD, or NAFLD in lean individuals, is defined as hepatic steatosis with a BMI <25 kg/m2 (or <23 kg/m2 in Asian individuals) in the absence of “significant” alcohol intake.
Although first described in Asian populations, it is recognized that between 5% and 45% of patients with NAFLD are lean; even among European individuals, approximately 20% of patients are considered lean.
Although those with lean NAFLD have a better metabolic and histological profile compared with their counterpart obese subjects, their natural history is poorly defined, with some data suggesting they may have a worse outcome and accelerated disease progression,
More recent data propose that lean NAFLD comprises a distinct pathophysiological entity from that in obese subjects, which extends beyond just simple differences in BMI. In that study, lean patients had distinct metabolic and gut microbiota profiles compared with their obese counterparts and lean healthy controls. Specifically, they had intact metabolic adaptation in response to an obesogenic environment via increased bile acids and farnesoid X receptor activity that likely helped them to maintain an obesity-resistant phenotype. Notably, either this adaptation tends to be lost with advancement of disease or the failure to adapt promotes disease progression. Other intriguing aspects from a subset of the patients suggests that they have a distinct gut microbiota profile, with enrichment of species implicated in the generation of liver fat, and a genetic profile with an increased prevalence of the TM6SF2 risk allele,
Further studies will be required to explore whether the metabolic adaptation observed in lean NAFLD is seen in other subtypes of patients. 目前，瘦 NAFLD 或瘦个体中的 NAFLD 被定义为 BMI <25 kg/m 2 （或亚洲个体 <23 kg/m 2 ）的肝脂肪变性。没有“大量”饮酒。
Consistently, a recent prospective study including probands with NAFLD-cirrhosis and their first-degree relatives indicated that the risk of advanced fibrosis among first-degree relatives of patients with cirrhosis is 18%.
This is substantially higher than the risk of cirrhosis in the general population and points toward further substratification of the population by family history of cirrhosis due to NAFLD. 来自经过成像量化肝脏脂肪和纤维化的特征明确的双胞胎队列的数据表明，这两者都是可遗传的特征。
Genome-wide association and large candidate studies have identified multiple loci associated with NAFLD and NASH. Although in-depth discussion is beyond our scope, the topic has recently been reviewed.
At least 5 common variants in different genes have been associated with NAFLD, namely PNPLA3, transmembrane 6 superfamily member 2 (TM6SF2), glucokinase regulator (GCKR), MBOAT7, and hydroxysteroid 17-beta dehydrogenase-13 (HSD17B13).
Multiple other genes have reported associations, including polymorphisms in inflammatory, immune and metabolism-related, oxidative stress, adipokine, and myokine-related genes.
It is noteworthy, however, that all known variants explain only a small proportion of NAFLD, suggesting the existence of heritability factors that are yet to be defined.
Exploring the role of other types of genetic variation, gene-gene and gene-environment interactions, epigenetics, common variants that do not reach genome-wide significance, and rare and less common variants will help dissect the missing heritability.
Increased hepatic fat in overweight Hispanic youth influenced by interaction between genetic variation in PNPLA3 and high dietary carbohydrate and sugar consumption.
Increased hepatic fat in overweight Hispanic youth influenced by interaction between genetic variation in PNPLA3 and high dietary carbohydrate and sugar consumption.
Of interest, described NAFLD-related variants show divergent metabolic effects. Multiple reports indicate an association of a genetic variant of TM6SF2 (encoding p.Glu167Lys) with lower serum lipid levels and lower risk of coronary artery disease, but with increased risk of fatty liver and advanced fibrosis,
Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk.
An association of PNPLA3 rs738409 and TM6SF2 rs58542926 with type 2 diabetes has also been demonstrated beside the known association of GCKR rs1260326 with diabetes.
Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk.
Reversible epigenetic changes represent a plausible bridge between genes and the environment; their dysregulation is implicated in several diseases, including NAFLD.
Numerous microRNAs (miRNAs) have been linked to NAFLD. A recent meta-analysis demonstrated that in particular, miRNA-122, miRNA-34a, and miRNA-192 could be biomarkers of fatty liver disease.
miRNA-122 and miRNA-192 showed upregulation in NAFLD compared with healthy controls, whereas miRNA-34a was upregulated in NAFLD and correlated with disease severity.
Data on the role of long noncoding RNAs (lncRNAs) and other type of noncoding RNAs in NAFLD is limited. Some data suggest alterations in lncRNAs in NASH, such as a hepatic-specific lnc18q22.2,
Metastasis-associated lung adenocarcinoma transcript 1 as a common molecular driver in the pathogenesis of nonalcoholic steatohepatitis and chronic immune mediated liver damage.
The role of lncRNAs in steatohepatitis remains to be further elucidated in larger cohorts. 关于长非编码 RNA (lncRNA) 和其他类型非编码 RNA 在 NAFLD 中的作用的数据有限。一些数据表明 NASH 中 lncRNA 发生改变，例如肝脏特异性 lnc18q22.2、
Metastasis-associated lung adenocarcinoma transcript 1 as a common molecular driver in the pathogenesis of nonalcoholic steatohepatitis and chronic immune mediated liver damage.
Several studies show wide alterations in the methylation signature of hepatic as well as peripheral blood-derived DNA, including regulatory loci for key metabolic, inflammatory, and fibrotic pathways, in patients with NAFLD. Some of these signatures appear to reverse following bariatric surgery.
Targeted-bisulfite sequence analysis of the methylation of CpG islands in genes encoding PNPLA3, SAMM50, and PARVB of patients with non-alcoholic fatty liver disease.
More recently, a series of studies have shown evidence of methylation of the key mitochondrial urea cycle enzymes carbamoyl phosphate synthase-1 and ornithine transcarbamylase enzymes resulting in a reduction in their function and hyperammonemia in patients with NAFLD.
; treatment of hyperammonemia using ornithine phenylacetate prevented progression of fibrosis in an animal model, suggesting a potential novel metabolic therapeutic strategy.
Targeted-bisulfite sequence analysis of the methylation of CpG islands in genes encoding PNPLA3, SAMM50, and PARVB of patients with non-alcoholic fatty liver disease.
with growing evidence that the earliest origins of NAFLD extend to in utero experiences. Data from animals suggest that a maternal diet high in fat triggers widespread epigenetic alterations in fetal hepatic DNA, accompanied by metabolic maladaptation that favors an increase in the risk of developing NAFLD in the offspring.
Although data in humans are still limited, maternal obesity and patterns of infant nutrition are risk factors for the development of NAFLD in adolescence and adulthood. For instance, normal pregestational BMI and breast-feeding for more than 6 months reduces the risk of developing NAFLD in the mother during mid-life
Similarly, an increase in methylation of the peroxisome proliferator-activated receptor γ coactivator 1 (PGC1) gene that controls several aspects of energy metabolism in liver
Epigenetic regulation of insulin resistance in nonalcoholic fatty liver disease: impact of liver methylation of the peroxisome proliferator-activated receptor gamma coactivator 1alpha promoter.
Epigenetic regulation of insulin resistance in nonalcoholic fatty liver disease: impact of liver methylation of the peroxisome proliferator-activated receptor gamma coactivator 1alpha promoter.
Why Do We Need to Consider NAFLD Heterogeneity in Clinical Practice? 为什么我们在临床实践中需要考虑 NAFLD 的异质性？
Impact on the Performance of Noninvasive Assessment of Fibrosis 对纤维化无创评估性能的影响
Noninvasive fibrosis scores are commonly used to identify or exclude significant or advanced fibrosis in patients with fatty liver disease. However, a recent study suggested that the performance of scores such as the NAFLD fibrosis score and fibrosis 4 may vary across the life span, with lower specificity among older adults and lower accuracy in young adults.
The performance of noninvasive scores and the used Transient Elastography liver stiffness cutoffs in different ethnic populations and in special subpopulations such as diabetic and obese individuals also need to be considered. For example, it has been shown that blood biomarkers are less accurate in South Asian compared with European individuals, regardless of metabolic indices.
As it is likely that blood-based biomarkers or imaging techniques will supplant liver biopsy for the diagnosis of disease in patients who would benefit from drug treatment, equally it implies that any future marker should be validated in more precisely defined cohorts. Thus, the consensus group suggests that the factors that shape the heterogeneity of NAFLD be considered when devising and applying risk-stratification scores and algorithms. This approach will continue to evolve as new contributors to disease variability are identified. 非侵入性纤维化评分通常用于识别或排除脂肪肝患者的显着或晚期纤维化。然而，最近的一项研究表明，NAFLD 纤维化评分和纤维化 4 等评分的表现可能在整个生命周期中有所不同，老年人的特异性较低，年轻人的准确性较低。
This represents both a barrier to the development of novel therapeutics but also an opportunity to better understand steatohepatitis pathogenesis based on different drivers of disease. Considering that NAFLD as described today is not a single entity, exploring the overlapping features of preclinical models with subtypes of NAFLD may help in overcoming these challenges. For instance, it has been reported that the methionine adenosyltransferase 1A (Mat1a)-deficient mouse can recapitulate a subtype of human NAFLD,
Despite the range of available models, there remains a need to develop improved in vitro and in vivo model systems. 人类 NASH 的复杂性与动物模型的异质性以及这些模型无法复制所有疾病的能力相平行。
Impact on Clinical Trials Design and the Ability to Find Treatments 对临床试验设计和寻找治疗方法的影响
The growing magnitude of NAFLD and the lack of effective drug treatments is reflected in intense clinical trial activity that has jumped from just 8 in 2013 to more than 300 ongoing in 2018.
Unfortunately, response rates remain modest, with <20% to 30% of participants demonstrating NASH resolution and fibrosis regression. This low response can be attributed to many factors, including heterogeneity in population selection, lack of stratification based on the underlying dominant driver mechanisms, and the Hawthorne (placebo) effect.
Therefore, the standard clinical trial design that does not take into consideration disease heterogeneity may not be the best option for studying a complex disease. Thus, future clinical trials will likely target patients with specific characteristics (sex, hormonal status, genetic predisposition, metabolic and microbiota signatures, and the presence or absence of comorbid conditions) once the relationships between the characteristics and the treatment targets are understood. Such trial design will likely include rational combination approaches.
Considering alternative innovative trial designs might be a viable option (Figure 3). Recently, using overarching or master protocols designed to address multiple questions by investigating different drugs (more than 1 or 2 therapies that might even include direct comparisons of competing drugs) in different conditions (more than 1 patient type or disease), all within the same overall trial structure has been suggested.
Adaptive trial designs that provide flexibility for altering 1 or more aspects of the basic features of the study design based on responses in earlier phases is also an option,
although this will add substantial complexity to data interpretation. Notably, given the heterogeneity of NAFLD according to ethnicity and geographic region, regional stratification or performing separate trials in different geographic regions should be considered for key trials. 考虑替代创新试验设计可能是一个可行的选择（图 3）。最近，使用旨在解决多个问题的总体或主协议，通过研究不同条件（超过 1 种患者类型或疾病）下的不同药物（超过 1 种或 2 种疗法，甚至可能包括竞争药物的直接比较），所有这些都在同一条件下进行提出了总体试验结构。
Figure 3Innovative clinical trials for MAFLD. The substantial heterogeneity of patients with MAFLD and the limited responses to investigational targets in current clinical trials imply that innovative trial designs are required. Trial designs such as umbrella, basket, and adaptive designs have been suggested to overcome the challenges; however, such designs add complexity to the trial analysis. 图 3 MAFLD 的创新临床试验。 MAFLD 患者的显着异质性以及当前临床试验中对研究目标的有限反应意味着需要创新的试验设计。建议进行雨伞、篮子和适应性设计等试验设计来克服这些挑战；然而，这种设计增加了试验分析的复杂性。
Is NAFLD the Right Name for Metabolic Liver Disease? NAFLD 是代谢性肝病的正确名称吗？
How do the preceding considerations influence our thinking on the need to revise the definition and nomenclature for NAFLD? It is clearly the time to do this. The suggestion of this consensus focuses on 4 aspects. 上述考虑因素如何影响我们对修改 NAFLD 定义和命名的必要性的思考？显然是时候这样做了。本共识的建议主要集中在4个方面。
First, NAFLD was described as a condition of “exclusion,” which means that it exists only when other conditions, such as viral hepatitis B and C, autoimmune diseases, or alcohol intake above a particular threshold, are absent. However, with advancements in our understanding of the underlying pathological processes, it is clearly a disease that must be defined by inclusion, rather than by exclusion. Further, given its high prevalence in most affluent populations, especially those consuming a westernized diet, fatty liver disease is recognized to coexist with other conditions such as viral hepatitis, autoimmune diseases, and alcohol,
The nomenclature for fatty liver disease and criteria for diagnosis need to reflect this new knowledge. 首先，NAFLD 被描述为一种“排除”病症，这意味着它仅在不存在其他病症（例如病毒性乙型和丙型肝炎、自身免疫性疾病或酒精摄入量超过特定阈值）时才存在。然而，随着我们对潜在病理过程理解的进步，它显然是一种必须通过包容而不是排除来定义的疾病。此外，鉴于其在大多数富裕人群中的高患病率，尤其是那些食用西化饮食的人群，脂肪肝疾病被认为与病毒性肝炎、自身免疫性疾病和酒精等其他疾病共存，
Second, there remains debate about the safe limit of alcohol intake. Updating a diagnosis of NAFLD to zero or near to zero alcohol consumption as has been suggested by some is clearly impractical, as recently discussed.
Furthermore, there are significant methodological challenges in questionnaires used for measuring alcohol consumption including documenting prior and over-life use, low amounts of intake, patient underreporting, and recall bias, as well as marked variability in defining terms such as “social drinking” and “binging” in individuals with NAFLD. Thus, linking metabolic fatty liver disease, a distinct entity, to alcohol in its name is problematic. Moreover, including the term “nonalcoholic” in the name is disappointing for abstemious patients and links this entity to the stigma of alcohol consumption. Confounding terms in the name of these diseases should be replaced as has already been done with primary biliary cirrhosis becoming primary biliary cholangitis, with sometimes redundant but more accurate and clear words, defining the entity.
More importantly, there is an urgent need to identify coexisting metabolic and alcohol liver disease so that they may be treated appropriately. This group of patients is distinct from those with pure or predominant alcoholic cirrhosis. Such patients are currently excluded from all NASH trials. 其次，关于酒精摄入量的安全限度仍存在争议。正如最近所讨论的，将一些人建议的 NAFLD 诊断更新为零或接近零饮酒显然是不切实际的。
Third, although in clinical practice we segregate patients into those with NASH and those without, whether this is appropriate is a matter of debate. As we know, there is tremendous plasticity in metabolic liver disease over the life span and strong evidence that fibrosis is the major determinant of adverse outcomes.
Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi-national cohort study.
Hence, the current classification may be misleading and perhaps metabolic dysfunction associated fatty liver disease should be considered similar to other chronic liver diseases with some degree of activity and a stage of fibrosis, without dichotomous stratification into NASH and non-NASH. From a pathological perspective, this will result in improved disease classification, at least in the context of liver biopsy.
Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi-national cohort study.
Fourth, the heterogeneous nature of fatty liver diseases suggests that they cannot be considered or managed as a single condition with a “one size fits all” approach to therapy. Lack of consideration of heterogeneity impacts and detracts from our ability to precisely define the natural history of fatty liver phenotypes, to appropriately select for clinical trials that are weighted to demonstrate meaningful benefits, and to compare or pool results from the trials. For these reasons, an updated and appropriate nomenclature for the disease is the first step in the long path to deconvolution of disease heterogeneity. 第四，脂肪肝疾病的异质性表明，不能将其视为单一病症或采用“一刀切”的治疗方法进行管理。缺乏对异质性的考虑会影响和减损我们精确定义脂肪肝表型自然史、适当选择经加权以证明有意义的益处的临床试验以及比较或汇总试验结果的能力。由于这些原因，对该疾病进行更新且适当的命名是消除疾病异质性的漫长道路上的第一步。
Based on the preceding, participants agreed on the need for a revised and updated terminology; the bulk of respondents in the first round of survey suggested that the words metabolism, fat, and liver be included in some form in the name. The final vote favored Metabolic Associated Fatty Liver ± Disease (MAFL/MAFLD) (supported by 72.4% of participants). The second preference, Metabolic Fatty Liver ± Disease (MEFL/MEFLD), was supported by 17.2% (Supplementary Table 1). Thus, the panel suggests we eliminate the term “NAFLD” from the lexicon and replace it with metabolic associated fatty liver “MAFLD.” The term MAFLD represents the overarching umbrella of the common disease we treat and will have multiple subphenotypes, reflecting the dominant driver of disease. Obviously, many, if not most, patients will have overlapping contributions from other and distinct liver diseases that range from alcohol (regardless the amount) to viral hepatitis. The natural history of these latter groups is likely very different from those with pure metabolic dysfunction. 基于上述，与会者一致认为需要修订和更新术语；第一轮调查中的大部分受访者建议在名称中以某种形式包含新陈代谢、脂肪和肝脏等词。最终投票赞成代谢相关脂肪肝疾病 (MAFL/MAFLD)（72.4% 的参与者支持）。第二个偏好是代谢性脂肪肝 ± 疾病 (MEFL/MEFLD)，得到 17.2% 的支持（补充表 1）。因此，专家组建议我们从词典中删除术语“NAFLD”，并用代谢相关脂肪肝“MAFLD”取代。 MAFLD 一词代表了我们治疗的常见疾病的总体范围，并且具有多种亚表型，反映了疾病的主要驱动因素。显然，许多（如果不是大多数）患者都会受到其他不同肝脏疾病的重叠影响，这些疾病包括酒精（无论数量多少）到病毒性肝炎。后面这些群体的自然史可能与纯粹代谢功能障碍的群体有很大不同。
Conclusion 结论
The outdated NAFLD/NASH acronyms, the criteria for diagnosis, and a lack of adequate consideration of heterogeneity in risk profiles and treatment responsiveness represent barriers that hamper progress toward effective treatments. The consensus group has suggested an acronym (MAFLD) that we believe more accurately reflects current knowledge of fatty liver diseases associated with metabolic dysfunction that should replace NAFLD/NASH. In addition, we have identified gaps in current knowledge and highlight new strategies and tools to overcome the challenges (Supplementary Table 2). A summary of suggestions is provided in Table 1. The group acknowledges the many investigators in the field who have made similar well-reasoned pleas for a change in nomenclature. This work also opens up for wider consultation with the public, patients, regulators, and nonhepatology health care workers, the necessity for a nomenclature update. Future studies will allow us to further characterize and subphenotype the disease and its drivers as a necessary prerequisite for the design of more appropriate clinical trials and for patient management and to consider the implications of the updated nomenclature on clinical practice and public health policy (Figure 4). 过时的 NAFLD/NASH 缩写、诊断标准以及缺乏对风险状况和治疗反应异质性的充分考虑，都是阻碍有效治疗进展的障碍。共识小组提出了一个缩写词（MAFLD），我们认为它更准确地反映了当前对与代谢功能障碍相关的脂肪肝疾病的认识，应取代 NAFLD/NASH。此外，我们还发现了当前知识的差距，并强调了克服挑战的新策略和工具（补充表 2）。表 1 提供了建议摘要。该小组感谢该领域的许多研究人员对命名法的更改提出了类似的合理请求。这项工作还为公众、患者、监管机构和非肝病保健工作者提供了更广泛的咨询，这是更新术语的必要性。未来的研究将使我们能够进一步描述疾病及其驱动因素的特征和亚表型，作为设计更合适的临床试验和患者管理的必要先决条件，并考虑更新的命名法对临床实践和公共卫生政策的影响（图 4） ）。
Table 1Statements of the Consensus Panel 表 1 共识小组的声明
Nomenclature and definition of metabolic associated fatty liver disease (MAFLD) 代谢相关脂肪肝病 (MAFLD) 的命名和定义
•
We suggest that the nomenclature of NAFLD should be updated to MAFLD. 我们建议将 NAFLD 的命名更新为 MAFLD。
•
The diagnosis of MAFLD should be based on the presence of metabolic dysfunction not the absence of other conditions. MAFLD 的诊断应基于代谢功能障碍的存在，而不是不存在其他情况。
•
MAFLD can coexist with other liver diseases. MAFLD 可与其他肝脏疾病共存。
•
A reference to alcohol should not be included in the MAFLD acronym. MAFLD 首字母缩略词中不应包含对酒精的提及。
•
Patients with both MAFLD and a contribution from alcohol to their liver disease represent a large and important group that requires further investigation and characterization. 同时患有 MAFLD 和酒精导致肝病的患者是一个庞大且重要的群体，需要进一步研究和表征。
MAFLD heterogeneity MAFLD异质性
•
MAFLD is a heterogeneous entity. MAFLD 是一个异构实体。
•
Appropriate patient stratification must be considered when noninvasive fibrosis scores are developed and in clinical trial design. 在制定无创纤维化评分和临床试验设计时，必须考虑适当的患者分层。
•
Studies are required to map the landscape of MAFLD and to precisely define subtypes of the disease. 需要进行研究来绘制 MAFLD 的概况并精确定义该疾病的亚型。
Clinical trials for MAFLD MAFLD 的临床试验
•
Detailed patient stratification and tailoring clinical trial inclusion criteria based on drivers of disease will likely yield more informative and meaningful results. 详细的患者分层和根据疾病驱动因素定制临床试验纳入标准可能会产生更多信息和更有意义的结果。
•
Innovative designs for clinical trials and personalized combination therapy approaches will likely be required to overcome the challenges of disease heterogeneity and for optimal clinical efficacy. 可能需要临床试验和个性化联合治疗方法的创新设计来克服疾病异质性的挑战并获得最佳临床疗效。
Figure 4Implications of the proposed update to the MAFLD nomenclature. The growing burden of MAFLD in the absence of effective therapies requires an updated process map to address the challenges. The first step is an update of nomenclature, as without precise terminology, neither patient care nor science can be adequately served. This update of nomenclature we expect will be a step toward further characterization of disease heterogeneity. In turn, detailed phenotyping can guide the development of better preclinical models and identify novel therapies that are likely to be effective for particular patient subtypes, but not others. This will lead to improved clinical trial designs, allowing us to compare and pool results and thereby help reduce the impact of disease burden. 图 4 建议更新 MAFLD 术语的影响。在缺乏有效治疗的情况下，MAFLD 的负担日益沉重，需要更新流程图来应对挑战。第一步是更新术语，因为如果没有精确的术语，患者护理和科学都无法得到充分服务。我们期望这一命名法的更新将成为进一步表征疾病异质性的一步。反过来，详细的表型分析可以指导更好的临床前模型的开发，并确定可能对特定患者亚型有效但对其他亚型无效的新疗法。这将改进临床试验设计，使我们能够比较和汇总结果，从而有助于减轻疾病负担的影响。
Members of the International Consensus Panel: 国际共识小组成员：
Arun Sanyal, Virginia Commonwealth University School of Medicine, Richmond, Virginia. 阿伦·桑亚尔 (Arun Sanyal)，弗吉尼亚联邦大学医学院，弗吉尼亚州里士满。
Brent Neuschwander-Tetri, Division of Gastroenterology and Hepatology, Saint Louis University, St. Louis, Missouri. Brent Neuschwander-Tetri，密苏里州圣路易斯圣路易斯大学胃肠病学和肝病学部。
Claudio Tiribelli, Liver Center, Italian Liver Foundation, Trieste, Italy. Claudio Tiribelli，意大利肝脏基金会肝脏中心，意大利的里雅斯特。
David E. Kleiner, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. David E. Kleiner，马里兰州贝塞斯达国家癌症研究所癌症研究中心病理学实验室。
Elizabeth Brunt, Department of Pathology and Immunology Washington University School of Medicine, St, Louis, Missouri. Elizabeth Brunt，华盛顿大学医学院病理学和免疫学系，密苏里州圣路易斯。
Elisabetta Bugianesi, Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Turin, Turin, Italy. Elisabetta Bugianesi，意大利都灵大学医学科学系胃肠病学和肝病科。
Hannele Yki-Järvinen, Department of Medicine, University of Helsinki and Helsinki University Hospital, and Minerva Foundation Institute for Medical Research, Helsinki, Finland. Hannele Yki-Järvinen，赫尔辛基大学和赫尔辛基大学医院医学系，以及芬兰赫尔辛基密涅瓦基金会医学研究所。
Henning Grønbæk, Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark. Henning Grønbæk，丹麦奥胡斯大学医院肝病和胃肠病学系。
Helena Cortez-Pinto, Clínica Universitária de Gastrenterologia, Laboratório de Nutrição, Faculdade de Medicina, Universidade de Lisboa, Portugal. Helena Cortez-Pinto，葡萄牙里斯本大学医学院营养实验室胃肠病学大学诊所。
Jacob George, Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia Jacob George，斯托尔肝脏中心、韦斯特米德医学研究所、韦斯特米德医院和悉尼大学，新南威尔士州，澳大利亚
Jiangao Fan, Center for Fatty Liver, Department of Gastroenterology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. 范建高，上海交通大学医学院附属新华医院消化内科脂肪肝中心，中国上海。
Luca Valenti, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, and Translational Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy. Luca Valenti，米兰大学病理生理学和移植系，以及意大利米兰 IRCCS Ca' Granda Ospedale Maggiore Policlinico 基金会输血医学和血液学系转化医学。
Manal Abdelmalek, Department of Medicine, Duke University, Durham, North Carolina. Manal Abdelmalek，北卡罗来纳州达勒姆杜克大学医学系。
Manuel Romero-Gomez, Hospital Universitario Virgen del Rocío de Sevilla, Instituto de Biomedicina de Sevilla, Biomedical Research Networking Center in Hepatic and Digestive Diseases, Sevilla, Spain. Manuel Romero-Gomez，塞维利亚圣女罗西奥大学医院，塞维利亚生物医学研究所，肝脏和消化系统疾病生物医学研究网络中心，西班牙塞维利亚。
Mary Rinella, Department of Gastroenterology, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Mary Rinella，伊利诺伊州芝加哥西北大学范伯格医学院胃肠病学系。
Marco Arrese, Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile. Marco Arrese，智利圣地亚哥天主教大学医学院胃肠病学系。
Mohammed Eslam, Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia. Mohammed Eslam，斯托尔肝脏中心、韦斯特米德医学研究所、韦斯特米德医院和澳大利亚新南威尔士州悉尼大学。
Pierre Bedossa, Department of Pathology, Physiology and Imaging, Beaujon Hospital Paris Diderot University, Paris, France. Pierre Bedossa，法国巴黎巴黎狄德罗大学 Beaujon 医院病理学、生理学和影像学系。
Philip N. Newsome, National Institute for Health Research Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, UK; Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, UK; Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK. Philip N. Newsome，伯明翰 NHS 基金会信托大学医院和英国伯明翰大学国家健康研究所生物医学研究中心；英国伯明翰大学免疫学和免疫治疗研究所肝脏和胃肠研究中心；英国伯明翰大学医院 NHS 基金会信托基金会肝脏科。
Quentin M. Anstee, Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom. Quentin M. Anstee，纽卡斯尔大学医学科学院细胞医学研究所，泰恩河畔纽卡斯尔，英国；纽卡斯尔 NIHR 生物医学研究中心、纽卡斯尔医院 NHS 基金会信托基金，英国泰恩河畔纽卡斯尔。
Rajiv Jalan, Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom. Rajiv Jalan，英国伦敦皇家自由校区肝脏和消化健康研究所肝衰竭小组。
Ramon Bataller, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Ramon Bataller，宾夕法尼亚州匹兹堡匹兹堡大学医学中心胃肠病学、肝病学和营养科。
Rohit Loomba, Division of Epidemiology, Department of Family Medicine and Public Health, University of California at San Diego, La Jolla, California. Rohit Loomba，加利福尼亚大学圣地亚哥分校家庭医学和公共卫生系流行病学部，加利福尼亚州拉霍亚。
Silvia Sookoian, Department of Clinical and Molecular Hepatology, National Scientific and Technical Research Council (CONICET), University of Buenos Aires, Institute of Medical Research (IDIM), Ciudad Autónoma de Buenos Aires, Argentina. Silvia Sookoian，临床和分子肝病学系，国家科学技术研究委员会 (CONICET)，布宜诺斯艾利斯大学，医学研究所 (IDIM)，布宜诺斯艾利斯自治城，阿根廷。
Shiv K. Sarin, Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India. Shiv K. Sarin，印度新德里肝脏和胆道科学研究所肝病科。
Stephen Harrison, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. Stephen Harrison，英国牛津大学拉德克利夫医学系。
Takumi Kawaguchi, Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan. Takumi Kawaguchi，日本久留米大学医学院医学系胃肠病科。
Vincent Wai-Sun Wong, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong. Vincent Wai-Sun Wong，香港中文大学医学及治疗学系。
Vlad Ratziu, Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié Salpêtrière, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France. Vlad Ratziu，索邦大学、巴黎公共医院援助中心、Pitié Salpêtrière 医院、心脏代谢和营养研究所 (ICAN)，法国巴黎。
Yusuf Yilmaz, Department of Gastroenterology, School of Medicine, Marmara University, Istanbul, Turkey; Institute of Gastroenterology, Marmara University, Istanbul, Turkey. Yusuf Yilmaz，土耳其伊斯坦布尔马尔马拉大学医学院胃肠病学系；土耳其伊斯坦布尔马尔马拉大学胃肠病学研究所。
Zobair Younossi, Center for Liver Diseases, Department of Medicine, Inova Fairfax Hospital, Falls Church, Virginia. Zobair Younossi，弗吉尼亚州福尔斯彻奇伊诺瓦费尔法克斯医院医学部肝病中心。
Supplementary Material 补充材料
Supplementary Figure 1Conceptual framework of metabolic dysfunction and pathogenesis of MAFLD. For metabolic homeostasis, the neuroendocrine axes elicit multiple and complex responses that orchestrate with caloric intake, muscle mass, and physical activity, as well as with the enterohepatic circulation, including gut microbiota, bile acids, and their metabolites. These circles are interconnected at various levels. For example, adiponectin signaling from adipose tissue to liver, the liver (fibroblast growth factor 21) to the central nervous system, the duodenum (cholecystokinin) to the brain, and so on. These various inputs are integrated in the liver. Dysfunctional homeostatic responses at any of multiple levels are implicated in the heterogeneous pathogenesis of MAFLD. CNS, central nervous system. 补充图 1 代谢功能障碍和 MAFLD 发病机制的概念框架。为了实现代谢稳态，神经内分泌轴引发多种复杂的反应，这些反应与热量摄入、肌肉质量和身体活动以及肠肝循环（包括肠道微生物群、胆汁酸及其代谢物）协调一致。这些圈子在各个层面上相互关联。例如，脂联素信号从脂肪组织到肝脏，肝脏（成纤维细胞生长因子21）到中枢神经系统，十二指肠（胆囊收缩素）到大脑等。这些不同的输入被整合到肝脏中。任何多个水平的功能失调的稳态反应都与 MAFLD 的异质性发病机制有关。 CNS，中枢神经系统。
Supplementary Table 2Research Gaps and Future Directions 补充表 2 研究差距和未来方向
Metabolic associated fatty liver disease (MAFLD) diagnosis and classification: 代谢相关性脂肪肝（MAFLD）的诊断和分类：
1)
Define diagnostic criteria for MAFLD. 定义 MAFLD 的诊断标准。
2)
Define criteria for diagnosing MAFLD in the context of a second liver disease, for example, the level of alcohol consumption used to distinguish MAFLD from dual MAFLD and alcohol-associated liver disease. 定义在第二种肝脏疾病的情况下诊断 MAFLD 的标准，例如，用于区分 MAFLD 与双重 MAFLD 和酒精相关性肝病的饮酒水平。
3)
Should MAFLD be classified based on disease activity and stage rather than as a dichotomous state based on steatohepatitis and nonsteatohepatitis MAFLD. MAFLD 是否应根据疾病活动度和分期进行分类，而不是根据脂肪性肝炎和非脂肪性肝炎 MAFLD 进行二分法分类。
Deconvolution of MAFLD heterogeneity MAFLD 异质性的反卷积
Research to define MAFLD subtypes. 研究定义 MAFLD 亚型。
Implications of the update on nomenclature 术语更新的影响
Implications of this update on clinical practice, the International Classification of Diseases systems and Disease Related Groups, and public health policy. 此更新对临床实践、国际疾病分类系统和疾病相关群体以及公共卫生政策的影响。
Obese boys at increased risk for nonalcoholic liver disease: evaluation of 16 390 overweight or obese children and adolescents. 肥胖男孩患非酒精性肝病的风险增加：对 16 390 名超重或肥胖儿童和青少年的评估。
Int J Obes (Lond).2010; 34: 1468-1474 Int J Obes（伦敦）。 2010； 34：1468-1474
Heterogeneity of fibrosis patterns in non-alcoholic fatty liver disease supports the presence of multiple fibrogenic pathways. 非酒精性脂肪性肝病纤维化模式的异质性支持多种纤维化途径的存在。
“Not all forms of NAFLD were created equal.” Do metabolic syndrome-related NAFLD and PNPLA3-related NAFLD exert a variable impact on the risk of early carotid atherosclerosis?. “并非所有形式的 NAFLD 都是一样的。”代谢综合征相关的 NAFLD 和 PNPLA3 相关的 NAFLD 对早期颈动脉粥样硬化的风险有不同的影响吗？
Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. 肝纤维化与非酒精性脂肪肝患者的长期结局相关，但没有其他组织学特征。
Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi-national cohort study. 纤维化严重程度作为晚期非酒精性脂肪肝患者特定原因死亡率的决定因素：一项多国队列研究。
Hepatocellular carcinoma in the absence of cirrhosis in United States veterans is associated with nonalcoholic fatty liver disease. 美国退伍军人中没有肝硬化的肝细胞癌与非酒精性脂肪肝相关。
Fibrosis progression in nonalcoholic fatty liver versus nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. 非酒精性脂肪肝与非酒精性脂肪性肝炎的纤维化进展：配对活检研究的系统评价和荟萃分析。
Rates of and factors associated with placebo response in trials of pharmacotherapies for nonalcoholic steatohepatitis: systematic review and meta-analysis. 非酒精性脂肪性肝炎药物治疗试验中安慰剂反应的发生率及其相关因素：系统评价和荟萃分析。
Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. 使用配对活检证明 NAFLD 从脂肪变性进展为纤维化脂肪性肝炎：对预后和临床管理的影响。
The role of senescence in the development of non-alcoholic fatty liver disease and progression to non-alcoholic steatohepatitis. 衰老在非酒精性脂肪肝发展和非酒精性脂肪性肝炎进展中的作用。
Sarcopaenia is associated with NAFLD independently of obesity and insulin resistance: Nationwide surveys (KNHANES 2008–2011). 肌少症与 NAFLD 相关，与肥胖和胰岛素抵抗无关：全国调查（KNHANES 2008-2011）。
Sarcopenia is associated with significant liver fibrosis independently of obesity and insulin resistance in nonalcoholic fatty liver disease: nationwide surveys (KNHANES 2008–2011). 在非酒精性脂肪性肝病中，肌肉减少症与显着的肝纤维化相关，与肥胖和胰岛素抵抗无关：全国调查（KNHANES 2008-2011）。
The influence of menopause on the development of hepatic fibrosis in nonobese women with nonalcoholic fatty liver disease: reply. 更年期对患有非酒精性脂肪肝病的非肥胖女性肝纤维化发展的影响：答复。
A longer duration of estrogen deficiency increases fibrosis risk among postmenopausal women with nonalcoholic fatty liver disease. 雌激素缺乏持续时间较长会增加患有非酒精性脂肪肝的绝经后女性纤维化的风险。
Racial and ethnic disparities in nonalcoholic fatty liver disease prevalence, severity, and outcomes in the United States: a systematic review and meta-analysis. 美国非酒精性脂肪肝患病率、严重程度和结果的种族和民族差异：系统评价和荟萃分析。
Unexpected rapid increase in the burden of nonalcoholic fatty liver disease in China From 2008 to 2018: a systematic review and meta-analysis. 2008年至2018年中国非酒精性脂肪肝疾病负担意外快速增加：系统评价和荟萃分析。
Nonalcoholic fatty liver disease across ethno-racial groups: do Asian-American adults represent a new at-risk population?. 跨种族群体的非酒精性脂肪肝：亚裔美国成年人是否代表新的高危人群？
Prevalence of non-alcoholic fatty liver disease and advanced fibrosis in Hong Kong Chinese: a population study using proton-magnetic resonance spectroscopy and transient elastography. 香港华人非酒精性脂肪肝和晚期纤维化的患病率：使用质子磁共振波谱和瞬时弹性成像进行的人群研究。
Worldwide trends in insufficient physical activity from 2001 to 2016: a pooled analysis of 358 population-based surveys with 1.9 million participants. 2001 年至 2016 年全球身体活动不足趋势：对 190 万名参与者的 358 项人口调查进行汇总分析。
The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. 非酒精性脂肪肝的诊断和治疗：美国肝病研究协会的实践指南。
Modest alcohol consumption is associated with decreased prevalence of steatohepatitis in patients with non-alcoholic fatty liver disease (NAFLD). 适量饮酒与非酒精性脂肪肝 (NAFLD) 患者脂肪肝炎患病率降低相关。
Alcohol use and burden for 195 countries and territories, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016 (vol 392, pg 1015, 2018). 1990-2016 年 195 个国家和地区的酒精使用和负担：2016 年全球疾病负担研究的系统分析（第 392 卷，第 1015 页，2018 年）。
Interaction between alcohol consumption and metabolic syndrome in predicting severe liver disease in the general population. 饮酒与代谢综合征之间的相互作用在预测一般人群的严重肝病中。
Nonheavy drinking and worsening of noninvasive fibrosis markers in nonalcoholic fatty liver disease: a cohort study. 非酒精性脂肪肝病中非大量饮酒和非侵袭性纤维化标志物恶化：一项队列研究。
Effects of alcohol consumption and metabolic syndrome on mortality in patients with non-alcoholic and alcohol-related fatty liver disease. 饮酒和代谢综合征对非酒精性和酒精相关性脂肪肝患者死亡率的影响。
Åberg F, Puukka P, Salomaa V, et al. Risks of light and moderate alcohol use in fatty liver disease–follow-up of population cohorts [published online ahead of print July 19, 2019]. Hepatology https://doi.org/10.1002/hep.30864.
Among patients with nonalcoholic fatty liver disease, modest alcohol use is associated with less improvement in histologic steatosis and steatohepatitis. 在非酒精性脂肪肝患者中，适量饮酒与组织学脂肪变性和脂肪性肝炎改善较少相关。
Primary prevention of cardiovascular disease with a mediterranean diet supplemented with extra-virgin olive oil or nuts. 通过补充特级初榨橄榄油或坚果的地中海饮食对心血管疾病进行一级预防。
N Engl J Med.2018; 378: e34 N 英格兰医学杂志。 2018； 378：e34
Gut microbiome-based metagenomic signature for non-invasive detection of advanced fibrosis in human nonalcoholic fatty liver disease. 基于肠道微生物组的宏基因组特征，用于非侵入性检测人类非酒精性脂肪肝晚期纤维化。
Link between gut-microbiome derived metabolite and shared gene-effects with hepatic steatosis and fibrosis in NAFLD. 肠道微生物组衍生的代谢物与 NAFLD 中肝脂肪变性和纤维化的共同基因效应之间的联系。
Toll-like receptor 2 and palmitic acid cooperatively contribute to the development of nonalcoholic steatohepatitis through inflammasome activation in mice. Toll 样受体 2 和棕榈酸通过激活小鼠炎症小体共同促进非酒精性脂肪性肝炎的发生。
Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota. 全基因组关联分析确定了维生素 D 受体和影响肠道微生物群的其他宿主因素的变化。
Transition from metabolic healthy to unhealthy phenotypes and association with cardiovascular disease risk across BMI categories in 90 257 women (the Nurses' Health Study): 30 year follow-up from a prospective cohort study. 90 257 名女性的 BMI 类别从代谢健康表型向不健康表型的转变以及与心血管疾病风险的关联（护士健康研究）：前瞻性队列研究的 30 年随访。
Separate and combined associations of obesity and metabolic health with coronary heart disease: a pan-European case-cohort analysis. 肥胖和代谢健康与冠心病的单独和组合关联：泛欧洲病例队列分析。
Genome-wide and abdominal MRI-imaging data provides evidence that a genetically determined favourable adiposity phenotype is characterized by lower ectopic liver fat and lower risk of type 2 diabetes, heart disease and hypertension.
Increased hepatic fat in overweight Hispanic youth influenced by interaction between genetic variation in PNPLA3 and high dietary carbohydrate and sugar consumption.
Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk.
Metastasis-associated lung adenocarcinoma transcript 1 as a common molecular driver in the pathogenesis of nonalcoholic steatohepatitis and chronic immune mediated liver damage.
Targeted-bisulfite sequence analysis of the methylation of CpG islands in genes encoding PNPLA3, SAMM50, and PARVB of patients with non-alcoholic fatty liver disease.
Epigenetic regulation of insulin resistance in nonalcoholic fatty liver disease: impact of liver methylation of the peroxisome proliferator-activated receptor gamma coactivator 1alpha promoter.
Conflicts of interest The authors disclose the following: Rajiv Jalan, on the international consensus panel, has research collaborations with Takeda and Yaqrit, and consults for Akaza and Yaqrit. Rajiv Jalan is the founder of Yaqrit Limited, which is developing UCL inventions for treatment of patients with cirrhosis. Rajiv Jalan is an inventor of ornithine phenylacetate, which was licensed by UCL to Mallinckrodt. He is also the inventor of Yaq-001, DIALIVE, and Yaq-005, the patents for which have been licensed by his university into a UCL spinout company, Yaqrit Ltd. The rest of authors declare no competing interests for this manuscript. The remaining authors disclose no conflicts.
Funding Mohammed Eslam and Jacob George are supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney; a National Health and Medical Research Council of Australia (NHMRC) Program Grant (APP1053206, APP1149976); and Project Grants (APP1107178 and APP1108422). Philip N. Newsome, on the international consensus panel, is funded and supported by the National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham. The views expressed are those of the authors and not necessarily those of the NIHR, the Department of Health and Social Care or the NHS.
Figure 1Heterogeneity of MAFLD. The heterogeneity in clinical presentation and course of fatty liver disease is influenced by a multitude of factors, including age, sex, ethnicity, alcohol intake, dietary habits, hormonal status, genetic predisposition, and epigenetic factors, the microbiota, and metabolic status. It is likely that there is a differential impact in the contribution of the various factors in any individual over time and among individuals that then shapes disease phenotype and course.
Figure 2Interindividual variation in the predominant drivers of MAFLD. MAFLD is a complex phenotype shaped by the dynamic interaction of genetic predisposition with environmental factors and components of the metabolic syndrome. The effect size of genetic variants and the predominant drivers can exhibit marked interindividual variation. As an example, disease in patient 1 is driven predominantly by environmental influences with less contribution from genetic predisposition; in patient 2, metabolic syndrome is the predominant driver, whereas disease in patient 3 is driven by genetic factors with a limited contribution from other factors. Identification of the predominant drivers in every patient can help in personalization of medicine.
Figure 3Innovative clinical trials for MAFLD. The substantial heterogeneity of patients with MAFLD and the limited responses to investigational targets in current clinical trials imply that innovative trial designs are required. Trial designs such as umbrella, basket, and adaptive designs have been suggested to overcome the challenges; however, such designs add complexity to the trial analysis.
Figure 4Implications of the proposed update to the MAFLD nomenclature. The growing burden of MAFLD in the absence of effective therapies requires an updated process map to address the challenges. The first step is an update of nomenclature, as without precise terminology, neither patient care nor science can be adequately served. This update of nomenclature we expect will be a step toward further characterization of disease heterogeneity. In turn, detailed phenotyping can guide the development of better preclinical models and identify novel therapies that are likely to be effective for particular patient subtypes, but not others. This will lead to improved clinical trial designs, allowing us to compare and pool results and thereby help reduce the impact of disease burden.
Supplementary Figure 1Conceptual framework of metabolic dysfunction and pathogenesis of MAFLD. For metabolic homeostasis, the neuroendocrine axes elicit multiple and complex responses that orchestrate with caloric intake, muscle mass, and physical activity, as well as with the enterohepatic circulation, including gut microbiota, bile acids, and their metabolites. These circles are interconnected at various levels. For example, adiponectin signaling from adipose tissue to liver, the liver (fibroblast growth factor 21) to the central nervous system, the duodenum (cholecystokinin) to the brain, and so on. These various inputs are integrated in the liver. Dysfunctional homeostatic responses at any of multiple levels are implicated in the heterogeneous pathogenesis of MAFLD. CNS, central nervous system.
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