Redefining non-alcoholic fatty liver disease to metabolic associated fatty liver disease: Is this plausible?

Recently, a single letter change has taken the world by storm. A group of experts have developed a consensus to upgrade the term non-alcoholic fatty liver disease (NAFLD) to metabolic associated fatty liver disease (MAFLD), suggesting that MAFLD would more accurately reflect not only the disease pathogenesis but would also help in patient stratification for management with NAFLD. However, the difference of opinion exists, which has made the NAFLD vs MAFLD debate the current talk of the town. This review will focus on the plausibility and implications of redefining NAFLD as MAFLD.     

Transition of an acronym from nonalcoholic fatty liver disease to metabolic dysfunction-associated fatty liver disease

Nonalcoholic fatty liver disease(NAFLD) is a global public health concern owing to its substantial contribution to chronic liver diseases. The disease is closely linked to metabolic syndrome(MS), suggesting a common biological pathway and shared disease mechanism for both ailments. Previous studies revealed a close relationship of NAFLD with the components of MS including abdominal obesity,dyslipidemia, hypertension, and hyperglycemia. Hence, a group of experts recently renamed NAFLD as metabolic dysfunction-associated fatty liver disease(MAFLD) in order to encompass a more appropriate pathogenesis of the disease.NAFLD was first named to describe a condition similar to alcoholic hepatitis in absence of significant alcohol consumption. However, knowledge pertaining to the etiopathogenesis of the disease has evolved over the past four decades. Recent evidence endorses NAFLD as a terminology of exclusion and suggests that it may often leads to misdiagnosis or inappropriate management of patients, particularly in clinical practice. On the other hand, the new definition is useful in addressing hepatic steatosis with metabolic dysfunction, which ultimately covers most of the patients with such illness. Therefore, it seems to be helpful in improving clinical diagnosis and managing high-risk patients with fatty liver disease. However, it is imperative to validate the new terminology at the population level to ensure a holistic approach to reduce the global burden of this heterogeneous disease condition.     

酒精性脂肪肝（附25例肝活检病理分析）

本文报道我院１９８９年～１９９４年６月临床和病理证实的１２２例酒精性肝病（ＡＩＤ）中之２５例酒精性脂肪肝（ＡＦＬ），其中单纯酒精性脂肪肝１１例（占９．Ｏ％），余１４例分别合并酒精性肝炎、酒精性肝纤维化及酒精性肝硬化。制订低倍镜下脂变肝细胞占肝小叶的３０～５０％为轻度；５０～７０％为中度；７０％以上为重度脂肪肝的分级标准。对脂肪肝的诊断标准；饮酒时间与量和脂肪肝形成的关系；临床症状，实验室所见的参考价值；戒酒后脂肪肝消失的时间，Ｂ超对脂肪肝的诊断价值等进行了讨论。     

Non-alcoholic fatty liver disease: a multicentre clinical study by the Italian Association for the Study of the Liver

AIM: To define the characteristics of the Italian patient presenting non-alcoholic fatty liver disease. PATIENTS AND METHODS: A total of 305 patients with abnormally high plasma aminotransferase and/or gamma-glutamyl-transpeptidase levels for at least 12 months, with no known cause of chronic liver damage, were consecutively enrolled in the study. Clinical, routine biochemical and liver histology investigations were carried out in all patients. Also evaluated were: (a) oral glucose load; (b) insulinaemia and insulin-resistance using the HOMA test model; and (c) plasma endotoxaemia, total antioxidant plasma capability, tumour necrosis factor-alpha, plasma interleukin-6 and -10 levels. Malondialdehyde and 4-hydroxynonenal content were determined on liver samples from 120 patients. RESULTS: The majority of patients were young overweight or obese males, with dyslipidaemia (20-60%), diabetes (10.5%), hyperinsulinaemia (40%), hyperferritinaemia (35%). Endotoxaemia was negative in all patients and cytokines were only sporadically altered. Total antioxidant plasma capability was decreased in 38.4% of the patients. Eighty percent of the cases had histological steatosis with a mild degree of inflammation and fibrosis. Seven patients had cirrhosis. Lipid peroxidation markers were increased in 90% of the cases, inversely correlated with fibrosis. Even if at univariate analysis, age, ferritin and tissue 4-hydroxynonenal were independent factors of steatosis (P < 0.01), and insulin, HOMA and ferritin of inflammation and fibrosis (P < 0.01), at multivariate analysis no single factor was found to be an independent predictor of hepatic lesions. CONCLUSIONS: The typical Italian patient with non-alcoholic fatty liver disease is a young male, obese, not diabetic, with a variable incidence of dyslipidaemia and hyperinsulinaemia. Only liver biopsy may define the type of liver damage.     

细胞因子在脂肪性肝病中的作用

无论是酒精性脂肪肝还是非酒精性脂肪肝,其发病机制都与细胞因子息息相关.此文综述了多种细胞因子在脂肪肝发生发展过程中的作用,以及其介导的细胞凋亡在脂肪肝发病机制中的作用,阐述了某些细胞因子对脂肪肝的治疗应用.     

Characterization of patients with both alcoholic and nonalcoholic fatty liver disease in a large United States cohort

BACKGROUND Nonalcoholic fatty liver disease(NAFLD) is the hepatic manifestation of the metabolic syndrome(Met S) and is characterized by steatosis in the absence of significant alcohol consumption. However, Met S and significant alcohol intake coexist in certain individuals which may lead to the development of BAFLD.AIM To assess the clinical characteristics of patients with both alcoholic and NAFLD(BAFLD) in a large cohort in the United States.METHODS Adults from the National Health and Nutrition Examination Survey between2003-2014 were included. NAFLD was diagnosed based on elevated alanine aminotransferase(ALT) and being overweight or obese in the absence of other liver diseases. BAFLD patients met the criteria for NAFLD but also had either Met S or type 2 diabetes and consumed excessive amounts of alcohol. Univariable and multivariable analysis were performed to assess differences between NAFLD and BAFLD and to compare severity based on a validated fibrosis score(FIB4 index).RESULTS The prevalence of NAFLD was at 25.9%(95%CI; 25.1-26.8) and that of BAFLD was 0.84%(0.67, 1.02) which corresponds to an estimated 1.24 million Americans affected by BAFLD. Compared to NAFLD, patients with BAFLD were more likely to be male, smokers, have higher ALT, aspartate aminotransferase,triglycerides, and lower platelets; P 0.01 for all. More importantly, after adjusting for Met S components, BAFLD patients were significantly more likely to have advanced fibrosis [adjusted OR(95%CI) based on FIB4 index 2.67 was 3.2(1.4, 7.0), P = 0.004].CONCLUSION A significant percentage of the American general population is afflicted by BAFLD and these patients tend to have more advanced liver fibrosis.     

代谢相关脂肪性肝病肝外并发症研究进展与现状

代谢相关脂肪性肝病(metabolic associated fatty liver disease,MAFLD)是作为描述这种疾病的一个更合适的总括述语,新的定义将代谢功能障碍列为肝病的重要病因,论证了MAFLD的高异质性,加快了向新治疗的转化路径.MAFLD的肝外并发症其发生率和相关疾病,远远超过肝病本身,严重威脅着人类健康.鉴于当前人们对其严重性认识不足,且对肝外并发病的疾病范围、发病机制、诊断的研究还不完善,尤其当前对其缺乏有效的药物治疗,有鉴于此本文就MAFLD肝外并发症研究现状与进展作一介绍与述评,与广大读者共享.     

Non-alcoholic fatty liver disease: an overview

Non-alcoholic fatty liver disease (NAFL) includes a spectrum of clinicopathological conditions with increasing prevalence in the developed world. Although steatosis alone seems to have a benign course, those patients with the diagnosis of non-alcoholic steatohepatitis (NASH) can have a progressive course. Additionally, there is now evolving, indirect evidence that some of the patients with cryptogenic cirrhosis may be the result of 'burned-out' NASH. Although NAFL and NASH are associated with insulin-resistance syndrome, some patients with NAFL may have no obvious risk factors. Despite preliminary data from a number of pilot studies, no established therapies can be offered to patients with NASH. Over the next few years, a number of exciting research projects dealing with the epidemiology as well as the pathogenesis of NAFL are expected to be completed. It is anticipated that, through a better understanding of NAFL, more effective treatment protocols can be developed targeting only those patients with NASH that are at the highest risk for progression to cirrhosis and liver failure.     

Significance of gut microbiota in alcoholic and non-alcoholic fatty liver diseases

Liver-gut communication is vital in fatty liver diseases, and gut microbes are the key regulators in maintaining liver homeostasis. Chronic alcohol abuse and persistent overnutrition create dysbiosis in gut ecology, which can contribute to fatty liver disease. In this review, we discuss the gut microbial compositional changes that occur in alcoholic and nonalcoholic fatty liver diseases and how this gut microbial dysbiosis and its metabolic products are involved in fatty liver disease pathophysiology. We also summarize the new approaches related to gut microbes that might help in the diagnosis and treatment of fatty liver disease.     

Intestinal virome: An important research direction for alcoholic and nonalcoholic liver diseases

In recent years, the interaction between the gut microflora and liver diseases has attracted much attention. The intestinal microflora is composed of bacteria, archaea, fungi and viruses. There are few studies on the intestinal virome, and whether it has a causal relationship with bacterial changes in the gut is still unclear. However, it is undeniable that the intestinal virome is also a very important portion of the blueprint for the development of liver diseases and the diagnosis and therapeutic modalities in the future.     

内毒素与脂肪肝的关系研究进展

脂肪肝时常伴有肠源性内毒素血症,内毒素不仅对肝细胞有直接的损伤作用,而且可通过激活库普弗细胞(KC)释放一系列生物活性物质,以及可能促进肝脏自然杀伤T细胞减少,导致促炎和抗炎免疫反应失衡,引起肝脏损害,从而加重内毒素的作用.     

Unmet needs in pediatric NAFLD research: what do we need to prioritize for the future?

ABSTRACT

Introduction: Pediatric nonalcoholic fatty liver disease (NAFLD) is common disorder that has complex pathophysiology and unquantified clinical significance. Though there have been major advances in the field, there is much yet to be understood.

Areas covered: PubMed/MEDLINE and Embase were searched for articles related to pediatric NAFLD and nonalcoholic steatohepatitis (NASH) between January 1998 and January 2018. The areas considered to be ‘unmet needs’ were the relationship between the intestinal microbiome and perinatal events, clinical event risk stratification, and mechanisms underlying portal inflammation.

Expert commentary: In utero and ex utero factors have been associated with NAFLD and also with the intestinal microbiome, but it is not yet known how intestinal dysbiosis can be reversed and whether intervention in high-risk neonates could alter their propensity for the metabolic syndrome. Children with NAFLD are at increased risk of cardiovascular, diabetic, and hepatic diseases, but it is unclear how best to stratify children into appropriate risk groups for targeted interventions. Finally, the immune processes underlying pediatric NASH are thought to differ to those in adult NASH, yet the events surrounding activation of periportal lymphocytes are poorly understood. Deepening our understanding of these topics may lead to novel therapeutic targets.     

Comparison between metabolic-associated fatty liver disease and nonalcoholic fatty liver disease: From nomenclature to clinical outcomes

As a result of the obesity epidemic, Nonalcoholic fatty liver disease (NAFLD) and its complications have increased among millions of people. Consequently, a group of experts recommended changing the term NAFLD to an inclusive terminology more reflective of the underlying pathogenesis; metabolic-associated fatty liver disease (MAFLD). This new term of MAFLD has its own disease epidemiology and clinical outcomes prompting efforts in studying its differences from NAFLD. This article discusses the rationale behind the nomenclature change, the main differences, and its clinical implications.     

How common is non‐alcoholic fatty liver disease in the Asia–Pacific region and are there local differences?

Risk factors for development of non-alcoholic steatohepatitis include obesity, especially central adiposity, glucose intolerance or type 2 diabetes mellitus (T2DM), and dyslipidemia. Non-alcoholic fatty liver disease (NAFLD) is now considered a manifestation of metabolic syndrome. During the last two decades, NAFLD has become the most common chronic liver disease in North America and Europe, but until recently was thought to be uncommon (perhaps due to the lack of study) in Asia. Fatty liver can be identified on imaging modalities (ultrasonography, computed tomography scans, and magnetic resonance imaging) with high sensitivity, but steatohepatitis and fibrosis cannot be distinguished. Thus, an inherent drawback in studying the epidemiology of NAFLD is the lack of definitive laboratory tests, no uniform definition-with different studies using cut-off values of alcohol consumption from <20 g/week to 210 g/week, and case selections where biopsy was used for definition. In studies outside the region, the prevalence of NAFLD varies from 16% to 42% by imaging, and 15-39% of liver biopsies. The major risk factors for NAFLD, central obesity, T2DM, dyslipidemia, and metabolic syndrome, are now widely prevalent and are increasing geometrically in the Asia-Pacific region. It is therefore not surprising that NAFLD is common in this region. Estimates of current prevalence range from 5% to 30%, depending on the population studied. Central obesity, diabetes, and metabolic syndrome are the major risk factors. To date, however, data on the natural history and impact of NAFLD causing serious significant chronic liver disease are lacking and there is a need for prospective, cooperative studies.     

Fatty Liver: a Link to Cardiovascular Disease – Its Natural History,Pathogenesis, and Treatment

Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent liver disease in western society and is increasing in parallel with the worldwide epidemic of obesity. It exists in a simple form, steatosis, or a more complex and more dangerous form, steatohepatitis, and it is often but not always associated with the metabolic syndrome. NAFLD can progress to cirrhosis and hepatocellular carcinoma. It is responsible for the majority of cryptogenic cirrhosis cases. Increasingly, NAFLD and its more sinister form, steatohepatitis, have been linked to the increased incidence of cardiovascular disease (CVD) worldwide, independent of the metabolic syndrome. Death from CVD surpasses death from liver complications, but that is beginning to change as people are living longer with CVD. In this article, we will review nonalcoholic fatty liver disease and its epidemiology, prevalence, pathology, and link to CVD.     

Concurrent nonalcoholic fatty liver disease and type 2 diabetes: diagnostic and therapeutic considerations

ABSTRACT

Introduction: The relationship between nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) is complex and bidirectional. NAFLD increases the risk of incident diabetes and is very prevalent in T2DM patients and T2DM is an aggravating factor for NAFLD. Timely T2DM diagnosis and treatment in subjects with NAFLD and diagnosis, staging and treatment of NAFLD in those with T2DM are critical issues.

Areas covered: PubMed/MEDLINE was searched for articles related to concomitant occurrence of NAFLD and T2DM between January 2013 and May 2019. Areas covered included epidemiological, diagnostic and therapeutic aspects.

Expert opinion: there is a need for increased awareness on NAFLD adding liver disease as an end-organ complication of T2DM. Emphasis on use of simple non-invasive tools to triage patients with potentially severe liver disease should be made. Management of patients with NAFLD and T2DM relies on lifestyle optimization to achieve significant weight loss. Currently, there is no drug approved for treatment of NAFLD in patients with T2DM although Vitamin E and pioglitazone might be used in selected patients. Approved diabetic medications hold promise for NAFLD treatment and several liver-specific drugs are in evaluation clinical trials. A combination approach will likely represent the future of NAFLD therapeutics.     

Characteristics of intestinal bacteria with fatty liver diseases and cirrhosis

Non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD) are significant health burdens worldwide with a substantial rise in prevalence. Both can progress to liver cirrhosis. Recent studies have shown that the gut microbiome was associated with NAFLD/AFLD development and progression. The present review focuses on the characteristics of bacteria in NAFLD, AFLD and liver cirrhosis. The similarities and differences of intestinal bacteria are discussed.This study reviews the existing literatures on the microbiota, fatty liver disease, and liver cirrhosis based on Pubmed database.The study showed NAFLD was characterized by increased amounts of Lachnospiraceae from the phylum Firmicutes and Roseburia from the Lachnospiraceae family, and the proportion of Enterobacteria and Proteobacteria was increased after alcohol intake. Reduced Bacteroidetes was observed in cirrhosis. Microbiota can improve or aggravate the above liver diseases through several mechanisms, like increasing liver lipid metabolism, increasing alcohol production, increasing intestinal permeability, bacterial translocation, intestinal bacterial overgrowth, enteric dysbiosis, and impairing bile secretion.Different hepatic diseases owned different intestinal bacterial characters. Microbiota can improve or aggravate three kinds of liver diseases through several mechanisms. However, the depletion of these bacteria is needed to verify their role in liver disease.