Despite the substantial gains in our understanding of NAFLD/NASH over the past 2 decades, there has been some dissatisfaction with the terminology “non‐alcoholic” which overemphasizes “alcohol” and ...underemphasizes the root cause of this liver disease, namely, the predisposing metabolic risk factors. As a potential remedy, a name change from NAFLD to metabolic associated fatty liver disease (MAFLD) has been proposed. Although MAFLD reflects the relevant risk factors for this liver disease, this term is still suboptimal, leaving a great deal of ambiguity. Here, we caution that changing the name without understanding its broad implications can have a negative impact on the field. In this context, changing the terminology without new understanding of the molecular basis of the disease entity, new insights in risk stratification or other important aspect of this liver disease, can create unnecessary confusion which could negatively impact the field. At a time when the field is facing substantial challenges around disease awareness as well as clarity of acceptable endpoints for drug development and biomarker discovery, changing the terminology from one suboptimal name to another suboptimal name without full assessment is expected to deepen these challenges. In the context of this debate about terminology, we recommend the creation of a true international consensus group to include all the relevant scientific liver societies (AASLD, EASL, ALEH, APASL), patient advocacy organizations, bio‐pharmaceutical industry, regulatory agencies and policy makers. A consensus meeting must assess the impact and consequences of changing the terminology based on the available evidence and make recommendations that will move the field forward. By this approach, a true collaborative international and inclusive consensus can be adopted by all stakeholders dealing with this important global liver disease.
Abstract The exposure of hepatocytes to high concentrations of lipids and carbohydrates and the ensuing hepatocellular injury are termed lipotoxicity and glucotoxicity, respectively. A common ...denominator is metabolic derangement, especially in regards to intracellular energy homeostasis, which is brought on by glucose intolerance and insulin resistance in tissues. In this review, we highlight the lipids and carbohydrates that provoke hepatocyte injury and the mechanisms involved in lipotoxicity and glucotoxicity, including endoplasmic reticulum stress, oxidative stress and mitochondrial impairment. Through upregulation of proteins involved in various pathways including PKR-like ER kinase (PERK), CCAAT/enhancer-binding homologous protein (CHOP), c-Jun NH2-terminal kinase-1 (JNK), Bcl-2 interacting mediator (BIM), p53 upregulated modulator of apoptosis (PUMA), and eventually caspases, hepatocytes in lipotoxic states ultimately undergo apoptosis. The protective role of certain lipids and possible targets for pharmacological therapy are explored. Finally, we discuss the role of high fructose and glucose diets in contributing to organelle impairment and poor glucose transport mechanisms, which perpetuate hyperglycemia and hyperlipidemia by shunting of excess carbohydrates into lipogenesis.
Aims
To conduct a systematic literature review to identify recent epidemiological, biomarker, genetic and clinical evidence that expands our understanding of nonalcoholic fatty liver disease (NAFLD) ...as a metabolic disorder.
Materials and Methods
We performed a literature search using PubMed to identify trials, observational studies and meta‐analyses published in the past 5 years.
Results
A total of 95 publications met prespecified inclusion criteria and reported on the interplay between NAFLD/nonalcoholic steatohepatitis (NASH) and metabolic dysfunction, in terms of disease burden and/or epidemiology (n = 10), pathophysiology, risk factors and associated conditions (n = 29), diagnosis and biomarkers (n = 34), and treatment approaches (n = 22). There is a growing body of evidence on the links between NAFLD/NASH pathogenesis and mechanisms of metabolic dysfunction, through liver lipid accumulation, insulin resistance, inflammation, apoptosis, and fibrogenic remodelling within the liver. The frequent co‐occurrence of NAFLD with obesity, metabolic syndrome and type 2 diabetes supports this premise. Therapeutic approaches originally envisaged for type 2 diabetes or obesity (such as glucagon‐like peptide‐1 receptor agonists, sodium‐glucose co‐transporter‐2 inhibitors, insulin sensitizers and bariatric surgery) have shown promising signs of benefit for patients with NAFLD/NASH.
Conclusions
Given the complex interplay between NAFLD and metabolic dysfunction, there is an urgent need for multidisciplinary collaboration and established protocols for care of patients with NAFLD that are individualized and ideally support reduction of overall metabolic risk as well as treatment for NASH.
Most patients with hepatocellular carcinoma (HCC) have liver cirrhosis, which develops following long periods of chronic liver disease. Cirrhosis is characterized by a decrease in hepatocyte ...proliferation, indicating an exhaustion of the regenerative capacity of the liver, and results in an increase in fibrous tissue and a destruction of liver cells, which may ultimately lead to the development of cancerous nodules. Half of all cases of HCC are associated with hepatitis B virus infection, with a further 25% associated with hepatitis C virus. Other risk factors for developing HCC include alcoholic liver disease, nonalcoholic steatohepatitis, intake of aflatoxin‐contaminated food, diabetes, and obesity. There are multiple factors involved in the etiology of HCC, all of which have a direct impact on patient characteristics and disease course, and although a causative agent can often be identified, HCC remains an extremely complex condition associated with a poor prognosis. Additionally, the geographic variation in etiology means that information from different countries is needed in order to optimize surveillance methods and develop effective chemoprevention strategies. Unfortunately, there are still many gaps in our current understanding, and further research efforts are needed to fully elucidate the diverse mechanisms involved in the pathogenesis of HCC and offer optimal prevention strategies for those at risk.
The etiology of hepatocellular carcinoma and the mechanisms thought to be involved in hepatocarcinogenesis are reviewed, and the influence of differing etiologies on patient management is considered.
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease (CLD) in North America. It is a growing contributor to the burden of CDL requiring liver transplantation. ...Cirrhosis is also associated with an increased risk of hepatocellular cancer, which may occur even in the absence of cirrhosis in subjects with nonalcoholic steatohepatitis (NASH), the histological form of NAFLD associated with increased liver‐related mortality. The diagnosis of NASH currently requires a liver biopsy. There are also no U.S. Food and Drug Administration (FDA)‐approved therapies for NASH. Therefore, there is a need to develop better diagnostic and therapeutic strategies for patients with NASH, targeting both those with early‐stage disease as well as those with advanced liver fibrosis. There are unique challenges in the design of studies for these target populations. The long relatively asymptomatic time interval in the progression of NAFLD and NASH to cirrhosis and ultimately liver failure, along with gaps in knowledge regarding disease modifiers, combine to present significant challenges in trial design. Therefore, there is an urgent need to develop methods to identify the populations at particular risk of disease progression and validate endpoints that reflect meaningful changes in health status in this population. This article summarizes the discussion at a joint workshop held September 5 and 6, 2013 in Silver Spring, Maryland, sponsored by the FDA and the American Association for the Study of Liver Diseases to develop guidance on diagnostic and therapeutic modalities for NASH. (Hepatology 2015;61:1392–1405)
Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of conditions characterized histologically by mainly macrovesicular hepatic steatosis and occurs in those who do not consume alcohol in ...amounts generally considered to be harmful to the liver. There are 2 histologic patterns of NAFLD: fatty liver alone and steatohepatitis. NAFLD is an increasingly recognized cause of liver-related morbidity and mortality. In this review, the existing literature regarding the nomenclature, clinical and histologic spectrum, natural history, diagnosis, and management of this condition are discussed.
GASTROENTEROLOGY 2002;123:1705-1725
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.
PDF
