273 © Springer Nature Switzerland AG 2020 F. Radu-Ionita et al. (eds.), Liver Diseases, https://doi.org/10.1007/978-3-030-24432-3_26 Nonalcoholic Fatty Liver Disease: A Wide Spectrum Disease Natalia Rosso and Stefano Bellentani 26.1 Introduction In 1980, Ludwig et al. [1] used the term Nonalcoholic Fatty Liver Disease (NAFLD) to describe a panel of liver injuries similar to alcoholic hepatitis that occurred in absence of rel- evant alcohol consumption or other known causes of chronic liver disease (HCV, HBV, drugs, etc.). Nowadays NAFLD has emerged as a major cause of chronic liver disease. Particularly, NASH is increasing as an etiology for end-stage liver disease as well as for hepatocel- lular carcinoma (HCC)-related liver transplantation and is expected to surpass hepatitis C for this indication in the next years. NAFLD is strongly related to insulin resistance (IR) and is associated to clinical conditions such as overweight or obesity, type 2 diabetes mellitus (T2DM), hypertension, hypertriglyceridemia and low HDL-cholesterol (all of which constitute essential elements in the spectrum of metabolic syndrome (MS)). Overweight and obesity global epidemic burdens in both developed and developing countries. Such is the magnitude of the problem that the World Health Organization (WHO) has introduced the term “Globesity” to defne the phenomenon. This booming of obesity is in paral- lel with the increasing incidence of NAFLD and NASH. NAFLD is not only referred to adults, but there is now growing evidence indicating that NAFLD is the most com- mon cause of liver disease also in the pediatric population. This worrisome trend is a mirror of the spread of hyperca- loric diets and sedentary life habits among children and ado- lescents. Thus, its incidence in this young population represents the major threat to the upcoming years. To date, there is no consensus concerning an effective pharmacological treatment for NASH, and the only currently recommended treatment is based on lifestyle modifcations (diet and physical activity). However, the lack of compliance is still the main obstacle to overcome. Nowadays, drug inter- ventions consist of the association of several drugs as an attempt to reverse the co-morbidities of the MetS. Interestingly, it worth to be mentioned that NAFLD, although at a lower prevalence, might occur also in nonobese subjects (the so-called “lean” NAFLD) suggesting that other genetic factors different from obesity might play a determi- nant role in the onset of this disorder. Despite the signifcant role that NAFLD has on health care systems worldwide and more than 200 clinical trials ongoing around the world, NAFLD and NASH still remain without any approved therapy. In this chapter, readers will fnd information about the most recent data regarding the epidemiology, associated risk factors, pathogenesis, available experimental models, diag- nosis and the available treatment options for NAFLD. N. Rosso (*) Fondazione Italiana Fegato, Basovizza, Trieste, Italy e-mail: natalia.rosso@fegato.it S. Bellentani (*) Clinica Santa Chiara SA, Locarno, Switzerland e-mail: s.bellentani@clinicasantachiara.ch 26 Key Concepts • NAFLD is a major cause of chronic liver disease, and its estimated global prevalence is 24% • NAFLD is expected to become in few years the most frequent cause for the indication of liver transplantation • The increasing worldwide incidence of NAFLD is tightly associated with the booming of obesity and Type 2 Diabetes Mellitus • NAFLD is not only referred to adults but is the most common cause of liver disease also in the pediatric population • It is a wide spectrum progressive disease that affects several organs • To date, the proposed nutraceutical and pharmaceu- tical treatments have not yet provided solid results