Non-Alcoholic Fatty Liver Disease A 360-degree Overview Elisabetta Bugianesi Editor 123 Non-Alcoholic Fatty Liver Disease Elisabetta Bugianesi Editor Non-Alcoholic Fatty Liver Disease A 360-degree Overview Editor Elisabetta Bugianesi Department of Medical Sciences Division of Gastroentrology and Hepatology University of Turin Turin Italy ISBN 978-3-319-95827-9 ISBN 978-3-319-95828-6 (eBook) https://doi.org/10.1007/978-3-319-95828-6 © Springer Nature Switzerland AG 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. 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This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland To our cherished colleague and friend Valerio Nobili, a brilliant scientist and an extraordinary person. Preface The term “nonalcoholic fatty liver disease” (NAFLD) was coined by gastroenter- ologists almost 20 years ago to define a spectrum of progressive liver disease that encompasses simple steatosis, nonalcoholic steatohepatitis (NASH, which is char- acterized by the presence of steatosis, necroinflammation, with/without fibrosis), and ultimately cirrhosis. The same entity was also well known to diabetologists and regarded as an epiphenomenon of the metabolic syndrome. Dramatic changes in the lifestyle of the global population have been fueling a worldwide increase of obesity and its comorbidities, including NAFLD. It is estimated that the burden of end-stage liver disease will increase two- to threefold in both Western nations as well as sev- eral Asian countries by 2030, and NAFLD is set to replace viral hepatitis as the primary cause of end-stage liver disease and liver transplantation over the next decade or so, with the disease affecting both adults and children. It is clear that NAFLD is a complex disease, with considerable variation in severity among indi- viduals as a result of the interplay between host genetics, the environment (diet in particular) and other factors, such as the gut microbiota. Accurate diagnosis and staging of NAFLD are of utmost importance, with histological examination the gold standard in diagnosis so far. However, novel noninvasive methods to diagnose liver disease are rapidly evolving. Upon diagnosis of NAFLD or NASH, appropriate management must be started. Importantly, NAFLD can be managed successfully with diet and lifestyle changes, but pharmacological intervention is warranted when these methods fail. Many challenges lie ahead in the NAFLD field. NAFLD is a global problem, and, ultimately, from a societal perspective, it will be essential to attack the root cause of NAFLD to reduce the burden of diseases related to caloric excess and disordered metabolism. This goal will require a broad effort of all stake- holders to address the social, economic, cultural, and medical underpinning of obe- sity and its related conditions, including NAFLD. The aim of this book is to provide a comprehensive review of the present stand- ing of NAFLD. I wish to thank the Authors, whose brilliant work has been of utmost importance for the current understanding of this disease, for sharing their knowl- edge in this book. Turin, Italy Elisabetta Bugianesi vii Contents 1 Obesity and NAFLD: Same Problem? . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Lucia Brodosi, Francesca Alessandra Barbanti, Maria Letizia Petroni, Francesca Marchignoli, and Giulio Marchesini 2 The Burden of NAFLD Worldwide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Zobair Younossi and Linda Henry 3 Histopathology of Nonalcoholic Fatty Liver Disease . . . . . . . . . . . . . . . 25 Dina G. Tiniakos and Stratigoula Sakellariou 4 NAFLD and Insulin Resistance: A Multisystemic Disease . . . . . . . . . . 49 A. Gastaldelli 5 Etiopathogenesis of NAFLD: Diet, Gut, and NASH . . . . . . . . . . . . . . . 73 Luca Miele, Marco Biolato, Caterina Conte, Francesca Mangiola, Antonio Liguori, Antonio Gasbarrini, and Antonio Grieco 6 Mechanisms of Fibrogenesis in NASH . . . . . . . . . . . . . . . . . . . . . . . . . . 97 Mirella Pastore, Alessandra Gentilini, and Fabio Marra 7 The Natural History of NAFLD: Environmental vs. Genetic Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . 129 Luca Valenti and Serena Pelusi 8 NAFLD, Diabetes, and Other Endocrine Diseases: Clinical Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 Giovanni Targher and Alessandro Mantovani 9 NAFLD and Cardiovascular and Cardiac Disease: Clinical Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169 Eleonora Scorletti and Christopher D. Byrne 10 NAFLD, Hepatocellular Carcinoma, and Extrahepatic Cancers . . . . . 199 Ramy Younes and Elisabetta Bugianesi 11 NAFLD in Children: Implication for the Future . . . . . . . . . . . . . . . . . . 211 Claudia Della Corte, Antonella Mosca, Andrea Pietrobattista, Maria Sole Basso, and Valerio Nobili ix x Contents 12 Diagnostic Algorithm for the Identification of NAFLD in Primary Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 Helena Cortez-Pinto 13 Non-invasive Diagnostic Approach to NASH: Biological Markers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235 Salvatore Petta and Aurora Giannetti 14 Noninvasive Diagnostic Approach to NASH: Radiological Diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257 Monica A. Tincopa and Stephen A. Harrison 15 Dietary Approach to NAFLD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271 Yolanda Sánchez-Torrijos, Leticia Álvarez-Amor, Rocío Aller, Pedro Pablo García-Luna, Franz Martín, and Manuel Romero-Gómez 16 Physical Activity in NAFLD: What and How Much? . . . . . . . . . . . . . . 289 K. Hallsworth and M. Trenell 17 Pharmacological Options for NASH . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309 Christiane Stern and Vlad Ratziu 18 Bariatric Surgery and NASH: A Feasible Option . . . . . . . . . . . . . . . . . 329 Lidia Castagneto-Gissey, James R. Casella-Mariolo, and Geltrude Mingrone 19 Liver Transplantation and NAFLD/NASH . . . . . . . . . . . . . . . . . . . . . . . 343 Damiano Patrono, Silvia Martini, and Renato Romagnoli Obesity and NAFLD: Same Problem? 1 Lucia Brodosi, Francesca Alessandra Barbanti, Maria Letizia Petroni, Francesca Marchignoli, and Giulio Marchesini 1.1 Obesity, Lipotoxicity, and the Metabolic Syndrome 1.1.1 Pathophysiology Obesity, i.e., accumulation of body fat, stems from positive energy balance, inde- pendently of the absolute amount of calorie intake and energy expenditure via phys- ical activity. According to Unger hypothesis [1], adipocytes were specifically developed to protect organs and tissues during periods of overnutrition, also provid- ing reserve for periods of undernutrition. To satisfy these needs, the adipocytes turned into a versatile endocrine gland, able to regulate food intake via leptin, acting on hypothalamus. A second hormone, adiponectin, counterbalances the action of leptin and is reduced in obesity [2]. Mutation in leptin and leptin receptors genes and changes in leptin and adiponectin levels might regulate fat accumulation, but unhealthy lifestyle probably remains the most relevant factor responsible for increased total body fat. Under these conditions, fatty acid recirculation may exceed the anti-steatotic potential of adipose tissue, and lipotoxic disease develops, charac- terized by fatty infiltration of non-adipose organs and tissues, including the liver. The secretion of pro-inflammatory cytokines and pro-oxidant substances by adipose tissue favors insulin resistance on glucose and lipid metabolism, leading to a cluster of metabolic changes grouped to define the metabolic syndrome (MetSyn). The definition of MetSyn changed in the course of the years; obesity per se has never been considered a mandatory feature, but waist circumference (a surrogate marker of visceral obesity) was always included and the cutoffs, also related to gender and ethnic differences, were progressively reduced to include cases classified in the L. Brodosi · F. A. Barbanti · M. L. Petroni · F. Marchignoli · G. Marchesini (*) Department of Medical and Surgical Sciences, “Alma Mater” University of Bologna, Bologna, Italy e-mail: [email protected]; [email protected]; [email protected] © Springer Nature Switzerland AG 2020 1 E. Bugianesi (ed.), Non-Alcoholic Fatty Liver Disease, https://doi.org/10.1007/978-3-319-95828-6_1 2 L. Brodosi et al. overweight range by body mass index (BMI). Alberti and Zimmet first proposed enlarged waist circumference as mandatory feature [3], and the proposal was fol- lowed by the International Diabetes Federation [4] and is now widely accepted. In a pivotal study based on statistical analysis of factors associated with the so-called insulin-resistance syndrome, Maison et al. identified BMI and waist-to-hip ratio (a surrogate marker of visceral obesity) as the core components of MetSyn, supporting recent classifications [5]. However, many more metabolic alterations stem from insulin resistance, which have never been included in the definition (Fig. 1.1). The sequence of events starting from liver fat accumulation (steatosis) to hepatic necro- inflammation with/without fibrosis (steatohepatitis) to cirrhosis, when unrelated to alcohol abuse, constitutes another nominated but not elected component of MetSyn (nonalcoholic fatty liver disease—NAFLD). NAFLD is one of the most prevalent liver diseases worldwide, occurring in all countries and all ethnic groups [6], largely associated with obesity and other components of MetSyn [7, 8]. Fatty liver may also occur in normal-weight individuals (approx. 10–15% of total cases) [9], but it is much more prevalent in overweight/obese people and also in these cases liver fat positively correlates with insulin resistance [10, 11]: accordingly, nonalcoholic NAFLD and its progressive states (nonalcoholic steatohepatitis—NASH—and NASH-cirrhosis) may be considered the hepatic manifestation of MetSyn [12]. The NAFLD Insulin resistance Other metabolic changes Overweight/obesity Metabolic Syndrome Visceral Prediabetes/diabetes obesity High/high-normal blood pressure Low HDL- High triglycerides cholesterol Fig. 1.1 Representation of the metabolic syndrome, having visceral obesity as the core compo- nents, and its relationship with NAFLD. Note the possible interdependence of NAFLD and meta- bolic changes, pointing at a causal and reverse causal association