2021 
       REVERSING FATTY LIVER DISEASE 
             WITH HEALTHY LIFESTYLE 
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
                                                             1 
        
      Authors: Massimiliano Ruscica, Paola Dongiovanni, 
            Leen Heyens, Geert Robaeys 
                                                       Affiliations of the authors: 
                                                                    
                                                                             1
                                                         Massimiliano Ruscica 
                                                          Paola Dongiovanni2 
                                                            Leen Heyens3-5 
                                                          Geert Robaeys3,5,6 
                                                                    
                1 Università degli studi di Milano, Department of Pharmacological and Biomolecular Sciences, Milan, Italy 
               2 General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 
                                                              Milan, Italy 
                              3 Hasselt University, Faculty of Health and Life Sciences, Diepenbeek, Belgium 
              4 Maastricht University, School of Nutrition and Translational Research in Metabolism, NUTRIM, Maastricht, the 
                                                             Netherlands 
                     5 Ziekenhuis Oost-Limburg, Department of Gastro-enterology and Hepatology, Genk, Belgium 
                   6 University Hospital KU Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium 
                                                                    
                                                                Editor:  
                                                                    
                                                         Stephanie De Vriese7 
                                                                    
                                                    7 Secretary of Alpro Foundation 
                                                                    
                                                                    
                                                                    
                                                                    
                      This review is fully supported by the Scientific Advisory Committee of the Alpro Foundation:  
                              Harry Aiking (VU University Amsterdam); Anna Arnoldi (University Milano);  
                      Peter Clarys (Vrije Universiteit Brussel); Christine Debeuf (Alpro); Stephanie De Vriese (Alpro);  
                           Helmut Heseker (University Paderborn); Sander Kersten (University Wageningen);  
                                  Ian Rowland (University Reading); Cesare Sirtori (University Milano);  
                                                 and Kurt Widhalm (University Vienna)  
                                                                    
                                                                    
              
                                                                    
                                                            Date: June 2021
              
      CONTENT 
       
       
      Introduction .............................................................................................................................................................................. 4 
      Genetic and environmental factors associated with NAFLD ......................................................................................... 6 
      Primary therapeutic advice: lifestyle changes emphasizing weight reduction........................................................ 7 
       Mediterranean diet ............................................................................................................................................................................... 9 
       Role of plant protein .......................................................................................................................................................................... 10 
       The role of gut microbiome ..............................................................................................................................................................11   
       Other treatment options .....................................................................................................................................................................11   
      NAFLD and childhood ........................................................................................................................................................... 12 
      Conclusion ............................................................................................................................................................................... 12 
      References ............................................................................................................................................................................... 13 
       
       
           
       
       
              INTRODUCTION 
               
              Non-alcoholic fatty liver disease  (NAFLD) is                people with type 2 diabetes (T2DM) and up to 80% 
              considered the most frequent cause of liver                  of people with obesity.  However, some people 
              disorders with a prevalence above 30% in many                with a healthy body  mass index  (BMI)  can still 
              adult populations.1,2  The highest prevalence is             develop NAFLD, often described as non-obese or 
              reported in the Middle East (32%) and South                  lean NAFLD. These patients usually have central 
              America (31%), followed by Asia (27%), USA (24%)             obesity or other metabolic risk factors.3
                                                                                                                         Patients 
              and Europe (23%), with the lowest in Africa (14%).           with NAFLD have 2.5 times higher incidence of 
              Because of its close association with metabolic              cardiovascular disease (CVD).  
              syndrome (MetS), NAFLD is seen in 47.3–63.7% of  
               
               
               
               
               
               
              FIGURE 1. THE NATURAL EVOLUTION OF NAFLD OR METABOLIC ASSOCIATED FATTY LIVER DISEASE (MAFLD). 
              The mechanisms underlying NAFLD pathogenesis are multifactorial. Histologically, NAFLD encompasses a continuum including steatosis 
              with or without mild inflammation (NAFL), NASH with/without fibrosis, cirrhosis, and hepatocellular carcinoma. Equally, environment, gut 
              microbiota, genetics, and epigenetics influence the disease onset and progression. The first step in NAFLD development is hepatic fat 
              infiltration, mainly due to IR. This leads to a rise in the adipose tissue lipolysis with the consequent efflux of free fatty acids to the liver. The 
              compensatory hyperinsulinemia exacerbates fat accumulation. Excess fat is cleared from the liver by an enhanced lipoprotein secretion 
              and mitochondrial β-oxidation. The latter results in increased reactive oxygen species production leading to the activation of inflammatory 
              pathways.  
              Abbreviations: IR, insulin resistance; MAFLD, metabolic associated fatty liver disease; NAFL, non-alcoholic fatty liver; NAFLD, non-alcoholic 
              fatty liver disease; NASH, non-alcoholic steatohepatitis. 
              Adapted from: Dongiovanni P et al. 2021 and Heyens LJM et al. 2021. 68,69 
               
               
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