MAFLD: a multisystem disease

Abstract

Nonalcoholic fatty liver disease (NAFLD), affecting about 25% of general population and more than 50% of dysmetabolic patients, is an emerging cause of chronic liver disease and its complications. Recently, an international consensus of experts proposed to rename this disease as 'Metabolic dysfunction-Associated Fatty Liver Disease' (MAFLD) to focus on the bidirectional interplay between fatty liver and metabolic alterations and to stress the need of assessing fatty liver independently from alcohol consumption and other coexisting causes of liver disease. The peculiarity of NAFLD/MAFLD lies in the presence of a higher risk of not only - as expected - liver-related events but also of extrahepatic events, mostly cardiovascular and cancers. Available evidence suggests that these associations are not only the expression of sharing the same risk factors but shed light about the ability of NAFLD/MAFLD and particularly of its progressive form - nonalcoholic/metabolic dysfunction-associated steatohepatitis - to act as an independent risk factor via promotion of atherogenic dyslipidemia and a proinflammatory, profibrogenic, and procoagulant systemic environment. The present review summarizes available epidemiological and clinical evidence supporting the concept of NAFLD/MAFLD as a multisystemic disease, and highlights potential explanatory mechanisms underlying the association between NAFLD/MAFLD and extrahepatic disorders.

Keywords: MAFLD; NAFLD; fatty liver.

Figure 1.

Bidirectional relationship between NAFLD/MAFLD and metabolic outcomes. CVD risk factors, including metabolic syndrome, hypertension, hypertriglyceridemia, IFG and type 2 diabetes at baseline are associated with increased risk of developing fatty liver. In the other direction, greater baseline liver fat is associated with a greater risk of incident arterial hypertension and type 2 diabetes. This suggests bidirectional relationship between NAFLD/MAFLD and CVD risk factors.

Figure 2.

Liver inflammatory pathways activation and lipotoxicity induction linking NAFLD/MAFLD to extrahepatic disease. Pathogenic pathways involved in the development and progression of NAFLD are influenced by multiple, genetic, such as PNPLA3, Il148M, and TM6SF2 variants, metabolic and inflammatory factors. IR, induced by marked expansion and inflamed adipose tissue, impairs hepatic metabolic FFA utilization. Intrahepatic accumulation of toxic lipids produces inflammation and oxidative stress, driving NAFLD/MAFLD progression to NASH/MASH and contributes to cardiovascular complication. Hepatic necro-inflammation leads to endothelial dysfunction and atherogenic dyslipidemia, increasing production of acute-phase proteins and cytokines inflammatory, increasing risk of incidence of CVD and atherosclerosis. Altered adipokines production, together with IR, creates a microenvironment appropriate for cancer development, stimulating IGF-1 axis, JAK/STAT, and MAPK pathways. PNPLA3, patatin-like phospholipase domain containing 3; TM6SF2, transmembrane 6 superfamily 2; FFA, free fatty acids; TNF-α, tumor necrosis factor alpha; IL-6, interleukin 6; PAI-1, plasminogen activator inhibitor-1; MCP-1, monocyte chemoattractant protein-1; ChREBP, carbohydrate response element-binding protein; SREBP, sterol regulatory-element binding protein 1c; VLDL, very low-density lipoprotein; HDL, high-density lipoprotein; TG, triglyceride; NASH, nonalcoholic steatohepatitis; oxLDL, oxidized low-density lipoprotein; JAK/STAT, Janus kinase/signal transduction and activator of transcription; MAPK, mitogen-activated protein kinase.

Figure 3.

Summary of the major extrahepatic complications of NAFLD/MAFLD. NAFLD/MAFLD could be framed as a multisystemic disease. Sharing metabolic comorbidities, genetic background, and the severity of liver disease can modulate the risk of extrahepatic complications, even if the key question is whether NAFLD/MAFLD per se, via proinflammatory and profibrogenic pathways, is a real risk factor or it is only a surrogate of aging and of different metabolic and inflammatory risk factors. The mechanisms underlying these associations and their long-term clinical meaning need to be further investigated.