MAFLD: From epidemiology, to pathogenesis, natural history and management

Metabolic (dysfunction) associated fatty liver disease or MAFLD is the commonest liver disease globally, affecting on latest analysis, up to 50% of the global population. The pathogenesis of this disease is complex and multifactorial, representing the interaction of genes and epigenetics with the environment and the metabolic milieu of the individual. In turn, this milieu is an outcome of crosstalk between multiple organs including the brain, adipose tissues, muscle, pancreas, the gastrointestinal tract and the liver. The milieu results in meta-inflammation affecting multiple organs, of which the liver is but one target. Given its multi-system pathogenesis, it is to be expected that the natural history of MAFLD will be impacted by the competing risks of morbidity from other associated diseases particularly extra hepatic cancers and cardiovascular disease. As liver disease stage increases, and particularly with the onset of advanced fibrosis and cirrhosis, liver-related morbidity increases. However, even in this context, many patients die from extra-hepatic disease.
Treatment of MAFLD should aim to treat the primary cause - the dysfunctional metabolic milieu, which can ultimately result in improved metabolic health and reduced extrahepatic and hepatic death. In the broadest societal context, treatment as prevention is the best approach, but requires a consilience of efforts from government, policy makers and industry to tackle the challenges of the built environment and food patterns. To date, such an approach has not been forthcoming. At an individual level, lifestyle intervention is the cornerstone and includes strategies for weight reduction, improved food composition and increased physical activity.
While cardiovascular risk factor control should be at the forefront of management of any patient with MAFLD, disease-specific pharmacotherapy is also an active areas of investigation, with >200 clinical trials in various phases underway. Many drugs have either failed or not met their primary end point, or alternatively have not progressed because of safety issues. Despite this, there are several phase three trials underway and the likelihood that we will have treatments for patient most in need (those with F2 or greater fibrosis) is high. Some of the results will be discussed. Overall MAFLD pharmacotherapy trials have matured and we are likely to see the availability of useful agents in the not too distant future.