Heterogeneity of metabolic dysfunction-associated steatotic liver disease

About 70 percent of obese people have metabolic dysfunction-associated steatotic liver disease (MASLD). However, MASLD is also found in lean people. Paradoxically, some effective pharmacological approaches to improve liver health in people with MASLD are associated with no change in bodyweight or even with weight gain, and similar response heterogeneity has been observed for changes in cardiometabolic risk factors. In a review article in The Lancet Diabetes & Endocrinology, Norbert Stefan, Hannele Yki-Järvinen and Brent Neuschwander-Tetri discuss novel findings about this heterogeneity of MASLD with respect to its pathogenesis, outcomes, and metabolism-based treatment responses. They highlight how the knowledge about this heterogeneity might help achieving the goal for the implementation of precision medicine for risk prediction, prevention, and treatment of MASLD, in the future.

One challenge to the desire to segregate patients into separate categories is that the dietary, anthropomorphic, clinical, and genetic drivers are not mutually exclusive, therefore, individual patients have varying degrees of the various drivers. Nonetheless, if patients can be characterised by their dominant underlying mechanisms, this could facilitate therapies directed towards those mechanisms. In this respect Professor Brent Neuschwander-Tetri from the Saint Louis University, St. Louis, USA emphasizes: ‘Besides lifestyle intervention involving a healthy diet and increased exercise, that mostly decrease fat mass, in the near future we can expect to have at hands several pharmacological compounds that help us to better treat MASLD. Some of them most recently proved very effective to bring about a resolution of MASH and improvement of fibrosis. Interestingly, they have different major modes of action, e.g. resulting in decrease of fat mass, no change in fat mass and even increase in subcutaneous fat mass.’

The authors of the review believe that in the future, the knowledge about these concepts will enable a personalized risk prognosis and individualized treatment of MASLD. In addition, researchers will be able to specifically develop lifestyle modification programs and drugs for the respective subtypes based on the various aspects of this disease.

MASLD has become a world-wide epidemic. People with MASLD can progress to cirrhosis and hepatocellular carcinoma and are at increased risk of developing type 2 diabetes, cardiovascular disease, chronic kidney disease, and extrahepatic cancers. Worldwide about 38% of adults and 3-10% of children have MASLD. These numbers increase to about 70% and 40% in adults and children with obesity and/or diabetes. These numbers are alarming, because MASLD, and more so metabolic dysfunction-associated steatohepatitis (MASH) and MASLD-associated hepatic fibrosis, increase the risk of advanced liver diseases (e.g. hepatic cirrhosis, hepatic cancer) and cardiometabolic diseases (e.g. cardiovascular disease, type 2 diabetes) and extrahepatic cancers.

Professor Norbert Stefan from the University of Tübingen, Helmholtz Munich, and German Center for Diabetes Research (DZD) Germany, highlights: ‘Because the highest prevalence of MASH and hepatic fibrosis is observed in patients with obesity and type 2 diabetes, the diseases which epidemically increased during the past decades, focusing on the interplay of MASLD with obesity and type 2 diabetes may help to better understand the major mechanisms that drive the worldwide increase of MASLD. Furthermore, because most people with MASLD die from cardiac-related causes, it is important to focus on the metabolic alterations that are observed in people with MASLD.’ By doing just that, the authors identify a relatively large heterogeneity in the pathogenesis of MASLD. They describe 3 major pathomechanisms: MASLD with a dominant hepatic genetic component, MASLD with a dominant metabolic component related to hepatic de novo lipogenesis (new generation of lipids) and MASLD with a dominant metabolic component related to adipose tissue dysfunction. Professor Hannele Yki-Järvinen from the University of Helsinki, Helsinki, Finland, adds: ‘My colleagues and I have been studying the different major causes of MASLD for several years. For example, among people with MASLD we identified a group with a dominant component of metabolic drivers and another group with a dominant component of genetic drivers, and as might be expected since these drivers are not mutually exclusive, a group with features of both. Importantly, these groups have different risk factors of cardiovascular disease and type 2 diabetes.’

One challenge to the desire to segregate patients into separate categories is that the dietary, anthropomorphic, clinical, and genetic drivers are not mutually exclusive, therefore, individual patients have varying degrees of the various drivers. Nonetheless, if patients can be characterised by their dominant underlying mechanisms, this could facilitate therapies directed towards those mechanisms. In this respect Professor Brent Neuschwander-Tetri from the Saint Louis University, St. Louis, USA emphasizes: ‘Besides lifestyle intervention involving a healthy diet and increased exercise, that mostly decrease fat mass, in the near future we can expect to have at hands several pharmacological compounds that help us to better treat MASLD. Some of them most recently proved very effective to bring about a resolution of MASH and improvement of fibrosis. Interestingly, they have different major modes of action, e.g. resulting in decrease of fat mass, no change in fat mass and even increase in subcutaneous fat mass.’

The authors of the review believe that in the future, the knowledge about these concepts will enable a personalized risk prognosis and individualized treatment of MASLD. In addition, researchers will be able to specifically develop lifestyle modification programs and drugs for the respective subtypes based on the various aspects of this disease.

One challenge to the desire to segregate patients into separate categories is that the dietary, anthropomorphic, clinical, and genetic drivers are not mutually exclusive, therefore, individual patients have varying degrees of the various drivers. Nonetheless, if patients can be characterised by their dominant underlying mechanisms, this could facilitate therapies directed towards those mechanisms. In this respect Professor Brent Neuschwander-Tetri from the Saint Louis University, St. Louis, USA emphasizes: ‘Besides lifestyle intervention involving a healthy diet and increased exercise, that mostly decrease fat mass, in the near future we can expect to have at hands several pharmacological compounds that help us to better treat MASLD. Some of them most recently proved very effective to bring about a resolution of MASH and improvement of fibrosis. Interestingly, they have different major modes of action, e.g. resulting in decrease of fat mass, no change in fat mass and even increase in subcutaneous fat mass.’

The authors of the review believe that in the future, the knowledge about these concepts will enable a personalized risk prognosis and individualized treatment of MASLD. In addition, researchers will be able to specifically develop lifestyle modification programs and drugs for the respective subtypes based on the various aspects of this disease.

One challenge to the desire to segregate patients into separate categories is that the dietary, anthropomorphic, clinical, and genetic drivers are not mutually exclusive, therefore, individual patients have varying degrees of the various drivers. Nonetheless, if patients can be characterised by their dominant underlying mechanisms, this could facilitate therapies directed towards those mechanisms. In this respect Professor Brent Neuschwander-Tetri from the Saint Louis University, St. Louis, USA emphasizes: ‘Besides lifestyle intervention involving a healthy diet and increased exercise, that mostly decrease fat mass, in the near future we can expect to have at hands several pharmacological compounds that help us to better treat MASLD. Some of them most recently proved very effective to bring about a resolution of MASH and improvement of fibrosis. Interestingly, they have different major modes of action, e.g. resulting in decrease of fat mass, no change in fat mass and even increase in subcutaneous fat mass.’

The authors of the review believe that in the future, the knowledge about these concepts will enable a personalized risk prognosis and individualized treatment of MASLD. In addition, researchers will be able to specifically develop lifestyle modification programs and drugs for the respective subtypes based on the various aspects of this disease.