Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease, affecting an estimated 38 per cent of adults worldwide. Its progressive form, MASH, is characterised by inflammation and damage to liver cells and can lead to liver cirrhosis and liver cancer, among other complications. MASH is also becoming an increasingly important reason for liver transplantation. The disease is frequently associated with type 2 diabetes, cardiovascular and kidney disease. Diets high in sugar and fat as well as physical inactivity are among the factors contributing to its increasing prevalence. MASH is also becoming increasingly common in children.
MASH develops through the interplay of many factors
Our understanding of how the disease develops has also changed fundamentally. Previously, MASH was thought to follow a relatively linear sequence: fat first accumulates in the liver, followed by lipotoxicity and oxidative stress, which lead to inflammation and further damage, potentially progressing to fibrosis, liver cirrhosis and liver cancer.
Today, growing evidence suggests that multiple processes occur simultaneously, interact with one another and reinforce each other. Even at early stages of the disease, immune cells and platelets, for example, can actively interfere with liver metabolism. At the same time, insulin resistance, genetic factors, adipose tissue, the gut and microbiome, the brain and skeletal muscle, as well as environmental and lifestyle factors, all influence the disease.
“We no longer understand MASH as an isolated disease of the liver, but as a systemic condition involving numerous organs and biological processes. These interactions work in both directions: other organ systems influence liver disease, while the diseased liver in turn affects processes throughout the body,” says Professor Mathias Heikenwälder, Scientific Director at the M3 Research Center of the Faculty of Medicine at the University of Tübingen. “This understanding has evolved over many years and is also changing the way we think about treatment.”
Not all MASH is the same
Another important finding is that MASH is not a uniform disease. Patients differ considerably in their genetic predisposition, metabolism, immune responses, microbiome and comorbidities. Studies point to several molecular and metabolic subtypes. In some patients, for example, the risk of liver cancer is predominant, while in others cardiovascular disease and diabetes play a greater role.
This heterogeneity has direct implications for treatment. “If different mechanisms drive the disease, it is unlikely that a single therapy will be equally suitable for all patients in the long term,” says Heikenwälder. The aim, therefore, should be to characterise patients more precisely in future and select therapies in a more targeted and individualised way.
First medicines available – but development is far from over
The therapeutic landscape is also undergoing major change. Alongside dietary changes, weight loss and physical activity, medicines are now available for the first time for certain groups of patients with non-cirrhotic MASH and advanced fibrosis. At the same time, further treatments targeting different disease mechanisms are being investigated – from metabolism and inflammatory and fibrotic processes to the gut–liver axis.
The authors see this as only the beginning of a new phase in MASH treatment. Not all patients benefit equally from the available therapeutic approaches, and side effects can also limit treatment. In future, different groups of patients could therefore receive targeted liver-directed, systemic metabolic or combination therapies – similar to precision medicine in cancer treatment.
“Recent advances are not the end point. Determining which combination of lifestyle intervention and drug therapy is optimal for which patients and at what stage remains an important open research question and could have a decisive impact on future treatment,” says Heikenwälder. “The key will be to better understand the biological differences and use this knowledge to develop more individualised treatment strategies.”
Nature
Molecular mechanisms and pathogenesis of MASH