Non-invasive Assessment and Therapeutic Targeting in Metabolic Dysfunction-Associated Steatohepatitis (MASH):...

Despite two decades of therapeutic clinical trials in metabolic dysfunction-associated steatotic liver disease (MASLD), only two drugs have been approved so far for those with metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis but not cirrhosis. Treatment responses are variable and difficult to predict, reflecting the complexity of disease pathophysiology as well as the current inability to capture disease heterogeneity, all precluding making informed individualized choices that potentially might improve treatment results. Liver biopsy for diagnosis and efficacy assessment is to date a prerequisite in late-stage trials, which limits large-scale trials and translation to routine clinical practice, and also fails to capture that heterogeneity. Several non-invasive tests (NITs) have been developed as a diagnostic surrogate to reflect disease severity, mostly addressing fibrosis, which is the strongest predictor of liver-related outcomes. This article highlights the dissonance between drug development for 'at-risk' MASH that targets both active disease and fibrosis relying on strict histological criteria, and current NITs that have been proposed for patient selection for pharmacotherapy and monitoring in clinical practice but largely reflect fibrosis. Although increasing evidence suggests their usefulness in diagnosis and follow-up, their ability to capture disease heterogeneity and select the right patients for the right treatments seems limited. Emerging NITs are derived from disease pathophysiological mechanisms and integrate lipidomic and proteomic analysis with existing biomarkers, as well as with other parameters such as the genetic background, the liver microenvironment, or the gut microbiome. Utilizing novel NITs therefore has the potential to identify appropriate candidates for therapy and also monitor responses, allowing in the future for true personalized medicine. Furthermore, understanding the complex pathophysiological mechanisms can potentially unravel not only novel diagnostics but also innovative therapeutic targets. This could lead to (personalized) choices of drugs and drug combinations that engage multiple pathways to improve efficacy, not only in terms of liver disease, but also in relation to the cardiometabolic risk profile. Moving towards precision medicine in MASLD, information provided non-invasively via circulating biomarkers (liquid liver biopsy) may hence guide risk stratification and therapeutic decisions in the near future.