Targeted identification of populations at risk of MASLD and liver-related complications

This thesis aims to advance the understanding and clinical implementation of non-invasive diagnostics for metabolic dysfunction-associated steatotic liver disease (MASLD) and its complications. Given the growing prevalence of MASLD and the limitations of liver biopsy, the overarching research question was how diagnosis and risk stratification of MASLD can be improved through non-invasive tests (NITs).
First, the prevalence and diagnostic challenges of MASLD were explored in a general population cohort, demonstrating that MASLD is highly prevalent even among individuals with normal liver enzymes, while existing steatosis scores showed limited accuracy. Second, novel circulating biomarkers were investigated. Extracellular vesicle–derived protein signatures were associated with key histopathological features of MASLD, and specific biomarkers showed promising accuracy for detecting steatohepatitis and advanced fibrosis. Additionally, a fibrosis-related molecular signature was shown to precede histological fibrosis, supporting the potential for early disease identification.
Subsequently, strategies to optimise diagnostic pathways were evaluated. Two-step care pathways substantially improved the detection of advanced MASLD fibrosis in low-prevalence settings, particularly pathways combining simple risk scores with vibration-controlled transient elastography. Refinements in biomarker handling enabled broader clinical implementation, and advanced imaging-based models improved diagnostic performance for selected disease stages, though not consistently outperforming established NITs.
Finally, the thesis addressed MASLD-related complications, highlighting the role of the extracellular matrix in hepatocarcinogenesis and demonstrating rising incidence rates of MASLD-related hepatocellular carcinoma in the Netherlands. Collectively, these findings support a more effective, scalable, and earlier non-invasive diagnostic approach for MASLD.