Published On: 4/3/2025

An Overview of MASH: Advancements in Diagnosis, Treatment, and the Role of Real-World Data

Metabolic dysfunction-associated steatohepatitis (MASH), previously known as nonalcoholic steatohepatitis (NASH), is a progressive liver disease that is placing an increasing burden on patients and healthcare systems. The shift in terminology to metabolic dysfunction-associated steatotic liver disease (MASLD) from nonalcoholic fatty liver disease (NAFLD) reflects a broad update in terminology to a non-stigmatizing diagnosis and a definition that better reflects the underlying pathophysiology of cardiometabolic disease. Patients with MASLD have evidence of hepatic steatosis along with at least one cardiometabolic risk factor with no other cause identified and those with MASLD and steatohepatitis are classified as MASH. MASLD falls under a broad category of steatotic liver disease (SLD), which also includes alcohol-associated (alcohol-related) liver disease (ALD), SLD with a specific etiology such as drug-induced liver disease (DILI), and cryptogenic SLD which includes those without metabolic parameters or a known cause of liver disease. Additionally, a new category, metabolic dysfunction and alcohol associated/related liver disease (MetALD) includes patients with MASLD who have an alcohol intake greater than that allowed by the MASLD definition. The term MetALD has been introduced to describe cases where metabolic dysfunction and steatotic liver disease coexist with increased alcohol intake. This new comprehensive terminology more accurately describes the disease spectrum of steatotic liver disease and MASLD and reduces the stigma associated with the prior terminology which used terms such as ‘fatty’ and ‘nonalcoholic’. 1,2   

To assess the continued validity of prior research using legacy NASH definitions, which were developed by clinical experts and utilize clinical criteria as well as liver biopsy fibrosis stage if available, the concordance between the previous Target RWE NAFLD pragmatic criteria and the new MASLD definition was examined. We found high concordance between the new MASLD nomenclature and our previously utilized pragmatic definitions when applied to both the adult and pediatric cohorts, supporting the continued relevance of insights and findings from prior analyses. In fact, among adults and pediatric patients enrolled in the United States (US) in TARGET-NASH, approximately 99% of participants met the new diagnostic standards for MASLD including those for MASH (formerly NASH) and cirrhosis. This high level of concordance, outlined in our publications "High Concordance Between Nonalcoholic Fatty Liver Disease and Metabolic Dysfunction-Associated Steatotic Liver Disease in the TARGET-NASH Real-World Cohort” and “Concordance of MASLD and NAFLD Nomenclature in Youth Participating in the TARGET-NASH Real-world Cohort”, underscores the robustness of the Target RWE pragmatic definitions for MASLD/MASH and their continued applicability to the evolving clinical landscape.3, 4, 5   

Additional important insights were gained from these analyses. For example, similar to a prior analysis in adults designed to validate our clinical definition for MASH (formerly NASH), we assessed a subset of the >800 pediatric patients enrolled in TARGET-NASH and found high concordance between the histological diagnosis of MASH by an expert pathologist and those diagnosed using the Target RWE MASH clinical criteria, supporting the diagnosis of MASH noninvasively without the need for a liver biopsy in pediatric patients.5, 6  In another study utilizing data from the adult cohort, we identified a sub-population who met initial criteria for MetALD, which warrants further study given the growing importance of this group of patients.4   

From Invasive Procedures to Non-Invasive Diagnostics 

For decades liver biopsy has been considered the gold standard for diagnosing liver disorders and assessing the severity of disease, particularly in clinical trials.  This costly and invasive procedure involves removing a small sample of liver tissue for microscopic examination, which can provide valuable insights such as the extent of fibrosis present in the biopsied sample. However, biopsies are not without significant drawbacks. Patients may experience pain, bleeding, infection or other complications following the procedure. Additionally, biopsies may be impacted by sampling variability if the disease is not uniformly distributed throughout the liver, leading to potential misdiagnosis, and interpretation of the biopsy may be impacted by inter- and intra-reader variability among pathologists.  

Considering these limitations, the medical field has made significant strides in developing non-invasive diagnostic tools, or noninvasive liver disease assessments (NILDA), that offer safer and more convenient alternatives to liver biopsy. These advancements have been crucial in improving the diagnosis and management of MASH, allowing for more frequent monitoring of liver health with minimal risk. 

Vibration-controlled transient elastography (VCTE), commonly known as FibroScan®, is an imaging tool adopted in some clinical practices that offers an effective noninvasive alternative to liver biopsy and is particularly useful to identify advanced fibrosis in patients with MASH and other chronic liver diseases. FibroScan has several advantages relative to liver biopsy, including relative ease of use, assessment of a larger proportion of the liver, and reduced risk and associated costs. There are some limitations to VCTE such as reduced reliability at higher BMI levels7, 8 and lack of availability across practice locations.  Other imaging techniques including magnetic resonance elastography (MRE) and magnetic resonance imaging proton density fat fraction (MRI-PDFF) can be useful for assessing significant fibrosis and cirrhosis though its use may be limited by availability at practice locations and other factors such as cost.9 

 Other non-invasive assessments such as serum markers and scoring systems such as FIB-4, AST-to-platelet ratio index (APRI), NAFLD fibrosis score (NFS) and enhanced liver fibrosis (ELF™) offer alternative methods for evaluating liver disease. FIB-4 is a widely used index that leverages readily available clinical data to assess risk of advanced fibrosis. Other simple blood based noninvasive tests include APRI and NFS, which are algorithms that utilize clinical data such as routine laboratory test results and readily available clinical variables.  The ELF test received marketing authorization in 2021 in the US and is a proprietary blood-based biomarker test designed to assess the likelihood of patients with advanced fibrosis and MASH to progress to cirrhosis and other liver-related clinical events. These and other non-invasive tests may be useful for the long-term management of MASH and provide cost-effective and less invasive alternatives to biopsies for assessing liver health, enabling early detection and management of MASLD.  As recommended by the AASLD Practice Guidelines on noninvasive liver disease assessment of hepatic fibrosis and steatosis, combining blood-based and imaging-based noninvasive tests may be useful for the detection of significant to advanced fibrosis and cirrhosis in chronic liver disease.9,10 

Given the importance of validating the use of simple noninvasive measures in real world settings, Target RWE evaluated a practical clinical risk-based classification system in our MASLD cohort.  We assessed the feasibility of using simple noninvasive assessments such as FIB-4 and liver stiffness measurement by VCTE to identify those at risk of adverse outcomes from MASLD.  Adults enrolled in the longitudinal observational TARGET-NASH cohort were classified into three risk categories (low, medium, high) based on FIB-4 and liver stiffness measurements.  Classification into these risk categories was mostly driven by FIB-4, and clinical outcomes such as death, liver associated events, major cardiovascular events, liver cancer and chronic kidney disease increased from the low- to high-risk groups.  This analysis provided evidence for the prognostic utility of risk-based classification in MASLD, particularly via FIB-4, in a real-world clinical setting using readily available noninvasive measurements to assess risk for adverse clinical outcomes.11  

Expanding the Scope of Liver Disease Progression 

Building on the success of our initial longitudinal observational studies, including TARGET-NASH, Target RWE has strengthened its commitment to generating comprehensive real-world data to advance the understanding of chronic liver disease and outcomes by initiating the TARGET-LIVER DISEASE (TARGET-LD) protocol. The TARGET-LD protocol was developed to broadly capture patients across a wide array of chronic liver diseases, including MASLD/MASH, across multi-center healthcare systems in the US. Patients are initially enrolled under a waiver of informed consent thus reducing the usual bias of enrolling patients in traditional clinical studies. Patients are followed longitudinally, and key variables are curated from the medical record to allow for the characterization of patients and assessment of important clinical outcomes over time.  The protocol was also designed to capture data from patients with cirrhosis to support our collaboration with the American Association for the Study of Liver Diseases (AASLD) and their Cirrhosis Quality Collaborative (CQC). The TARGET-LD protocol ensures a holistic view of disease progression by capturing patients at various stages of disease and offers several advantages: 

• Broad Representation: Target RWE is enrolling patients into a large cohort across numerous liver diseases, such as MASLD/MASH, ALD and hepatitis B, as well as those that are less common, such as primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and alpha-1 antitrypsin deficiency. Patients represent a diverse spectrum and include those often excluded from clinical trials. This diversity strengthens the generalizability of research findings from this cohort. 
• Longitudinal Data Collection: The TARGET-LD protocol facilitates the collection of longitudinal data, with up to 5 years of retrospective data collection prior to enrollment and up to 15 years of prospective data collection during follow up, allowing for the assessment of treatment patterns, clinical outcomes and disease progression over time. This allows researchers to examine how factors such as patient characteristics, disease severity and treatments influence disease trajectory. 
• Standardized Variables: We curate key variables across multi-center healthcare systems to allow for the characterization of populations of interest and to assess the natural history of disease and treatment patterns prospectively across multi-center healthcare systems.  
• Biosamples and Patient-reported Outcome Measures: TARGET-LD has the unique feature of allowing for the deployment and customization of a consented cohort for the collection of additional measures such as patient reported outcomes and biosamples, which are linked to the existing robust longitudinal clinical data.   

To enhance the clinical data available from patients enrolled in TARGET-LD, Target RWE integrates insights from unstructured clinical notes and reports, curating key data points from narratives to provide a more comprehensive understanding of patient characteristics, treatments and liver disease progression. This approach enables the capture of critical insights often hidden in routine clinical documentation, enhancing coverage of critical data points for analysis. Additionally, the large patient population enrolled in TARGET-LD ensures a robust representation of diverse liver conditions across understudied populations, strengthening the generalizability and impact of research findings. By incorporating both structured data and curated insights from unstructured sources, TARGET-LD supports a more nuanced, patient-centric approach to liver disease research. 

Collaborative Research for Better Management of MASLD, MASH, and Liver Disease 

The evolving understanding of MASH, increasing number of MASH drug development programs and availability of new treatments underscore the importance of real-world data combined with innovative research approaches. Target RWE’s MASLD cohort provides long-term prospective data for the characterization of disease and clinical outcomes based on structured data from the EHR as well as unstructured clinician notes with the ability to customize solutions based on research questions.  We combine this robust data with disease area expertise supported by academic key opinion leaders to develop approaches for analyses collaboratively to address important research questions, such as those that contribute to the management of MASH and other liver diseases.  

Target RWE’s liver disease data is a valuable resource for investigating patients with chronic liver disease and developing more effective treatment strategies to improve patient care.  

Contact info@targetrwe.com or visit our website to learn more! 

References

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