Fat and Iron-Corrected Quantitative MRI T1 Mapping for Evaluation of Chronic Liver Disease

Project Summary Metabolic-associated steatotic liver disease (MASLD), previously referred to as nonalcoholic fatty liver disease (NAFLD), affects approximately 25% of the global population. It is the most common cause of chronic liver disease (CLD) and is the leading cause of liver-related morbidity and mortality. MASLD encompasses a spectrum of liver diseases, ranging from simple steatosis to metabolic-associated steatohepatitis (MASH) – formerly known as nonalcoholic steatohepatitis (NASH). The main characteristic of MASH involves hepatic inflammation and chronic cellular injury, which can further lead to liver fibrosis and cirrhosis. In March 2024, the FDA approved Rezdiffra (resmetirom, Madrigal Pharmaceuticals) as the first medication for treating adult patients with MASH who have moderate to advanced liver fibrosis. Despite its potential, recent clinical findings suggest that ~50% of the patients do not respond well to this treatment. Liver biopsy is the current gold standard for assessing MASH and was used to assess treatment response in the clinical trial that led to the FDA approval of Rezdiffra. However, liver biopsy poses significant challenges that limit its routine use in clinical settings for monitoring treatment response. As a result, novel non-invasive markers that can simultaneously assess liver fat, inflammation, and fibrosis – the three pivotal aspects of liver pathology in MASH – are highly desirable. MRI is a promising modality to meet this need, providing different imaging markers for CLD, including proton density fat fraction (PDFF), T2*/R2*, and MR elastography (MRE)-derived stiffness for quantifying liver fat, iron, and fibrosis, respectively. However, none of these markers adequately captures lobular inflammation in the liver, a crucial pathological hallmark of MASH. T1 relaxation time is an MRI parameter that could potentially serve as a useful marker for inflammation and fibrosis in the liver. However, standard T1 mapping methods typically measure composite (fat/water/iron-mixed) T1 of the liver. This can result in substantial bias due to the increased fat and iron content in fatty livers. Therefore, accurate T1 mapping of the liver needs to include appropriate compensation for the influence of both fat and iron. Thanks to the initial support from the NIH (R21EB032917, PI: Feng), our team has developed a new MRI technique called MP-Dixon-GRASP (Magnetization-Prepared Golden-angle RAdial Sparse Parallel Dixon-MRI), which enables rapid 3D quantification of PDFF, R2*, and iron-corrected water-only T1 (referred to as c-water T1) in the liver during free breathing. The broad objective of this application is to continue the development, optimization, and validation of MP-Dixon-GRASP as a rapid and robust multiparametric MRI technique for the evaluation of MASH. Our Central Hypothesis is that c-water T1 can be an effective marker for chronic liver inflammation, and its combination with MRE-stiffness can provide complementary information to facilitate the non-invasive monitoring of treatment responses in patients undergoing therapy with Rezdiffra, thereby improving the management of this patient cohort.