Diagnostic accuracy of Magnetic Resonance (MR) biomarkers (2D MRE, 3D MRE, MRI-PDFF, iron-corrected T1, and native T1) for ‘at-risk NASH’, and for significant liver fibrosis (F2), in NAFLD: A protocol for a systematic review and meta-analysis
Creators: name: Sirlin, Claude B.
name: Fladger, Anne
name: Pasek, Alex
name: Weeks, James
name: Shabanan, Sedighe Hosseini
name: Rohit Loomba
name: Middleton, Michael Simca
name: Pierce, Theodore
name: Arinc Ozturk
name: Bain, Paul A.
name: Samir, Anthony
name: Wolfson, Tanya
name: Sertic, Madeleine
name: Fowler, Kathryn J.
name: Obuchowski, Nancy A
name: Sherlock, Sarah P.
Publisher: name: Open Science Framework
Year: 2023
Subjects: subject: Radiology
subject: Medicine and Health Sciences
subject: Medical Specialties
subject: Gastroenterology
subject: Magnetic resonance imaging
subject: Non-alcoholic steatohepatitis
subject: Liver fibrosis
subject: T1 Mapping
subject: Non-alcoholic fatty liver disease

description: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide, and prevalence of NAFLD is increasing owing to upward trends of obesity and diabetes (24042449). Nonalcoholic steatohepatitis (NASH) is an advanced stage of NAFLD with a higher risk of progression to complications related to cirrhosis, is currently the second most common indication for liver transplantation in the United States, and is expected to become the leading cause in the near future (24768810, 25461851, 25920090). Despite the large societal burden of NASH, there is no safe, effective medication approved by the United States Food and Drug Administration (FDA) (27646933). Most clinical trials for NASH require as an eligibility criterion the presence of ‘at-risk NASH’, defined as diagnosed NASH, NAFLD activity score (NAS) ≥ 4 and significant fibrosis (F≥2). The rationale is that these patients are at substantial risk for progression to complications of cirrhosis, and so might benefit from participating in NASH drug development clinical trials. By comparison, patients without NASH, with NAS ≤ 3, or with F&lt;2 are less likely to benefit from participation, and so should be excluded from those trials. The requirement for ‘at-risk NASH’ or significant fibrosis poses a major challenge for clinical trials because histologic confirmation remains necessary for diagnosis, risk stratification, and longitudinal evaluation of NASH. Liver biopsy is costly, invasive in nature, and prone to sampling errors, given the spatial heterogeneity of steatosis in liver (15940625, 24574716). Moreover, it has been shown that only about 30% of patients recruited and screened for clinical trial participation meet histologic criteria for inclusion. The other 70% have too little or too much disease on biopsy, and are excluded. This ~70% screen failure rate is problematic because it exposes potential participants to unnecessary risk from invasive biopsy, and drives up trial costs. To reduce risks and costs, there is a need for diagnostic enrichment strategies to identify patients most likely to have ‘at-risk NASH’ or F2, and to reserve biopsy only for such patients. Non-invasive imaging biomarkers as well as serum parameters can be used to enhance diagnostic confidence when conducting research trials. Several Magnetic Resonance (MR) imaging biomarkers have emerged for liver fibrosis staging and NASH diagnosis which might be helpful for diagnostic enrichment in NASH clinical trials, including magnetic resonance elastography (MRE), both two- and three-dimensional (2D- and 3D-MRE), MR-Proton Density Fat Fraction (PDFF), iron-corrected T1 (cT1), and T1 mapping (also known as native T1). However, there is a critical lack of consensus on diagnostic thresholds of each of these MR imaging biomarkers which might vary based on hardware, context of use, and fibrosis level. Moreover, estimations of their diagnostic accuracies vary across studies. Thus, the primary goal of this review is to synthesize the existing literature by conducting a systematic literature review, and if possible, meta-analysis on diagnostic performance of the five aforementioned MR biomarkers to inform optimal thresholds for the diagnosis of ‘at-risk NASH’ and clinically significant liver fibrosis (stage ≥ F2).