Abstract
IntroductionLate stage clinical trials in non-alcoholic steatohepatitis (NASH) are currently required by the FDA to use liver biopsy as a primary endpoint. The well-reported limitations with biopsy, such as associated risks and sampling error, coupled with patient preference, are driving investigation into non-invasive alternatives. MRI-derived biomarkers proton density fat fraction (PDFF) and iron-corrected T1 mapping (cT1) are gaining traction as emerging alternatives to biopsy for NASH. Our aim was to explore the correlations between cT1 and PDFF (from LiverMultiScan®), with the histological components on the NAFLD-NASH spectrum in a large cohort of cross-sectional data, in order to calibrate the measurement to histology, and to infer what might constitute a clinically meaningful change when related to the FDA’s criteria.Materials and MethodsIn a retrospective analysis of data combined from three previously published observational NASH studies, in which adult participants who underwent liver biopsy on suspicion of NAFLD or NASH and had an MRI scan measuring cT1 and PDFF (LiverMultiScan®, Perspectum Ltd, UK), associations between imaging biomarkers and histology were tested using Spearman’s rank correlation coefficient (rs), and further exploration of the relationships between the imaging variables and histology were performed using linear regression.ResultsN = 264 patients with mean age of 54 (SD:9.9), 39% female, and 69% with BMI ≥ 30kg.m−2 were included in the analysis. cT1 and PDFF both correlated with all features of the NAFLD activity score (NAS). cT1 was also positively correlated with Kleiner-Brunt fibrosis. Partial correlations, adjusting for steatosis, revealed cT1 correlated with inflammation and fibrosis, whereas PDFF did not, and both were still associated with the NAS, but correlation was weaker with PDFF than cT1. An estimated difference of 88 ms in cT1, or 21% relative difference in PDFF was related to a two-point difference in overall NAS.ConclusionThe correlations between cT1 and PDFF with the histopathological hallmarks of NASH demonstrate the potential utility of both cT1 and PDFF as non-invasive biomarkers to detect a pharmacodynamic change in NASH, with cT1 showing superiority for detecting changes in inflammation and fibrosis, rather than liver fat alone.
Highlights
Late stage clinical trials in non-alcoholic steatohepatitis (NASH) are currently required by the FDA to use liver biopsy as a primary endpoint
This serves to demonstrate the complex interactions between the nature and timing of the pathology in NAFL and NASH, and to demonstrate how increasing levels of hepatic steatosis are associated with more profound hepatocyte injury, that can result in fibrosis [37], the downstream consequence of NASH linked to poor clinical outcomes [38]
While a change in proton density fat fraction (PDFF) is a common endpoint in proof-of-concept Phase 2 NASH studies [31, 32], our study revealed an interesting observation when controlling for steatosis in the correlation analyses
Summary
Late stage clinical trials in non-alcoholic steatohepatitis (NASH) are currently required by the FDA to use liver biopsy as a primary endpoint. Liver biopsy is the current gold standard measurement for both clinical diagnosis and as endpoints in clinical trials, a method that is expensive, invasive, and suffers from high discordance rate among pathologists [6], likely related to the uneven distribution of the disease [7]. This has driven the need to identify alternative, non-invasive, endpoints which the FDA has strongly encouraged [8]. Vendor-neutral and scalable MRI-derived measurements of proton density fat fraction (PDFF) and iron corrected T1 mapping (cT1) are emerging as promising quantitative imaging biomarkers (QIBs) for NASH
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