Correlations Between MRI Biomarkers PDFF and cT1 With Histopathological Features of Non-Alcoholic Steatohepatitis

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.

EDP-305 in patients with NASH: A phase II double-blind placebo-controlled dose-ranging study

“…Importantly, the larger the reduction in MRI-PDFF measured steatosis, the higher the response rate for resolution of NASH 12 .…”

Safety, Tolerability, and Biologic Activity of AXA1125 and AXA1957 in Subjects With Nonalcoholic Fatty Liver Disease

“…At week 16, responder analysis showed a greater proportion of subjects treated with AXA1125 vs placebo achieved clinically relevant thresholds of biologic activity across several markers, each of which has been correlated to histologic improvements in the NAFLD activity score and fibrosis ( 14 – 16 ): 38.5% vs 8.3% of subjects had ≥30% relative reduction in MRI-PDFF (Figure 5 a), 38.5% vs 25% had ≥17-IU/L reduction in ALT (Figure 5 b), and 34.6% vs 16.7% had ≥80-ms reduction in cT1 (Figure 5 c). Proportion of subjects who achieved these clinically relevant thresholds in 2 or more biomarkers (i.e., ≥30% ↓PDFF + ≥17-IU/L ↓ALT) was 23.1% with AXA1125 vs 0.0% with placebo; similarly, a higher proportion of subjects receiving AXA1125 had changes in 2 or more biomarkers when cT1 was also considered (data not shown).…”

“…By contrast, with isocaloric and isonitrogenous AXA1957, changes from baseline in several of these biomarkers were lower magnitude and inconsistently observed. At week 16, a greater proportion of subjects who received AXA1125 (∼35%–40%) vs placebo (∼8%–25%) achieved ≥30% ↓MRI-PDFF, ≥17-IU/L ↓ALT, and ≥80-ms ↓cT1; each of these thresholds has been correlated to improved histopathologic outcomes ( 14 – 16 ) and some (e.g., cT1) with treatment response ( 20 ).…”

Human Genetics to Identify Therapeutic Targets for NAFLD: Challenges and Opportunities

“…A recently published protocol for multiparametric magnetic resonance (MR) has bridged that gap. MR derived iron-corrected T1 (cT1) is a novel noninvasive method to assess fibrosis ( 64 ), and it correlates with all the histological features of NASH ( 65 , 66 ).…”