Assessment of treatment response in non‐alcoholic steatohepatitis using advanced magnetic resonance imaging

Abstract

Background Magnetic resonance imaging derived measures of liver fat and volume are emerging as accurate, non-invasive imaging biomarkers in non-alcoholic steatohepatitis (NASH). Little is known about these measures in relation to histology longitudinally. Aims This study examines this relationship between MRI-derived proton-density fat-fraction (PDFF), total liver volume (TLV), total liver fat index (TLFI), vs. histology in a NASH trial. Methods This is a secondary analysis of a 24-week randomized, double-blind, placebo-controlled trial of 50 patients with biopsy-proven NASH randomized to oral ezetimibe 10mg daily (n=25) vs. placebo (n=25). Baseline and post-treatment anthropometrics, biochemical profiling, MRI, and biopsies were obtained. Results Baseline mean PDFF correlated strongly with TLFI (Spearman’s ρ=0.94, n=45, P<0.0001) and had good correlation with TLV (ρ=0.57, n=45, P<0.0001). Mean TLV correlated strongly with TLFI (ρ=0.78, n=45, P<0.0001). After 24 weeks, PDFF remained strongly correlated with TLFI (ρ=0.94, n=45, P<0.0001), maintaining good correlation with TLV (ρ=0.51, n=45, P=0.0004). TLV remained strongly correlated with TLFI (ρ=0.74, n=45, P<0.0001). Patients with Grade 1 vs. 3 steatosis had lower PDFF, TLV, and TLFI (P<0.0001, P=0.0003, P<0.0001, respectively). Regression analysis of changes in MRI-PDFF vs. TLV indicates that 10% reduction in MRI-PDFF predicts 257 mL reduction in TLV. Conclusions MRI-PDFF and TLV strongly correlated with TLFI. Decreases in steatosis were associated with an improvement in hepatomegaly. Lower values of these measures reflect lower histologic-steatosis grades. MRI-derived measures of liver fat and volume may be used as dynamic and more responsive imaging biomarkers in a NASH trial than histology. ClinicalTrials.gov number, NCT01766713.

Imaging-Based Assessment of Steatosis, Inflammation and Fibrosis in NAFLD

“…Patients with grade 3 steatosis on index biopsy had significantly higher PDFF, TLV and TFLI than those with grade 1 steatosis on index biopsy [31]. At week 24, the correlations between the MRI measured indices remained similar, indicating longitudinal reliability [31]. The change in PDFF over the 24-week period also correlated significantly with change in TLV [31].…”

“…At week 24, the correlations between the MRI measured indices remained similar, indicating longitudinal reliability [31]. The change in PDFF over the 24-week period also correlated significantly with change in TLV [31]. There was no significant association between the change in TLV and change in histological steatosis at 24 weeks [31].…”

“…The change in PDFF over the 24-week period also correlated significantly with change in TLV [31]. There was no significant association between the change in TLV and change in histological steatosis at 24 weeks [31]. The authors speculated that within the context of other published studies [32] [19], MRI-PDFF may be more responsive than histological steatosis in detecting incremental hepatic fat change.…”

“…MRI-PDFF has shown promise in longitudinal studies assessing changes in steatosis with treatment [30][31][32]. In the FLINT study, a randomized controlled trial (RCT) of obeticholic acid vs. placebo for 72 weeks, MRI-PDFF accurately differentiated steatosis S0-1 from S2-3 (AUROC 0.95) and S0-2 from S3 (AUROC 0.96) at baseline [33•].…”

“…A secondary analysis of the MOZART trial (RCT of ezetimibe versus placebo for 24 weeks in NASH; n = 50) showed a strong correlation between MRI-PDFF and total liver volume (TLV) (r = 0.57, p < 0.0001) and MRI-PDFF and total liver fat index (TLFI) (r = 0.94, p < 0.0001) at week 0 [31]. Patients with grade 3 steatosis on index biopsy had significantly higher PDFF, TLV and TFLI than those with grade 1 steatosis on index biopsy [31].…”