Association of noninvasive quantitative decline in liver fat content on MRI with histologic response in nonalcoholic steatohepatitis

Abstract

Background: Magnetic resonance imaging-estimated proton-density-fat-fraction (MRI-PDFF) has been shown to be a noninvasive, accurate and reproducible imaging-based biomarker for assessing steatosis and treatment response in nonalcoholic steatohepatitis (NASH) clinical trials. However, there are no data on the magnitude of MRI-PDFF reduction corresponding to histologic response in the setting of a NASH clinical trial. The aim of this study was to quantitatively compare the magnitude of MRI-PDFF reduction between histologic responders versus histologic nonresponders in NASH patients. Methods: This study is a secondary analysis of the MOZART trial, which included 50 patients with biopsy-proven NASH randomized to ezetimibe 10 mg/day orally or placebo for 24 weeks. The primary aim was to perform a head-to-head comparative analysis of histologic responders [defined as a ⩾2-point reduction in the nonalcoholic fatty liver disease (NAFLD) Activity Score (NAS) without worsening fibrosis] versus nonresponders, and the corresponding quantitative change in liver fat content measured via MRI-PDFF. Results: Of the 35 patients who underwent paired liver biopsy and MRI-PDFF assessment at the beginning and end of treatment, 10 demonstrated a histologic response. Compared with histologic nonresponders, histologic responders had a statistically significant reduction in MRI-PDFF of −4.1% ± 4.9 versus −0.6 ± 4.1 ( p < 0.04) with a mean relative percent change of −29.3% ± 33.0 versus +2.0% ± 24.0 ( p < 0.004), respectively. Conclusions: Utilizing paired MRI-PDFF and liver histology data, we demonstrate that a relative reduction of 29% in liver fat on MRI-PDFF is associated with a histologic response in NASH. After external validation by independent research groups, these results can be incorporated into designing future NASH clinical trials, especially those utilizing change in hepatic fat quantified by MRI-PDFF, as a treatment endpoint.

Magnetic resonance elastography vs. transient elastography in detection of fibrosis and noninvasive measurement of steatosis in patients with biopsy-proven nonalcoholic fatty liver disease

“…Furthermore, the prognostic significance of changes in liver fat have not yet been assessed in long-term clinical trials, reduction in liver fat content by MRI-PDFF may have utility in short term trials, as previously shown. 34,45,46 Our study shows that MRI-based techniques are superior to TE for detecting any fibrosis and steatosis in NAFLD patients who may be at increased risk for mortality and other poor prognostic outcomes. Other advantages of MRI-based techniques over TE include larger area of the liver measured, which may reduce sampling variability secondary to heterogeneity of fibrosis, 9,11 and the utility of MRI-PDFF for assessing longitudinal changes in steatosis.…”

Noninvasive, Quantitative Assessment of Liver Fat by MRI‐PDFF as an Endpoint in NASH Trials

“…Therefore, investigators have initiated seminal studies that aim to solve this puzzle by answering questions that can be answered in the near future. One such attempt was made by Patel et al ( ) using paired MRI‐PDFF and liver histology data from two high‐quality randomized trials. The investigators demonstrated that a relative reduction of 29% in liver fat on MRI‐PDFF is associated with a histologic response in NASH (defined as a 2‐point improvement in NAFLD Activity Score).…”

Agreement Between Magnetic Resonance Imaging Proton Density Fat Fraction Measurements and Pathologist-Assigned Steatosis Grades of Liver Biopsies From Adults With Nonalcoholic Steatohepatitis

“…The performance of PDFF as a biomarker for hepatic steatosis has also been investigated in single-center longitudinal treatment trials. In the MOZART trial (35 subjects, diagnosed NASH, treated with ezetimibe vs placebo for 24 weeks), histologic responders (reduction in NAFLD Activity Score [NAS] of two or more points) had greater relative PDFF reduction (29.3%) than non-responders (2.0%) [21]. In another randomized trial (34 subjects, diagnosed NASH, treated with N-3 fish oil vs placebo for one year), subjects treated with N3 lost more weight and showed a greater decrease in PDFF than those treated with placebo, although there were no differences in histologic response [22].…”