Ezetimibe inhibits intestinal cholesterol absorption and lowers low-density lipoprotein cholesterol. Uncontrolled studies have suggested that it reduces liver fat as estimated by ultrasound in nonalcoholic steatohepatitis (NASH). Therefore, we aimed to examine the efficacy of ezetimibe versus placebo in reducing liver fat by the magnetic resonance imaging-derived proton density-fat fraction (MRI-PDFF) and liver histology in patients with biopsy-proven NASH. In this randomized, double-blind, placebo-controlled trial, 50 patients with biopsy-proven NASH were randomized to either ezetimibe 10 mg orally daily or placebo for 24 weeks. The primary outcome was a change in liver fat as measured by MRI-PDFF in colocalized regions of interest within each of the nine liver segments. Novel assessment by two-dimensional and three-dimensional magnetic resonance elastography was also performed. Ezetimibe was not significantly better than placebo at reducing liver fat as measured by MRI-PDFF (mean difference between the ezetimibe and placebo arms -1.3%, P = 0.4). Compared to baseline, however, end-of-treatment MRI-PDFF was significantly lower in the ezetimibe arm (15%-11.6%, P < 0.016) but not in the placebo arm (18.5%-16.4%, P = 0.15). There were no significant differences in histologic response rates, serum alanine aminotransferase and aspartate aminotransferase levels, or longitudinal changes in two-dimensional and three-dimensional magnetic resonance elastography-derived liver stiffness between the ezetimibe and placebo arms. Compared to histologic nonresponders (25/35), histologic responders (10/35) had a significantly greater reduction in MRI-PDFF (-4.35 ± 4.9% versus -0.30 ± 4.1%, P < 0.019). Conclusions: Ezetimibe did not significantly reduce liver fat in NASH. This trial demonstrates the application of colocalization of MRI-PDFF-derived fat maps and magnetic resonance elastography-derived stiffness maps of the liver before and after treatment to noninvasively assess treatment response in NASH. (Hepatology 2015;61:1239–1250)

Background & Aims Uncontrolled studies show sitagliptin, an oral DPP-4 inhibitor, may improve alanine aminotransferase (ALT) and liver histology in nonalcoholic fatty liver disease (NAFLD) patients. We aimed to compare sitagliptin versus placebo's efficacy in reducing liver fat measured by MRI-derived proton density-fat fraction (MRI-PDFF). Methods This randomized, double-blind, allocation-concealed, placebo-controlled trial included 50 NAFLD patients with pre-diabetes or early diabetes randomized to sitagliptin orally 100 mg/day or placebo for 24 weeks. Primary outcome was liver fat change measured by MRI-PDFF in co-localized regions of interest within each of nine liver segments. Additional advanced assessments included MR spectroscopy (MRS) for internal validation of MRI-PDFF's accuracy, and MR elastography (MRE) and FIBROSpect® II to assess liver fibrosis. Results Sitagliptin was not significantly better than placebo in reducing liver fat measured by MRI-PDFF (mean difference between sitagliptin and placebo arms: −1.3%, p=0.4). Compared to baseline, there were no significant differences in end-of-treatment MRI-PDFF for sitagliptin (18.1% to 16.9%, p=0.27) or placebo (16.6% to 14.0%, p=0.07). The groups had no significant differences for changes in ALT, aspartate aminotransferase, low-density lipoprotein, homeostatic model assessment insulin resistance, and MRE-derived liver stiffness. In both groups at baseline and post-treatment, MRI-PDFF and MRS showed robust correlation coefficients ranging from r2=0.96 to r2=0.99 (p<0.0001), demonstrating the findings’ strong internal validity. FIBROSpect® II showed no changes in the sitagliptin group but was significantly increased in the placebo group (p=0.03). Conclusions Sitagliptin was safe but not better than placebo in reducing liver fat in prediabetic or diabetic patients with NAFLD.

Objective Recent studies show two-dimensional (2D)-MRE is accurate in diagnosing advanced fibrosis (stages 3 and 4) in nonalcoholic fatty liver disease (NAFLD) patients. 3D-MRE is a more advanced version of the technology that can image shear-wave fields in 3D of the entire liver. The aim of this study was to prospectively compare the diagnostic accuracy of 3D-MRE and 2D-MRE for diagnosing advanced fibrosis in patients with biopsy-proven NAFLD. Design This cross-sectional analysis of a prospective study included 100 consecutive patients (56% women) with biopsy-proven NAFLD who also underwent MRE. Area under the receiver operating characteristic (AUROC) ana3lysis was performed to assess the accuracy of 2D and 3D-MRE in diagnosing advanced fibrosis. Results The mean (±sd) of age and BMI was 50.2 (±13.6) yrs and 32.1 (±5.0) kg/m2, respectively. The AUROC for diagnosing advanced fibrosis was 0.981 for 3D-MRE at 40 Hz, 0.927 for 3D-MRE at 60 Hz (standard shear-wave frequency), and 0.921 for 2D-MRE at 60 Hz (standard shear-wave frequency). At a threshold of 2.43 kPa, 3D-MRE at 40 Hz had sensitivity 1.0, specificity 0.94, positive predictive value 0.72, and negative predictive value 1.0 for diagnosing advanced fibrosis. 3D-MRE at 40 Hz had significantly higher AUROC (p<0.05) than 2D-MRE at 60 Hz for diagnosing advanced fibrosis. Conclusion Utilizing a prospective study design, we demonstrate that 3D MRE at 40 Hz has the highest diagnostic accuracy in diagnosing NAFLD advanced fibrosis. Both 2D and 3D-MRE at 60 Hz, the standard shear-wave frequency, are also highly accurate in diagnosing NAFLD advanced fibrosis.

Magnetic resonance elastography (MRE), an advanced MR-based imaging technique, and acoustic radiation force impulse (ARFI), an ultrasound-based imaging technique, have been shown to be accurate for diagnosing nonalcoholic fatty liver disease (NAFLD) fibrosis. However, no head-to-head comparisons between MRE and ARFI for diagnosing NAFLD fibrosis have been performed. We aimed to compare MRE versus ARFI head-to-head for diagnosing fibrosis in well-characterized patients with biopsy-proven NAFLD. Methods This cross-sectional analysis of a prospective cohort involved 125 patients (54.4% female) who underwent MRE, ARFI, and contemporaneous liver biopsies scored using the Nonalcoholic Steatohepatitis Clinical Research Network histological scoring system. MRE versus ARFI’s performances for diagnosing fibrosis were evaluated using area under receiver operating characteristic curves (AUROCs). Results The mean (±SD) age and BMI were 48.9 (±15.4) years and 31.8 (±7.0) kg/m2, respectively. For diagnosing any fibrosis (≥ stage 1), MRE’s AUROC was 0.799 (95% CI, 0.723–0.875), significantly (p=0.012) higher than ARFI’s AUROC of 0.664 (95% CI, 0.568–0.760). In stratified analysis by presence/absence of obesity, MRE was superior to ARFI for diagnosing any fibrosis in obese patients (p<0.001) but not in non-obese patients (p=0.722). MRE’s AUROCs for diagnosing ≥ stages 2, 3, and 4 fibrosis were 0.885 (95% CI, 0.816–0.953), 0.934 (95% CI, 0.863–1.000), and 0.882 (95% CI, 0.729–1.000), and ARFI’s AUROCs were 0.848 (95% CI, 0.776–0.921), 0.896 (95% CI, 0.824–0.968), and 0.862 (95% CI, 0.721–1.000). MRE had higher AUROCs than ARFI for discriminating dichotomized fibrosis stages at all dichotomization cut-points, but the AUROC differences decreased as the cut-points (fibrosis stages) increased. Conclusions MRE is more accurate than ARFI for diagnosing any fibrosis in all NAFLD patients and obese NAFLD patients, although not in non-obese NAFLD patients.

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.