SUMMARY The presence of advanced fibrosis in nonalcoholic fatty liver disease (NAFLD) is the most important predictor of liver mortality. There are limited data on the diagnostic accuracy of gut microbiota derived signature for predicting the presence of advanced fibrosis. In this prospective study, we characterized the gut microbiome compositions using whole-genome shotgun sequencing of DNA extracted from stool samples. This study included 86 uniquely well-characterized patients with biopsy-proven NAFLD, 72 of which had mild/moderate (stage 0–2 fibrosis) NAFLD, and 14 had advanced fibrosis (stage 3 or 4 fibrosis). We identified a set of forty features (p-value <0.006), which included 37 bacterial species that were used to construct a Random Forest classifier model to distinguish mild/moderate NAFLD from advanced fibrosis. The model had a robust diagnostic accuracy (AUC 0.936) for detecting advanced fibrosis. This study provides preliminary evidence for a novel fecal-microbiome derived metagenomic signature to detect advanced fibrosis in NAFLD.

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.

No abstract