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Molecular MR Imaging of Myeloperoxidase Distinguishes Steatosis from Steatohepatitis in Nonalcoholic Fatty Liver Disease.

ABSTRACT: Purpose To test whether MPO-Gd, an activatable molecular magnetic resonance (MR) imaging agent specific for myeloperoxidase (MPO) activity, could detect MPO activity in nonalcoholic steatohepatitis (NASH) mouse models and human liver biopsy samples. Materials and Methods In this study, 20 leptin receptor-deficient and three MPO knockout mice were injected with endotoxin (lipopolysaccharide) or fed a methionine and choline-deficient (MCD) diet to induce experimental NASH and underwent MR imaging with MPO-Gd. Saline-injected and control diet-fed leptin receptor-deficient mice were used as respective controls. MPO protein and activity measurements and histologic analyses were performed. Eleven human liver biopsy samples underwent MPO-Gd-enhanced MR imaging ex vivo and subsequent histologic evaluation. Results were compared with Student t test or Mann-Whitney U test. Results With endotoxin, a significantly increased contrast-to-noise ratio (CNR) was found compared with sham (mean CNR, 1.81 [95% confidence interval {CI}: 1.53, 2.10] vs 1.02 [95% CI: 0.89, 1.14]; P = .03) at MPO-Gd MR imaging. In the diet-induced NASH model, an increased CNR was also found compared with sham mice (mean CNR, 1.33 [95% CI: 1.27, 1.40] vs 0.98 [95% CI: 0.83, 1.12]; P = .008). Conversely, CNR remained at baseline in NASH mice imaged with gadopentetate dimeglumine and in MPO knockout NASH mice with MPO-Gd, which proves specificity of MPO-Gd. Ex vivo molecular MR imaging of liver biopsy samples from NASH and control patients confirmed results from animal studies (mean CNR for NASH vs control patients, 2.61 [95% CI: 1.48, 3.74] vs 1.29 [95% CI: 1.06, 1.52]; P = .004). Conclusion MPO-Gd showed elevated MPO activity in NAFLD mouse models and human liver biopsy samples. © RSNA, 2017 Online supplemental material is available for this article. An earlier incorrect version of this article appeared online. This article was corrected on April 6, 2017.

SUBMITTER: Pulli B

PROVIDER: S-EPMC5548451 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Molecular MR Imaging of Myeloperoxidase Distinguishes Steatosis from Steatohepatitis in Nonalcoholic Fatty Liver Disease.

Pulli Benjamin B Wojtkiewicz Gregory G Iwamoto Yoshiko Y Ali Muhammad M Zeller Matthias W MW Bure Lionel L Wang Cuihua C Choi Yuri Y Masia Ricard R Guimaraes Alex R AR Corey Kathleen E KE Chen John W JW

Radiology 20170330 2

Purpose To test whether MPO-Gd, an activatable molecular magnetic resonance (MR) imaging agent specific for myeloperoxidase (MPO) activity, could detect MPO activity in nonalcoholic steatohepatitis (NASH) mouse models and human liver biopsy samples. Materials and Methods In this study, 20 leptin receptor-deficient and three MPO knockout mice were injected with endotoxin (lipopolysaccharide) or fed a methionine and choline-deficient (MCD) diet to induce experimental NASH and underwent MR imaging ...[more]

PMID: 28358240

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Project description:Background & aimsPatients with nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH) often require histologic assessment via liver biopsy. Magnetic resonance imaging (MRI)-based methods for measuring liver triglycerides based on proton density fat fraction (PDFF) are increasingly used as a noninvasive tool to identify patients with hepatic steatosis and to assess for change in liver fat over time. We aimed to determine whether MRI-PDFF accurately reflects a variety of liver histology features in patients with NAFLD or NASH.MethodsWe performed a retrospective analysis of pooled data from 3 phase 2a trials of pharmacotherapies for NAFLD or NASH. We collected baseline clinical, laboratory, and histopathology data on all subjects who had undergone MRI analysis in 1 of the trials. We assessed the relationship between liver PDFF values and liver histologic findings using correlation and area under the receiver operating characteristic (AUROC) analyses. As an ancillary analysis, we also simulated a clinical trial selection process and calculated subject exclusion rates and differences in population characteristics caused by PDFF inclusion thresholds of 6% to 15%.ResultsIn 370 subjects, the mean baseline PDFF was 17.4% ± 8.6%. Baseline PDFF values correlated with several histopathology parameters, including steatosis grade (r = 0.78; P < .001), NAFLD activity score (NAS, r = 0.54; P < .001), and fibrosis stage (r = -0.59; P < .001). However, PDFF did not accurately identify patients with NAS ≥ 4 (AUROC = 0.72) or fibrosis stage ≥3 (AUROC = 0.66). In a theoretical trial of these subjects, exclusion rates increased as PDFF minimum threshold level increased. There were no significant differences in cohort demographics when PDFF thresholds ranging from 6% to 15% were used, and differences in laboratory and histopathology data were small.ConclusionsIn an analysis of patients with NAFLD or NASH, we determined that although The MRI-PDFF correlated with steatosis grade and NAS, and inversely with fibrosis stage, it was suboptimal in identification of patients with NAS >4 or advanced fibrosis. Although MRI-PDFF is an important imaging biomarker for continued evaluation of this patient population, liver biopsy analysis is still necessary.

Project description:BACKGROUND & AIMS:Cross-sectional studies of patients with nonalcoholic fatty liver disease (NAFLD) have reported a lower prevalence of severe disease among modest drinkers compared with nondrinkers. We collected data from adult participants in the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network to evaluate the longitudinal association between modest use of alcohol and histology findings in patients with NAFLD, using paired liver biopsies collected more than 1 year apart. METHODS:We studied NASH Clinical Research Network participants 21 years or older, not receiving pharmacologic therapy, from whom 2 or more liver biopsies and data on alcohol use within 2 years of the initial biopsy were available. Alcohol consumption was evaluated at study entry using the Alcohol Use Disorders Identification Test and Skinner Lifetime Drinking History questionnaires. At each follow-up visit participants were asked about alcohol use frequency, number of drinks on a typical day, and frequency of heavy drinking. The association between baseline drinking status and changes in fibrosis stage, NASH histology, and the NAFLD Activity Score and its individual components were evaluated by analysis of covariance. The association between change in drinking status and change in histology was evaluated using adjusted logistic regression. RESULTS:Of 285 participants (82% white, 70% female, mean age, 47 y) meeting entry criteria, 168 (59%) were modest alcohol users (?2 drinks/d) and the remaining 117 were abstinent. At baseline, a higher proportion of modest alcohol users were white (86% vs 76% nonwhite) (P = .04) and a lower proportion of modest alcohol users were diagnosed with definite NASH (57% vs 74% without NASH; P = .01). During a mean follow-up period of 47 months between biopsies, nondrinkers had a greater mean reduction in steatosis grade (reduction, 0.49) than modest drinkers (reduction, 0.30; P = .04) and a greater reduction in mean level of aspartate transaminase (reduction, 7 U/L vs an increase of 2 U/L in modest drinkers; P = .04). Modest drinkers had significantly lower odds of NASH resolution compared with nondrinkers (adjusted odds ratio, 0.32; 95% CI, 0.11-0.92; P = .04) on adjusted analysis. CONCLUSIONS:In a longitudinal analysis of liver biopsies from patients with NAFLD not receiving pharmacologic therapy, modest alcohol use was associated with less improvement in steatosis and level of aspartate transaminase, as well as lower odds of NASH resolution, compared with no use of alcohol.

Dataset Information

Molecular MR Imaging of Myeloperoxidase Distinguishes Steatosis from Steatohepatitis in Nonalcoholic Fatty Liver Disease.

Publications

Molecular MR Imaging of Myeloperoxidase Distinguishes Steatosis from Steatohepatitis in Nonalcoholic Fatty Liver Disease.

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