title: 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.
authors.affiliation: From the Center for Systems Biology (B.P., G.W., Y.I., M.A., M.W.Z., L.B., C.W., A.R.G., J.W.C.), Department of Radiology (B.P., A.R.G., J.W.C.), Liver Center and Gastrointestinal Division (Y.C., K.E.C.), and Department of Pathology (R.M.), Massachusetts General Hospital and Harvard Medical School, Richard B. Simches Research Center, 185 Cambridge St, Boston, MA 02114.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Pulli
authors.affiliation: From the Center for Systems Biology (B.P., G.W., Y.I., M.A., M.W.Z., L.B., C.W., A.R.G., J.W.C.), Department of Radiology (B.P., A.R.G., J.W.C.), Liver Center and Gastrointestinal Division (Y.C., K.E.C.), and Department of Pathology (R.M.), Massachusetts General Hospital and Harvard Medical School, Richard B. Simches Research Center, 185 Cambridge St, Boston, MA 02114.
authors.forename: Gregory
authors.initials: G
authors.lastname: Wojtkiewicz
authors.affiliation: From the Center for Systems Biology (B.P., G.W., Y.I., M.A., M.W.Z., L.B., C.W., A.R.G., J.W.C.), Department of Radiology (B.P., A.R.G., J.W.C.), Liver Center and Gastrointestinal Division (Y.C., K.E.C.), and Department of Pathology (R.M.), Massachusetts General Hospital and Harvard Medical School, Richard B. Simches Research Center, 185 Cambridge St, Boston, MA 02114.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Iwamoto
authors.affiliation: From the Center for Systems Biology (B.P., G.W., Y.I., M.A., M.W.Z., L.B., C.W., A.R.G., J.W.C.), Department of Radiology (B.P., A.R.G., J.W.C.), Liver Center and Gastrointestinal Division (Y.C., K.E.C.), and Department of Pathology (R.M.), Massachusetts General Hospital and Harvard Medical School, Richard B. Simches Research Center, 185 Cambridge St, Boston, MA 02114.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ali
authors.affiliation: From the Center for Systems Biology (B.P., G.W., Y.I., M.A., M.W.Z., L.B., C.W., A.R.G., J.W.C.), Department of Radiology (B.P., A.R.G., J.W.C.), Liver Center and Gastrointestinal Division (Y.C., K.E.C.), and Department of Pathology (R.M.), Massachusetts General Hospital and Harvard Medical School, Richard B. Simches Research Center, 185 Cambridge St, Boston, MA 02114.
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Zeller
authors.affiliation: From the Center for Systems Biology (B.P., G.W., Y.I., M.A., M.W.Z., L.B., C.W., A.R.G., J.W.C.), Department of Radiology (B.P., A.R.G., J.W.C.), Liver Center and Gastrointestinal Division (Y.C., K.E.C.), and Department of Pathology (R.M.), Massachusetts General Hospital and Harvard Medical School, Richard B. Simches Research Center, 185 Cambridge St, Boston, MA 02114.
authors.forename: Lionel
authors.initials: L
authors.lastname: Bure
authors.affiliation: From the Center for Systems Biology (B.P., G.W., Y.I., M.A., M.W.Z., L.B., C.W., A.R.G., J.W.C.), Department of Radiology (B.P., A.R.G., J.W.C.), Liver Center and Gastrointestinal Division (Y.C., K.E.C.), and Department of Pathology (R.M.), Massachusetts General Hospital and Harvard Medical School, Richard B. Simches Research Center, 185 Cambridge St, Boston, MA 02114.
authors.forename: Cuihua
authors.initials: C
authors.lastname: Wang
authors.affiliation: From the Center for Systems Biology (B.P., G.W., Y.I., M.A., M.W.Z., L.B., C.W., A.R.G., J.W.C.), Department of Radiology (B.P., A.R.G., J.W.C.), Liver Center and Gastrointestinal Division (Y.C., K.E.C.), and Department of Pathology (R.M.), Massachusetts General Hospital and Harvard Medical School, Richard B. Simches Research Center, 185 Cambridge St, Boston, MA 02114.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Choi
authors.affiliation: From the Center for Systems Biology (B.P., G.W., Y.I., M.A., M.W.Z., L.B., C.W., A.R.G., J.W.C.), Department of Radiology (B.P., A.R.G., J.W.C.), Liver Center and Gastrointestinal Division (Y.C., K.E.C.), and Department of Pathology (R.M.), Massachusetts General Hospital and Harvard Medical School, Richard B. Simches Research Center, 185 Cambridge St, Boston, MA 02114.
authors.forename: Ricard
authors.initials: R
authors.lastname: Masia
authors.affiliation: From the Center for Systems Biology (B.P., G.W., Y.I., M.A., M.W.Z., L.B., C.W., A.R.G., J.W.C.), Department of Radiology (B.P., A.R.G., J.W.C.), Liver Center and Gastrointestinal Division (Y.C., K.E.C.), and Department of Pathology (R.M.), Massachusetts General Hospital and Harvard Medical School, Richard B. Simches Research Center, 185 Cambridge St, Boston, MA 02114.
authors.forename: Alex R
authors.initials: AR
authors.lastname: Guimaraes
authors.affiliation: From the Center for Systems Biology (B.P., G.W., Y.I., M.A., M.W.Z., L.B., C.W., A.R.G., J.W.C.), Department of Radiology (B.P., A.R.G., J.W.C.), Liver Center and Gastrointestinal Division (Y.C., K.E.C.), and Department of Pathology (R.M.), Massachusetts General Hospital and Harvard Medical School, Richard B. Simches Research Center, 185 Cambridge St, Boston, MA 02114.
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Corey
authors.affiliation: From the Center for Systems Biology (B.P., G.W., Y.I., M.A., M.W.Z., L.B., C.W., A.R.G., J.W.C.), Department of Radiology (B.P., A.R.G., J.W.C.), Liver Center and Gastrointestinal Division (Y.C., K.E.C.), and Department of Pathology (R.M.), Massachusetts General Hospital and Harvard Medical School, Richard B. Simches Research Center, 185 Cambridge St, Boston, MA 02114.
authors.forename: John W
authors.initials: JW
authors.lastname: Chen
mesh_terms: D000328:Adult; D000818:Animals; D001706:Biopsy; D003287:Contrast Media / Q000008:administration & dosage; D003937:Diagnosis, Differential; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000000981:diagnostic imaging* / Q000201:enzymology*; D005260:Female; D019786:Gadolinium DTPA / Q000008:administration & dosage; D006801:Humans; D007124:Immunoenzyme Techniques; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008875:Middle Aged; D057054:Molecular Imaging / Q000379:methods*; D065626:Non-alcoholic Fatty Liver Disease / Q000000981:diagnostic imaging* / Q000201:enzymology*; D018384:Oxidative Stress; D009195:Peroxidase / Q000008:administration & dosage*
chemical_list: D003287:Contrast Media; D009195:Peroxidase; D019786:Gadolinium DTPA