title: Molecular MRI of collagen to diagnose and stage liver fibrosis.
abstract: OBJECTIVE
  The gold standard in assessing liver fibrosis is biopsy despite limitations like invasiveness and sampling error and complications including morbidity and mortality. Therefore, there is a major unmet medical need to quantify fibrosis non-invasively to facilitate early diagnosis of chronic liver disease and provide a means to monitor disease progression. The goal of this study was to evaluate the ability of several magnetic resonance imaging (MRI) techniques to stage liver fibrosis.
  
  
  METHODS
  A gadolinium (Gd)-based MRI probe targeted to type I collagen (termed EP-3533) was utilized to non-invasively stage liver fibrosis in a carbon tetrachloride (CCl4) mouse model and the results were compared to other MRI techniques including relaxation times, diffusion, and magnetization transfer measurements.
  
  
  RESULTS
  The most sensitive MR biomarker was the change in liver:muscle contrast to noise ratio (ΔCNR) after EP-3533 injection. We observed a strong positive linear correlation between ΔCNR and liver hydroxyproline (i.e. collagen) levels (r=0.89) as well as ΔCNR and conventional Ishak fibrosis scoring. In addition, the area under the receiver operating curve (AUR0C) for distinguishing early (Ishak ≤ 3) from late (Ishak ≥ 4) fibrosis was 0.942 ± 0.052 (p<0.001). By comparison, other MRI techniques were not as sensitive to changes in fibrosis in this model.
  
  
  CONCLUSIONS
  We have developed an MRI technique using a collagen-specific probe for diagnosing and staging liver fibrosis, and validated it in the CCl4 mouse model. This approach should provide a better means to monitor disease progression in patients.
authors.affiliation: Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, 55 Fruit St., WRN 401, Boston, MA 02114, United States.
authors.forename: Bryan C
authors.initials: BC
authors.lastname: Fuchs
authors.forename: Huifang
authors.initials: H
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.forename: Lan
authors.initials: L
authors.lastname: Wei
authors.forename: Miloslav
authors.initials: M
authors.lastname: Polasek
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Schühle
authors.forename: Gregory Y
authors.initials: GY
authors.lastname: Lauwers
authors.forename: Ashfaq
authors.initials: A
authors.lastname: Parkar
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Sinskey
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Tanabe
authors.forename: Peter
authors.initials: P
authors.lastname: Caravan
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride / Q000009:adverse effects; D024042:Collagen Type I / Q000032:analysis; D004195:Disease Models, Animal; D018450:Disease Progression; D005682:Gadolinium; D008099:Liver / Q000737:chemistry / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000175:diagnosis* / Q000473:pathology*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015335:Molecular Probes; D012372:ROC Curve; D012720:Severity of Illness Index
chemical_list: D024042:Collagen Type I; D015335:Molecular Probes; D005682:Gadolinium; D002251:Carbon Tetrachloride
keywords: ADC; AUROC; CCl(4); CNR; ELF; EP-3533; Fibrosis; Gadolinium; Gd; HCC; MR elastography; MRE; MRI; MTR; Molecular imaging; Non-invasive; ROC; SD; SI; SL; TE; TI; Type 1 collagen; apparent diffusion coefficient; area under the ROC; carbon tetrachloride; contrast to noise ratio; echo time; enhanced liver fibrosis; gadolinium; hepatocellular carcinoma; intravenous; inversion time; iv; magnetic resonance imaging; magnetization transfer ratio; receiver operating curve; signal intensity; spin lock time; standard deviation