Molecular MRI of collagen to diagnose and stage liver fibrosis

J Hepatol. 2013 Nov;59(5):992-8. doi: 10.1016/j.jhep.2013.06.026. Epub 2013 Jul 6.


Background & aims: 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.

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.

Publication types

  • Evaluation Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carbon Tetrachloride / adverse effects
  • Collagen Type I* / analysis
  • Disease Models, Animal
  • Disease Progression*
  • Gadolinium
  • Liver / chemistry
  • Liver / pathology
  • Liver Cirrhosis / chemically induced
  • Liver Cirrhosis / diagnosis*
  • Liver Cirrhosis / pathology*
  • Magnetic Resonance Imaging / methods*
  • Male
  • Mice
  • Mice, Inbred Strains
  • Molecular Probes
  • ROC Curve
  • Severity of Illness Index


  • Collagen Type I
  • Molecular Probes
  • Gadolinium
  • Carbon Tetrachloride