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

Molecular MRI of collagen to diagnose and stage liver fibrosis

Bryan C Fuchs  1 , Huifang Wang, Yan Yang, Lan Wei, Miloslav Polasek, Daniel T Schühle, Gregory Y Lauwers, Ashfaq Parkar, Anthony J Sinskey, Kenneth K Tanabe, Peter Caravan
Affiliations

Molecular MRI of collagen to diagnose and stage liver fibrosis

Bryan C Fuchs et al. J Hepatol. 2013 Nov.

Abstract

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.

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Conflict of interest statement

Conflict of interests: P.C. has >5% equity in Collagen Medical, LLC, a company working to commercialize the MRI probe used in this study. All other authors have no conflicts.

Figures

Fig. 1
Fig. 1. Characterization of a CCl4-induced mouse model of liver fibrosis
(A) Representative images of Sirius red staining after CCl4 administration for 6, 12 or 18 weeks. (B) Total collagen as assessed by hydroxyproline analysis was calculated as disease progressed as determined by Ishak scoring. (C) Sirius red staining was quantified using Image J software and compared to disease progression. (D) Correlation between total collagen (hydroxyproline) and Sirius red quantification. **p<0.001 and ***p<0.0001.
Fig. 2
Fig. 2. Staging of liver fibrosis using collagen-enhanced MRI
(A) Representative axial MR images of a control (Ishak 0) and fibrotic (Ishak 5) mouse showing the liver, stomach and dorsal muscle. False color overlay is the difference image between post- and pre-injection images of EP-3533. Both images rendered at the same scale. (B) ΔCNR(liver:muscle) was calculated as disease progressed as determined by Ishak scoring. (C) The amount of probe present in the ex vivo liver (% Injected Dose Gd/g Liver) was calculated as disease progressed as determined by Ishak scoring. (D) Correlation between ΔCNR(liver:muscle) and total collagen (hydroxyproline). (E) Correlation between ΔCNR(liver:muscle) and Sirius red quantification. #p<0.05, *p<0.01 and ***p<0.0001.
Fig. 3
Fig. 3. Analysis of other MR measurements for diagnosing liver fibrosis
Correlation of MR measurements with Ishak score and total liver collagen (hydroxyproline, Hyp). (A) T1 relaxation time vs Ishak; (B) apparent diffusion coefficient (ADC) vs Ishak; (C) T1ρ relaxation time vs Ishak; (D) T2 relaxation time vs Ishak; (E) magnetization transfer ratio (MTR) vs Ishak; (F) T1 vs Hyp; (G) ADC vs Hyp; (H) T1ρ vs Hyp; (I) T2 vs Hyp; (J) MTR vs Hyp. #p<0.05.
Fig. 4
Fig. 4. Collagen-targeted MRI of liver fibrosis after CCl4 withdrawal
(A) Representative images of Sirius red staining of livers from mice treated with either CCl4 for 18 weeks (CCl4) or CCl4 for 9 weeks followed by 9 weeks of withdrawal (Withdrawal). Control animals received oral gavage of vehicle only. Sirius red staining was (B) quantified using Image J software or (C) assessed by Ishak scoring. (D) ΔCNR(liver:muscle) was calculated. (E) Total collagen was determined by hydroxyproline analysis. #p< 0.05, *p<0.01, **p<0.001 and ***p<0.0001.
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