Molecular MR imaging of liver fibrosis: A feasibility study using rat and mouse models

Abstract

Background & Aims Liver biopsy, the current clinical gold standard for assessment of fibrosis, is invasive and has sampling errors, and is not optimal for screening, monitoring, or clinical decision-making. Fibrosis is characterized by excessive accumulation of extracellular matrix proteins including type I collagen. We hypothesize that molecular magnetic resonance imaging (MRI) with a probe targeted to type I collagen could provide a direct and non-invasive method for assessment of fibrosis. Methods Liver fibrosis was generated in rats with diethylnitrosamine and in mice with carbon tetrachloride. Animals were imaged prior to and immediately following i.v. administration of either collagen-targeted probe EP-3533 or non-targeted control Gd-DTPA. Magnetic resonance (MR) signal wash-out characteristics were evaluated from T1 maps and T1-weighted images. Liver tissue was subjected to pathologic scoring of fibrosis and analyzed for gadolinium and hydroxyproline. Results EP-3533 enhanced MR showed greater signal intensity on delayed imaging (normalized signal enhancement mice: control = 0.39±0.04, fibrotic = 0.55±0.03, p <0.01) and slower signal washout in fibrotic liver compared to controls (liver t1/2 = 51.3±3.6 vs 42.0±2.5 min, p <0.05 and 54.5±1.9 vs 44.1±2.9 min, p <0.01 for fibrotic vs controls in rat and mouse models, respectively). Gd-DTPA enhanced MR could not distinguish fibrotic from control animals. EP-3533 gadolinium concentration in liver showed strong positive correlations with hydroxyproline levels (r = 0.74 (rats), r = 0.77 (mice)) and with Ishak scoring (r = 0.84 (rats), r = 0.79 (mice)). Conclusion Molecular MRI of liver fibrosis with a collagen-specific probe identifies fibrotic tissue in two rodent models of disease.

Molecular magnetic resonance imaging accurately measures the antifibrotic effect of EDP‐305, a novel farnesoid X receptor agonist

“…1F) 21. Consistent with the histologic, biochemical, and gene expression assessments of hepatic fibrosis, EDP‐305 30 mg/kg treatment was associated with a reduction in liver ΔR1 compared to BDL control (ΔR1 = 0.75 ± 0.07 second –1 versus 1.04 ± 0.10 second –1 , respectively; P ≤ 0.05) (Fig.…”

“…The imaging methods used in this study thus have potential for future clinical application 19, 21. Other modalities for imaging hepatic fibrosis are being trialed.…”

“…Collagen proportional area (CPA) and hepatic lipid vacuolization were calculated from whole‐slide scanned sections using ImageJ (National Institutes of Health). Hydroxyproline was quantified by high‐performance liquid chromatography analysis 19, 20, 21, 22…”

Elastin-based molecular MRI of liver fibrosis

“…1C,F). Although these findings require further investigation (with regard to fibrosis stage, ESMA dose, timing, specificity, and quantification), they demonstrate that elastin-based molecular MRI, like collagen-based molecular MRI, 3 may be suitable for noninvasive monitoring of ECM remodeling during liver fibrosis. As the collagen-to-elastin-ratio changes during the progression and regression of liver fibrosis, 2 the selective or combined use of different molecular MR probes might be a promising strategy for translating the differential regulation of ECM proteins during fibrosis pro-and regression into novel noninvasive imaging techniques for the clinic.…”

“…1 In the June 2012 issue of HEPATOLOGY, Pellicoro et al 2 elegantly demonstrate that elastin accumulation represents a distinct feature of advanced-stage liver fibrosis, because of both increased synthesis and decreased macrophage metalloelastase (MMP12)-mediated degradation. Taking these findings, and the results recently reported by Polasek et al 3 on a collagen-specific magnetic resonance (MR) contrast agent into account, we reasoned that elastin might be a promising novel target for molecular MR monitoring of ECM-remodeling during hepatic fibrosis.…”