Multi-Scale Spatial Heterogeneity of Liver Fibrosis Evaluated by MR Elastography in Rat Models

While liver stiffness heterogeneity by MR elastography (MRE) is clinically important, whether MRE reflects multi-scale liver fibrosis heterogeneity and explains histopathological-MRE staging discordance remains unclear.

To assess spatial heterogeneity of liver fibrosis at multiple scales using MRE, correlating with histopathology.

Prospective.

Male Sprague-Dawley rats (N = 72) with liver fibrosis via carbon tetrachloride intoxication or bile duct ligation (N = 27 in each) and sham controls (N = 18).

3.0 T spin-echo echo-planar imaging multi-frequency (60-200 Hz) three-dimensional vector MRE sequence.

Three-dimensional vector MRE at 200 Hz quantified liver stiffness across four lobes. Liver fibrosis heterogeneity was evaluated at three scales via histopathology and MRE: whole-liver (≥ 2 stage difference; liver stiffness variability as percentage difference between highest and lowest mean lobar stiffness), inter-lobe (1-3 stage difference; stiffness comparisons between paired lobes), and intra-lobe (≥ 2 stage difference between predominant and secondary fibrosis patterns; coefficient of variation of stiffness).

Spearman correlation, Kruskal-Wallis test with Dunn correction, area under the receiver operating characteristic curves (AUC), and DeLong's test. p < 0.05 was considered significant.

Fibrotic livers (2.84 ± 0.59 kPa) showed significantly higher stiffness than non-fibrotic livers (1.90 ± 0.23 kPa). AUCs for fibrosis staging were lower at the rat level (0.78-0.94) than at the lobe level (0.94-0.98), significant for ≥ F2 and ≥ F3 stages. Based on optimal cutoffs, liver stiffness variability classified 80.6% (58/72) of whole-liver heterogeneity, and CV of liver stiffness identified 85.5% (53/62) of intra-lobe heterogeneity. Additionally, liver stiffness detected 75% (120/160) of inter-lobe heterogeneity. MRE-defined heterogeneity explained 70.6% (whole-liver scale) and 78.6% (intra-lobe scale) of cases with ≥ 2 stage MRE-histopathology discordance.

MRE depicts multi-scale hepatic fibrosis heterogeneity that correlates with histopathology and may provide a mechanism to explain histopathological-MRE staging discordance, potentially improving diagnostic accuracy with sampling limitations.

1.

Stage 2.