Dual-input dual-compartmental uptake and efflux model based on Gd-EOB-DTPA-enhanced MRI for simultaneously assessing...

Liver function assessment and fibrosis staging are crucial for monitoring therapeutic efficacy and guiding surgical management in patients with chronic liver disease. This study aimed to determine whether pharmacokinetic parameters derived from dual-input dual-compartmental uptake and efflux model based on Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) could simultaneously assess liver function and fibrosis.

Thirty rats were enrolled in this study. Thioacetamide (TAA) was administered for 2, 4, 6, and 8 weeks to induce liver fibrosis. The METAVIR system (F0-F4) was used to stage fibrosis. Pharmacokinetic modeling was performed in a voxel-wise manner to generate parametric maps, from which mean values were extracted using liver regions of interest (ROIs). Pharmacokinetic parameters, including plasma flow rate (F _p), extracellular space (v _ecs), arterial supply fraction (f _a), mean uptake (k _i) and efflux (k _ef) rate of hepatocytes, were compared across fibrosis groups. The expression of hepatic transporters, including the organic anion-transporting polypeptide 1a1 (Oatp1a1) and the multidrug resistance-associated protein 2 (Mrp2), served as a reference for liver function. The relationship between pharmacokinetic parameters and hepatic transporters expression was assessed. Receiver operating characteristic (ROC) curve analysis was conducted to assess the diagnostic performance of pharmacokinetic parameters in staging fibrosis.

There were 6, 11, and 13 rats designated into the control (F0), early fibrosis (F1-2), and advanced fibrosis groups (F3-4), respectively. With the progression of liver fibrosis, F _p and k _i decreased significantly, while v _ecs and f _a increased significantly. Compared with the control group, the expression of Oatp1a1 and Mrp2 decreased in rats with liver fibrosis. Significant correlations were observed between F _p, v _ecs, k _i, f _a and Oatp1a1 expression (r=0.877, -0.762, 0.722, -0.460; P<0.05 for all); k_i and f_a were also significantly correlated with Mrp2 expression (r=0.435, P=0.02 and r=-0.475, P=0.008). Further multiple linear regression analysis identified k _i as the only parameter significantly associated with Oatp1a1 expression (beta =0.474; P=0.002), while no parameters were significantly related to Mrp2 expression (P>0.05 for all). For detecting fibrosis (F0 vs. F1-4), the areas under the curve (AUCs) of F _p, v _ecs, and k _i were 0.903, 0.917, and 1.000, respectively. For distinguishing advanced fibrosis (F0-2 vs. F3-4), the AUCs of F _p, v _ecs, and k _i were 1.000, 0.916, and 0.862, respectively.

The pharmacokinetic parameters derived from dual-input dual-compartmental uptake and efflux model, especially for k _i, showed potential for simultaneously assessing liver function and staging fibrosis.