Objective:To analyze the change rules of quantitative parameters of magnetic resonance-perfusion weighted imaging (MR-PWI) in cynomolgus monkeys with different degrees of liver fibrosis, and to explore the best parameter of MR-PWI in evaluating the severity of liver fibrosis.Methods:Liver fibrosis models of twenty-two cynomolgus monkeys were successfully established by subcutaneous injection of carbon tetrachloride and feeding with high-fat food. Among them, 15 cynomolgus monkeys developed into early liver cirrhosis (stage S4 of liver fibrosis). Compatibility group design was adopted, the comparative study on MR-PWI of exchange double blood supply model of liver was carried out in these 15 cynomolgus monkeys with a complete development process of liver fibrosis. The quantitative parameters of MR-PWI included endothelial transfer constant ( ktrans), reflux rate constant ( kep), extravascular extracellular space fractional volume ( ve), fractional plasma volume ( vp) and hepatic artery perfusion index (HPI). The change rules of the above parameters and their correlation with the severity of hepatic fibrosis were analyzed. The best parameter of MR-PWI was explored. Compatibility group design (randomized block design), analysis of variance, SNK- q test, Spearman rank correlation analysis and receiver operating characteristic (ROC) curve analysis were used for statistical analysis. Results:ktrans and kep of MR-PWI of cynomolgus monkeys decreased along with the progress of hepatic fibrosis, and the differences were statistically significant ( F=685.228, 99.718, both P<0.01). There were statistically significant differences between each stage of hepatic fibrosis (S1 to S4) and normal liver tissue (S0) ((0.527±0.038), (0.479±0.035), (0.432±0.032) and (0.387±0.031) mL/min vs.(0.584±0.044) mL/min, all P<0.01; (2.193±0.307), (1.997±0.301), (1.624±0.174) and (1.532±0.130) mL/min vs. (2.565±0.482) mL/min, all P<0.01). There were statistically significant in ktrans and kep between stage S3, S4 severe liver fibrosis and stage S1 mild liver fibrosis, stage S2 moderate liver fibrosis (all P<0.01), however there were no statistically significant differences between stage S3 and stage S4 liver fibrosis, between stage S1 and stage S2 liver fibrosis (all P>0.05). Along with the development of the severity of liver fibrosis, HPIs increased gradually, and the differences were statistically significant ( F=839.883, P<0.01). The HPIs of stage S0 to S4 were 0.244±0.022, 0.317±0.035, 0.421±0.046, 0.546±0.043 and 0.651±0.058, respectively, and there were statistically significant differences between groups (all P<0.01). Along with the progression of the severity of liver fibrosis, vp decreased while ve increased gradually, but there were no statistically significant differences among groups (all P>0.05). The results of Spearman rank correlation analysis indicated that ktrans and kep were negatively correlated with the severity of liver fibrosis ( rs=-0.875 and -0.797, both P<0.01), however HPI was positively correlated with the severity of liver fibrosis ( rs=0.959, P<0.01). The results of ROC curve analysis showed that area under curves (AUCs) of ktrans, kep and HPI in the diagnosis of early cirrhosis were 0.852 (95% CI 0.767 to 0.937), 0.799 (95% CI 0.700 to 0.897) and 0.967 (95% CI 0.932 to 1.002), respectively. The best cut-off values were 0.395 mL/min, 1.561 mL/min and 0.590, respectively. The sensitivity was 86.7%, 79.6% and 97.4%, respectively and the specificity was 77.4%, 71.9% and 93.1%, respectively. The thresholds of HPI in the diagnosis of liver fibrosis at stage S1, stage S2, stage S3 and stage S4 were 0.291, 0.376, 0.503 and 0.590, respectively; the sensitivity was 95.7%, 93.8% and 94.4% and 97.4%, respectively and the specificity was 89.5%, 84.7%, 91.3% and 92.7%, respectively. Conclusions:The parameters of MR-PWI change regularly with the development of liver fibrosis in the cynomolgus monkey model, among which HPI is the best parameter for quantitative evaluation of the severity of liver fibrosis.

Objective:To investigate the changing rules with 1H magnetic resonance spectroscopy ( 1H-MRS) in order to provide human research theoretical basis with varying degrees of liver fibrosis in cynomolgus monkeys. Methods:Liver fibrosis model in twenty-two cynomolgus monkey was successfully established with carbon tetrachloride (CCl 4). Among them, fifteen cynomolgus monkey developed to early-stage liver cirrhosis (S4 stage). A comparative study was conducted in 15 cynomolgus monkeys that had fully developed liver fibrosis. The changing rules for varying degrees of liver fibrosis in cynomolgus monkeys were analyzed with 1H-MRS. Supplementary methods: statistical analysis was performed using compatibility group design and analysis of variance for each research indicators. SNK-q test was used for pairwise comparison between the groups. The correlation between the 1H-MRS research indicators and the severity of liver fibrosis was analyzed by Spearman’s rank correlation. Results:The Cho of 1H-MRS was increased with the severity of liver fibrosis in cynomolgus monkeys. Moreover, there were statistically significant ( P < 0.01) differences between liver fibrosis staging (S1 ~ S4) and normal liver tissue (S0 stage), severe liver fibrosis staging (S3 and S4) and mild to moderate liver fibrosis staging (S1 and S2). Compared with S0 stage, the peak value of lipid in S1 stage was significantly higher than that of S2 stage, and the peak value of lipid in S3 and S4 stage was significantly lower than that of S0 stage, and the differences between S1, S3, S4 and S0 stages were statistically significant ( P < 0.01). The Cho/lipid ratio had gradually increased with the severity of liver fibrosis progression and the differences between groups were statistical significant ( P < 0.01). Spearman’s rank correlation coefficient between Cho / lipid ratio and pathological stage of liver fibrosis was 0.98 ( P = 0.000). ROC curve analysis showed that Cho / lipid ratio was the most significant diagnostic indicator for liver fibrosis. The threshold values of CHO/lipid ratio were≥ 0.028, and≥ 0.131 ( P < 0.01) for the diagnosis of liver fibrosis and early-stage cirrhosis. Conclusion:1H-MRS of the cynomolgus monkey liver fibrosis model changes rules regularly with the aggravation of severity of liver fibrosis. Among them, the Cho/lipid ratio is the most valuable indicator for the diagnosis of liver fibrosis staging, which may provide a theoretical basis for the study of human liver fibrosis.