ObjectiveThe purpose of the current study was to determine the usefulness of the usage of the spleen as a reference organ to normalize liver ADC to improve the diagnostic performance of diffusion weighted imaging (DWI) for assessing liver fibrosis. Materials and methodsForty-nine subjects, 34 patients with liver disease and 15 control subjects were assessed with diffusion-weighted imaging. Liver ADC and normalized liver ADC (defined as the ratio of liver ADC to spleen ADC) were compared between patients and the control groups as well as among patients with different stages of fibrosis. Receiver operating characteristic (ROC) analysis was used to determine the performance of ADC and normalized liver ADC for prediction of liver fibrosis and cirrhosis. ResultsThere was no significant difference between spleen ADC values among patients in comparison to control (1.107±0.07×10−3mm2/s vs. 1.12±0.068×10−3mm2/s, p=0.998) or among patients with different stages of fibrosis (p=0.59–0.89). The mean liver ADC and mean normalized liver ADC values were significantly lower in patients with hepatic fibrosis compared to volunteers (P=0.01,<0.001 respectively), however liver ADC could not significantly differentiate different stages of fibrosis except between stages 0 and 4. The mean normalized liver ADC was significantly different between stage 0 and stages 2, 3, and 4 as well as between stage 1 and stage 4. In addition, it had a trend toward significance between stage 0 and 1, stage 2 and 4 as well as stage 3 and 4. Both liver ADC and normalized liver ADC had a significant negative correlation with the grade of fibrosis, however it was more powerful for normalized liver ADC in comparison to liver ADC (r=−0.694 vs. −0.361, p=0.01 vs. 0.05). ROC analysis showed higher performance using normalized liver ADC in comparison to liver ADC, with higher AUC, sensitivity, and specificity for detection of fibrotic stages ⩾2 (0.88, 92.5% and 76.2% Vs 0.72, 82.1%, and 57.1% respectively). The corresponding values for stages ⩾3 were 0.83, 100%, and 55% vs. 0.69, 77.3%, and 44.4% respectively), while the corresponding values for cirrhosis (stage 4) were 0.87, 81.8%, and 81.8% for normalized liver ADC vs. 0.74, 69.2%, 72.2%.for ADC liver. ConclusionThe utility of using the spleen as a reference organ could improve the diagnostic performance of ADC measurement for the diagnosis of liver fibrosis. The application of this technique for the evaluation of liver fibrosis is promising.