## 4 Conclusions
The main reason for this lower ARFI cut-off level was the suppression of liver inflammation by anti-HBV therapy [31; 32]. ARFIs and FibroScans measure liver stiffness by shear-wave velocity. Both of them are greatly influenced by inflammation [33; 34]. This is especially a problem in patients with chronic hepatitis B [16]. The inflammatory activity in chronic hepatitis B is not constant and is characterized by intermittent acute exacerbation [35]. There is additional problem in this study: we included patients with hepatocellular carcinoma. ARFI may miss a tumor area according to imaging that is more suitable than the FibroScan in the present study. We correlated ARFI with Metavir score over different durations of treatment. The values of ARFI tended to be higher than those of histology when the duration of treatment was shorter than or equal to 12 months (Table 3). This could have been because inflammation was not completely suppressed. The ARFI was correlated rather well with the Metavir score between 12 and 31 months after treatment. At this period, the inflammation was suppressed to a minimal level, as evidenced by a low ALT level in most cases. Therefore, the optimal timing for ARFI to measure liver fibrosis will be the second year of nucleos(t)ide analogues therapy. After that, the ARFI level tended to be lower than the histological fibrosis grading. These biases were not related to the small liver sample. Most of the mismatches between ARFI and histology were patients of HCC. These findings indicated that a decrease in liver stiffness identified by ARFI precedes the morphological changes of fibrosis. These observations also confirm that the improvement in liver stiffness at the initial stage is mainly due to reduced necroinflammation [36]. In the non-treatment group, the AUROC of lower ARFI was 0.827 (Figure 1), which was better than that in our previous study (lower ARFI AUROC: 0.707) [16]. Both studies used two-location measurements. This difference may be related to a lower level of inflammation in the current study than in the previous study. The previous study enrolled patients with chronic hepatitis B who intended to receive anti-HBV therapy. In this study, most of the patients were HCC who were hospitalized for surgical resection. The ALT level was lower in this study than in the previous study (91.90 IU/L vs. 117.19 IU/L). The other major difference was that a single operator performed most of the measurements in this study, while the previous study was conducted by several hepatologists. We believe that it is essential to measure ARFI using a standardized protocol and to limit the operator to one or two well-trained, full-time technicians. These measures may decrease the variation and make the data more reliable. In 27 patients in this series, both Fibrosan and ARFI two-location measurements are employed. The correlation is quite good (Figure 4; Pearson correlation: 0.794). For those patients without anti-HBV therapy, a simple way to reduce the influence of inflammation is to exclude patients with a high ALT level. After excluding those with an ALT level greater than 5x ULN, we found that the cut-off value for diagnosis of liver cirrhosis was similar to that of the entire series (Table 2). However, the sensitivity and specificity are improved. Further reduction or ALT level to 2x ULN did not improve the sensitivity or the specificity. It is our limitation that ALT is a somewhat indirect marker of liver inflammation. Other serological markers of liver inflammation could potentially help to select patients for ARFI studies. We excluded patients with advance cirrhosis. Our cut-off value was lower than most of the studies in Western countries [9; 10; 22]. However, the cut-off value is similar to reports from Korea [37] and China with low ALT levels [38]. Therefore, we set the mean ARFI cut-off value for liver cirrhosis to be 1.523 m/sec for the non-treatment group. For patients receiving anti-HBV therapy, the cut-off value will be lower than untreated patients and is treatment duration dependence.