AIM: To investigate the factors other than fibrosis stage correlating with acoustic radiation force impulse (ARFI) elastograpy in chronic hepatitis C.
METHODS: ARFI elastograpy was performed in 108 consecutive patients with chronic hepatitis C who underwent a liver biopsy. The proportion of fibrosis area in the biopsy specimens was measured by computer-assisted morphometric image analysis.
RESULTS: ARFI correlated significantly with fibrosis stage (β = 0.1865, P < 0.0001) and hyaluronic acid levels ( β = 0.0008, P = 0.0039) in all patients by multiple regression analysis. Fibrosis area correlated significantly with ARFI by Spearman’s rank correlation testbut not by multiple regression analysis. ARFI correlatedsignificantly with body mass index (BMI) ( β = -0.0334, P = 0.0001) in F0 or F1, with γ-glutamyltranspeptidase levels ( β = 0.0048, P = 0.0012) in F2, and with fibrosis stage (β = 0.2921, P = 0.0044) and hyaluronic acid levels ( β = 0.0012, P = 0.0025) in F3 or F4. The ARFIcutoff value was 1.28 m/s for F ≥ 2, 1.44 m/s for F ≥ 3, and 1.73 m/s for F4.
ARFI correlated with fibrosis stage and hyaluronic acid but not with inflammation. ARFI was affected by BMI, γ-glutamyltranspeptidase, and hyaluronic acid in each fibrosis stage.
© 2014 Baishideng Publishing Group Co., Limited. All rights reserved
Core tip: The assessment of liver fibrosis stage is important to estimate prognosis and to identify the patients requiring antiviral treatment in chronic hepatitis C. Liver biopsy is a gold standard for assessing fibrosis, but is invasive. Thus methods for noninvasively assessing fibrosis have been developed. Liver stiffness measurement (LSM) by Fibroscan and acoustic radiation force impulse correlate with fibrosis stage. However, LSM may be affected by factors other than fibrosis, such as edema, steatosis, and inflammation.
The assessment of fibrosis stage is important to estimate prognosis and to identify the patients requiring antiviral treatment in chronic hepatitis C. A lot of noninvasive methods to assess liver fibrosis stage other than liver biopsy are available, for example, ARFI, TE, real-timeelastography , and algorithm of serum fibrosis markers such as FibroTest  and APRI . They provide good performances in estimation of fibrosis stage, while there are problems such as influence of inflammation. In the present study, factors other than fibrosis stage that affect ARFI were investigated in patients with chronic hepatitis C.
The present study confirmed findings reported previously that ARFI correlates with fibrosis stage [10-13,26,27].
The ARFI cutoff values for different fibrosis stages were 1.28 m/s for F ≥ 1, 1.28 m/s for F ≥ 2, 1.44 m/s for F ≥ 3 and 1.73 m/s for F4. This result suggests that distinguishing between F0 and F1 is impossible, as the cutoff value for F ≥ 1 and that for F ≥ 2 are the same. However, Sporea et al  reported that the cutoff value is 1.19 m/s for F ≥ 1, 1.33 m/s for F ≥ 2, 1.43 m/s for F ≥ 3, and 1.55 m/s for F4 . Rizzo et al  reported that the cutoff value is 1.3 m/s for F ≥ 2, 1.7 m/s for F ≥ 3 and 2.0 m/s for F4 . Thus, discrepancies are apparent among the cutoff values reported in different studies. The discrepancies are probably attributed to the difference in the population studied. Further studies should be conducted to establish standard ARFI cutoff values for staging fibrosis.
In the present study, AST, ALT and inflammatory grade were correlated with ARFI in the univariate analysis that included all patients, but were not selected as factors independently correlating with ARFI in the multiple regression analysis. In addition, inflammatory factors did not correlate with ARFI when patients with different fibrosis stages were analyzed separately. These results suggest that inflammatory activity does not affect ARFI in patients with chronic hepatitis C. Rizzo et al  also reported that ARFI is not associated with ALT, BMI, Metavir grade, or liver steatosis, whereas TE is significantly correlated with ALT. Bota et al  reported that discordance of at least two fibrosis stages between ARFI and histologic assessment were associated with female sex, interquartile range interval (IQR) ≥ 30%, high AST and high ALT in univariate analysis,while, in multivariate analysis, the female gender and IQR ≥ 30% (P = 0.004) were associated with the discordances. In contrast, Yoon et al  reported that the optimum ARFI cutoff values are 1.13 m/s for F ≥ 2 and 1.98 m/s for F4, whereas these values decreased to 1.09 m/s for F ≥ 2 and 1.81 m/s for F4 when patients with normal ALT levelswere selected. Chen et al  reported that ALT, ActiTest A score, Metavir activity (A) grade, Metavir F stage, BMI, and platelet count are independently associated with ARFI and suggested that a 100 IU/L increase in serum ALT levels augmented ARFI by approximately 0.155 m/s. In the present study, only 25 patients had ALT levels of 100 IU/L or higher. The low ALT levels among the patients studied may be a reason why ALT was not correlated with ARFI.
A multiple linear regression analysis in our previous study on TE selected fibrosis area, ALT levels, γ-GTP levels, prothrombin time, and hyaluronic acid levels as factors correlating with TE. Many studies on TE have reported that LSM is affected by ALT levels. Franquelli et al  reported that TE fibrosis staging is overestimated by necroinflammatory activity and steatosis. Coco et al  found that LSM is higher in patients with an elevated ALT than in those with either spontaneous biochemical remission or after antiviral therapy. Thus, it is probable that ALT or inflammatory activity affects TE. However, it is still unclear whether they also affect ARFI. Further studies are needed to clarify factors that affect ARFI other than fibrosis stage. ARFI was significantly correlated with BMI in the 31 patients with stage F0 or F1; the higher the BMI, the lower the ARFI. However, ARFI was not associated with steatosis grade. Motosugi et al  reported that fat deposition in the liver does not affect ARFI. Thus, the negativecorrelation between BMI and ARFI could not be attributed to steatosis, which accompanies higher BMI .
Actually, BMI and steatosis grade were not correlated in patients with stage F0 or F1 in the present study (data not shown). The mechanism of the association between higher BMI and lower ARFI is unclear. Because a higher BMI is associated with lower ARFI, and may cause anunderestimation of fibrosis staging, careful attention should be paid to BMI during ARFI staging of fibrosis in patients with stage F0 or F1 disease.
ARFI significantly correlated with γ-GTP levels in patients with F2 and with fibrosis stage and hyaluronic acid levels in patients with stage F3 or F4. γ-GTP[24,31] and hyaluronic acid [32,33] levels have been regarded as the most informative fibrosis markers. Thus, it is reasonable that γ-GTP and hyaluronic acid levels independently correlated with ARFI. Isgro et al  showed that the collagen proportional area has a better relationship with TE and with hepaticvenous pressure gradient compared with Ishak stage. In the present study, fibrosis area was correlated significantly with fibrosis stage, but only fibrosis stage and hyaluronic acid levels were selected as factors independently correlating with ARFI. Our previous study demonstrated a better correlation of TE with fibrosis stage than with fibrosis area in patients with chronic hepatitis C. The Metavir stages represent categories of increasing fibrosis severity based on a combination of location and quantity of scarring as well as whether the fibrous tissue forms septa, bridges, or nodules. Fibrosis area represents only the quantity of fibrosis in liver tissues. Our results indicate that not only the quantity of fibrosis but also other histological factors such as patterns of fibrosis also affect ARFI.
The present study demonstrated that ARFI correlated with fibrosis stage but was not associated with inflammation. BMI negatively correlated with ARFI in the patients with stage F0 or F1. γ-GTP and hyaluronic acid levels were positively correlated in those with stage F2 and in those with F3 or F4, respectively. Thus, careful attention should be paid to BMI, γ-GTP levels, and hyaluronic acid levels when estimating fibrosis stage by ARFI. Fibrosis stage showed a better correlation with ARFI than fibrosis area, indicating that not only the quantity of fibrosis but also other factors such as patterns of fibrosis also affect ARFI. Since the number of the patients studied is small,further studies are needed to confirm the conclusion of the present study.