Background
Hepatitis B virus (HBV) infection remains a severe global public hygiene and clinical problem: approximately 240 million people have HBV in the world. People infected with HBV have increased risk of developing liver fibrosis or cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC) [
1]. Liver fibrosis (LF) is important in determining whether, when and how to initiate antiviral therapy. The degree of LF or cirrhosis is an independent factor to predict the mortality in chronic hepatitis B (CHB) patients [
2]. The 1-year mortality rates decreased from 57% in those with severe cirrhosis to 1% in patients with early-stage LF. Moreover, about 10–17% liver cirrhosis patient will develop HCC in 5 years [
2]. Early accurate assessment of LF in patients infected with HBV is essential not only for the better outcomes associated with early initiation of antiviral treatment, but also for predicting the long-term clinical prognosis [
2,
3].
At present, the gold standard for the diagnosis of LF or cirrhosis is liver biopsy [
2,
4]. However, liver biopsy was an invasive technique that maybe induce the patient physical or/and mental discomfort, complications and contraindications, which restricted it widespread utilization in routine practice. Sometimes, sampling errors may affect the accuracy of liver biopsy. Furthermore, intraobserver and interobserver discrepancies may induce bias in staging LF when analysing the same liver biopsy sample [
2,
4,
5]. Therefore, a few alternative noninvasive methods have been developed intensely and have improved evaluation of the LF stage, such as fibrosis index based on four factors (FIB-4), sonographic transient elastography (Fibroscan), the aspartate aminotransferase-to-platelet ratio index (APRI) and real-time tissue elastography [
3,
5‐
10]. As noninvasive methods, the APRI and FIB-4 have been recommended to determine the stage of LF in resource-limited countries by the WHO guidelines and many other guidelines [
1,
10‐
13].
Fibroscan, recently reported by many studies, is a noninvasive device that can be used to grade the stage of liver fibrosis or cirrhosis [
3,
5,
9,
14]. Fibroscan can not only predict cirrhosis-linked complications in patients with HBV, but also forecast the recurrence of HCC after curative resection. However, Fibroscan may be difficult to detect liver stiffness in obese patients, in narrow intercostal spaces patients and in ascites patients [
14‐
18]. Fibroscan is still expensive and it can only be used in main hospitals in some big cities in China. Thus, it’s urgent to found a simple, cheap and noninvasive LF or cirrhosis detection system in China.
Real-time ultrasound elastography (RTE) is a new sonography-based noninvasive technique for assessing liver tissue elasticity. RTE detects the propagation speed of shear waves for assessing LF or cirrhosis, which is technically different from Fibroscan [
6,
19‐
23]. RTE can capture the 2D strain images induced by internal heartbeats. These strain images show that more patchiness is, the higher degree LF or cirrhosis is [
24]. Therefore, RTE may be utilized in the ascites patients or obese patients.
In recent, RTE has been reported to be effective in chronic hepatitis C patients [
25]. However, to date there are only a few available reports on the diagnostic efficacy of RTE for measuring LF or cirrhosis in people with HBV in China. The aims of this study were to assess the accuracy of the quantitative measurement of LF in patients with HBV by RTE, to determine the LF fibrosis index (LFI) for different stages of LF and to compare the accuracy among the LFI, the APRI, and the FIB-4 for grading the stages of LF in patients using liver biopsy as the reference standard.
Discussion
Early diagnosis and accuracy measurement of the degree of LF or cirrhosis is essential not only for CHB patients making decisions to accept antiviral treatment as soon as possible, but also for controlling disease progression [
6,
21,
28]. Liver biopsy remains the gold standard for assessing the stage of LF or cirrhosis, but this procedure is invasiveness, complication and may cause physical and mental discomfort [
25]. Moreover, because of sampling errors, liver biopsy is susceptible to intraobserver and interobserver variability, and its poor reproducibility also need to be recognized again [
8,
26]. Many scientists have focused on noninvasive techniques to identify LF grades or cirrhosis [
4,
6,
8,
15,
16,
29]. The ideal noninvasive measurement of LF or cirrhosis, such as the APRI, FIB-4 and LFI, should be reproducible, reliable, simple, inexpensive and accurate for grading LF. Especially in resource-limited settings in China, the application of these noninvasive methods maybe reduces or replaces the need for liver biopsy in CHB patients [
12,
13,
30].
The APRI, FIB-4 and LFI could differentiate the stage of LF in CHB patients because these indexes were significantly different for each stage of LF [
28,
31]. As reported by Ren et al., the median of the APRI in stage F0, F1, F2, F3 and F4 LF was 0.21, 0.49, 0.49, 0.73 and 0.74, respectively, and that of the FIB-4 was 0.84, 1.09, 1.63, 1.59 and 2.03, respectively [
31]. The APRI (
P = 0.03) and FIB-4 (
P < 0.001) were significantly different in different stages of fibrosis [
31]. The APRI between stage F1 and F2 and between stage F3 and F4 were not significantly different. These results were partly consistent with the results in our study and another meta-analysis [
32]. Though the APRI (
P < 0.001) and FIB-4 (
P < 0.001) were significantly different between stages of LF, no significant differences in the APRI and FIB-4 were found between stage F0 and F1 or between stage F3 and F4 in our study or another Egyptian study [
28]. The APRI and FIB-4 may be influenced by many factors, such as age and the degree of liver inflammation. Age and AST in our study were higher than those reported by Ren et al. AS a fast, simple, safe and reliable noninvasive method recommended by the guidelines, [
33] the LFI was not only significantly different between various ranges fibrosis stage, but also between each stage of fibrosis, which was proved by our study and other studies [
20,
34]. The APRI, FIB-4 and LFI showed a significant correlation with the stages of fibrosis in our study and in some previous studies [
20,
30,
34,
35]. As a noninvasive method, the LFI showed a better ability to differentiate the stage of liver fibrosis than did the APRI and FIB-4.
AUC < 0.7, the accuracy of identify is poor or fail; 0.7 ≤ AUC ≤ 0.9, the accuracy of identify is good; 0.9 < AUC ≤ 1, the accuracy of identify is excellent. The sensitivity or specificity of liver fibrosis measurements higher than 80% are applicable. Given that the APRI and FIB-4 are two readily available noninvasive methods for diagnosing LF, these methods have been recommended to determine the fibrosis stage in resource-limited countries by the WHO guidelines and by many other guidelines [
1,
11‐
13]. Teshale et al. investigated the predictive ability of the APRI and FIB-4 for staging LF in a large cohort of CHB patients and found that the APRI and FIB-4 distinguished stage F2–F4 from stage F0-F1 with good sensitivity and specificity [
30,
36]. The APRI and FIB-4 were also reported to have a high AUC for detecting significant fibrosis, advanced fibrosis and cirrhosis in 200 CHB patients in East Africa [
28]. Hang et al. analysed four noninvasive tools, including the APRI and FIB-4, in a large Asian CHB patient cohort to diagnose significant fibrosis and obtained adjusted AUCs of 0.73 and 0.61 [
35]. Zhang et al. analysed the APRI and FIB-4 in 1543 patients with HBV infection to predict cirrhosis and obtained adjusted AUCs of 0.71 and 0.79 in China [
37]. In the 170 Chinese treatment-naive CHB patient cohort, the AUCs of the APRI for detecting significant fibrosis, advanced fibrosis and cirrhosis were 0.70, 0.63, and 0.71, respectively, and 0.76, 0.70, and 0.68, respectively for the FIB-4 [
30]. In our study, the AUCs of the APRI for the prediction of significant LF, advanced LF and liver cirrhosis were 0.73, 0.70 and 0.75, respectively. However, a meta-analysis suggested that the APRI and FIB-4 could identify LF with only moderate sensitivity and accuracy in CHB patients and were not ideal replacement tests for liver biopsy [
38,
39]. In our study, the APRI and FIB-4 could diagnose the LF stages with only moderate sensitivity and accuracy, and the results were consistent with previous studies [
3,
28,
30,
35,
36]. As the LFI showed a better ability to differentiate the stage of LF than the APRI and FIB-4, the ability of the LFI to distinguish the liver fibrosis stage was analysed in our study. The AUC, sensitivity and specificity of the LFI for predicting mild, significant, advanced LF and cirrhosis were better than those of the APRI and FIB-4 in this study, which was consistent with the results of previous reports [
9,
20]. The low (high sensitivity) and the high (high specificity) cut-off values were recommended by WHO guideline [
11]:0.5 and 1.5 to distinguish F0–1 and F2–4,1.0 and 2.0 to differentiate F0–3 and F4 for APRI, 1.45 and 3.25 to distinguish F0–2 and F3–4 for FIB-4. In this study, a single cut-off value was chosen at maximizing of the sensitivity and specificity. The cut-off values of APRI was consistent with the values recommended by WHO guideline [
11]. The single cut-off values for the diagnosis of significant LF and advanced LF and liver in this study was higher than those recommended by WHO guideline, but the sensitivity and specificity were only moderate. FIB-4 was not recommended for diagnosis of liver cirrhosis by WHO guideline. Though single cut-off value (7.83) could be used to diagnose liver cirrhosis, the sensitivity (59.08%) and specificity (58.83%) were not very well, in this study. For the diagnosis of F > F1, F2, F3 at the cut-off value 2.61, 3.20, 3.92 respectively, the sensitivity and specificity were better than those of APRI and FIB-4.
The LFI calculated using RTE with an HI VISION 900 ultrasound system had the highest predictive ability for identifying significant, advanced LF and cirrhosis among the studied noninvasive LF indexes in CHB patients in China, with higher sensitivity and accuracy than the APRI and FIB-4.
We acknowledge several limitations in our study. First, our patients were enrolled from a single referral centre, which may be have led to selection bias. Second, the LFI is influenced by several factors, such as patient cooperation with breathing, heart rate and selection of the ROI; thus, further studies with a larger sample population are needed. Third, the degree of fatty infiltration was not investigated. For the resource limitation, the LFI detected by RTE did not compared the results of Fibroscan in this study.
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