European Journal of Radiology 124 (2020) 108839

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European Journal of Radiology

journal homepage: www.elsevier.com/locate/ejrad

Meta-analyses

Two-dimensional shear wave elastography for significant liver fibrosis in T

patients with chronic hepatitis B: A systematic review and meta-analysis
Hong Wei, Han-Yu Jiang, Mou Li, Tong Zhang, Bin Song*
Department of Radiology, Sichuan University West China Hospital, Chengdu, Sichuan Province, China

A R T I C LE I N FO A B S T R A C T

Keywords: Purpose: To determine the diagnostic performance and cutoff value of two-dimensional shear wave elastography
Chronic hepatitis B (2D SWE) for detecting significant liver fibrosis in patients with chronic hepatitis B (CHB).
Liver fibrosis Methods: A systematic literature search of the PubMed, EMBASE, Cochrane Library databases and Web of
Meta-analysis Science was conducted. Bivariate modelling and summary receiver-operating-characteristic (ROC) modelling
Systematic review
were constructed to summarize the diagnostic performance of 2D SWE. Meta-regression analyses were per-
Two-dimensional shear wave elastography
formed to explore the source of heterogeneity.
Results: Eleven eligible studies with 2623 patients were included. 2D SWE showed a summary sensitivity of 88 %
(95 % CI: 83–91), specificity of 83 % (95 % CI: 78–88) and area under the ROC curve of 0.92 (95 % CI:
0.89–0.94) for detecting significant fibrosis in CHB patients. The mean threshold of 2D SWE was 7.91 kPa (range:
6.73–10.00 kPa). Notably, the cutoffs of studies excluding patients with history of prior antiviral therapy were
generally lower than that of studies without excluding those who had received antiviral treatment, with an
average of 7.15 kPa and 8.87 kPa, respectively (p < 0.01). Meta-regression analysis revealed that enrollment of
consecutive patients was the only significant factor influencing heterogeneity (p < 0.01). Specifically, studies
recruiting consecutive patients with CHB had significantly lower sensitivity than those with absence of con-
secutive enrolment (0.83 vs 0.92, p < 0.01).
Conclusions: 2D SWE is an excellent modality for predicting significant liver fibrosis in CHB populations. Further
work is required to establish the cutoffs that account for antiviral treatment as a potential confounding factor.

1. Introduction
Chronic hepatitis B virus (HBV) infection represents a major public
health threat worldwide [1]. Patients infected with HBV are at in-
creased risk for progression to cirrhosis, which may have potential life-
threatening complications, such as portal hypertension, liver failure,
and hepatocellular carcinoma (HCC). Globally, chronic HBV infection
accounts for approximately 50 % of patients with HCC, and up to 80 %
of HCC patients have concurrent cirrhosis, with a high incidence in Asia
(except for Japan) and Sub-Saharan Africa [2]. When significant liver
fibrosis is identified, therapeutic interventions should be considered for
patients with chronic hepatitis B (CHB) [1]. There is growing evidence
that liver fibrosis and cirrhosis can be reversed if the replication of HBV
is suppressed via effective antiviral therapy [4,5]. In this scenario, ac-
curate assessment of the severity of liver fibrosis is crucial for treatment
and potential for disease reversibility.
Liver biopsy has been the gold standard for fibrosis staging,
nevertheless, it is limited by several weaknesses including sampling
errors, interobserver variability and potential complications such as
pain, bleeding and even death [6]. An alternative method for fibrosis
assessment is the use of serum-based biomarkers, such as aspartate
transaminase-to-platelet ratio index (APRI) and fibrosis index based on
four factors (FIB-4) [1]. However, it is still in controversy whether these
biomarkers can accurately predict the severity of liver fibrosis [7].
Another surrogate marker for fibrosis estimation is elastography, in-
cluding magnetic resonance elastography (MRE) and ultrasonographic

Abbreviations: HBV, hepatitis B virus; HCC, hepatocellular carcinoma; CHB, chronic hepatitis B; APRI, aspartate transaminase-to-platelet ratio index; FIB-4, fibrosis
index based on four factors; MRE, magnetic resonance elastography; US, ultrasonographic; TE, transient elastography; 2D SWE, two-dimensional shear wave
elastography; CLD, chronic liver disease; PRISMA, Preferred Reporting Items for Systematic Review and Meta-Analysis; QUADAS-2, Quality Assessment of Diagnostic
Accuracy Studies-2; CIs, confidence intervals; ROC, receiver operating characteristic; SROC, summary receiver-operating-characteristic; AUC, area under the ROC
curve; LSMs, liver stiffness measurements; ALT, alanine aminotransferase
⁎
Corresponding author at: Department of Radiology, Sichuan University West China Hospital, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan Province, China.
E-mail address: songlab_radiology@163.com (B. Song).

https://doi.org/10.1016/j.ejrad.2020.108839
Received 23 October 2019; Received in revised form 7 January 2020; Accepted 9 January 2020
0720-048X/ © 2020 Published by Elsevier B.V.
H. Wei, et al.
(US) elastography [8]. MRE has been proven to be a non-invasive
imaging technique with high validity and reproducibility in the staging
of liver fibrosis [9,10]. US elastography, i.e., transient elastography
(TE), is recommended by several guidelines for the assessment of liver
fibrosis in view of its high feasibility and wide availability [1,11].
Quantitative US elastography modalities include TE, point shear wave
elastography (p-SWE) and two-dimensional shear wave elastography
(2D SWE). TE (FibroScan; Echosens, Paris, France) is the most in-
tensively assessed shear wave-based elastographic technique. In con-
trast to TE in which shear waves are generated by delivering 50-Hz
mechanical impulses to the skin surface, 2D-SWE (SuperSonic Imagine;
Aixplorer, Aix-enProvence, France) uses acoustic radiation force im-
pulses of 100–500 Hz to deform hepatic tissues and generate shear
waves [8]. Then the shear-wave speed is measured from sequential
measurement points, and converted into Young modulus and reported
in kilopascals [3,8]. 2D SWE represents a novel US elastography tech-
nique with the following strengths. Firstly, it incorporates conventional
B-mode ultrasound with color-coded elasticity map in real time, so that
operators could exactly locate the region of interest (ROI) for high-
quality measurements [12]. Additionally, 2D-SWE measures liver
stiffness in a flexible ROI that is larger than both TE and pSWE [3,8].
Furthermore, 2D-SWE can also be used to depict focal hepatic lesions,
estimate liver morphological changes and monitor blood flow altera-
tions [13]. Besides, it is insusceptible to the influence of ascites com-
pared with TE [14].
Despite several meta-analyses on 2D SWE for fibrosis estimation
have been published, the majority of these studies focused on patients
with mixed etiologies of chronic liver diseases (CLD) [15–17]. To the
best of our knowledge, there was probably just one published meta-
analysis that had assessed the diagnostic performance of 2D SWE for the
staging of liver fibrosis in CHB patients [18]; however, this study was
based on individual patient data from several international clinical
centers instead of the published results. In addition, the number of CHB
patients in the previous meta-analysis is limited (n = 400). Therefore,
in the present study, we aimed at performing a systematic review and
meta-analysis based on the published data to determine the diagnostic
performance and cutoff value of 2D SWE for the prediction of sig-
nificant liver fibrosis in CHB populations.
2. Materials and methods
Preferred Reporting Items for Systematic Review and Meta-Analysis
(PRISMA) guidelines for conducting and reporting meta-analysis data
were followed [19].
2.1. Search strategy
A systematic literature search of PubMed, EMBASE, Cochrane
Library databases and Web of Science was conducted for studies pub-
lished from database inception to 25 September 2019. The search was
performed with the following keywords: “chronic hepatitis B”, “chronic
hepatitis B virus infection”, “hepatitis B virus infection, chronic”, “he-
patic fibrosis”, “liver fibrosis”, “shear wave elastography”, “shear-wave
elastography”, “SWE”, “supersonic shear imaging” and “sensitivity or
specificity”. A detailed description of the search strategies used for
PubMed is presented in Supporting Information 1. No filters were ap-
plied (i.e., language). In addition, references of the initially identified
studies were also examined for additional relevant papers.
2.2. Study selection
The titles and abstracts of each identified study were screened for
potential eligibility, and the full texts of potentially eligible studies
were independently reviewed for final inclusion by two reviewers (H.
Wei with 2 years of experience as a radiologist and H.Y. Jiang with 4
years of experience in performing systematic reviews and meta-
2
European Journal of Radiology 124 (2020) 108839
analyses). Any discrepancies were resolved by consensus via discussion
with a third reviewer (M. Li with 6 years of experience in performing
systematic reviews and meta-analyses). Studies were included in our
research according to the following criteria: (1) patients (> 18 years
old) with CHB were diagnosed with hepatic fibrosis; (2) 2D SWE were
used for the liver fibrosis estimation; (3) liver biopsy served as the re-
ference standard; and (4) the sensitivity and specificity of 2D SWE for
the staging of liver fibrosis were the outcomes. The exclusion criteria
were as follows: (1) non–original research articles, including case re-
ports, review articles, editorials, letters, comments, and conference
abstracts; (2) studies unrelated to the topic; (3) studies with insufficient
information to construct 2 × 2 contingency tables; (4) studies with a
small population (n < 20); (5) duplicate publications (in these cases,
studies with the smaller population were excluded); and (6) studies
published in non-English.
2.3. Definition of liver fibrosis
Significant fibrosis was defined as stage F2-F4 (≥F2) using the
Brunt & Kleiner, Ludwig, Metavir, SAF or Scheuer scoring system
[20–22].
2.4. Data extraction and quality assessment
The following data were extracted from the included studies: (1)
study characteristics: first author and year of publication, affiliation,
duration of patient recruitment, center, study design, consecutive en-
rollment; (2) clinical and histopathological characteristics: sample size,
mean age, male/female ratio, whether patients with history of prior
antiviral treatment were excluded, reference standard and histopatho-
logical hepatic fibrosis staging system, time interval between 2D SWE
and reference, distribution of fibrosis and cutoff values; (3) 2D SWE
characteristics: number of reader, experience of operator in US elasto-
graphy, machine, mode of measurement, probe, mean diameter of re-
gion of interest, number of measurement, method for processing mea-
surement, breath hold, technical failure rate. In addition, for building
the 2 × 2 contingency tables, the raw data including true-positive,
false-positive, false-negative, and true-negative results were retrieved
from the selected studies or calculated according to the reported sen-
sitivity and specificity.
The quality of the selected studies was assessed with the revised
Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool
[23]. Data extraction and quality assessment were performed by two
independent reviewers (H. Wei and H.Y. Jiang), with a third reviewer
(M. Li) adjudicating on disagreements.
2.5. Data synthesis and analysis
The performance of 2D SWE for the prediction of significant liver
fibrosis was assessed as the focus of this meta-analysis. The summary
sensitivity, specificity and the corresponding 95 % confidence intervals
(CIs) were calculated using a random-effect coefficient binary regres-
sion model. The summary receiver operating characteristic (ROC) curve
was constructed and summary area under the ROC curve (AUC) was
obtained.
Heterogeneity was assessed using the Cochran’s Q-test (P < 0.1 in-
dicated significant heterogeneity) and inconsistency index (I2) (0–40 %,
absent or mild heterogeneity; 30–60 %, moderate heterogeneity; 50–90
%, substantial heterogeneity; and 75–100 %, considerable hetero-
geneity) [24]. Threshold effect was evaluated by calculating the
Spearman correlation coefficient. A strong positive correlation with
p < 0.05 would suggest the existence of a threshold effect [25]. Pub-
lication bias was evaluated using a Deeks’ funnel plot and Deeks’
asymmetry test (P < 0.05 suggested significant bias) [26].
For exploration of the potential sources of heterogeneity, meta-re-
gression analyses were performed using the following covariates: (1)
H. Wei, et al.
Fig. 1. Flow diagram of the study.
publication year (≥2017 [median of all included studies] vs. < 2017);
(2) sample size (≥155 [median of all included studies] vs. < 155); (3)
study design (prospective vs. retrospective); (4) consecutive enrollment
of patients (yes vs. no); (5) percentage of males (≥80 % [median of all
included studies] vs. < 80 %); (6) whether patients with history of prior
antiviral therapy were excluded (yes vs. no); (7) method of processing
measurement (mean vs. median); (8) cutoff values (≥7.6 kPa [median
of all included studies] vs. < 7.6 kPa); (9) time interval between index
test and reference standard (the same day vs. others). In addition, the
study institution was included as a covariate, since several of the in-
cluded studies were performed by the same institution (The Third
Affiliated Hospital of Sun Yat-sen University group vs. other institu-
tions). All statistical analyses were performed by using Stata Version
12.0 (StataCorp LP, College Station, TX, USA).
3. Results
3.1. Literature search
Fig. 1 presents a flow diagram for the literature selection process. A
total of 877 records were retrieved. After removing duplications, 706
records were retained. After excluding non-original researches, studies
not in the field of interest, non-English studies, etc., 27 full-text articles
were downloaded for careful screening. Finally, eleven eligible studies
with 2623 patients were included for narrative synthesis [27–37] and 9
studies including 1977 patients were selected for meta-analysis
[28–32,34–37].
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European Journal of Radiology 124 (2020) 108839
3.2. Study and technical characteristics
Table 1 summarizes the basic characteristics of the included studies.
Most studies were from China [27–31,33–37], while only 1 study came
from Korea [32]. There were six prospective studies [27,30,33,35–37]
and 5 retrospective studies [28,29,31,32,34]. Six studies recruited
consecutive patients [27,29,30,34,36,37], while inconsecutive enroll-
ments were found in 5 studies [28,31–33,35]. The mean age of the
patients was 43.6 years (range: 35.8–56.8 years). Male patients ac-
counted for approximately 73.9 % (range: 43.5 %–83.9 %) of all pa-
tients. Seven studies excluded patients with a history of prior antiviral
therapy [27,30,32,33,35–37], while 4 studies did not exclude patients
who had received antiviral treatment [28,29,31,34].
Table 2 shows the technical characteristics of 2D-SWE. The average
of technical failure rate was 1.4 % (range: 0.2 %–5.2 %). Six studies
used a circular region of interest with 20 mm diameter inside the
stiffness sample box [29,31,33,35–37]; 8 studies conducted 5 con-
secutive image acquisitions for each patient [27,29,32–37]. Six studies
used the mean values of liver stiffness measurements (LSMs) for sta-
tistical analysis [28–32,35], while 5 studies calculated the median va-
lues of LSMs as the final results [27,33,34,36,37].
Different studies reported by the same first author were included in
the final meta-analysis [36,37]; nevertheless, these studies were con-
firmed not to overlap due to the use of different study periods.
3.3. Quality assessment
Table 3 shows the overall quality of the included studies. In general,
the quality of the selected studies was moderate. The decreased quality
 H. Wei, et al.

Table 1
Basic characteristics of the included studies.
First author and Affiliation Duration of patient Center Study design Consec- Samp-le Mean Male/ Patients with Reference 2D SWE- Distribution of Cutoff
year of recruitment utive size age, Female AVT were standard (scoring reference time fibrosis values
publication enroll-ment years excluded system) interval (kPa)

Gao Y 2018 [27] Chinese PLA General 2015.01–2016.01 Multicenter Prospective Yes 248 37.5 181/67 Yesc Liver biopsy Within 7 days ≥F2; F4 5.9; 13.3
b
Hospital, Beijing, China (METAVIR)
Jian ZC 2019 Beijing Friendship 2016.09–2017.09 Single Center Retrospective No 46 45.1 20/26 No Liver biopsy The same day ≥F1; ≥F2; 5.97; 8.67;
[28]a Hospital, Capital Medical (METAVIR) ≥F3; F4 11.03;
University, China 13.00
Jin K 2019 [29]a Zhongshan Hospital, Fudan 2017.04–2017.12 Single Center Retrospective Yes 68 56.8 55/13 No Liver biopsy Within 14 days ≥F2; F4 10.00;
University, Shanghai (METAVIR) 11.60
Institute of Medical
Imaging, China
Leung VY 2013 Prince of Wales Hospital, 2011.04–2012.03 Single Center Prospective Yes 226 48.8 146/80 Yes Liver biopsy Within 12 ≥F1; ≥F2; 6.5; 7.1;
[30]a The Chinese University of (METAVIR) months ≥F3; F4 7.9; 10.1
Hong Kong, China
Liu JH 2017 The Fourth Affiliated 2014–2016 Single Center Retrospective No 111 39.4 70/41 No Liver biopsy The same day ≥F1; ≥F2; 6.82; 8.62;
[31]a Hospital of Kunming (METAVIR) ≥F3; F4 10.30;
Medical University, China 10.72
Park HS 2019 Konkuk University Medical 2013.03–2018.02 Single Center Retrospective No 63 50d 37/26 Yes Liver biopsy Within 14 days ≥F2; F4 6.73; 9.50
[32]a Center (METAVIR)
c
Wang K 2019 The Third Affiliated 2015.01–2016.01 Multicenter Prospective No 266 38.8 175/91 Yes Liver biopsy Within 7 days ≥F2; ≥F3; F4 NA

4
[33] b Hospital of Sun Yat-sen 132 38.1 90/42 Yesc (METAVIR) ≥F2; ≥F3; F4 NA
University, Guangzhou,
China
Wu T 2016 [34]a The Third Affiliated 2011.09–2014.07 Single Center Retrospective Yes 437 35.8 334/103 No Liver biopsy The same day ≥F2; F4 8.2; 11.26
Hospital of Sun Yat-sen (METAVIR)
University, Guangzhou,
China
Zhuang Y 2017 Zhongshan Hospital, Fudan 2015.07–2016.05 Single Center Prospective No 304 54.7 255/49 Yes Liver biopsy Within 3 days ≥S2; ≥S3; S4 7.6; 9.2;
[35]a University, Shanghai, (Scheuer) 10.4
China 155 54.8 126/29 Yes ≥S2; ≥S3; S4 7.6; 9.2;
10.4
Zeng J 2017 The Third Affiliated 2013.08–2015.04 Single Center Prospective Yes 257 36.7 199/58 Yes Liver biopsy The same day ≥F2; ≥F3; F4 7.1; 8.3;
[36]a Hospital of Sun Yat-sen (METAVIR) 11.3
University, Guangzhou,
China
Zeng J 2014 The Third Affiliated 2011.05–2012.11 Single Center Prospective Yes 206 36.3 169/37 Yes Liver biopsy Within 3 days ≥F2; ≥F3; F4 7.2; 9.1;
[37]a Hospital of Sun Yat-sen (METAVIR) 11.7
University, Guangzhou, 104 37.2 82/22 Yes ≥F2; ≥F3; F4 7.2; 9.1;
China 11.7

AVT, antiviral treatment; NA, not available.

a
Studies for quantitative and qualitative analysis.
b
Studies for qualitative analysis.
c
Patients who did not accepted AVT in the previous 6 months of 2D SWE examination.
d
Median.
European Journal of Radiology 124 (2020) 108839
 H. Wei, et al.

Table 2
Technical characteristics of two-dimensional shear wave elastography.
First author and year of No. of Experience of operator in Machine Mode of Probe Mean diameter of No. of measur- Method for processing Breath hold Technical failure
publication Reader US elastography measurement (MHz) region of interest ement measurement rate

Gao Y 2018 [27]** 2 NA Aixplorer (SuperSonic SSI 1–6 10 mm 5 Median Yes 1.5 % (6/408)
Imagine)
Jian ZC 2019 [28]* 1 NA Aixplorer (SuperSonic SSI 1–6 15 ± 2 mm 3 Mean Yes 4.3 % (2/46)
Imagine)
Jin K 2019 [29]* 3 NA Aixplorer (SuperSonic SSI 1–6 20 mm 5 Mean Yes 5.2 % (6/115)
Imagine)
Leung VY 2013 [30]* 1 NA Aixplorer (SuperSonic SSI 1–6 NA 3 Mean Yes 1.1 % (5/454)
Imagine)
Liu JH 2017 [31]* NA NA Aixplorer (SuperSonic SSI 3.5–5.0 20 mm 4 Mean NA 1.8 % (2/111)
Imagine)

5
Park HS 2019 [32]* 1 More than 1 year Aixplorer (SuperSonic SSI 1–6 10 mm 5 Mean Yes 4.5 % (3/67)
Imagine)
Wang K 2019 [33]** 2 NA Aixplorer (SuperSonic SSI 1–6 20 mm 5 Median Yes 1.3 % (6/479)
Imagine)
Wu T 2016 [34]* 1 At least 3 months Aixplorer (SuperSonic SSI 1–6 NA 5 Median Yes 0.2 % (1/453)
Imagine)
Zhuang Y 2017 [35]* 2 NA Aixplorer (SuperSonic SSI 1–6 20 mm 5 Mean Yes 1.8 % (10/549)
Imagine)
Zeng J 2017 [36]* 2 At least 6 months Aixplorer (SuperSonic SSI 1–6 20 mm 5 Median Yes 0.8 % (2/257)
Imagine)
Zeng J 2014 [37]* 2 At least 3 months Aixplorer (SuperSonic SSI 1–6 30 mm 5 Median Yes 1.3 % (4/310)
Imagine)

US, ultrasound; SSI, supersonic shear imaging; NA, not available.

* Studies for quantitative and qualitative analysis.
** Studies for qualitative analysis.
European Journal of Radiology 124 (2020) 108839
H. Wei, et al. European Journal of Radiology 124 (2020) 108839

Table 3
Risk of bias and concerns regarding the applicability of the included studies according to QUADAS-2 criteria.
Studies Risk of Bias Applicability Concerns

Patient selection Index test Reference standard Flow and timing Patient selection Index test Reference standard

Gao Y 2018 Low High Low Low Low Low Low

Jian ZC 2019 High High Low Low Low Low Low
Jin K 2019 Low High Low Low Low Low Low
Leung VY 2013 Low High Low High Low Low Low
Liu JH 2017 High High Low Unclear Low Low Low
Park HS 2019 High High Low Low Low Low Low
Wang K 2019 High High Low Low Low Low Low
Wu T 2016 Low High Low Unclear Low Low Low
Zhuang Y 2017 High High Unclear Low Low Low Low
Zeng J 2017 Low High Low Low Low Low Low
Zeng J 2014 Low High Low Low Low Low Low

is mainly attributed to the high risks of bias in the index test domain
and patient selection domain. With respect to the index test domain,
there was a high risk of bias in all selected studies that chose optimized
cutoffs rather than prespecified thresholds to determine the diagnostic
performance of 2D SWE. In regard to the patient selection domain,
there was a high risk of bias in 5 studies with absence of consecutive
enrollment of patients [28,31–33,35].
[37]) were generally lower than that of studies without excluding those
who had received antiviral treatment (e.g., 8.67 kPa [28], 10.00 kPa
[29], 8.62 kPa [31], 8.20 kPa [34]), with an average of 7.15 kPa and
8.87 kPa, respectively (p < 0.01).
Fig. 3 shows the summary AUC was 0.92 (95 %CI: 0.89–0.94). There
was no evidence of publication bias in this meta-analysis (Fig. 4).

3.5. Exploration of heterogeneity

3.4. Diagnostic accuracy
Nine of the 11 studies were included for the quantitative analysis
[28–32,34–37]. No threshold effect was observed as depicted by the
Spearman correlation coefficient of −0.018 (95 % CI: −0.594–0.558)
(p > 0.5). Higgins’ I2 statistic showed substantial heterogeneity with
regard to the summary sensitivity (I2 = 73.96 %) and specificity (I2 =
66.22 %) (Fig. 2).
Fig. 2 demonstrates that, for 2D SWE, the summary sensitivity and
specificity for the prediction of ≥ F2 in CHB patients were 88 % (95
%CI: 83–91) and 83 % (95 %CI: 78–88), respectively, with a mean
cutoff of 7.91 kPa (range: 6.73–10.00 kPa). Notably, the cutoffs of
studies excluding patients with history of prior antiviral therapy (e.g.,
7.10 kPa [30], 6.73 kPa [32], 7.60 kPa [35], 7.10 kPa [36],7.20 kPa
Table 4 shows the results of the meta-regression analyses. Among
the 10 estimated covariates, consecutive enrollment of patients was
shown to be the only significant factor influencing heterogeneity
(p < 0.01). Specifically, studies enrolling consecutive patients with
CHB had significantly lower sensitivity than those without recruiting
consecutive populations (0.83 [95 % CI, 0.79–0.87] vs 0.92 [95 % CI,
0.89–0.95], p < 0.01). All other covariates, including institution (p =
0.22), publication year (p = 0.06), sample size (p = 0.26), study design
(p = 0.20), percentage of males (p = 0.89), whether patients with
history of prior antiviral therapy were excluded (p = 0.56), method of
processing measurement (p = 0.22), cutoffs (p = 0.80), time interval
between 2D SWE and reference standard (p = 0.15), were not sig-
nificant factors.

Fig. 2. Coupled forest plots of the summary sensitivity and specificity of 2D SWE for the prediction of significant liver fibrosis (≥ F2) in CHB patients, including 9
relevant studies.

6
H. Wei, et al.
Fig. 3. Summary receiver-operating-characteristic (SROC) curve of the diag-
nostic performance of 2D SWE for the prediction of significant liver fibrosis (≥
F2) in CHB patients.
Fig. 4. Deeks’ funnel plot used to assess publication bias.
4. Discussion
In this systematic review and meta-analysis, we identified 11 studies
to assess the performance of 2D SWE for the prediction of significant
liver fibrosis (≥F2) in patients with CHB. Pooled analysis of 9 selected
studies showed that 2D SWE provided excellent diagnostic perfor-
mance, with a sensitivity of 88 % (95 %CI: 83–91), specificity of 83 %
(95 %CI: 78–88), and AUC of 0.92 (95 %CI: 0.89–0.94). Significant liver
fibrosis is one of the indications for antiviral therapy [1], therefore, 2D
SWE can be used as an effective technique to guide the therapeutic
strategies for patients with CHB.
There were several published meta-analysis assessing 2D SWE for
the detection of liver fibrosis in patients with chronic liver disease
(CLD) [15–18]. In a recent meta-analysis based on the individual pa-
tient data, 2D SWE demonstrated the summary sensitivity, specificity
and AUC of 88 %, 74 % and 0.91 for diagnosing significant liver fibrosis
in patients with CHB (n = 400) [18]. The summary sensitivity and AUC
in that study corresponded well with our results, whereas the pooled
specificity in the previous study was lower. The discrepancy between
our results and that of the prior study may be attributed to the het-
erogeneity of study population and readers’ expertise. For the staging of
7
European Journal of Radiology 124 (2020) 108839
significant fibrosis, other published meta-analyses examining 2D SWE
in patients with mixed CLD revealed summary sensitivities, specificities
and AUCs of 84 %–85 %, 79 %–83 % and 0.81–0.88, respectively
[15–17,38,39]. Taken together, it appears that 2D SWE had slightly
higher diagnostic accuracy in CHB populations than those with mixed
CLD. Consistent findings were found in a previous study, in which 2D
SWE showed the AUC for diagnosing significant fibrosis was 0.91 and
0.86 in patients with CHB and those with mixed etiologies (CHB,
chronic hepatitis C and nonalcoholic fatty liver disease), respectively
[18].
Traditionally, TE is considered as an alternative to biopsy and a
reference technique for defining fibrosis staging for other novel SWE
technologies, including 2D SWE [40]. However, a previous study
showed only moderate concordance of different SWE techniques with
TE results for the staging of significant fibrosis, suggesting that TE
thresholds cannot be directly transferred to other elastography ma-
chines [41]. Consequently, specific thresholds for fibrosis staging, ≥F2
in particular, would be required for each specific piece of equipment
grounded on scientific research [40]. Nonetheless, the optimal cutoff
values proposed for 2D SWE varied across the published studies. In this
meta-analysis, with histology as a reference standard, 2D SWE showed a
mean cutoff of 7.91 kPa (range: 6.73–10.00 kPa) for diagnosing sig-
nificant liver fibrosis in patients with CHB. However, in a previous
meta-analysis, a threshold of 7.10 kPa was proposed for 2D SWE for
predicting significant fibrosis in CHB populations [18]. Intriguingly, on
further exploration, we found that studies exclusively including anti-
viral treatment-naïve patients showed a mean cutoff of 7.15 kPa, which
is comparable to that of the previous study [18].
In addition, we found that the mean threshold of studies excluding
patients who had history of prior antiviral therapy was significantly
lower than that of studies without excluding those with history of an-
tiviral treatment (7.15 kPa vs. 8.87 kPa, p < 0.01). We speculate that
one possible explanation is patients with history of antiviral treatment
may have higher fibrosis stage (i.e., advanced fibrosis and cirrhosis)
and apparent clinical symptoms, in other words, they are more likely to
have liver function damage combined with elevated alanine amino-
transferase (ALT) levels than antiviral treatment-naïve patients who
may have less severe fibrosis and no overt symptoms. Previous studies
consistently found that not only fibrosis stage but hepatic necroin-
flammation could exert an impact on the liver stiffness values, and the
elevated serum ALT level is one of the major confounding factors for
liver stiffness measurements [42–44]. Theoretically, for most patients
with CHB, antiviral therapy can effectively suppress hepatic necroin-
flammation and normalize serum ALT level, thereby decreasing the
liver stiffness values [45–47]. However, in the present meta-analysis,
the therapeutic efficacy of patients who had received antiviral treat-
ment is unclear, put another way, the liver stiffness of these patients
probably decreases slightly but remains at a high level during antiviral
treatment. In addition, in view of the heterogeneity of liver fibrosis
distribution, the diversity of study population and the difference in
processing measurement method, the causes of the different thresholds
between studies with and without excluding treated patients remain
undetermined. Nevertheless, further work is required to establish the
cutoffs that account for antiviral treatment as a potential confounding
factor.
There was substantial heterogeneity among the included studies.
According to the meta-regression analyses, the enrollment of con-
secutive patients was the only significant factor influencing hetero-
geneity. Specifically, studies that included consecutive patients with
CHB showed significantly lower sensitivity than studies with absence of
consecutive enrollments. This can be attributed to the fact that studies
recruiting inconsecutive patients may miss some “difficult-to-diagnose”
patients, which may result in the overestimated sensitivity [23].
Nevertheless, in view of the limited sample size in the subgroups, fur-
ther validation of our results remains warranted.
There were several limitations in the present study. Firstly, a small
H. Wei, et al. European Journal of Radiology 124 (2020) 108839

Table 4
Results of meta-regression analysis.
Meta-analytic summary estimates

Parameter Subgroup No. of studies Sensitivity, % (95 %CI) Specificity, % (95 %CI) LRT Chi- P value
Square

Institution Third Affiliated Hospital of Sun Yat- sen 4 0.85 [0.78–0.92] 0.82 [0.76–0.89] 3.02 0.22
University
Others 7 0.90 [0.86–0.94] 0.85 [0.79–0.91]
Publication year ≥2017a 7 0.89 [0.86–0.93] 0.79 [0.74–0.85] 5.63 0.06
< 2017 4 0.83 [0.78–0.88] 0.87 [0.83–0.91]
Sample size ≥155a 6 0.88 [0.83–0.92] 0.86 [0.81–0.91] 2.70 0.26
< 155 5 0.88 [0.81–0.94] 0.78 [0.69–0.87]
Study design Prospective 6 0.89 [0.85–0.93] 0.85 [0.80–0.91] 3.19 0.20
Retrospective 5 0.85 [0.79–0.92] 0.80 [0.72–0.88]
Consecutive enrollment Yes 6 0.83 [0.79–0.87] 0.85 [0.80–0.90] 9.26 0.01b
No 5 0.92 [0.89–0.95] 0.81 [0.72–0.89]
Percentage of males ≥80 %a 6 0.88 [0.83–0.93] 0.84 [0.78–0.91] 0.24 0.89
< 80 % 5 0.88 [0.82–0.94] 0.82 [0.75–0.89]
Patients with history of ANT were Yes 7 0.89 [0.85–0.93] 0.84 [0.79–0.90] 1.17 0.56
excluded No 4 0.86 [0.78–0.93] 0.81 [0.73–0.90]
Method of processing measurement Mean 7 0.90 [0.86–0.94] 0.85 [0.79–0.91] 3.02 0.22
Median 4 0.85 [0.78–0.92] 0.82 [0.76–0.89]
Cutoffs ≥7.6kPaa 6 0.89 [0.84–0.94] 0.84 [0.77–0.90] 0.45 0.80
< 7.6kPa 5 0.86 [0.80–0.93] 0.83 [0.77–0.90]
2D SWE-reference time interval The same day 4 0.90 [0.84–0.96] 0.78 [0.72–0.85] 3.80 0.15
others 7 0.87 [0.82–0.92] 0.87 [0.83–0.91]

AVT, antiviral treatment; CI, confidence interval; LRT, likelihood ratio test.
a
Median of all included studies.
b
Statistically significant results from meta-regression analysis.

number of studies were included in our research, and the number of
prospective studies is also limited. Secondly, substantial heterogeneity
was detected in our study. Nevertheless, the significant factor asso-
ciated with the heterogeneity was identified in the meta-regression
analyses. Thirdly, Chinese patients accounted for a large proportion of
our study populations, which might result in a patient selection bias.
However, chronic HBV infection has extremely high prevalence in
China, we thus consider this study could provide some insights into the
clinical practice of 2D SWE for fibrosis detection. Nonetheless, further
validation with prospective, multicenter and international cohorts is
also required. Lastly, only studies published in English were included,
indicating that a language bias may exist in our study.
5. Conclusion
In conclusion, 2D SWE is an excellent modality for the prediction of
the significant liver fibrosis in patients with chronic hepatitis B. Further
work is required to establish the cutoffs that account for antiviral
treatment as a confounding factor.
Declaration of Competing Interest
None.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (No. 81771797) and the 1.3.5 project for dis-
ciplines of excellence, West China Hospital, Sichuan University
(ZYJC18008).
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