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Liver Fibrosis with Two-dimensional US

Shear-Wave Elastography in Participants with
Chronic Hepatitis B: A Prospective Multicenter Study
Yongyan Gao, MD* •  Jian Zheng, MD*  •  Ping Liang, MD •  Minghui Tong, MD  •  Jiabing Wang, MD  • 
Changjun Wu, MD  •  Xin He, MD  •  Changzhu Liu, MD  •  Shumei Zhang, MD  •  Liping Huang, MD  • 
Tian’an Jiang, MD  •  Chao Cheng, MD  •  Fankun Meng, MD  •  Xiaojie Mu, MD  •  Yongping Lu, MD  • 
Yunyan Li, MD  •  Hong Ai, MD  •  Xudong Qiao, MD  •  Xiao-Yan Xie, MD •  Wei Wang, MD •  Li-ping Yin, MD  • 
Yi-yun Wu, MD  •  Rongqin Zheng, MD
From the Department of Interventional Ultrasound, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853, China (Y.G., P.L.); Department of Ultrasound, The
General Hospital of Chinese People’s Armed Police Forces, Beijing, China (Y.G.); Department of Ultrasound, Guangdong Key Laboratory of Liver Disease Research, The
Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (J.Z., R.Z.); Department of Ultrasound, Third People’s Hospital of Longgang District of Shenzhen,
Shenzhen, China (J.Z.); Functional Examination Department of Children’s Hospital, Lanzhou University Second Hospital, Lanzhou, China (M.T., J.W.); Ultrasound
Department, The First Affiliated Hospital of Harbin Medical University, Harbin, China (C.W., X.H.); Ultrasound Department, Guangzhou the Eighth People’s Hospital,
Guangzhou, China (C.L., S.Z.); Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, China (L.H.); Department of Ultrasonography,
the First Affiliated Hospital, Medical College of Zhejiang University, Hangzhou, China (T.J., C.C.); Function Diagnosis Center, Beijing Youan Hospital, Affiliated to
Capital Medical University, Beijing, China (F.M., X.M.); Ultrasound Department, The Second People’s Hospital of Yunnan Province, Kunming, China (Y. Lu, Y. Li);
Ultrasound Department, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China (H.A., X.Q.); Department of Medical Ultrasonics, Institute of Diagnostic
and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China (X.Y.X., W.W.); and Department of Ultrasound, Jiangsu
Province Hospital of TCM, Affiliated Hospital of Nanjing University of TCM, Nanjing, China (L.P.Y., Y.Y.W.). Received November 17, 2017; revision requested January
25, 2018; final revision received May 11; accepted May 18. Address correspondence to P.L. (e-mail: liangping301@hotmail.com).
*Y.G. and J.Z. contributed equally to this work.
Conflicts of interest are listed at the end of this article.
See also the editorial by Chauhan in this issue.

Radiology 2018; 289:407–415 • https://doi.org/10.1148/radiol.2018172479 • Content codes:

Purpose:  To investigate the diagnostic performance of two-dimensional (2D) shear-wave elastography (SWE) in chronic hepatitis B.

Materials and Methods:  This prospective multicenter study from January 2015 to January 2016 was conducted at 12 hospitals
and included 654 participants with chronic hepatitis B who had undergone liver biopsy and 2D SWE examination. Participants
were divided into chronic infection and chronic hepatitis groups. The diagnostic performance of 2D SWE was compared with the
aspartate amino transferase–to-platelet ratio index (APRI), the Fibrosis-4 index (FIB-4), and transient elastography (TE) by using
a DeLong test and was also compared between two subgroups. Dual cutoff values for cirrhosis were determined with multilevel
likelihood ratio analysis.

Results:  Overall, 402 participants with chronic hepatitis B were enrolled (154 with chronic infection and 248 with chronic
hepatitis). The areas under the receiver operating characteristic curve of 2D SWE (0.87; 95% confidence interval [CI]: 0.83, 0.90)
were higher than those of TE (0.80; 95% CI: 0.68, 0.88), APRI (0.70; 95% CI: 0.65, 0.74), and FIB-4 (0.73; 95% CI: 0.69,
0.78) in cirrhosis. The high area under the receiver operating characteristic curve (0.92; 95% CI: 0.87, 0.96) was achieved in the
chronic infection group and was significantly higher than that of the chronic hepatitis group (0.84; 95% CI: 0.78, 0.88; P = .017).
Dual cutoff values with the likelihood ratios below 0.1 and above 10 (8.4 kPa and 11.0 kPa to rule out and rule in a diagnosis of
cirrhosis, respectively) were effectively determined in chronic infection; a total of 81.2% (125 of 154) participants with cirrhosis
were definitively diagnosed.

Conclusion:  The performance of two-dimensional (2D) shear-wave elastography (SWE) was higher than that of other noninvasive
methods. 2D SWE was most effective in ruling in and ruling out cirrhosis in participants with chronic infection, which may
prompt antiviral treatment.
© RSNA, 2018

Online supplemental material is available for this article.

Iproblem. The reliable evaluation of liver fibrosis

nfection with hepatitis B virus is a major public health
stages is crucial for the treatment of patients with
chronic hepatitis B (1). Although liver biopsy remains
the reference standard to assess liver fibrosis, it is
limited by its invasiveness and potential complications
(2). Recently, liver elastography, especially transient
elastography (TE), was introduced by the European
Association for the Study of the Liver, the Asian-Pacific
Association for the Study of the Liver, and the World
Health Organization as a possible first-line method to
assess liver fibrosis and cirrhosis (3,4).
Two-dimensional (2D) shear-wave elastography (SWE)
by using the supersonic shear imaging technique is the first
US-based real-time 2D SWE imaging technique (5) with
several advantages. First, it can be used to measure liver
stiffness, to depict focal liver tumors, and to evaluate liver
morphologic and blood flow changes. It is widely applied
in China for liver and extrahepatic organ examination.
Second, the guidance provided by B-mode US and the
Liver Fibrosis with 2D US Shear-Wave Elastography in Chronic Hepatitis B
Abbreviations
APRI = aspartate aminotransferase–to-platelet ratio index, AUC =
area under the receiver operating characteristic curve, CI = confidence
interval, FIB-4 = fibrosis-4 index, SWE = shear-wave elastography, TE =
transient elastography, 2D = two-dimensional.
Summary
This prospective multicenter study confirmed that the performance
of two-dimensional shear-wave elastography is superior to other
noninvasive methods for noninvasive assessment of cirrhosis.
Implications for Patient Care
nn Two-dimensional shear-wave elastography is superior to transient
elastography and serologic methods in diagnosing liver fibrosis.
nn Two-dimensional shear-wave elastography was most effective in
the chronic infection group to assess cirrhosis.
nn With the dual cutoffs of 8.4 kPa and 11.0 kPa to rule out and rule
in cirrhosis, 81.2% (125 of 154) participants could avoid liver biopsy.
visible 2D elasticity map help to avoid nontarget structure and
elastic artifacts and to improve measurement reliability. Third, it
can be used in patients with ascites.
The results of recent studies (6,7) have shown that 2D
SWE is equal or superior to TE in assessing liver fibrosis in
patients with chronic hepatitis C. However, studies (8–12)
focused on patients with chronic hepatitis B are relatively
rare, and all of them were single-center studies with small
sample sizes, including several previous articles from a
center of our team (9–12). Furthermore, these studies
have provided different areas under the receiver operating
characteristic curves (AUCs), ranging from 0.77 to 0.97
for the diagnosis of significant fibrosis and from 0.82 to
0.98 for the diagnosis of cirrhosis (13,14). In addition,
the diagnostic cutoffs proposed for the evaluation of liver
fibrosis stages varied among different studies and might not
be practical for clinical use (8,12–14). Hence, a prospective
multicenter study with strict quality control is needed to
confirm the efficacy of 2D SWE and to propose practical
cutoffs for guidance in routine clinical use.
Therefore, this prospective multicenter study with 2D SWE
sought to investigate the diagnostic performance of 2D SWE by
using histologic analysis as a reference in comparison with TE
and serum makers, and to determine diagnostic cutoff values for
2D SWE to detect cirrhosis.
Materials and Methods
This prospective multicenter study was organized by the Chi-
nese Medical Association and included 12 centers (Clinical-
Trials.gov registration no. NCT02313649). All investigators
received centralized training at the initial phase of the study
for 2D SWE image acquisition and elastography measure-
ments by using a standardized procedure. The sponsor of the
study, SuperSonic Imagine, provided technical and practical
support during the training phase but was not involved in
other phases of the study (ie, study design, case enrollment,
data analysis, and manuscript writing) and did not provide
any material or financial support. Investigators of the study
408 radiology.rsna.org  n  Radiology: Volume 289: Number 2—November 2018
controlled all research data. None of the investigators are em-
ployees of or consultants for the sponsor, and each of them
has been an employee of his or her respective clinical site.
This study protocol was approved by the ethical committee of
the principal investigator’s hospital. The ethical committees
from other participating centers approved and registered the
ethical committee approval from the principal investigator’s
hospital for this study. All participants provided informed
consent to participate in this study.
Technical Training
Before participant recruitment started, a meeting to provide
technical training was held by the Chinese Medical Association.
The training included system operation, image acquisition, 2D
SWE measurement (J.Z.), and liver biopsy sample acquisition
(Y.G.). Each investigator was required to have experience with at
least 300 abdominal US scans or at least 50 2D SWE examina-
tions under appropriate supervision. Each center provided US
systems (SuperSonic Imagine; Aix-en-Provence, France) and the
corresponding liver biopsy samples of five participants after ini-
tial training for practice quality control. Only qualified centers
were allowed to recruit participants in the study.
The criteria for satisfactory quality of 2D SWE images were
color filling of the 2D SWE region of interest of at least two-
thirds of its surface, and avoidance of both large vessels and
biliary tracts. The criteria for satisfactory quality of liver biopsy
samples were that the embedded samples were at least 10 mm
long and included at least six portal tracts.
Two co-principle investigators controlled the whole study,
while each recruiting center had its own leading investigator
who was responsible for the center’s quality control. Of
17 centers that were trained, five were excluded because
of inadequate biopsy samples, leaving 12 hospitals that
participated in the study.
Study Design
From January 2015 to January 2016, 654 consecutive par-
ticipants with chronic hepatitis B underwent liver biopsy and
2D SWE examination. All examinations for each participant
in this study, including serologic examinations, 2D SWE, TE,
and biopsy, were all performed within 7 days. None of the
study results have been previously reported.
Considering the guidance of clinical antiviral treatments,
participants were divided into two groups, the chronic infec-
tion group and the chronic hepatitis group. The details of the
definition were summarized in a table that was originally intro-
duced in the 2017 European Association for the Study of the
Liver guidelines (Table 1) (4). In brief, the definition of the two
groups is based on the hepatitis B virus infection status (HBeAg,
HBsAg, and hepatitis B virus DNA levels) and the severity of
liver necroinflammatory activity (serum alanine aminotransfer-
ase level). The diagnostic performance of 2D SWE was com-
pared with that of TE and serum markers. The diagnostic perfor-
mances were also compared between the chronic infection and
chronic hepatitis groups. The dual cutoffs were defined to rule
in and rule out cirrhosis in different participant groups and to
guide clinical practice.
 Gao et al

Participant Enrollment Table 1: Natural History and Assessment of Participants with Chronic Hepatitis B Virus
The inclusion criteria were Infection Based on Hepatitis B Virus and Liver Disease Marker
as follows: (a) findings posi-
tive for the hepatitis B sur- Positive for HBeAg Negative for HBeAg
face antigen for more than Variable Chronic Infection Chronic Hepatitis Chronic Infection Chronic Hepatitis
6 months; (b) age 18 years
HBsAg High High or intermediate Low Intermediate
or older; and (c) histologic
HBeAg Positive Positive Negative Negative
staging of liver fibrosis se- Hepatitis B DNA .107 IU/mL 104-107 IU/mL ,2000 IU/mL* .2000 IU/mL
verity from liver biopsy. Alanine Normal Elevated Normal Elevated†
The exclusion criteria were  aminotransferase
as follows: (a) diagnosis of Liver disease None or minimal Moderate or severe None Moderate or severe
alcoholic chronic liver dis- Old terminology Immune tolerant Immune reactive Inactive carrier HBeAg negative
ease, nonalcoholic steato-   HBeAg positive   chronic hepatitis
hepatitis, hemochromato- Note.—Adapted from reference 4.
sis, autoimmune hepatitis, * Hepatitis B virus DNA levels can be between 2000 IU/mL and 20 000 IU/mL in some patients without
or intrahepatic biliary tract signs of chronic hepatitis.
disease; (b) coinfection with †
Indicates persistently or intermittently elevated levels.
human immunodeficiency
virus or any other viral hep-
atitis; (c) previous liver transplantation; (d) antiviral treatment in For quality control, liver biopsy specimens were centralized
the previous 6 months; (e) missing serologic results; or (f) liver in one site and read by two experienced liver pathologists (with
biopsy samples not meeting the predefined quality criteria. The more than 6 years of experience). The pathologists were blinded
demographic and clinical data of participants (sex, age, height, to any clinical data of the participants.
weight, and body mass index) were recorded.
Serum Biomarker Assays
Two-dimensional SWE Measurement Liver function tests, blood counts, and coagulation function
The 2D SWE operators were blinded to the liver biopsy analyses were performed on site. The platelet count, fasting blood
results. The 2D SWE examination procedure was performed glucose, aspartate aminotransferase, alanine aminotransferase,
by using the Aixplorer system (SuperSonic Imagine) with a g-glutamyl transpeptidase, total bilirubin, direct bilirubin,
SC6–1 (frequency of 1–6 MHz) convex probe. Participants indirect bilirubin, albumin, and prothrombin activity
fasted for at least 2 hours. The examination methods, levels were recorded. On the basis of these biologic parameters,
including participants’ position, scanning approach, depth, the following noninvasive fibrosis scores were calculated:
location, size of region of interest, and Q-box of 2D SWE aspartate aminotransferase–to-platelet ratio index (APRI)
measurement, were uniform, as described in our previous = [(aspartate aminotransferase/upper limit of normal
study (12,15). The scale of the elastogram was set to 40 kPa. aspartate aminotransferase) 3 100]/platelet count (109/L)
The median value and the interquartile range of five separate (16) and Fibrosis-4 index (FIB-4) = [age (y)] 3 [aspartate
2D SWE measurements were calculated for statistical analysis. aminotransferase (U/L)]/[platelet count (109/L)] 3 alanine
Measurements were considered failed or unqualified when no aminotransferase (U/L)1/2] (17). Persistently or intermittently
more than two-thirds signal filled in the 2D SWE region of elevated levels of alanine aminotransferase and hepatitis B virus
interest or when the big vessels and biliary tracts were not DNA within 1 year were also recorded.
avoided for every acquisition.
For quality control, two experienced 2D SWE operators (Y.G. TE Procedure
and J.Z., who each have more than 10 years of US experience TE was performed by experienced operators who had performed
and have conducted more than 100 2D SWE examinations) at least 50 TE procedures, as previously recommended (18).
reviewed all of the 2D SWE images to exclude nondiagnostic The procedure was performed through the intercostal space in
images and cases. the right liver lobe at a depth of 25–65 mm (M probe). At least
10 measurements in the same participant, with a success rate of
Liver Biopsy and Histologic Stages 60%, were required for eligibility.
US-guided liver biopsy was performed intercostally in the right
liver lobe with a 16-gauge or 18-gauge automated edge-cutting Statistical Analysis
biopsy needle (Bard Magnum; Covington, Ga). The samples Sample size calculation was performed for design accuracy in
were then fixed in formalin, embedded in paraffin, stained with diagnostic test studies according to our previous study (10).
hematoxylin-eosin, and then counterstained with one of two The largest sample size was determined for the differentiation
stains (either reticulin or Masson). The fibrosis stage and necro- of significant fibrosis or worse (METAVIR score F2), cor-
inflammatory activity were evaluated by using METAVIR scores responding to a minimum of 359 participants (in two groups,
(ranging from stage F0 to F4). Significant fibrosis was defined sensibility of 0.86 and specificity of 0.87, respectively; u0.05
as stage F2 or higher, whereas cirrhosis was defined as stage F4. = 1.960; sampling error of 0.05). Estimating about 20%

Radiology: Volume 289: Number 2—November 2018  n  radiology.rsna.org 409

Liver Fibrosis with 2D US Shear-Wave Elastography in Chronic Hepatitis B

Table 2: Participant Characteristics

Characteristic Standard Value (Range) Chronic Infection Chronic Hepatitis P Value

No. of participants* NA 154 (38.3) 248 (61.7) …
Age (y) NA 38.0 (30.8–45.3) 37.5 (29.0–46.0) .90
Male sex* NA 87 (56.5) 181 (73.0) .001
Body mass index (kg/m2) NA 22.4 (20.7–24.2) 22.7 (20.6–25.5) .13
Fasting blood glucose (g/L) 3.9–6.1 4.9 (4.6–5.3) 4.9 (4.5–5.4) .50
Platelet count (3109/L) 100–350 179.0 (135.0–220.5) 177.5 (131.3–209.0) .70
Aspartate aminotransferase (IU/L) 15–40 26.4 (22.0–32.0) 51.7 (35.1–101.8) ,.001
Alanine aminotransferase (IU/L) 3–35 26.8 (20.0–32.0) 69.25 (52.7–137.8) ,.001
g-Glutamyl transpeptidase (IU/L) 10–60 22.0 (15.0–33.1) 37.9 (23.0–61.0) ,.001
Total bilirubin (µmol/L) 4–23.9 13.5 (10.1–18.0) 14.4 (10.8–19.2) .31
Direct bilirubin (µmol/L) 0.4–6.2 4.0 (2.7–6.0) 4.0 (3.0–6.1) .18
Indirect bilirubin (µmol/L) 1–20 9.5 (7.4–12.3) 9.9 (7.4–12.5) .40
Alkaline phosphatase (IU/L) 45–125 74.0 (60.0–89.0) 84.0 (65.0–103.0) ,.001
Albumin (g/L) 36–51 43.9 (40.4–47.1) 43.3 (40.0–45.9) .07
Prothrombin activity (%) 70–120 92.0 (84.0–100.0) 89.0 (81.0–98.6) .06
Fibrosis stages*
 F0–F1 NA 28 (18.2) 38 (15.3) .53
 F2 NA 49 (31.8) 61 (24.6) .15
 F3 NA 48 (31.2) 79 (31.9) .97
 F4 NA 29 (18.8) 70 (28.2) .045
Note.—Unless otherwise noted, data are medians, with ranges in parentheses. NA = not applicable.
* Data in parentheses are percentages.

of missing data, we proposed to recruit a minimum of 431
participants.
The quantitative variables are expressed as the medians
and interquartile range (25th–75th percentile), whereas the
qualitative variables are expressed as the absolute and relative
frequencies. Comparisons between groups were made with
the Student t test or the Mann-Whitney test, when appropri-
ate, for quantitative variables and with the x2 or Fisher test
for qualitative variables. The intraobserver reproducibility for
five 2D SWE measurements was assessed with the intraclass
correlation coefficient.
The mean 2D SWE values among different fibrosis stages
were analyzed by one-way analysis of variance and the Stu-
dent-Newman-Keuls test. The 2D SWE values between the
chronic infection group and chronic hepatitis group were
compared by using unpaired t test. The diagnostic perfor-
mance of 2D SWE, TE, APRI, and FIB-4 was estimated
by using receiver operating characteristic curves. Differences
between the AUCs were compared by using a DeLong test
(19). Single cutoff values for 2D SWE were determined to
achieve sensitivity of 90% in predicting significant fibrosis
or specificity of 90% in predicting cirrhosis. Dual cutoffs
of 2D SWE for cirrhosis were determined by using multi-
level likelihood ratios. Likelihood ratios above 10 and below
0.1 were considered strong evidence to rule in or rule out
the diagnosis, respectively (20). Decision curve analysis was
performed to determine the net benefit of the risk model
(21). All of the statistical tests were two-sided and a was
set at .05. The statistical analyses were performed by using
SPSS software for Windows (version 13.0; SPSS, Chicago,
Ill) and MedCalc software (version 11.2; MedCalc, Mar-
iakerke, Belgium).
Results
Participant Characteristics
Among the 654 potentially eligible study participants, 246 of
654 (37.6%) were excluded, mostly because of antiviral treat-
ment history (24.6%, 161 of 654), inadequate histologic sam-
ples (10.6%, 69 of 654), or the presence of additional liver
diseases (2.1%, 14 of 654) (Table 2). Among the remaining
408 participants, 2D SWE acquisitions failed in six partici-
pants because of the inability to hold their breath (n = 3) or
obesity (n = 3) (Fig 1). No disqualified case was excluded be-
cause of unsatisfactory image quality. In total, 402 participants
were included in the statistical analysis (98.5%, 402 of 408).
There were 154 participants in the chronic infection group
and 248 participants in the chronic hepatitis group (defined as
indicated previously, per the European Association for the Study
of the Liver guidelines [Table 1]).
Comparison of 2D SWE Values between Different
Fibrosis Stages
The liver stiffness measured with 2D SWE ranged from 3.2
kPa to 39.6 kPa (Fig 2, Table E1 [online]). Mean 2D SWE
values were in the same range for participants with stage F0–
F1 and participants with stage F2 (stage F0–F1 vs stage F2
in chronic infection group and in chronic hepatitis group, P
= .34 and P = .71, respectively) and slightly higher in partici-
pants with stage F3 (stage F2 vs stage F3 in chronic infection

410 radiology.rsna.org  n  Radiology: Volume 289: Number 2—November 2018

 Gao et al

group and in chronic hepatitis group, P = .004 and P = .009,
respectively). Participants with cirrhosis had markedly higher
2D SWE values (stage F3 vs stage F4 in chronic infection
group and in chronic hepatitis group, P , .001) (Table E1
[online]). The 2D SWE values were higher in the chronic
hepatitis group than in the chronic infection group, with sig-
nificant differences in stage F0–F1 (P = .002) and stage F2 (P
= .034) (Table E1 [online]).
Assessment of Liver Cirrhosis
2D SWE values lower than 8.4 kPa and values equal to or
greater than 11.0 kPa were adequate to rule out and rule in
stage F4 with high diagnostic accuracy (95%, 119 of 125).
Among the 27 participants identified as having cirrhosis, the
test generated only one (3.7%) false-positive result; among
the 98 participants identified as not having cirrhosis, the test
generated only five (5.1%) false-negative results. Overall, a
total of 81.2% (125 of 154) participants (63.7%, 98 of 154
and 17.5%, 27 of 154) could have been correctly diagnosed

Diagnostic performance of 2D SWE and comparison

with APRI, FIB-4, and TE.—The AUCs of 2D SWE (0.87;
95% confidence interval [CI]: 0.83, 0.90) were higher than
those of APRI (0.70; 95% CI: 0.65, 0.74; P , .0001) and
FIB-4 (0.73; 95% CI: 0.69, 0.78; P = .0001) (Table 3). In
participants with available TE measurements, the diagnostic
accuracy of TE was lower than that of 2D SWE (0.80; 95%
CI: 0.68, 0.88; P = .27).

Comparison of diagnostic performance of 2D SWE in

different inflammation status.—The AUC of 0.92 for 2D SWE
in the chronic infection group was significantly higher than
that in the chronic hepatitis group (0.84; P = .017) (Fig 3).
Similar results were obtained when participants were grouped
on the basis of their necroinflammatory activity grade,
from A0 to A4: the AUC of 0.88 in the low inflammation
group (A0–A2) was significantly higher than the AUC of
0.67 in the severe inflammation group (A3) (P , .001)
(Table 4). These results demonstrate that the necroinflamma-
tory activity is an important confounding factor of liver stiffness Figure 1:  Flowchart of study population. CHB =
chronic hepatitis B, NAFLD = nonalcoholic fatty liver
measurements by using 2D SWE for the diagnosis of cirrhosis in
disease, 2D-SWE = two-dimensional shear-wave
participants with chronic hepatitis B. elastography.

Diagnostic criteria of 2D SWE.—The

desired specificity level of 90% for the
diagnosis of stage F4 was achieved for
cutoff values of 10.1 kPa and 13.3 kPa
in the chronic infection group and the
chronic hepatitis group, respectively,
with sensitivities of 82.8% and 48.6%,
respectively (Table 3).
Because of the high performance
of 2D SWE in the chronic infection
group, dual cutoff strategy was estab-
lished by using likelihood ratio analysis
to diagnose liver cirrhosis. The results
of decision curve analysis showed that
the threshold probability range was
3%–57% when a participant obtains
net benefit (Fig E1 [online]). The cor-
responding 2D SWE values ranged
from 5.4 kPa to 13.8 kPa. The analysis
of multilevel likelihood ratios above 10 Figure 2:  Graphs show distribution of elasticity values according to METAVIR fibrosis stage
and below 0.1 was introduced to ob- in (a) chronic infection group and (b) chronic hepatitis group. Central line represents median
tain a dual cutoff for ruling in or ruling two-dimensional shear-wave elastography (2D-SWE) values of each stage, and P values were
2D-SWE values compared with different fibrosis stage.
out diagnoses. The results showed that

Radiology: Volume 289: Number 2—November 2018  n  radiology.rsna.org 411

412
Table 3: Diagnostic Accuracy Estimates of 2D SWE, Serum Biomarkers, and TE in the Prediction of Cirrhosis

No. of Percentage Cutoffs Positive Predictive Negative Predictive Positive Negative

Variable Participants* (%) (kPa) AUC Sensitivity (%) Specificity (%) Value (%) Value (%) Likelihood Ratio Likelihood Ratio
All participants
  2D SWE 99/402 24.6 12.0 0.87 (0.83, 0.90) 56.6 (46.2, 66.5) 90.1 (86.2, 93.2) 65.1 (54.0, 75.1) 86.4 (82.1, 90.0) 5.71 (4.80, 6.80) 0.48 (0.30, 0.70)
 TE 14/71 19.7 15.6 0.80 (0.68, 0.88)† 28.6 (8.4, 58.1) 89.5 (78.5. 96.0) 40.0 (11.1, 75.5) 83.6 (71.9, 91.8) 2.71 (1.20, 6.20) 0.8 (0.30, 1.80)
 APRI 98/400 24.5 1.04 0.70 (0.65, 0.74)‡ 27.6 (19.0, 37.5) 89.7 (85.7, 92.9) 46.6 (33.2, 60.2) 79.2 (74.5, 83.4) 2.68 (1.90, 3.70) 0.81 (0.60, 1.20)
  Fibrosis-4 index 98/399 24.6 2.21 0.73 (0.69, 0.78)‡ 38.8 (29.1, 49.2) 90.0 (86.1, 93.2) 55.9 (43.3, 67.9) 81.9 (77.3, 85.9) 3.89 (3.00, 5.00) 0.68 (0.50, 1.00)
Subgroup analysis
  Chronic infection 29/154 18.8 10.1 0.92 (0.87, 0.96) 82.8 (64.2, 94.2) 90.4 (83.8, 94.9) 66.7 (47.8, 80.9) 95 (89.3, 98.1) 8.62 (7.2, 10.3) 0.19 (0.07, 0.50)
  group
  Chronic hepatitis 70/248 28.2 13.3 0.84 (0.78, 0.88)‡ 48.6 (36.4, 60.8) 89.9 (84.5, 93.9) 65.4 (50.9, 78.0) 81.6 (75.5, 86.8) 4.80 (3.80, 6.10) 0.57 (0.30, 0.90)
  group
Note.—Unless otherwise specified, data in parentheses are 95% confidence intervals. Area under the receiver operating characteristic curve (AUC) for overall two-dimensional (2D) shear-wave
elastography (SWE) was compared with transient elastography (TE), aspartate aminotransferase–to-platelet ratio index (APRI) and Fibrosis-4 index (statistically significant if P , .05). AUCs
of chronic infection group were compared with those of chronic hepatitis group (statistically significant if P , .05).
* Data are numerators and denominators.
†
P = .27.
‡
P , .05.
Liver Fibrosis with 2D US Shear-Wave Elastography in Chronic Hepatitis B

B, cirrhosis.

diagnostic strategy.

Assessment of Significant Fibrosis

Figure 3:  Graphs show receiver operating
characteristic curves of two-dimensional shear-wave

ing stage F2 (0.62; 95% CI: 0.50, 0.73) (P , .001).

elastography in diagnosis of, A, significant fibrosis and,

radiology.rsna.org  n  Radiology: Volume 289: Number 2—November 2018

versus 0.73, respectively (P = .45) (Fig 3, Table 5). When par-
Comparison of diagnostic performance of 2D SWE de-
tic accuracy of TE was lower than that of 2D SWE in evaluat-
In participants with available TE measurements, the diagnos-
0.61 and 0.59; 95% CI: 0.54, 0.64, respectively) (P , .001).
for the diagnosis of at least stage F2 (0.56; 95% CI: 0.51,

ticipants were grouped together based on necroinflammatory

chronic infection group and the chronic hepatitis group: 0.78
difference was observed between AUCs obtained in the
pending on participants’ necroinflammatory status.—No
APRI, FIB-4, and TE.—The AUC of 2D SWE (0.75; 95% CI:
with cirrhosis and without cirrhosis by using the dual cutoff

Diagnostic performance of 2D SWE and comparison with

activity, the AUC was 0.68 (95% CI: 0.60, 0.75) in the low
0.70, 0.79) was higher than were those of APRI and FIB-4
 Gao et al

Table 4: Influence of Inflammation in Participants with

50 (28.7, 71.3) 1.58 (1.00, 2.40) 0.22 (0.10, 0.40)

Note.—Unless otherwise specified, data in parentheses are 95% confidence intervals. Area under the receiver operating characteristic curve (AUC) for overall two-dimensional (2D) shear-wave
Likelihood Ratio
Advanced Fibrosis for the AUCs of 2D SWE

0.3 (0.2, 0.4)

0.65 (0.3, 1.4)
0.96 (0.7, 1.3)
20.5 (9.3, 36.5) 1.03 (0.50, 2.00) 0.77 (0.5, 1.1)

0.42 (0.3, 0.7)

Variable Stage F2 Stage F3 Stage F4

elastography (SWE) was compared with transient elastography (TE), aspartate aminotransferase–to-platelet ratio index (APRI) and Fibrosis-4 index (statistically significant if P , .05).
Negative
Necro­
inflammation
stage
 A0–A2 0.68 (0.60, 0.75) 0.76 (0.71, 0.82) 0.88 (0.83, 0.94)

39.2 (25.8, 53.9) 1.3 (0.9, 1.9)

12.5 (0.2, 56.0) 1.07 (0.2, 6.4)
17.1 (7.2, 32.1) 1.00 (0.5, 2.0)

0.73 (0.68, 0.79)‡ 90.0 (85.1, 93.7) 23.7 (11.4, 40.2) 86.7 (81.4, 90.9) 30.0 (14.5, 49.8) 1.18 (0.7, 2.1)
 A3 0.69 (0.60, 0.79) 0.68 (0.48, 0.87) 0.69 (0.58, 0.79)

Likelihood
P Value .81 .42 .001*

Positive

Ratio
Note.—Unless otherwise specified, data in parentheses are 95%
confidence intervals. AUC = area under the receiver operator
characteristic curve, SWE = shear-wave elastography, 2D = two-
dimensional.
* In participants with cirrhosis, AUC of 2D SWE in A0–A2 is

Value (%)
Predictive
Negative
significantly higher than that in A3 (P , .05).

Table 5: Diagnostic Accuracy Estimates of 2D SWE, Serum Biomarkers, and TE in the Prediction of Significant Fibrosis
activity group (A0–A2) and 0.69 in the severe activity group

30.3 (19.6, 42.9) 86.9 (82.9, 90.2)

16.7 (0.4, 64.1) 92.1 (82.4, 97.4)
10.6 (4.4, 20.6) 83.6 (79.3, 87.2)
12.1 (5.4, 22.5) 83.9 (79.7, 87.5)

0.78 (0.71, 0.84) 90.5 (84.0, 95.0) 42.9 (24.5, 62.8) 87.7 (80.8, 92.8)
(A3) (P = .81) (Fig 3, Table 4).

Predictive
Value (%)
Diagnostic criteria of 2D SWE.—The desired sensitivity level

Positive
of 90% for the diagnosis of at least stage F2 was achieved at cut-
off values of 5.3 kPa and 5.9 kPa in the chronic infection group
and the chronic hepatitis group, respectively, with a correspond-

Specificity (%)
ing specificity of 48.4% and 26.7%, respectively (Table 5).

Intraobserver Reproducibility and Stability of 2D

SWE Measurements
90.8 (87.2, 93.6)
89.2 (79.1, 95.6)
89.8 (86.1, 92.8)
90.7 (87.0, 93.6)
The intraobserver reproducibility intraclass correlation coef-
Sensitivity (%)

ficient of 2D SWE among five separate SWE measurements

from different centers was 0.843–0.991, indicating high repro-
ducibility of 2D SWE (Table E2 [online]).
For stability of 2D SWE values, to exclude unreliable mea-
surements, we tried different quality criteria from the published
0.62 (0.50, 0.73)†
0.56 (0.51, 0.61)†
0.59 (0.54, 0.64)†
0.75 (0.70, 0.79)

literatures including minimum value less than or equal to 0.2

kPa (22), minimum value less than or equal to 1.0 kPa (23),
standard deviation of the elasticity less than or equal to 1.75
(kPa) AUC

(24), the ratio of interquartile range to median value less than or

equal to 30% (25), and the ratio of interquartile range to median
Percentage Cutoffs

value less than or equal to 10% (26). However, there were no dif-
0.23
0.52
5.5
4.5

5.3
5.9

ferences in the diagnostic performance of 2D SWE by using the

different criteria (Table E3 [online]).

Discussion
83.6
91.5
83.5
83.5

81.8
84.7
Participants* (%)

This relatively large prospective multicenter study focused on

* Data are numerators and denominators.

participants with chronic hepatitis B by using 2D SWE for

336/402

334/400
333/399

126/154
210/248

the purpose of investigating the diagnostic performance of 2D

No. of

65/71

SWE with histologic analysis as a reference and determining

diagnostic cutoff values for the diagnosis of cirrhosis.
  Chronic infection group
  Chronic hepatitis group

This study protocol relies on a strict quality control; its results

are reliable and representative. 2D SWE measurements showed
  Fibrosis-4 index

high intraobserver reproducibility and stability. The overall

Subgroup analysis
All participants

AUCs of 2D SWE for the diagnosis of significant fibrosis and

  2D SWE

cirrhosis were higher than were those of the FIB-4 and APRI
P , .05.
P = .45.
 APRI
Variable

(P , .001). The AUC of 2D SWE in the chronic infection group

 TE

was higher than that in the chronic hepatitis group (0.92 vs 0.84,
respectively; P = .017). Dual cutoff values (8.4 kPa and 11.0
†

Radiology: Volume 289: Number 2—November 2018  n  radiology.rsna.org 413

Liver Fibrosis with 2D US Shear-Wave Elastography in Chronic Hepatitis B
kPa to rule out and rule in cirrhosis, re-
spectively) were effectively determined in
participants with chronic infection, and a
total of 81.2% (125 of 154) participants
would have been definitively diagnosed.
The results of diagnostic performance of
2D SWE for cirrhosis may have clinical
significance of antiviral treatment deci-
sion in participants with hepatitis B virus.
Generally, antiviral treatment is deter-
mined based on the patients’ serum levels
of alanine aminotransferase, hepatitis B
virus DNA, and whether cirrhosis exists
(1). However, initiation of antiviral ther-
apy may also be delayed for patients with
chronic hepatitis B only with laboratory
Figure 4:  Diagram shows algorithm for two-dimensional shear-wave elastography (2D-SWE)
monitoring, leaving patients at risk for
management of liver cirrhosis in chronic hepatitis B. Source—Reference 4.
disease progression (27). For patients with
chronic hepatitis who have elevated levels
of alanine aminotransferase, antiviral treatment is needed regard-
less of cirrhosis. As for patients with chronic infection, levels of ala-
nine aminotransferase are usually normal and antiviral treatments
are not needed unless there is evidence of disease progression, es-
pecially cirrhosis. However, it is difficult to make a diagnosis of
cirrhosis in patients with chronic infection according to clinical
data. Therefore, liver stiffness is important for the judgement of
cirrhosis in these patients. Hence, our study mainly focused on
noninvasive assessment of liver fibrosis with 2D SWE, especially
in participants with chronic infection with cirrhosis.
According to the latest European Association for the Study
of the Liver guidelines (4), patients with chronic hepatitis B
should be divided into chronic infection and chronic hepati-
tis groups. For participants with cirrhosis, the finding that the
diagnostic performance of 2D SWE in the chronic infection
group was higher than that in the chronic hepatitis group
is encouraging, because it may be helpful for antiviral treat-
ment decisions. However, the relatively low performance of
2D SWE to diagnose cirrhosis in participants with chronic
hepatitis tends to support that liver stiffness assessment can-
not be the only criterion for fibrosis evaluation. In these
participants, treatment decision may rely on clinical data
rather than on liver stiffness values. In fact, inflammation was
proven to be an important confounding factor of liver stiff-
ness measurements in our study, which negatively impacted
the diagnostic performance of 2D SWE, as was shown in
previous studies (28,29). In this study, AUCs of 2D SWE
were higher in A0–A2 than were those in A3 in participants
with advanced fibrosis, and, especially in cirrhosis (P = .001).
Hence, 2D SWE is a good complement for the guidance of
antiviral treatment in participants with chronic infection.
Because a high diagnostic performance of 2D SWE was
achieved in participants with chronic infection to assess
cirrhosis, 2D SWE might be a simple and valuable method
in these conditions. To determine a practical diagnostic cutoff
value, a decision curve analysis was tried. However, the wide
threshold range (from 5.4 kPa to 13.8 kPa) made the possibility
of participants with low risk of liver cirrhosis to choose antiviral
414 radiology.rsna.org  n  Radiology: Volume 289: Number 2—November 2018
therapy. Therefore, we identified cutoff values to rule in and
rule out diagnoses as recommended previously (18). Our
results showed that 2D SWE values above 11.0 kPa indicated
a high risk of cirrhosis and may indicate a prioritization for
antiviral treatment. In contrast, 2D SWE values less than or
equal to 8.4 kPa indicate a low risk of cirrhosis, which may
favor follow-up instead of treatment. Over 80% (125 of 154)
of participants with chronic infection could benefit from
this dual cutoff algorithm and therefore avoid liver biopsy
(Fig 4). However, although effective in this study, these cutoffs
are not the final word, but rather a suggestion that requires
further validation.
The overall AUCs of 2D SWE were higher than were
those of the FIB-4 and APRI. However, the performance of
2D SWE might be lower than the AUCs reported by other
single-center studies, especially for stage F2. There are three
potential reasons for this difference. First, a multicenter study
is subject to more confounding factors than is a single-center
study. Differences between multicenter studies and single-
center studies were also observed in previous research on TE.
For instance, Degos et al (18) reported a multicenter research
study with lower AUCs for stage F2 in chronic viral hepati-
tis than did a single-center study (number of patients: 284
vs 202, respectively; AUC: 0.78 vs 0.87, respectively) (30).
Second, the centers that participated in our study were all
high-level teaching hospitals in different regions of China and
a prevalence bias was observed, in which participants were
more likely to be in the severe stages of disease. Third, inflam-
mation could impact the diagnostic performances of liver
stiffness measurement (28,29). Approximately two-thirds of
participants in our study were in the chronic hepatitis group,
which indicated that they were more likely to be in severe
stages of inflammation. The AUCs of 2D SWE in partici-
pants with hepatitis was low, which may have affected the
overall performance in participants with chronic hepatitis B.
There are no standardized criteria for evaluating the stability
and reliability of 2D SWE measurements in the European
Federation of Societies for Ultrasound in Medicine and Biology

guidelines (23). Our results showed that, regardless of whether
these unreliable measurements were excluded, there were no
statistically significant improvements in diagnostic performance,
indicating that the 2D SWE measurements were relatively stable
and reliable. On the other hand, the intraobserver intraclass
correlation coefficients in most centers of our study were above
0.9, indicating the high reproducibility of SWE measurements.
Our study had several limitations. First, there was a prevalence
bias. The number of stage F0–F1 fibrosis was relatively small,
leading to relatively lower performances of stage F2. However,
we considered the diagnosis of cirrhosis was more important than
that of significant fibrosis with regards to antiviral treatment.
Second, the sample size of participants who underwent TE was
small. However, the results of this study were comparable with
those of previous studies (13,14).
In conclusion, this prospective multicenter study confirmed
that the performance of 2D SWE is superior to other noninvasive
methods. We also provided rule-in and rule-out dual cutoffs of
2D SWE for the noninvasive assessments of cirrhosis, which
may be useful for the guidance of antiviral treatment.
Acknowledgments: The authors thank two pathologists, Rongkui Luo, MS
and Jing Zhao, MS (Department of Pathology at Zhongshan Hospital, Fudan Uni-
versity) for their assistance with reading all biopsy samples. We are also grateful to
Qiaolan Zheng, MSc (Department of Journal Center, Third Affiliated Hospital of
Sun Yat-Sen University) for her assistance with the statistical analyses.
Author contributions: Guarantors of integrity of entire study, P.L., R.Z.; study
concepts/study design or data acquisition or data analysis/interpretation, all authors;
manuscript drafting or manuscript revision for important intellectual content, all
authors; approval of final version of submitted manuscript, all authors; agrees to
ensure any questions related to the work are appropriately resolved, all authors;
literature research, Y.G., J.Z., C.W., S.Z., F.M., X.M., H.A., X.Q., X.Y.X., L.P.Y.;
clinical studies, all authors; statistical analysis, Y.G., J.Z., P.L., S.Z., F.M., X.M.,
H.A., X.Q., L.P.Y.; and manuscript editing, Y.G., J.Z., P.L., C.W., S.Z., F.M., X.M.,
H.A., X.Q., L.P.Y.
Disclosures of Conflicts of Interest: Y.G. disclosed no relevant relationships.
J.Z. disclosed no relevant relationships. P.L. disclosed no relevant relationships. M.T.
disclosed no relevant relationships. J.W. disclosed no relevant relationships. C.W.
disclosed no relevant relationships. X.H. disclosed no relevant relationships. C.L.
disclosed no relevant relationships. S.Z. disclosed no relevant relationships. L.H. dis-
closed no relevant relationships. T.J. disclosed no relevant relationships. C.C. disclosed
no relevant relationships. F.M. disclosed no relevant relationships. X.M. disclosed no
relevant relationships. Y. Lu disclosed no relevant relationships. Y.L. disclosed no rele-
vant relationships. H.A. disclosed no relevant relationships. X.Q. disclosed no relevant
relationships. X.Y.X. disclosed no relevant relationships. W.W. disclosed no relevant
relationships. L.P.Y. disclosed no relevant relationships. Y.W. disclosed no relevant
relationships. R.Z. disclosed no relevant relationships.
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