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SOUND JUDGMENT SERIES

Shear Wave Elastography for


Evaluation of Liver Fibrosis
Giovanna Ferraioli, MD, Parth Parekh, MD, Alexander B. Levitov, MD, RDCS, Carlo Filice, MD

Invited paper The prognosis and management of chronic viral hepatitis mainly depend on the extent
of liver fibrosis, particularly in chronic hepatitis C. Liver histologic analysis is still con-
sidered the reference standard in the assessment of liver fibrosis despite the interob-
server and interobserver variability in staging and some morbidity and mortality risks.
Thus, noninvasive methods for assessing liver fibrosis are of great clinical interest. In
the last decade, ultrasound-based techniques to estimate the stage of liver fibrosis have
The Sound Judgment Series consists of become commercially available. They all have the capability to noninvasively evaluate
invited articles highlighting the clinical value differences in the elastic properties of soft tissues by measuring tissue behavior when a
of using ultrasound first in specific clinical mechanical stress is applied. Shear wave elastography relies on the generation of shear
diagnoses where ultrasound has shown com- waves determined by the displacement of tissues induced by the force of a focused ultra-
parative or superior value. The series is meant sound beam or by an external push. This article reviews the results that have been
obtained with shear wave elastography for assessment of liver fibrosis.
to serve as an educational tool for medical
and sonography students and clinical prac- Key Words—chronic hepatitis; elastography; fibrosis; gastrointestinal ultrasound; liver;
titioners and may help integrate ultrasound ultrasound
into clinical practice.

Received August 19, 2013, from the Ultrasound


Unit, Department of Infectious Diseases, Fondazione
Istituto di Ricovero e Cura a Carattere Scientifico
I t is estimated that 500 million people are affected by chronic
viral hepatitis worldwide, of which 1 million people will die of
their illness every year, primarily from cirrhosis or hepato-
cellular carcinoma as a result of their infection.1 In the United States,
Policlinico San Matteo, University of Pavia more than 4 million people have this disease, with an annual mor-
Medical School, Pavia, Italy (G.F., C.F.); and tality rate of 15,000 people.2 The prognosis and management of
Division of Pulmonary and Critical Care chronic viral hepatitis mainly depend on the extent of liver fibrosis,
Medicine, Department of Internal Medicine, particularly in chronic hepatitis C. Long thought to be irreversible,
Eastern Virginia Medical School, Norfolk, recent studies have shown this idea to be false, even in its advanced
Virginia USA (P.P., A.B.L.). Revision requested
September 3, 2013. Revised manuscript accepted stages, thus stressing the importance of early diagnosis.3
for publication September 11, 2013. Liver histologic analysis is still considered the reference stan-
Drs Ferraioli and Filice received a research dard in the assessment of liver fibrosis despite the intraobserver and
grant from Philips Healthcare (Bothell, WA). interobserver variability in staging.4 Regev et al4 found approxi-
Address correspondence to Giovanna mately 25% of patients (30 of 124) to have a difference of at least
Ferraioli, MD, Ultrasound Unit, Department of one grade and 33% (41 of 124) to have at least one stage difference
Infectious Diseases, Fondazione Istituto di between the right and left lobes. Ultimately, Regev et al4 found an
Ricovero e Cura a Carattere Scientifico Policlinico
San Matteo, University of Pavia Medical School, underdiagnosis of cirrhosis in approximately 15% of patients. More-
Via Taramelli 5, 27100 Pavia, Italy. over, liver biopsy is a painful technique that is not well accepted by
E-mail: giovanna.ferraioli@unipv.it patients, has morbidity and mortality risks, and is not an ideal
method for following patients.
Abbreviations Thus, noninvasive methods for assessing liver fibrosis are of
SWE, ShearWave Elastography; VTTQ, great clinical interest. In the last decade, techniques to noninvasively
Virtual Touch Tissue Quantification
estimate the stage of liver fibrosis have become commercially avail-
doi:10.7863/ultra.33.2.197 able. They all have the capability to evaluate differences in the elas-

©2014 by the American Institute of Ultrasound in Medicine | J Ultrasound Med 2014; 33:197–203 | 0278-4297 | www.aium.org
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Ferraioli et al—Shear Wave Elastography for Evaluation of Liver Fibrosis

tic properties of soft tissues by measuring tissue behavior by a time-motion image, locates a liver portion at least 6
when a mechanical stress is applied. Ultrasound and mag- cm deep and free of large vascular structures (Figure 1).
netic resonance have been used for elasticity imaging. The device gives an estimate of the velocity of shear waves,
Magnetic resonance elastography, even though promis- which can be also expressed in kilopascals through the
ing, has some disadvantages. It cannot be performed in a Young modulus: E = 3 (vs · ρ), where E is the Young mod-
liver with an iron overload because of signal-to-noise lim- ulus, vs is the shear wave velocity, and ρ is the density of tis-
itations, the examination time is longer with respect to sue, assumed to be the same as water.
ultrasound elastography, and it is a costly procedure.5 The software of the device determines whether each
Shear wave elastography relies on the generation of measurement is successful. When a shot is unsuccessful,
shear waves determined by the displacement of tissues the machine does not give any value. The entire procedure
induced by the force of a focused ultrasound beam or by is considered to have failed when no value is obtained after
external pressure. The shear waves are lateral waves, with 10 shots. Successful measurements are validated by these
a motion perpendicular to the direction of the force that criteria: (1) 10 valid shots; (2) a ratio of valid shots to the
has generated them. They travel slowly (between 1 and 10 total number of shots of 60% or higher; and (3) variability
m/s) and are rapidly attenuated by tissue. The propaga- of measurements less than 30% of the median value of liver
tion velocity of the shear waves correlates with the elastic- stiffness measurements.15 Transient elastography has excel-
ity of tissue; ie, it increases with increasing stiffness of the lent intraobserver and interobserver reproducibility, with
liver parenchyma.6 an intraclass correlation coefficient of 0.98 even though the
To correctly read the results, it should be kept in mind interobserver agreement decreases in patients with a lower
that elastography assesses liver elasticity that could be degree of liver fibrosis, with liver steatosis, or with an
modified by factors other than fibrosis, such as edema, increased body mass index.16 In healthy blood donors, a
inflammation, extrahepatic cholestasis, and congestion.7–10 mean normal liver stiffness ± SD of 4.9 ± 1.7 kPa (1.28 ±
In fact, these factors may lead to overestimation of the liver 0.75 m/s) has been found.16 Several studies and meta-
stiffness for a sharp enlargement of the liver, which is cov- analyses13–25 have examined the diagnostic performance of
ered by the Glisson capsule, a poor distensible envelope. transient elastography in staging liver fibrosis in patients
Thus, the results obtained should always be interpreted in with different etiologies of chronic liver disease. Most of the
clinical settings. Examinations should be performed under studies have been conducted in patients with chronic hep-
fasting conditions because it has been demonstrated that atitis C and have shown high diagnostic accuracy of tran-
food intake may produce false-positive results.11,12 sient elastography in staging liver fibrosis. It should be
pointed out, however, that a substantial overlap of liver stiff-
Transient Elastography ness values between adjacent stages of liver fibrosis, partic-

The pioneer technique has been transient elastography,


which is performed with the FibroScan device (Echosens, Figure 1. Shear wave elastography with the FibroScan device: A, TM-
mode image; B, A-mode image; C, elastographic image. TM-mode and
Paris, France). A single-element ultrasound transducer A-mode images are used to locate a liver portion suitable for the meas-
operating at 5 MHz is built on the axis of a pistonlike vibra- urement. The slope of the white dotted line in C, which represents shear
tor.13 By pushing a button, low-frequency (50 Hz) tran- wave velocity, is a function of the fibrosis stage.
sient vibrations are transmitted, and the elastic shear waves
that are generated propagate through underlying tissues.
Pulse-echo ultrasound acquisitions are used to follow the
propagation of the shear wave and to measure its veloc-
ity.13 Transient elastography measures liver stiffness in a
volume that approximates a cylinder 1 cm wide and 4 cm
long between 25 and 65 mm below the skin surface. This
volume is at least 100 times bigger than a biopsy sample
and is therefore far more representative of the liver
parenchyma.14 Transient elastography is performed on a
patient lying supine with the right arm elevated to facilitate
access to the right liver. The tip of the probe contacts the
intercostal skin with coupling gel. The operator, assisted

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Ferraioli et al—Shear Wave Elastography for Evaluation of Liver Fibrosis

ularly for lower fibrosis stages, has been observed. Transient of liver stiffness at a single location is obtained (Figures 2
elastography more accurately detects cirrhosis than signif- and 3). They have been categorized as point–shear wave
icant fibrosis. Several meta-analyses have confirmed that elastography.27 The SWE technique is based on an ultrafast
transient elastography appears to be a reliable method for ultrasound imaging approach that allows detailed moni-
the diagnosis and exclusion of cirrhosis as opposed to pre- toring of the shear waves in a large area of liver parenchyma
dicting cirrhosis. For the diagnosis of cirrhosis, transient with real-time color-coded elasticity imaging inside a sam-
elastographic cutoff values have been found to be between ple box, and the measurement is obtained by placing a
11.8 and 14.6 kPa (1.98 and 2.21 m/s). In clinical practice, region of interest inside the sample box (Figure 4). This
liver stiffness values from 2.5 to 7.0 kPa (0.91–1.53 m/s) technique is 2-dimensional elastography.27
indicate mild or no fibrosis, and values greater than 12.5 kPa In all of the studies that have assessed the accuracy of
(2.04 m/s) are suggestive of cirrhosis.17 the different devices in staging liver fibrosis, right inter-
The European Association for the Study of the Liver costal access has been used. The patient is examined in the
has indicated that noninvasive methods can now be used dorsal decubitus position with the right arm elevated above
instead of liver biopsy in patients with chronic hepatitis C the head for optimal intercostal access in a resting respira-
to assess liver disease severity before therapy at a safe level
of predictability.26 Figure 2. Shear wave elastography of the liver performed with the
Transient elastography cannot technically be per- Siemens system through intercostal access. The measurement is given
formed in patients with ascites and has a high rate of failure in meters per seconds.
in patients with body mass indices greater than 30 kg/m2.
The recent availability of the FibroScan XL probe has over-
come this latter limitation.

Elastographic Techniques Based on Shear


Waves Generated by the Acoustic Beam

These techniques have the advantage of being integrated


into ultrasound systems; thus, conventional sonography,
which is advised every 6 to 12 months in patients with
chronic liver disease, could also be performed. As of today,
for the assessment of liver stiffness, these techniques are
commercially available in high-end ultrasound systems
made by Philips Healthcare (Bothell, WA; ElastPQ),
Siemens Medical Solutions (Mountain View, CA; Virtual
Touch Tissue Quantification [VTTQ]), and SuperSonic Figure 3. Shear wave elastography of the liver performed with the Philips
system through intercostal access. The measurement is shown in kilo-
Imagine, SA (Aix-en-Provence, France; ShearWave
pascals. In the bottom left corner, a scale shows the stiffness degree.
Elastography [SWE]). These techniques generate shear
waves inside the liver by using radiation force from a focused
ultrasound beam. The shear waves are generated near the
region of interest in the liver parenchyma and not on the sur-
face of the body, as happens with external vibration devices.
The ultrasound system monitors shear wave propagation
using a Doppler-like ultrasound technique and measures its
velocity. The shear wave velocity is displayed in meters per
second or kilopascals through the Young modulus. Unlike
transient elastography, the measurements are not limited by
the presence of ascites because the ultrasound beam, which
generates the shear waves, propagates through fluids.
With the VTTQ and ElastPQ techniques, the read-
ings of the shear wave speed are made by using a small sam-
ple box (usually 0.5 × 1 cm); thus, a quantitative estimate

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Ferraioli et al—Shear Wave Elastography for Evaluation of Liver Fibrosis

tory position. Measurements are performed at least 1.5 to disease, the diagnostic accuracy was comparable with that
2.0 cm beneath the Glisson capsule to avoid reverberation of transient elastography for the assessment of severe fibro-
artifacts. In case of physical conditions affecting the signal- sis, whereas higher performance of transient elastography
to-noise ratio, the Philips and Siemens devices do not give was seen for significant fibrosis and liver cirrhosis. In a
any measurement. With the SuperSonic Imagine device, a study by Rizzo et al,33 the technique was significantly more
measurement fails when no/little signals are obtained in accurate than transient elastography for diagnosing signif-
the sample box for all of the acquisitions. icant and severe fibrosis, whereas this difference was only
marginal for cirrhosis.
Siemens Technique (VTTQ)
The first one available was the Siemens technique, which SuperSonic Imagine Technique (SWE)
is commonly referred to as acoustic radiation force impulse
in the literature, which is technically the same force that The reproducibility of the SWE method is very high, with
generates shear waves for all 3 available techniques.27 intraobserver intraclass correlation coefficients of 0.95 and
Moreover, the term acoustic radiation force impulse is rather 0.93 for an expert and a novice operator, respectively, and
generic and does not identify shear wave–based methods. interobserver agreement of 0.88.36 As for conventional
In fact, acoustic radiation force impulse push pulses are also sonography, it is user dependent; thus, it is recommended
used in strain imaging of other organs, such as the breast that at least 50 supervised scans and measurements should
and thyroid. In recent years, the diagnostic accuracy of the be performed by a novice operator to obtain consistent
VTTQ technology for quantification of liver stiffness, measurements. Values obtained in a small series of healthy
mainly in patients with chronic hepatitis C, has been participants ranged from 4.92 kPa (1.28 m/s) to 5.39 kPa
investigated in several studies and a meta-analysis.28–34 (1.34 m/s).36
The technology has shown high interobserver agreement, In a pilot study conducted on 121 patients with
with an intraclass correlation coefficient of 0.86.35 Opera- chronic hepatitis C undergoing liver biopsy, the optimal
tor training does not seem to be required.28 The cutoff val- cutoff values were 7.1 kPa (1.54 m/s) for significant fibro-
ues obtained in a large meta-analysis were 1.34, 1.55, and sis (METAVIR fibrosis score of F2 or greater), 8.7 kPa
1.80 m/s for significant fibrosis (METAVIR fibrosis score (1.70 m/s) for advanced fibrosis (METAVIR fibrosis
of F2 or greater), severe fibrosis (METAVIR fibrosis score of F3 or greater), and 10.4 kPa (1.86 m/s) for
score of F3 or greater), and cirrhosis (METAVIR fibrosis cirrhosis (METAVIR fibrosis score of F4), and the
score of F4), respectively.34 In this meta-analysis, which technique was more accurate than transient elastography
included patients with several etiologies of chronic liver in assessing significant fibrosis.37 In another study, with
respect to transient elastography, the technique showed
higher accuracy in assessing mild and intermediate stages
Figure 4. Shear wave elastography of the liver performed with the Super- of fibrosis.38
Sonic Imagine system through intercostal access. The shade of blue in
the box is related to the speed of the shear waves. The velocity range (in Philips Technique (ElastPQ)
kilopascals) is shown in the vertical bar on the right: the colors go from
dark blue (soft tissues) to red (hard tissues).
The ElastPQ technique was the most recent to enter the
market; thus, only a few studies have been published so far.
With this technique, liver stiffness values in healthy volun-
teers have been reported to be less than 4.0 kPa (1.15
m/s).39,40 Ling et al39 found that men had higher values
than women (3.8 ± 0.7 versus 3.5 ± 0.4 kPa, or 1.13 ± 0.48
versus 1.08 ± 0.37 m/s) and liver stiffness was comparable
with different probe positions, examiners, and age groups.
In a series that comprised 88 patients with chronic viral
hepatitis and 33 healthy volunteers, the technique com-
pared favorably with transient elastography in staging liver
fibrosis, and healthy volunteers showed significantly lower
values than patients with nonsignificant fibrosis.40

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Limitations and Pitfalls both were associated with obesity or limited operator expe-
rience.42 Measurement failure with elastographic tech-
Working on phantoms, the Quantitative Imaging Bio- niques based on shear waves generated by the acoustic
marker Alliance created by the Radiological Society of beam has been reported in less than 3% of patients.34–37
North America has shown that a limitation of the tech-
nique is that there is a statistically significant difference in Clinical Cases
the shear wave velocity estimates among systems and with
depth into the phantom, which was shown with all imaging Case 1
systems, whereas no statistically significant differences A 43-year-old man has been infected with chronic hepatitis
were found among appraisers using the same or equivalent C for 20 years. He has had transiently elevated serum
systems.41 Because most studies have been conducted in aminotransferase levels in the past but has had normal val-
patients with chronic hepatitis C, the cutoffs need to be ues at follow-up for 2 years. To start an antiviral treatment,
further validated for other etiologies of diffuse liver disease. he has been scheduled for liver biopsy by the referring
In acute hepatitis, values could be very high even in physician. Biochemical test results obtained the day before
the absence of fibrosis, and there is a progressive normal- liver biopsy are within the normal range. Two shear wave
ization of stiffness values in parallel with the decrease in elastographic techniques are performed on the same day as
aminotransferase levels. In a study by Coco et al,8 the val- liver biopsy (Figure 5). The results of the noninvasive meth-
ues of liver stiffness assessed by transient elastography were ods are discordant with that of liver biopsy. In fact, both tech-
correlated with aminotransferase levels at the onset of niques give values of advanced fibrosis, whereas liver
acute viral hepatitis, when the presence of tissue inflam- histologic analysis shows METAVIR stage F1 (nonsignifi-
mation and edema is likely to be maximal. cant fibrosis). On the basis of the concordance between the
In patients with congestive heart failure, it has been two noninvasive methods the physician has decided to start
shown that liver stiffness directly depends on venous pres- antiviral therapy, and the patient is now receiving treatment.
sure. The stiffness increase could be due to the congestion Considering that liver biopsy is not a perfect reference
of the liver with dilatation of both venae cavae and hepatic standard, these different results could be due to a failure of
veins that causes enlargement of the liver, which is liver biopsy in correctly assessing liver fibrosis and could
enveloped by the Glisson capsule.9 Moreover, it has been be explained by the uneven distribution of fibrosis. In fact,
reported that cholestasis represents a confounding factor in histologic staging is based on a biopsy specimen that rep-
liver stiffness measurement.10 resents at most 1/50,000 of the total liver mass. In this
Transient elastography cannot be performed in regard, the sample size of elastographic techniques is more
patients with ascites. Failure to obtain any measurement representative of liver tissue than a liver biopsy specimen,
with transient elastography has been observed in 4% of and the evaluation could be done in several areas of the
examinations, and unreliable results were obtained in 17%; liver parenchyma. On the other hand, even when an expe-

Figure 5. Images from 43-year-old man infected with chronic hepatitis C for 20 years. Shear wave elastography of the liver performed with the Philips
system (A) and the SuperSonic Imagine system (B) show advanced fibrosis.
A B

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rienced physician performs a liver biopsy and an expert allows one to choose an area of liver parenchyma better
pathologist interprets the results, liver biopsy has a sam- suited for stiffness assessment (ie, free of large vessels and
pling error in diffuse liver disease staging.4,43 focal lesions).
These methods are all valid when information about
Case 2 fibrosis is needed. Liver biopsy should still be performed
A 57-year-old woman has been infected with chronic hep- when biochemical tests and imaging studies are inconclu-
atitis C for 28 years. Biochemical test results are within the sive or information other than liver fibrosis is required.
normal range. She has had follow-up with sonography
every 6 months. Sonographic findings are normal, whereas References
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