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Hepatic Elastography UsingUltrasound Waves
Edited By
Ioan Sporea and Roxana irli
Department of Gastroenterology and HepatologyVictor Babe
University of Medicine and Pharmacy Timioara
Romania
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ii
several editorial boards (i.e.: Ultraschall in der Medizin, Medical
Ultrasonography, Journal of Gastrointestinal and Liver Diseases). He is author
and co-author of 195 original papers published in medical journals (42 of them in
ISI journals and 96 PubMed publications), first author of 12 medical books, co-
author of 14 medical books, first author of 16 educational medical CDs and DVDs
(Ultrasound and Endoscopy). He coordinated or participated to numerous research
projects.
Special interest in: Contrast enhanced ultrasonography, Elastography, Ultrasound
in Inflammatory Bowell Disease.
ROXANA SIRLI
Roxana Sirli is an Assistant Professor, PhD, in the Department of
Gastroenterology and Hepatology of the Victor Babe University of Medicine
and Pharmacy Timioara. She is a senior attendant in Internal Medicine, specialist
in Gastroenterology, working in the Gastroenterology and Hepatology
Department of the Victor Babe University of Medicine and Pharmacy
Timioara. She is a level II specialist in general ultrasonography according to the
multilevel classification of SRUMB. She is a member of the Board of Directors ofthe Romanian Society of Ultrasound in Medicine and Biology (SRUMB). She is a
member of the WFUMB (World Federation of Ultrasound in Medicine and
Biology) Center of Excellence Timioara, also a faculty member of the
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Ultrasound Learning Center of UMF Timioara. She participated in several
courses and scientific sessions in Romania and abroad, mainly in gastroenterology
and ultrasound. She is author and co-author of 90 original papers published in
medical journals (32 of them in ISI journals and 58 PubMed publications), co-
author of 14 medical books, co-author of 6 educational ultrasound CDs and
DVDs. She participated in numerous research projects.
ALINA POPESCU
Alina Popescu is a Lecturer, PhD, in the Department of Gastroenterology and
Hepatology of the Victor Babe University of Medicine and Pharmacy Timioara.
She is a senior attendant in Internal Medicine, specialist in Gastroenterology,
working in the Gastroenterology and Hepatology Department of the Victor Babe
University of Medicine and Pharmacy Timioara. She is a level II specialist in
general ultrasonography according to the multilevel classification of the Romanian
Society for Ultrasound in Medicine and Biology (SRUMB) and she is a member of
the Board of Directors of SRUMB. She is a member of the WFUMB (World
Federation of Ultrasound in Medicine and Biology) Center of Excellence Timioara,
also a faculty member of the Ultrasound Learning Center of UMF Timioara. She isa member of the flying faculty of the International School for Clinical Ultrasound
ISCUS. She is author and co-author of several original papers published in medical
journals, medical books and chapters, educational CDs and DVDs.
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vi
FOREWORD
Since the introduction of the grey scale B-mode scanners, the liver has been the
organ with the most extensive and fruitful applications of ultrasonography in the
abdomen. Starting from the 80s focal liver lesions became detectable even when
small in size, targeted interventions were made possible with real-time guidance
even at the bed-side and, slightly later, duplex Doppler ultrasound provided
functional and not only morphological assessment of the liver vasculature and
new exciting diagnosis were made possible. It should be acknowledged that the
introduction of ultrasonography significantly contributed to the recognition of
hepatology as an independent discipline. In the next 15 years refinements in
ultrasound equipments were introduced by the industries, but no sustantial change
in the diagnostic capabilities did really appear. This remained true until the early
years 2000, which witnessed two revolutionary new ultrasound based techniques.
One is real-time low acoustic pressure contrast enhanced ultrasound (CEUS),
introduced into the market in 2002. This technique developed very rapidly and is
now fully mature and applied in the daily practice worldwide with well
established guidelines, such as those released by EFSUMB (European Federation
of Societies for Ultrasound in Medicine and Biology). The second one is
ultrasound elastography, which was first presented in the medical literature in
2003. Ultrasound elastography provides a functional assessment of the liver,informing on tissue elasticity and thus on the disease stage. This information is
obtained with greatest ease, non invasively and very rapidly at the bedside.
Accordingly, transient elastography has been recently incorporated into
international guidelines for the management of chronic viral hepatitis. It has also
applications in other conditions involving the liver, beside chronic hepatitis.
While contrast enhanced ultrasound underwent technical improvements, but is
substantially one single modality, elastography is somehow different and various
modalities are available, requiring different examination techniques and providing
slightly different clinical information. Most of these modalities have been
introduced only in the very last few years and their properties are still poorlyknown to clinical ultrasonographers. Therefore, the eBook by Prof. Ioan Sporea
on liver elastography is very timely presented and greatly desired. In fact the
ongoing spread of the technical possibility to perform liver elastography must be
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vii
paralleled by adequate knowledge of the clinicals information that can be obtained
by each of the different modalities. Worth to remind that beyond the self standing
transient elastography equipment, nowadays several ultrasound scanners can be
implemented with various elastographic techniques, either based on shear wave or
strain imaging modalities.
Reading the eBook will be an exciting time, with immediate applicability of the
information into the daily clinical practice for anyone involved in the management
of liver disease and the authors are to be commended for their efforts, based on
long standing clinical and research expertise in this field.
Fabio Piscaglia, MD PhD,
University of Bologna
Italy
President EFSUMB
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Hepatic Elastography Using Ultrasound Waves, 2012, 3-24 3
Ioan Sporea and Roxana irli (Eds)
All rights reserved- 2012 Bentham Science Publishers
CHAPTER 1
Physics and Technical Information
Ioan Lie*
Applied Electronics Department, Electronics and Telecommunications Faculty,
Politehnica University Timioara 2, Vasile Prvan Bv, 300223 Timioara
Romania
Abstract: US is defined as acoustic waves with higher frequencies than those that can
be detected by the human ear, ranging from about 20 kHz to several hundred MHz.
Medical US typically uses waves ranging from 1 to 15 MHz. A typical US transducer
employs an array of piezoelectric elements to generate short duration, broadband pulses.The array size determines the imaging systems aperture. The same transducer also
receives the backscattered signals which are then processed in order to obtain the US
image of the explored region.Elasticity is the physical property of materials to return to
their original shape after removing the force that caused the deformation. A
complementary concept of elasticity is stiffness, which is a measure of the resistance
opposed by an elastic material to deformation. Quantitative elastography is based on
shear waves production, tracking and detection. Different elastography methods use
different techniques for generating and tracking shear waves, but the stiffer the tissue is,
the higher the shear wave velocity is. Also liver stiffness increases with the severity of
fibrosis, since scaring tissue is less elastic than the normal liver parenchyma.
Keywords: Ultrasound waves, elasticity, stiffness, shear waves, liver fibrosis.
1. ULTRASOUND
The use of ultrasound (US) in medical practice has found a solid niche among the
various methods for body imaging. US is defined as acoustic waves with higher
frequencies than those that can be detected by the human ear, ranging from about
20 kHz to several hundred MHz [1]. Medical US typically uses only the portion of
the US spectrum ranging from 1 MHz to 10 MHz, due to the tradeoff between
frequency and penetration depth. US waves are generated by small acoustic
transducers, which are electrically driven and typically placed on the skin. The
*Address correspondence to Ioan Lie: Applied Electronics Department, Electronics andTelecommunications Faculty, Politehnica University Timioara 2, Vasile Prvan Bv, 300223 TimioaraRomania; E-mail: [email protected]
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4 Hepatic Elastography Using Ultrasound Waves Ioan Lie
waves propagate into the body tissue, where a portion is reflected from the myriad
interfaces between tissues with different acoustic properties [1].
The most commonly used modality in medical US is B-mode imaging, where an
ultrasound transducer is placed against the skin directly over the region of interest
(ROI). A typical US transducer employs an array of piezoelectric elements to
generate short duration, broadband pulses (with a center frequency of about 3-15
MHz). The array size determines the imaging systems aperture. The same
transducer also receives the backscattered signals. The transmission signals
passing to and the received signals passing from the array elements can be
individually delayed in time, defining a phased array. Phased arrays are used to
electronically steer and focus the sequence of acoustic pulses through the targetvolume which is known as beam forming. Processing these echo signals routinely
begins at the individual channel (element) level to produce A-lines (A-mode/ one
dimensional wave equation of sound energy reflected from the target). The
general formation of B-mode sequences (Fig. 1) commences with Radio
Frequency (RF) demodulation or envelope detection storing, resulting A-modes in
a 2D image matrix, followed by attenuation correction using time gain
compensation (TGC) or swept and lateral gains, to increase signal amplification
from increasing depths. Next scan conversion (an 8 bit digitization) allows the B-
mode to be displayed with a defined resolution (known as a B-scan), and finally
logarithmic compression is used to adjust the large echo dynamic range (60-100dB). The B-scan sequences captured and analyzed are those processed and
displayed by the US machine, with a uniform dynamic range intensities ranging
from 0 to 255 [2].
Generally, US image analysis is complex, due to the numerous tissue interfaces
and varying structure of biological tissues causing echogenicity, which is
described in terms of a speckle formation. A speckle is a structured noise from a
medium containing many scatterers. Speckle appearance is dependent on the
bandwidth, frequency and manufacturer of the employed transducer, in addition to
the geometry and sub-wavelength structure of the tissue. Echographic speckle
texture of the imaged tissue is mainly due to intensity scattering; implying
structures are smaller than the sampling volume (a product of spatial pulse length
and beam cross section). Upon visual inspection, a speckle consists of a relatively
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Elastography: Physics Hepatic Elastography Using Ultrasound Waves 5high grey level intensity, qualitatively ranging from a hyperechoic (bright) to a
hypoechoic (dark) domain. Scatter occurs when small imperfections (scatterers) in
the target cause seemingly random reflections and refractions of the sound wave.
The textures created do not correspond to the underlying structure, but the
intensity reflects the local echogenity of the underlying scatterers. Scatterers
account for a decrease in image quality, causing blurring and decreased intensity
at impedance boundaries, while within the medium they create speckling. The
signal statistics depend on the density of scatterers, with a large number of
randomly located scatterers following a Rayleigh distribution [1].
Figure 1: The processes used to generate a B-scan. B-scans are composed of a set of axial RF
signals representing the response magnitude from a pulse generator using a linear array transducer.Since the response magnitude delays exponentially with depth, it is log-amplified prior to
quantization and display [1].
Standard medical practice of soft tissue palpation is based on the qualitative
assessment of stiffness at low frequencies. It is generally known that pathological
changes are correlated with changes in tissue stiffness. In many cases, despite the
difference in stiffness, due to the small size of pathological lesions and/or depth to
which they are located in the body, their detection by palpation is impossible.
Generally, the lesion may or may not possess echogenic properties detectable with
US. For example, breast or prostate tumors may be invisible or barely visible in
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6 Hepatic Elastography Using Ultrasound Waves Ioan Lie
standard US examination, although they are much more rigid than the tissues they
are embedded into. In diffuse diseases such as liver cirrhosis, a significant
increase in tissue stiffness is characteristic, but it may occur normally in a
conventional US examination. Because tissue echogenity and stiffness are
generally uncorrelated, it is expected that mapping tissue stiffness or elasticity,
should provide new information on pathological tissues structure.
2. PHYSICAL FUNDAMENTALS OF ELASTOGRAPHY
Elasticity is the physical property of materials to return to their original shape
after removing the force that caused the deformation. For small deformations,
most materials show linear elasticity, i.e. a linear dependence between stress
(force per unit area) and relative deformation (relative change). This dependence
is known as Hooke's law. A complementary concept of elasticity is stiffness,
which is a measure of the resistance opposed by an elastic material to
deformation.
The elasticity modulus describes mathematical, elastic deformation tendency of an
object or material. The elasticity modulus of a material is defined as a slope of the
curve describing the dependence between mechanical stress and deformation,
considering the elastic deformation region of the curve. As the material is more
rigid, it will have a higher modulus. Depending on how the mechanical stress is
applied and how the deformation is measured, several types of elasticity modules
are defined. The most important are:
- Young's modulus (E) - this describes the deformation tendency of anobject following a certain axis, if the forces applied along the axis
have an opposite orientation.
- Shear modulus (G) - describes an object's tendency to change shapeand keep its volume, when mechanical stress is achieved by opposing
forces placed in parallel planes.
- The bulk modulus (K) - describes volumetric elasticity or an objectstendency to deform in all directions, when it supports mechanical
stress in all directions. It is defined as the ratio between the force per
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Elastography: Physics Hepatic Elastography Using Ultrasound Waves 7unit volume and the volumetric deformation. Inverse of the bulk
modulus is compressibility. The bulk modulus can be seen as a three-
dimensional extension of Young's modulus.
Poisson's coefficient is often used for the characterization of inhomogeneous
isotropic media. It is defined as the ratio between transverse contraction per unit
breadth and longitudinal extension per unit length. Lame's parameters are also
used in linear elasticity theory. They are a parameterization of elasticity modules
for homogeneous isotropic environments.
Lam's first parameter denoted by , expresses the relationship between the bulk
modulus and the shear modulus. The second parameter of Lam, noted
(formerly G) is the shear modulus.
The relationship between the Youngs modulus E, the Poisson coefficient and
the Lam parameters and , is given by:
3 2
2 ( )
E
(1)
The elasticity modulus should not be confused with stiffness. The elasticity
modulus is a property of the material constituting a certain structure. Stiffness is a
property of the structure and depends on the material, on its shape and boundary
condition.
For biological tissues, consisting mainly of water, compression module (several
gigaPascals) is much higher than the shear modulus (several kiloPascals) [3]. This
difference is explained by the fact that the volume change associated with
compression requires a much greater force than that required for the shear
deformation, which happens by changing shape at constant volume. The condition
>> leads to a value of Poisson ratio 0.5, which characterizes the quasi-
incompressible medium. In these conditions a simple relationship between
longitudinal and shear modules is established.
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8 Hepatic Elastography Using Ultrasound Waves Ioan Lie
E = 3G (2)
One way of assessing tissue elasticity is based on measuring the propagationvelocity of waves through the tissue. Propagation speed for any type of wave
depends on the properties of the environment in which they propagate. For
acoustic waves, the propagation speed depends on the elastic and inertial
properties. Physical entities associated with these properties are the density ()
and elasticity modulus. When applying a compressive mechanical stress,
longitudinal or volumetric waves will propagate through the material, whose
propagation direction coincides with the mechanical stress direction. Propagation
velocity of longitudinal waves is given by the following equation:
L
KV
(3a)
When the material is subjected to shear forces, shear waves will propagate
through it, which will produce material deformation perpendicular to the forces
direction. Shear waves propagate at a speed given by the equation:
S
GV
(3b)
Because the elasticity modules values are significantly different (K = 2.3 GPa
and G = 0.5-100 kPa) [4], the propagation speeds for the longitudinal waves and
shear waves are significantly different: VL = 1400-1700 ms-1
and vs. = 0.5 -10
ms1.
The shear modulus in tissue can be deduced from the shear wave velocity, Vs, and
the mass density, :
2
2
3
S
S
V
E V
(4)
In the hypothesis that soft tissue density is approximately constant (1000 kg/m3),
the value of elasticity modulus is obtained by measuring the shear wave speed.
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Elastography: Physics Hepatic Elastography Using Ultrasound Waves 9The relationship (4) is the basis for developing methods for the quantitative
assessment of elasticity. One of the methods used for measuring shear wave speed
exploits the big difference between shear wave speed and longitudinal waves
speed. The shear wave propagation in the region of interest is followed using
longitudinal ultrasonic beams.
Qualitative and quantitative description of a medium elasticity can be done in two
ways:
- By assessing the relative displacement caused by static or dynamicdeformation, or
- By measuring the shear waves propagation velocity and indirectdetermination of elasticity modulus.
Methods in the first category are implemented by qualitative techniques, which
estimate a deformation rate, which indirectly characterize environmental stiffness.
Quantitative Evaluation of environmental elasticity can be obtained by measuring
the shear waves propagation speed and by a simple calculation determining the
elasticity modulus. Corresponding to these two approachesstrainelastography or
qualitative elastography and shear wave elastography or quantitative
elastography were developed [4].
3. BACKGROUND OF QUALITATIVE (STRAIN) ELASTOGRAPHY
Consider a system with three springs with the same length without any application
of force (Fig. 2). Spring constant is defined as the force necessary to stretch (or
compress) a spring with a one unit length. In the considered system, the springs
have different spring constants; the spring in the middle has a higher spring
constant (is stiffer) as compared to the other two springs which have a lower
spring constant (are softer) than the one in the middle. On application of equal
forces to the springs, the less rigid spring will yield more displacement ascompared to the rigid one. The rigid spring is mechanically less elastic; thereby
producing less displacement vis--vis the less rigid spring, which deforms more
due to the same force [5].
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Elastography: Physics Hepatic Elastography Using Ultrasound Waves 11of the pre-compression and post-compression signals are compared by cross correlation. While the
early windowed segments exhibit virtually no delay, a finite delay (designated del (t)) is detected
between the later segments [8].
When an elastic medium is compressed with a constant, axial oriented pressure,
all points of the environment support a longitudinal deformation, whose main
component is oriented on the axis of compression. If one or more tissue
constituent elements have a different stiffness than the others, their deformation
will be different (lower if the element is stiffer). Longitudinal deformation is
estimated by analyzing the ultrasonic signals obtained with conventional
equipment in the following sequence [6]:
- The region of interest is scanned and the set of appropriate radio-frequency echoes is digitized and stored.
- A tissue compression force is applied to produce small linear elasticdeformation into the tissue. The ultrasonic transducer or a dedicated
compressor is used.
- The region of interest is scanned once again and a new set of echosignals is acquired.
Pairs of signals corresponding to the same directions of scanning are subdivided
into small time windows and then compared using cross-correlation techniques.
The windows are translated in small overlapping steps along the temporal axis of
the echo line, and the calculation is repeated for all depths. For each direction and
for each focal point in the direction considered, the differences between U.S.
wave propagation times are determined in two situations. Since the compressive
stress amplitude is small, deformation and thus differences in propagation times
will also be reduced.
4. THE STRESS EXCITATION METHODS
Evaluation of tissue elasticity requires its excitation. Excitation methods can beclassified, according to their temporal characteristics, into static methods and
dynamic methods. Static methods consist of applying a low value compressive
force, constantly and uniformly distributed. Induced displacements are measured
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14 Hepatic Elastography Using Ultrasound Waves Ioan Lie
conventional systems. To solve this limitation, elastography dedicated hardware
architectures have been designed.
Depending on how shear waves are generated, three types of US elastography
systems have been implemented.
6. INDUCTION OF SHEAR WAVES USING AN EXTERNAL ACTUATOR
TRANSIENT ELASTOGRAPHY
This method uses an external actuator to produce low-frequency vibrations with
frequencies in the 50-500 Hz range [9, 10]. The solution used in the "FibroScan"
commercialized by Echosens, France, combines the actuator and the ultrasonic
transducer in the same probe [4, 11-15]. Induced shear waves propagate throughthe tissue and produce its elastic deformation. Displacement is reflected in the
variation of the acquired echo signals. The ultrasonic transducer is used in pulse-
echo mode to measure displacements induced into the medium by the propagation
of low frequency shear waves. Both longitudinal and shear waves are generated
by the same probe and the ultrasonic beam is focused by the actuator axis. The
assumption of homogeneity and symmetry considerations shows that
displacement on the transducer axis is purely longitudinal. Diffraction effects
from the transducer result in a longitudinally polarized shear wave on the axis of
symmetry. The ultrasonic beam tracks its propagation (Fig. 4) [16].
By cross-correlating successive lines the tissue deformation is determined. The
system originally developed is based on single direction data acquisition and
therefore does not provide a conventional B-mode real time image. Such an image
is useful to guide the operator in positioning the transducer and choosing the place
where stiffness is measured.
Two dimensional representations are obtained when displacements induced by the
shear wave are measured using cross-correlation of successive high frame rate
ultrasound lines. From the recorded displacements a strain map is computed. The
shear wave speed is calculated based on the slope of the wave front visualized on
the strain map.
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Elastography: Physics Hepatic Elastography Using Ultrasound Waves 15
Figure 4: The low frequency shear wave (blue) and the ultrasound beams (red) are generated by
the same piston-like transducer. Under the assumption of homogeneity, the symmetryconsiderations impose that the displacements on the axis of the transducer be purely longitudinal
(white arrow).
7. INDUCTION OF SHEAR WAVES USING ACOUSTIC RADIATION
FORCE ARFI ELASTOGRAPHY
Acoustic radiation force is a phenomenon associated with the propagation of
acoustic waves in attenuating media [17, 18]. Attenuation includes both the
scattering and absorption of the acoustic wave. Attenuation is a frequency dependent
phenomenon, and in soft tissues it is dominated by absorption. With increasing
acoustic frequencies, the tissue does not respond fast enough to the transitions
between positive and negative pressures, thus its motion becomes out of phase withthe acoustic wave, and energy is deposited into the tissue. This energy results in a
momentum transfer in the direction of wave propagation and tissue heating. The
momentum transfer generates a force that causes tissue displacement, the time scale
of this response being much slower than that of ultrasonic wave propagation. This
interaction of sound with tissue can be used to derive additional information about
the tissue, beyond what is normally provided in an ultrasonic image. The magnitude,
location, spatial extent, and duration of acoustic radiation force can be controlled to
interrogate the mechanical properties of the tissue.
The radiation force method causes tissue displacement centered on the focal region.These displacements propagate through the tissue in the form of shear waves and the
US system is used to monitor the shear waves' propagation. This technique was
proposed by Sarvazyan [4] and has been adopted by several groups [19, 20].
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16 Hepatic Elastography Using Ultrasound Waves Ioan Lie
The Siemens systems, Acuson S2000, implement both the strain and the shear
wave elastography based on acoustic radiation force [21].
Principle of Acoustic Radiation Force Impulse
ARFI imaging involves transmission of an initial ultrasonic pulse at diagnostic
intensity levels, to obtain a baseline signal for later comparison. A short duration,
high-intensity acoustic "pushing pulse" is then transmitted by the same transducer,
followed by a series of diagnostic intensity pulses, which are used to track the
displacement of the tissue caused by the pushing pulse [17, 22, 23]. The tissue
response to the radiation force is observed using conventional B-mode imaging
pulses, and it is possible to display the quantitative shear-wave velocity (Vs; m/s)
of ARFI displacement. This velocity (m/s) is proportional to the square root oftissue elasticity. Because the shear wave velocity depends on tissue stiffness, it is
possible to apply ARFI technology to elastography. This technology was named
Virtual Touch Tissue Quantification by SIEMENS.
The applications for tissue stiffness assessment using investigative techniques
based on US provide quite different information as compared to conventional US
exam. For "Virtual Touch" application software [21], the data acquisition is
performed in three stages.
The first step is to obtain a reference B-mode image of the region of interest byconventional US. In the second stage the tissue is disturbed using a short acoustic
pulse of hundreds of microseconds, which propagates through the tissue. As a
result of energy transfer from the acoustic pulse to the tissue, it undergoes a
deformation process dependent on its specific rigidity. Quantitative displacement
size is tens of microns. Soft tissues, being elastic, will deform more than rigid
tissue whose elasticity is much lower. The deformation associated with high
intensity ultrasonic pulse propagation is followed by a process of relaxation after
which the tissue returns to its original configuration.
In the final phase, the region is scanned with a normal intensity (diagnostic) USbeam and a new B-mode image is acquired. By comparing it with the reference
image, displacements occurring in different areas can be calculated. Therefore this
technique uses different intensity ultrasonic waves to compress tissue and to
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Elastography: Physics Hepatic Elastography Using Ultrasound Waves 17observe their dynamic behavior due to acoustic radiation force action.
Commercial systems have implemented acoustic intensity adjustment
mechanisms, such as power peaks, to be controlled with conventional imaging
methods. Simultaneously, data processing algorithms allow higher resolution and
the system hardware has been refined for increased sensitivity to ultrasonic signal
reception. To determine the delay between two disturbing pulses, ROI size and
depth are taken into consideration.
ARFI Elastography Qualitative Approach
The application software "Virtual Touch Tissue Imaging" made by Siemens [1]
provides quality map data of relative stiffness of tissue in a ROI (elastogram). The
information is calculated by the examining of relative displacements ofelementary formations of tissue, arising from the acoustic pulse disturbing action.
On the elastogram, the elasticity is associated with image brightness. Nestled
beside a conventional ultrasound B-mode image and an elastogram regions of
tissue with different borders can be highlighted. This is explained by the fact that
the mechanisms for determining the contrast in tissue are completely different in
the two methods.
By combining lines resulting from successive evaluation mode A, on the
directions that describe the ROI, the software application synthesizes an image.
The procedure begins with the line positioned at one end of the ROI (left or right).A signal is obtained which describes, conventionally (mode A), the tissue in that
direction when it is at rest. Next application of disturbing impulse focused in this
direction will lead to displacement of tissue. Using conventional ultrasonic beams
focused on the direction, it acquires signals describing the state of the deformation
of tissue (Fig. 4). The two signals are compared using cross-correlation algorithm
and determine differences in tissue position in the relaxed and compressed state,
along the line considered. Differences calculated for each location relative to the
maximum, considered as reference, are a measure of tissue elastic properties
reported to tissue positioned in the location of reference. The process is repeated
for each line of the ROI, as in a conventional scanning B. Finally the entire ROI
calculated displacements are converted into an image format (elastogram) which
shows the relative hardness of the tissue.
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18 Hepatic Elastography Using Ultrasound Waves Ioan Lie
Figure 5: Virtual Touch Tissue Imaging utilizes acoustic push pulses (orange) and tracking beams
(green arrow), sequenced across a user-defined region of interest, to generate an elastogram
depicting the relative stiffness of tissue from [21].
ARFI Elastography Quantitative Approach
ARFI technology allows a quantitative assessment of tissue elasticity based on
shear wave velocity measurement. An appropriate application is "Virtual Touch
Tissue Imaging" made by Siemens [21].
According to the equation (4) shear wave velocity is directly proportional to the
square modulus of elasticity. Therefore, by measuring the shear wave velocity, we
obtain a direct characterization of the elastic properties of the tissue. Shear waves
are generated and propagate perpendicular to the disturbing pulse. Unlike
longitudinal ultrasonic waves used in conventional investigation, shear waves do
not interact with the transducer. They are attenuated more than 10,000 times faster
than conventional waves and therefore require a more sensitive measurement.
Displacements generated by the shear wave propagation through tissue can be
detected using ultrasonic beams which scan the ROI. Shear wave velocity arises
from the determination of the shear wave front position and its correlation with
the time elapsed between consecutive measurements (Fig. 6).
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Elastography: Physics Hepatic Elastography Using Ultrasound Waves 19A previously investigated region is identified by locating the ROI on a
conventional ultrasound image. Then a focused acoustic pulse in this region is
applied that will induce shear waves that will propagate through the ROI.
Tracking beams adjacent to the excitation path are sensitive to wavelengths much
smaller than the wavelength of sound. These are transmitted continuously until the
detection of the shear wave front. Locating position of peaks at different points in
time ensure accuracy and reproducibility of measurement results (Fig. 5).
Figure 6: Virtual Touch Tissue Quantification utilizes an acoustic push pulse (orange) to generate
shear waves (blue) through a user-placed region of interest. When detection pulses (green arrow)interact with a passing shear wave, they reveal the waves location at a specific time, allowing
calculation of the shear wave speed. This numerical value is related to the stiffness of the tissue
within the region of interest from [21].
8. SHEAR WAVE IMAGING
Shear wave imaging uses the same principles as the ones presented above. Shear
waves are generated using a pushing pulse and A-line correlation techniques areused to track them through the tissues. This technique has been developed by a
group led by Fink [20] and has been implemented commercially (Supersonic
Imagine, France) [24, 25].
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20 Hepatic Elastography Using Ultrasound Waves Ioan Lie
Shear Wave Initiation
Shear waves induced in the region of interest must be ample enough so that theirpropagation can be detected by focused beams. Initially, single pulses were used
to generate shear waves. Currently, available commercial systems use several
pulses, focused at different depths [20]. The cumulative effect of these pulses is
reflected in the increasing amplitude of shear waves, and in the expansion of the
region in which they can be tracked. This expands the area that can provide data
about shear waves and thus about the environment stiffness. Excitation pulses
form an excitation beam. Rapid change of beam focus depth is equivalent to
moving high intensity excitation sources through the tissue. If the source moves
with a higher speed than that of the generated shear wave, it is said that it moves
with supersonic speed - hence the term supersonic imaging. The shear waves frommultiple sources combine and propagate in the shape of a cone, called a "Mach-
cone" (Fig. 7).
Figure 7: Generation of the supersonic shear source: the source is sequentially moved along the
beam axis, creating two plane- and intense-shear waves [20].
Shear Wave Detection
To obtain a quantitative elasticity map of the medium, it is necessary to image the
propagation of the shear-wave and to measure its velocity. As the shear wavestypically propagate at a few meters per second, a frame rate of several kilohertz is
needed. This is not possible using conventional US scanners (they typically reach
a 50-Hz frame rate).
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Elastography: Physics Hepatic Elastography Using Ultrasound Waves 21So the use of an ultrafast, ultrasonic scanner is needed, able to remotely generate
the mechanical shear wave, by focusing US at a given location, and image the
medium during the wave propagation at a very high-frame rate (up to 6000
images/s) (Fig. 8). The ultrafast frame rate is achieved by reducing the emitting
mode to a single, plane-wave insonation. This technique allows the acquisition of
echographic images at a pulse repetition that can reach 6000 Hz.
Figure 8: Stages necessary to image the propagation of the shear-wave and to measure its velocity[20].
An ultrafast scanner is used, fully programmable, with a multichannel system made
of 128 channels, connected to the transducer. All backscattered radio frequency (RF)
echoes are stored in the memory of each channel and are transferred to a computer
after acquisition. The beam forming process is done only in the receive mode during
a post acquisition process. For each elementary transmit-receive sequence, a number
of parameters can be fixed on each channel independently; to create focalized or flat
transmits. The delays before and after emission are included, also the pointer
addresses of transmit and receive signals [20].
Generation of Radiation Force: To generate the radiation force, the ultrafast
scanner is used to create an ultrasound-focused beam at a chosen location. The
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22 Hepatic Elastography Using Ultrasound Waves Ioan Lie
typical US pulse is made of 400 oscillations at 4.3 MHz. This corresponds to a
pushing time of 100 s.
Acquisition Sequence: A first plane-wave insonation is performed to realize a
reference echographic image of the medium. The pushing sequence is then
realized by focusing the US beam at a chosen location. Just after the generation of
the pushing beam, the scanner begins an ultrafast imaging sequence by sending
plane-wave insonations at a high-frame rate, in order to catch the shear wave
created by the push.
Signal Processing: The RF data stored in the scanner memory are transferred to
the computer. A classical beam forming process then is applied to the data to
compute the set of echo images. All the images acquired after the push are then
correlated with the reference echo image using a 1-D correlation algorithm. The
results are a set of images giving the displacement induced by the shear wave at
each sample time.
The final data may be displayed in units of shear wave velocity (m.s-1
) or converted
into units of Youngs modulus (kPa) using the equation (4). Note that the equation
(4) requires knowledge of the tissue density. Information on how manufacturers
account for tissue density is not readily available. One possibility is that
manufacturers simply assume a value for the density, possibly an average value.
In practice shear wave images demonstrate considerable variability, with values
affected by the presence of boundaries and by blood vessels [20]. Improved
understanding of shear waves propagation through biological tissues may result
in new beam-forming regimes and new signal processing algorithms, which
improve image quality and reduce image variability.
CONFLICT OF INTEREST
The author(s) confirm that this chapter content has no conflict of interest.
ACKNOWLEDGEMENT
Declared none.
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24 Hepatic Elastography Using Ultrasound Waves Ioan Lie
[22] Palmeri ML, Frinkley KD, Zhai L, et al. Acoustic radiation force impulse (ARFI) imagingof the gastrointestinal tract. Ultrason Imag 2005; 27: 7588.
[23]
Dahl JJ, Pinton GF, Palmeri ML, et al. A parallel tracking method for acoustic radiationforce impulse imaging. IEEE Trans Ultrason Ferroelectr Freq Control2007; 54: 301312.
[24] 24 Tanter M, Bercoff J, Athanasiou A, et al. Quantitative assessment of breast lesionviscoelasticity: Initial clinical results using supersonic shearimaging. Ultrasound Med Biol
2008; 34: 13731386.
[25] Muller M, Gennisson JL, Deffieux T, et al. Quantitative viscoelasticity mapping of humanliver using supersonic shear imaging: preliminary in vivo feasability study. Ultrasound Med
Biol 2009; 35: 219229.
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Hepatic Elastography Using Ultrasound Waves, 2012, 25-51 25
Ioan Sporea and Roxana irli (Eds)
All rights reserved- 2012 Bentham Science Publishers
CHAPTER 2
Transient Elastography (TE)
Ioan Sporea and Roxana irli*
Department of Gastroenterology and Hepatology, Victor Babe University of
Medicine and Pharmacy, 10, Iosif Bulbuca Bv, 300736, Timioara, Romania
Abstract: Transient Elastography (TE) is the first ultrasound-based method for fibrosis
assessment, developed by Echosens (France). In order to obtain reliable liver stiffness
(LS) measurements by means of TE, the manufacturer recommends that at least 10 valid
shots should be obtained. They should have a success rate (SR: the ratio of valid shots
to the total number of shots) of at least 60% and an interquartile range (IQR, thedifference between the 75th percentile and the 25th percentile, essentially the range of the
middle 50% of the data) less than 30% of the median LS value. TE fails if no valid shots
can be obtained, and is unreliable if fewer than 10 valid shots are obtained. TE failure is
correlated with the body mass index, increasing in obese patients. Also, unreliable
results are obtained during aminotransferases flares that can lead to an overestimation of
fibrosis. The LS upper limit in healthy subjects was estimated to be 5.3 kPa. Several
meta-analyses assessed LS measurements by TE as a predictor of fibrosis, cut-offs for
F2 ranging from 7.2-7.6 kPa and for F=4 from 12.5-17.3 kPa, according to the
etiology of chronic liver disease. Several studies have been published regarding the
value of TE for predicting the occurrence of cirrhosis complications. The AUROCs for
predicting clinically significant portal hypertension were 0.945 - 0.99, for cut-off values
between 13.6 - 21 kPa, while for predicting esophageal bleeding the best cut-offs ranged
between 50.7 62.7kPa, with AUROCs 0.73-0.75.
Keywords: Transient elastography, liver stiffness, liver fibrosis, cirrhosis,
esophageal varices.
1. TE TECHNIQUE
Transient Elastography (TE) is an ultrasound-based method, developed by
Echosens (France), initiating from the principles of Hookes law, which
characterizes a materials strain response to external stress [1]. A FibroScan
device is used (Fig. 1), whose ultrasound transducer probe (Fig. 2), mounted on
*Address correspondence to Roxana irli: Department of Gastroenterology and Hepatology, VictorBabe University of Medicine and Pharmacy, 10, Iosif Bulbuca Bv, 300736, Timioara, Romania;E-mail: [email protected]
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26 Hepatic Elastography Using Ultrasound Waves Sporea andirli
the axis of a vibrator, transmits low-frequency vibrations from the right intercostal
space which creates an elastic shear wave that propagates into the liver. A pulse-
echo ultrasound acquisition is then used to detect wave propagation velocity,
which is proportional to tissue stiffness; faster wave progression occurs through
stiffer material. LS measurement is then performed and measured in kiloPascals
(kPa) (values between 2.5kPa and 75 kPa are expected).
Figure 1: The FibroScan device.
Figure 2: Pediatric (S), standard (M) and obese (XL) FibroScan probes.
Using TE, liver stiffness measurements (LSMs) are performed in the right liver
lobe through the intercostal spaces, while the patient lies in a dorsal decubitus
position with the right arm in maximal abduction. The tip of the transducer is
covered with coupling gel and placed on the skin between the ribs, aimed at the
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TE Hepatic Elastography Using Ultrasound Waves 27right liver lobe. The operator, assisted by ultrasound A-mode images provided by
the system, locates a portion of the liver at least 6 cm thick and free of large
vascular structures. Once the area of measurement had been located, the operator
presses the probe button to begin an acquisition. Acquisitions that do not have a
correct vibration shape or a correct follow-up of the vibration propagation are
automatically rejected by the software.
2. PITFALLS OF LS MEASUREMENTS BY MEANS OF TE
In order to obtain a reliable evaluation by means of TE, the manufacturer
recommends that at least 10 valid measurements should be obtained. They should
have a success rate (SR: the ratio of valid shots to the total number of shots) at
least 60% and an interquartile range (IQR, the difference between the 75 th
percentile and the 25th
percentile, essentially the range of the middle 50% of the
data) less than 30% of the median LSM value.
Thus, TE is consideredfailedif no valid shots can be obtained, and unreliable if
fewer than 10 valid shots are obtained, with an IQR greater than 30%, and/or a SR
less than 60% [2]. In a very large study published by Castera on more than 13,000
LSMs, the success rate of stiffness evaluation with TE was correlated with the
body mass index (BMI), decreasing in obese patients (in which it is less than
80%) [2], but the new probe for obese subjects (the XL probe) has increased the
percentage of cases with valid results.
Regarding factors associated with failure, an earlier study performed by Kettaneh
and et al. [3] on 935 HCV patients, showed that the probability of valid
measurements (correlated with the histological score) was higher if the operator
was experienced (with more than 50 FibroScan evaluations performed), if the
patient was young (OR 0.96/year) and not obese (OR 0.19 if obese). Another
study by Boursier et al. showed high measurement agreement between novices
and expert operators, even during the first 10 cases [4], so that a formal session by
a qualified trainer, followed by practice on 50 cases, should suffice for thetraining of most operators.
In a prospective study by Foucher et al. [5], the univariant analysis showed that
failure was associated with: BMI>28 (OR 9.1), diabetes mellitus (OR 2.1), age
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28 Hepatic Elastography Using Ultrasound Waves Sporea andirli
>50 years (OR 4.0) and steatohepatitis (OR 3.4). Failure to obtain VM was not
operator dependent and was not associated with the patients gender, or with the
aminotransferases level. In the multivariate analysis, the only factor associated
with failure to obtain VM was BMI>28 (OR 10.0).
In a study published by our group [6] on 1461 patients, failure to obtain valid
LSM was observed in 6.9% of the patients. Female gender (OR=1.946), older age
and higher BMI were significantly associated with failure to obtain valid LSM.
Also, there are factors that can impair the correlation of LS values by TE with
liver fibrosis. These factors are: aminotransferases level, liver congestion due to
heart failure, and extrahepatic cholestasis.
In a study performed by Coco et al., LS was evaluated considering the
aminotransferases level, proving that another factor than fibrosis, independently
associated with LS was ALT for patients with chronic hepatitis [7]. The LS
dynamics profiles paralleled those of ALT, increasing 1.3 to 3 fold during ALT
flares. This study also showed that LS remained unchanged in patients with a
stable biochemical activity. In an Italian study on 12 patients with acute HBV
hepatitis, repeatedly evaluated by TE and biological tests during a 24 weeks
follow-up period, Vigano et al. concluded that the initial high values of LS
mimicking LS cut-off of cirrhosis, likely reflect the liver cell inflammation,
edema and swelling as they progressively taper down during hepatitis resolution
[8]. In a study published in 2009, Chan et al. evaluated 161 patients with chronic
HBV hepatitis and concluded that patients with the same fibrosis staging, but
higher ALT levels, tend to have higher LSM, and the diagnostic performance for
low stage fibrosis was most seriously affected when ALT was elevated [9]. All
three studies confirmed previous results published by Arena and Sagir in 2008
[10, 11].
An initial observation of high LS values in a patient with cardiac failure,
normalized following heart transplantation [12], was confirmed by Millonig et al.in an experimental model on landrace pigs. It showed that the stepwise increase of
intravenous pressure to 36 cm of water column (3.5 kPa) linearly and reversibly
increased LS to the upper detection limit of 75 kPa [13]. The experimental data
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TE Hepatic Elastography Using Ultrasound Waves 29was confirmed in 10 patients with decompensated congestive heart failure, before
and after recompensation. Initial LS was elevated in all patients, in 8 of them to
values that suggested liver cirrhosis (median 40.7 kPa). Upon recompensation
with a median weight loss of 3.0 kg, LS decreased in all 10 patients down to a
median LS of 17.8 kPa [13].
The same group of researchers evaluated LS in patients with obstructive jaundice,
before and after drainage by endoscopic retrograde cholangio-pancreatography.
After successful biliary drainage, LS decreased by 2.2 to 9.1 kPa, in correlation
with bilirubin decrease [14]. This observation was confirmed in an animal model
of bile duct ligation in landrace pigs, where liver stiffness increased from 4.6 kPa
to 8.8 kPa during 120 minutes of bile duct ligation and decreased to 6.1 kPawithin 30 minutes after decompression [14].
A significant increase in liver stiffness was observed after food intake for up to 60
minutes, and the value normalized after 180 minutes. Even if the change was
modest in most cases (mean change 12 kPa), it determined misclassifications in
some [15].
There is conflicting data regarding the influence of steatosis on LS measurements.
Some studies state that the degree of hepatic steatosis does not appear to affect LS
[15, 16], while in the study of Lupor et al., the univariant regression analysis
demonstrated that fibrosis (R2=0.610, p
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30 Hepatic Elastography Using Ultrasound Waves Sporea andirli
subjects, in whom VMs were obtained, the mean LS value was 4.81.3 kPa,
ranging from 2.3 to 8.8 kPa. The mean values of LS in each age group did not
differ significantly (p=0.5263). (Table 1 and Fig. 3). Also the mean LS in women
was significantly lower than in men (4.61.2 kPa vs. 5.11.2 kPa, p=0.0082).
Table 1:Mean liver stiffness values in each age subgroup
Age group
(years)
No. of patients
with VM
Mean value of LS
SD (kPa)
Minimum (kPa) Maximum (kPa)
All patients 144 4.81.3 2.3 8.8
18-29 43 51.3 2.3 8.8
30-39 24 4.51.2 2.6 7.3
40-49 17 51.1 3.0 7.1
50-59 27 4.71.2 2.5 7.7
60-69 20 51.3 3.2 7.7
>70 13 4.71.4 3.0 7.1
Figure 3: Mean LS values according to the age subgroup.
In a study by Roulot performed on 429 consecutive apparently healthy subjects,
the mean LS value was 5.491.59 kPa [21], while in a study performed by
Corpechot et al. [22], a similar mean value (4.8 kPa) was obtained in a group of
71 healthy subjects. In both studies, LS values were higher in men than in women.
Overall, the upper limit of normal LS was estimated to be 5.3 kPa [21, 23].
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TE Hepatic Elastography Using Ultrasound Waves 314. TE IN CHRONIC HEPATOPATHIES
a) TE in Chronic HCV Hepatitis
TE assessment of LS was used initially for the evaluation of chronic HCV
hepatitis. Later, published articles that will be discussed in the following pages,
proved the methods value in other chronic hepatopathies, such as chronic HBV
hepatitis, hemochromatosis, primary biliary cirrhosis, human immunodeficiency
virus (HIV)/HCV co-infection or non-alcoholic steatohepatitis (NASH).
In HCV viremic patients, if the LS is greater than 6.87.6 kPa (according to the
results of several studies and meta-analysis) [24-28], there is a great probability of
finding significant fibrosis on the liver biopsy (F2-F4) and subsequently the
patient requires antiviral therapy. Probably, in these cases, LB is not required for a
treatment decision.
In a multicentre French study coordinated by Beaugrand [29], performed on 494
HCV patients who were evaluated by means of percutaneous LB (with a
significant fragment) and valid FibroScan examination, a significant correlation
was found (p
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32 Hepatic Elastography Using Ultrasound Waves Sporea andirli
activity, steatosis or biological activity (ALT) have an important role in the
assessment of LS by means of FibroScan, as shown in recent studies [7, 17].
In 324 consecutive patients with chronic HCV hepatitis, evaluated both by TE and
LB in the same session, the LS values were strongly correlated with fibrosis
(r=0.759, p
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34 Hepatic Elastography Using Ultrasound Waves Sporea andirli
In a study performed by Ogawa [40] on 68 patients with chronic HBV hepatitis,
the mean LS values were 3.5 kPa for F0, 6.4 kPa for F1, 9.5 kPa for F2, 11.4 kPa
for F3, and 15.4 kPa for F4 patients. The values were significantly correlated with
fibrosis stage (r=0.559, P=0.0093).
In a prospective study by Marcellin et al., on 202 patients with chronic HBV
hepatitis, LS was significantly (P
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TE Hepatic Elastography Using Ultrasound Waves 35A study published in 2011 by Cardoso et al. [43] on 202 HBV patients and 363
HCV subjects, revealed that TE exhibited comparable accuracies, sensitivities,
specificities, predictive values and likelihood ratios in HBV and HCV groups.
Contrary to studies in the Asian population [7-11], AUROC analysis showed no
influence of ALT levels on the performance of TE in HBV individuals. ALT-
specific cut-off values did not exhibit significantly higher diagnostic
performances for predicting fibrosis in HBV patients with elevated ALT.
In another Asian study, that compared TE performance in HBV vs. HCV patients, the
conclusion was that discrepancies between LS values and histological fibrosis are due
to the degree of serum ALT levels, rather than to the cause of hepatitis itself [44].
The results of these studies, showing a weaker correlation of LS with histological
fibrosis in HBV than in HCV patients, can be explained in part by the fact that
high levels of aminotransferases influence the LS values obtained by means of TE
[7-11]. Thus, LS measurements have to be interpreted in a biochemical context;
otherwise, there is a risk of overestimating the severity of fibrosis. Also this is
why LS measurements are not performed in acute hepatitis or during alanine
aminotransferase (ALT) flares in HBV chronic hepatitis [7, 45].
In order to minimize the risk of overestimating fibrosis during ALT flares, Chan
et al. [9] calculated LS cut-off values for various stages of fibrosis considering
also the aminotransferases levels. In this study, the LS cut-off value for F3 was 9
kPa in patients with normal ALT and 12 kPa in patients with ALT higher than 5
times the upper limit of normal. The cut-offs for cirrhosis were 12 kPa in patients
with normal ALT and 13.4 kPa in those with high ALT.
The Tsochatzis meta-analysis also assessed the predictive value of LS assessed by
TE in HBV patients. The pooled cut-off for F2 Metavir was 7 kPa (range 6.97.2,
lower than in HCV patients), with 0.84 pooled sensitivity and 0.78 pooled specificity
[32]. In a meta-analysis published by Marcellin, the standardized AUROC of LS
measurements by TE for F2 Metavir was 0.89 (95% CI 0.83-0.96) [46].
c) TE in other Chronic Hepatopathies
Regarding the value of LS measurements by TE in evaluating chronic
hepatopathies of other etiologies, several studies were performed, in order to
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36 Hepatic Elastography Using Ultrasound Waves Sporea andirli
identify significant fibrosis in patients with in HIV-HCV co-infection [47, 48], in
chronic cholestatic hepatopathies: primary biliary cirrhosis (PBC) and primary
sclerosing colangitis (PSC) [49] and in NASH [50]. In these studies, the AUROCs
varied between 0.72 and 0.93, and the cut-off values for F2 ranged between 4
and 8.7 kPa (Table 3).
Table 3: Performance of LS for evaluating significant fibrosis in patients with chronic
hepatopathies other than HCV (PPV Positive Predictive Value; NPV Negative Predictive
Value)
Authors De Ledinghen
et al. [47]
Vergara et al.
[48]
Corpechot et
al. [49]
Yoneda et al.
[50]
Etiology HCV-HIV HCV-HIV PBC and PSC NAFLD
No. of patients F 2 44 105 57 33
Proposed cut-off (kPa) 4.5 7.2 7.3 6.6
Sensitivity (%) 93.2 88 84 82.7
Specificity (%) 17.9 66 87 81.3
NPV (%) 61 75 79 59.1
PPV (%) 65 88 91 93.5
AUROC 0.72 0.83 0.92 0.87
RegardingHCV-HIV coinfection, several studies demonstrated that TE is a useful
method for fibrosis assessment in patients co-infected with HCV and HIV. In the
study performed by de Ledinghen et al., LS was significantly correlated to fibrosisstage (Kendall tau-b=0.48; P2, 0.93 (0.85-
1.00) for F>3 and 0.99 for F4 (cut-offs 7 kPa, 11 kPa and 14 kPa) [51].
The first study regarding LS by TE in cholestatic hepatitis (primary biliary
cirrhosis PBC and primary sclerosing colangitis PSC) was published in 2006[49]. In this study, LS was correlated to both fibrosis (Spearman's rho=0.84,
P
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TE Hepatic Elastography Using Ultrasound Waves 37curves were 0.92 for F2, 0.95 for F3 and 0.96 for F=4, for the following
optimal cut-off values 7.3, 9.8, and 17.3 kPa respectively. In another study
published in 2008 on 80 patients with PBC, LS by TE was significantly correlated
to the histological fibrosis stage (Kendall coefficient: 0.56; P2 and 0.96 for F=4 [52]. A smaller study in 45 patients
with PBC showed that the adjusted accuracy of LS by TE for the diagnosis of F2
was 80%, while for liver cirrhosis it was 95% [53].
Regarding TE evaluation with nonalcoholic fatty liver disease (NAFLD) and
nonalcoholic steato-hepatitis (NASH),a positive correlation was found between
LS values and the histological stage of fibrosis, since even if steatosis may
attenuate shear waves, it does not modify their speed [54]. LS measurements canbe difficult in patients with NAFLD or NASH, since these conditions are often
associated with obesity. A first step towards increasing the feasibility of TE in
these patients was the introduction of the XL probe that increased the number of
patients that could be evaluated by TE [55-57]. Yoneda et al. evaluated 97
NAFLD patients by TE and NASH [50]. LS was well correlated with the stage of
liver fibrosis (Kruskal-Wallis test p
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38 Hepatic Elastography Using Ultrasound Waves Sporea andirli
observed in 33 (13.4%) patients. By multivariate analysis, liver biopsy length less
than 20 mm and F0-2 disease were associated with discordance.
A new technique, related to TE and performed with a FibroScan device is the
Controlled Attenuation Parameter (CAP) and it enables steatosis quantification in
fatty liver. CAP was first validated as an estimate of ultrasonic attenuation at 3.5
MHz using Field II simulations and tissue-mimicking phantoms. Performance of
the CAP was then evaluated on 115 patients, taking the histological grade of
steatosis as reference. CAP was significantly correlated to steatosis (Spearman
=0.81, p10% and >33% steatosis
were 0.91 and 0.95 respectively [60].
Regarding TE evaluation in patients with alcoholic liver disease(ALD), one must
consider that in most of these patients, inflammation coexists with fibrosis and
steatosis and it can influence the results of LS measurements, as showed above.
Higher cut-off values for cirrhosis were reported in patients with ALD, than in
those with viral hepatitis: 19.5 kPa in the study by Nguyen-Khac et al. [61] and
22.6 kPa in the Nahon study [62], but the patients included in those studies had
high ALT levels that were not taken into consideration. In a study by Mueller et
al. [63], LS was evaluated by TE in a learning cohort of 50 patients with ALD,
admitted for alcohol detoxification, before and after normalization of serum
transaminases. LS decreased in almost all patients, within a mean observationinterval of 5.3 days. Of the serum transaminases, the decrease in LS correlated
best with the decrease in glutamic oxaloacetic transaminase (GOT). No significant
changes in LS were observed below GOT levels of 100 U/L. In the study cohort
of 101 patients with histologically confirmed ASH, LS was measured only in
patients with GOT >100 U/L at the time of LS assessment. In this group, the
AUROC for cirrhosis detection by FS improved from 0.921 to 0.945 while
specificity increased from 80% to 90%, at a sensitivity of 96%. A similar AUROC
was obtained for lower F3 fibrosis stage, if LS measurements were restricted to
patients with GOT
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TE Hepatic Elastography Using Ultrasound Waves 395. TE FOR THE DIAGNOSIS OF LIVER CIRRHOSIS
If the performances of TE for the differentiation of mild from significant fibrosisare only moderate, its real value is for the diagnosis of cirrhosis. Data from 9
studies were evaluated by Talwalkaret al. [24] showing that TE has 87% pooled
sensitivity [95% confidence interval (CI): 8490%)] and 91% pooled specificity
(95% CI: 8992%) for the diagnosis of cirrhosis. In a meta-analysis on 50 studies,
the mean AUROCs for the diagnosis of significant fibrosis, severe fibrosis, and
cirrhosis were 0.84, 0.89, and 0.94, respectively [25]. Another meta-analysis from
2010 [64] evaluated 22 published papers. For a cut-off value of 15.08 kPa, it
showed a pooled sensitivity of 84.45% (95% CI: 84.2-84.7%) with pooled
specificity of 94.69% (95% CI: 94.3%-95%). Finally, in a recently published
meta-analysis which included 40 studies, the summary sensitivity and specificity
of TE for diagnosing cirrhosis were 0.83 (95% CI: 0.79-0.86) and 0.89 (95% CI:
0.87-0.91), respectively [32]. The mean optimal cut-off was 154.1 kPa.
Different cut-off values for the diagnosis of cirrhosis were proposed for different
etiologies: 12.5 kPa in HCV infection [26]; 13.4 kPa in HBV infection [41]; 10.3
kPa in NAFLD [59]; 22.4 kPa in ASH [63]; 17.3 kPa in cholestatic chronic
diseases (primary biliary cirrhosis and primary sclerosing colangitis) [49].
6. TE FOR THE DIAGNOSIS OF CIRRHOSIS COMPLICATIONS
The advantage of FibroScan evaluation of liver fibrosis, on other non-invasive
methods, is that transient elastography can also assess the severity of cirrhosis
(values up to 75 kPa), as shown in some studies, which proposed cut-off values of
LS that predict the presence of cirrhosis complications (esophageal varices,
variceal bleeding, vascular decompensation or hepatocellular carcinoma).
Esophageal varices and upper digestive hemorrhage are feared complications of
cirrhosis. The hemorrhage risk depends on the varices size so that primary
prevention of variceal bleeding should be applied to patients with large EV (grade
2 or 3) diagnosis established by periodical upper digestive endoscopy (Baveno V
and AASLD Consensuses) [65, 66]. Such a screening program of periodical
gastroscopy in all cirrhotics would be very expensive, and repeated endoscopies
are poorly accepted by the patients. Published studies demonstrated that LS values
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40 Hepatic Elastography Using Ultrasound Waves Sporea andirli
10 mmHg AUROC 0.945).
Robic et al. compared LS measurement by TE to HVPG, as predictors of cirrhosis
complications. One hundred patients with chronic liver disease were evaluated in
the same session by TE and HVPG measurements and followed-up for 2 years.
HVPG and LS measurements showed similar performances for predicting portal
hypertension: AUROCs 0.830 vs. 0.845. All patients with LS lower than the 21.1
kPa cut-off value remained free of portal hypertension complications during the 2years follow-up, as compared to 47.5% of those with higher values. The
performances of LS and HVPG were similar also in the cirrhotic subgroup of
patients [73].
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TE Hepatic Elastography Using Ultrasound Waves 41Reibergeret al. performed a study on 122 cirrhotics with EV who were evaluated
by means of TE and HVPG. There was a better correlation of LS values assessed
by TE and HVPG in patients with HVPG 12 mmHg than in those with HVPG
>12 mmHg (r=0.951 vs. r=0.538). Also, the authors observed an improvement in
the correlation of LS with HVPG under beta-blockers, mainly in hemodynamic
responders (r=0.864), but not in non-responders (r=0.535), while changes of blood
pressure, heart rate and LS were similar in responders vs. non-responders. For
discriminating cirrhotic patients with at least grade 2 EV, from those with grade 1
EV, for a cut-off value of 47.5 kPa, LS had 80.6% sensitivity and 47.7%
specificity [74].
In a review published in 2011, Castera concluded that diagnostic performancesof TE are acceptable for the prediction of clinically significant portal
hypertension, but far from satisfactory to confidently predict the presence of OV
in clinical practice and to screen cirrhotic patients without endoscopy [75]. But
all the studies included in this review evaluated only small numbers of patients
(ranging from 47 to 211), with contradicting results (cut-off values for significant
EV ranging from 19.8 to 48 kPa, and AUROCs ranging from 0.73 to 0.87).
In a study published by our group [76], not available for the Castera review,
including 1000 consecutive cirrhotic patients, we found out that negative and
positive predictive values (NPV and PPV) for at least grade 2 EV were 76.2% and71.3%, respectively, for a cut-off value of 31 kPa, chosen to maximize the sum of
sensitivityand specificity. For >40 kPa criterion, chosen to have a PPV of more
than 85%, the sensitivity was 77.8%, the specificity 68.3%, with 86% PPV and
55% NPV (95%CI: 49.6060.23). We also searched for a cut-off value as close as
possible to a NPV of 90%, and we found out that for 17.1 kPa, the NPV was
89.3%, with 43.2% PPV, 92.6% sensitivity and 33.5% specificity (AUROC
0.7807). So, according to our data, at least 8 out of 10 patients with TE values >40
kPa will have significant portal hypertension, therefore it seems reasonable to
recommend prophylactic beta-blocker therapy in these patients, without
endoscopy. Similarly, 5 out of 10 patients with TE values
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42 Hepatic Elastography Using Ultrasound Waves Sporea andirli
evaluation, since they have only 1 in 10 risk to present significant EV (NPV
89.3%).
In our study group, we also observed that the mean LS value in patients with a
history of variceal bleeding was significantly higher than in those with no
bleeding history: 51.921.56 vs. 35.200.91kPa, p
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TE Hepatic Elastography Using Ultrasound Waves 43predictive value for diagnosis of fibrosis F2, with AUROC 0.90, while for F4 the
AUROC was 0.98 [79]. Another study that evaluated 95 transplanted HCV
patients by means of paired liver biopsies and TE, showed that LS changed in
parallel with grading (r=0.63) and staging (r=0.71), with good sensitivity (86%)
and specificity (92%) in predicting staging increases [80].
In a systematic review published in 2010, Cholongitas et al. showed that TE had a
good discrimination power for significant fibrosis (median AUROC: 0.88, median
sensitivity 0.86, median NPV 0.90 and median PPV 0.8) [85]. In a recent meta-
analysis, the pooled data of 5 studies that estimated at least F2 in transplant HCV
patients were 83% for sensitivity and specificity, 4.95 for the positive likelihood
ratio, 0.17 for the negative likelihood ratio, and 30.5 for the diagnostic odds ratio.Five studies assessed cirrhosis, and their pooled estimates were 98% for
sensitivity, 84% for specificity, 7 for the positive likelihood ratio, 0.06 for the
negative likelihood ratio, and 130 for the diagnostic odds ratio [86].
As demonstrated above, TE reliably predicts severity of recurrent HCV hepatitis
following liver transplantation, but its accuracy in non-viral liver graft damage is
unknown. Rigamontti et al. evaluated 69 transplant recipients (37 hepatitis B/D
recurrence-free, 20 autoimmune/cholestatic liver disease, 6 alcoholic liver disease
and 6 mixed) by means of both protocol or on demand liver biopsy and
concomitant TE. 94% of patients had reliable TE examinations during post-transplant follow-up (median 18 months, range 7-251). Liver biopsy showed graft
damage in 43% (28) patients. LS values were significantly higher in patients with
graft damage as compared to the ones without (median 7.8 kPa vs. 5.3 kPa,
p
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44 Hepatic Elastography Using Ultrasound Waves Sporea andirli
One hundred and sixteen consecutive children with various liver diseases were
evaluated, and only in one TE was not feasible. TE showed the best correlation to
clinical and biological severity parameters. Also, TE was significantly correlated
with the Metavir fibrosis score. The AUROCs of TE, FibroTest and APRI for
predicting cirrhosis were 0.88, 0.73 and 0.73, respectively.
Nobili et al. evaluated 52 consecutive NASH pediatric patients by means of LB
and TE [89]. Even if an adult probe was used and most patients were overweight
and obese, TE proved to be a highly feasible (96% of patients with reliable
measurements) and highly reproducible (intraclass correlation coefficient 0.961)
method in children. The AUROCs for prediction of any (>1), significant (>2),
or advanced fibrosis (>3) were 0.977, 0.992, and 1, for cut-offs
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TE Hepatic Elastography Using Ultrasound Waves 45could not be obtained [measurements with Success Rate (SR)
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REFERENCES
[1] Beaugrand M. Fibro Scan instructions for use. Journes Francophones de PathologieDigestive. Gastroenterol. Clin Biol 2006; 30: 513- 514.[2] Castera L, Foucher J, Bernard PH, et al. Pitfalls of Liver Stiffness Measurement: A 5-Year
Prospective Study of 13,369 Examinations. Hepatology 2010; 51: 828-835.
[3] Kettaneh A, Marcellin P, Douvin C, et al. Features associated with success rate andperformance of FibroScan measurements for the diagnosis of cirrhosis in HCV patients: a
prospective study of 935 patients. J Hepatol 2007; 46: 628-634.[4] Boursier J, Konate A, Guilluy M, et al. Learning curve and interobserver reproducibility
evaluation of liver stiffness measurement by transient elastography. Eur. J. Gastroenterol.Hepatol 2008; 20: 693701.
[5] Foucher J, Castera L, Bernard PH, et al. Prevalence and factors associated with failure ofliver stiffness measurement using FibroScan in a prospective study of 2114 examinations.Eur J Gastroenterol Hepatol 2006; 18: 411-412.
[6] irli R, Sporea I, Deleanu A, et al. Factors associated with failure of Liver Stiffnessmeasurement using Transient Elastography. Timisoara Med J2009: 49; 34-38.
[7] Coco B, Oliveri F, Maina AM, et al. Transient elastography; a new surrogate marker ofliver fibrosis influenced by major changes of transaminases. J Viral Hepat 2007; 14: 360-369.
[8] Vigan M, Massironi S, Lampertico P, et al. Transient elastography assessment of the liverstiffness dynamics during acute hepatitis B. Eur J Gastroenterol Hepatol 2010; 22: 180-184.
[9] Chan HL, Wong GL, Choi PC, et al. Alanine aminotransferase-based algorithms of liverstiffness measurement by transient elastography (Fibroscan) for liver fibrosis in chronic
hepatitis B. J Viral Hepatol 2009; 16: 36-44.[10] Sagir A, Erhardt A, Schmitt M, et al. Transient elastography is unreliable for detection of
cirrhosis in patients with acute liver damage. Hepatology 2008; 47: 592-595.
[11] Arena U, Vizzutti F, Corti G, et al. Acute viral hepatitis increases liver stiffness valuesmeasured by transient elastography. Hepatology 2008; 47: 380-384.
[12]
Millonig G, Friedrich S, Adolf S, et al. Liver stiffness is directly influenced by centralvenous pressure. J Hepatol 2010; 52: 206-210.
[13] Millonig G, Reimann FM, Friedrich S, et al. Extrahepatic cholestasis increases liverstiffness (FibroScan) irrespective of fibrosis. Hepatology 2008; 48: 1718-1723.
[14] Mederacke I, Wursthorn K, Kirschner J, et al. Food intake increases liver stiffness inpatients with chronic or resolved hepatitis C virus infection. Liver Int2009; 29: 15001506.
[15] Arena U, Vizzutti F, Abraldes JG, et al. Reliability of transient elastography for thediagnosis of advanced fibrosis in chronic hepatitis C. Gut 2008; 57: 12881293.
[16] Wong VW, Vergniol J, Wong GL, et al. Diagnosis of fibrosis and cirrhosis using liverstiffness measurement in nonalcoholic fatty liver disease. Hepatology2010; 51: 454462.
[17] Lupor M, Badea R, Stefnescu H, et al. Analysis of histopathological changes thatinfluence liver stiffness in chronic hepatitis C. Results from a cohort of 324 patients. J
Gastrointestin Liver Dis 2008; 17: 155-163.
[18] Fraquelli M, Rigamonti C, Casazza G, et al. Reproducibility of transient elastography in theevaluation of liver fibrosis in patients with chronic evaluation of liver fibrosis in patients
with chronic liver disease. Gut2007: 56; 968-973.
[19] Nobili V, Vizzutti F, Arena U, et al. Accuracy and reproducibility of transient elastographyfor the diagnosis of fibrosis in pediatric nonalcoholic steatohepatitis. Hepatology2008; 48:
442448.
7/30/2019 Hepatic Ultrasonography
59/130
TE Hepatic Elastography Using Ultrasound Waves 47[20] irli R, Sporea I, Tudora A, et al. Transient elastographic evaluation of subjects without
known hepatic pathology: does age change the liver stiffness? J Gastrointestin Liver Dis
2009; 18: 57-60.[21] Roulot D, Czernichow S, Le Clsiau H, et al. Liver stiffness values in apparently healthy
subjects: influence of gender and metabolic syndrome. J Hepatol 2008; 48: 606 -613.
[22] Corpechot C, El Naggar A, Poupon R. Gender and liver: is the liver stiffness weaker inweaker sex? Hepatology 2006; 44: 513514.
[23] Kim SU, Choi GH, Han WK, et al. What are true normal liver stiffness values usingFibroScan?: a prospective study in healthy living liver and kidney donors in South Korea.
Liver Int 2010; 30: 268274.
[24] Talwalkar JA. Kurtz DM, Schoenleber SJ, et al. Ultrasound-based transient elastographyfor the detection of hepatic fibrosis: systematic review and meta-analysis. Clin
Gastroenterol Hepatol 2007; 5: 1214-1220.
[25] Friedrich-Rust M, Ong MF, Martens S, et al. Performance of transient elastography for thestaging of liver fibrosis: a meta-analysis. Gastroenterology 2008; 134: 960-974.
[26] CasteraL, Vergniol J, Foucher J, et al. Prospective comparison of transient elastography,FibroTest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C.Gastroenterology 2005; 128: 343-350.
[27] Ziol M, Handra-Luca A, Kettaneh A, et al. Noninvasive assessment of liver fibrosis bymeasurement of stiffness in patients with chronic hepatitis C. Hepatology 2005; 41: 48-54.
[28] Sporea I, irli R, Deleanu A, et al. Comparison of the liver stiffness measurement bytransient elastography with the liver biopsy. World J Gastroenterol 2008; 14: 6513-6517.
[29] Beaugrand M, Ziol M, Marcelin P, et al. Liver stiffness cut off values in HCV patients:validation and comparison in an independent population. Hepatology 2006; 44 (Suppl. 1):
269.[30] irli R, Sporea I, Nicoli D, et al. Are there different values of liver stiffness evaluated by
means of transient elastography in patients with HBV or HCV chronic hepatitis?Gastroenterology 2011:140 (Suppl 1); S-978.
[31] Shaheen AA, Wan AF, Myers RP. FibroTest and FibroScan for the prediction of hepatitisC-related fibrosis: a ystematic review of diagnostic test accuracy. Am J Gastroenterol 2007;102: 25892600.
[32] Tsochatzis EA, Gurusamy KS, Ntaoula S, et al. Elastography for the diagnosis of severityof fibrosis in chronic liver disease: a meta-analysis of diagnostic accuracy. J Hepatol 2011;
54: 650-659.
[33] Castera L, Vergniol J, Foucher J, et al. Prospective comparison of transient elastography,FibroTest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C.
Gastroenterology 2005; 128: 343-350.
[34] Castera L, Sebastiani G, Le Bail B, et al. Prospective comparison of two algorithmscombining non-invasive methods for staging liver fibrosis in chronic hepatitis C. J Hepatol.
2010; 52: 191-198.
[35] Sporea I, irli R, Popescu A, et al. Is it better to use two elastographic methods for liverfibrosis assessment? World J Gastroenterol 2011; 17: 3824-3829.
[36] Hzode C, Castera L, Roudot-Thoraval F, et al. Liver stiffness diminishes with antiviralresponse in chronic hepatitis C. Aliment Pharmacol Ther 2011; 34: 656-663.
[37] Andersen ES, Moessner BK, Christensen PB, et al. Lower liver stiffness in patients withsustained virological response 4 years after treatment for chronic hepatitis C. Eur J
Gastroenterol Hepatol 2011; 23: 41-44.
7/30/2019 Hepatic Ultrasonography
60/130
48 Hepatic Elastography Using Ultrasound Waves Sporea andirli
[38] Ogawa E, Furusyo N, Toyoda K, et al. The longitudinal quantitative assessment bytransient elastography of chronic hepatitis C patients treated with pegylated interferon
alpha-2b and ribavirin. Antiviral Res 2009; 83: 127-134.[39] Wang JH, Changchien CS, Hung CH, et al. Liver stiffness decrease after effective antiviral
therapy in patients with chronic hepatitis C: Longitudinal study using FibroScan. J
Gastroenterol Hepatol 2010; 25: 964-969.
[40] Ogawa E, Furusyo N, Toyoda K, et al. Transient elastography for patients with chronichepatitis B and C virus infection: Non-invasive, quantitative assessment of liver fibrosis.
Hepatology Research 2007; 12: 1002-1010.
[41] Marcellin P, Ziol M, Bedossa P, et al. Non-invasive assessment of liver fibrosis by stiffnessmeasurement in patients with chronic hepatitis B. Liver Int 2009 ; 29: 242-247.
[42] Sporea I, irli R, Deleanu A, et al. Liver stiffness measurements in patients with HBV vs.HCV chronic hepatitis: a comparative study. World J Gastroenterol 2010 14; 16: 4832-
4837.
[43] Cardoso AC, Carvalho-Filho RJ, Stern C, et al. Direct comparison of diagnosticperformance of transient elastography in patients with chronic hepatitis B and chronichepatitis C. Liver Int 2011 Nov 22. doi: 10.1111/j.1478-3231.2011.02660.x. [Epub ahead
of print].
[44] Cho HJ, Seo YS, Lee KG, et al. Serum aminotransferase levels instead of etiology affectsthe accuracy of transient elastography in chronic viral hepatitis patients. J Gastroenterol
Hepatol 2011; 26: 492-500.
[45] Wong GL, Wong VW, Choi PC, et al. Increased liver stiffness
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