Hepatic Ultrasonography

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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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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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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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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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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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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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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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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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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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[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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>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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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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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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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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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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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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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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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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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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