Elastografía Hepática

Hepatic Elastography Using
Ultrasound Waves
Edited By
Ioan Sporea and Roxana Șirli
Department of Gastroenterology and Hepatology
“Victor Babeș”
University of Medicine and Pharmacy Timișoara
Romania

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CONTENTS
About the Authors i
Foreword vi
Preface viii
List of Contributors x
CHAPTERS
1. Physics and Technical Information 3
Ioan Lie
2. Transient Elastography (TE) 25
Ioan Sporea and Roxana Șirli
3. Acoustic Radiation Force Impulse (ARFI) Elastography 52
Simona Bota and Ioan Sporea
4. Real-Time Elastography (RT-E) 85
Ioan Sporea and Alina Popescu
5. Shear Wave Elastography (SWE) 96
Alina Popescu and Ioan Sporea
6. Combined Methods for Liver Fibrosis Evaluation 103
Ioan Sporea and Simona Bota
7. Elastography in Focal Liver Lesions 107
Ana Jurchiș
Index 118

i
ABOUT THE AUTHORS
IOAN SPOREA
Ioan Sporea is a Professor of Gastroenterology, PhD, Head of the Department of
Gastroenterology and Hepatology of the “Victor Babeș” University of Medicine
and Pharmacy Timișoara. He is a senior attendant of Gastroenterology and
Internal Medicine, working in the Gastroenterology and Hepatology of the
“Victor Babeș” University of Medicine and Pharmacy Timișoara. He is an expert
in general ultrasonography, according to the multilevel classification of SRUMB.
He is Past President of the Romanian Society of Ultrasound in Medicine and
Biology (SRUMB). During 1999-2002 he was a member of the Executive Board
of EFSUMB (European Federation of Societies for Ultrasound in Medicine and
Biology), during 1999 - 2005 member in the Educational Committee of
EFSUMB, and between 2007-2011 he was Honorary Treasurer of this society. He
is the Director of the WFUMB (World Federation of Ultrasound in Medicine and
Biology) Center of Excellence Timișoara. He is President Elect of the Romanian
Society of Gastroenterology and Hepatology. As a coordinator of the Ultrasound
Learning Center of the “Victor Babeș” University of Medicine and Pharmacy
Timișoara he contributed to the education of more than 1,200 MDs in the field of
ultrasound. He coordinated several courses and scientific sessions in Romania and
abroad, mainly regarding gastroenterology and ultrasound. He is a member of

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 Babeș” University of Medicine
and Pharmacy Timișoara. She is a senior attendant in Internal Medicine, specialist
in Gastroenterology, working in the Gastroenterology and Hepatology
Department of the “Victor Babeș” University of Medicine and Pharmacy
Timișoara. 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 of
the 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 Timișoara, also a faculty member of the

iii
Ultrasound Learning Center of UMF Timișoara. 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 Babeș” University of Medicine and Pharmacy Timișoara.
She is a senior attendant in Internal Medicine, specialist in Gastroenterology,
working in the Gastroenterology and Hepatology Department of the “Victor Babeș”
University of Medicine and Pharmacy Timișoara. 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 Timișoara,
also a faculty member of the Ultrasound Learning Center of UMF Timișoara. She is
a 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.

iv
IOAN LIE
Ioan Lie is an Associate Professor in the Faculty of Electronics and
Telecommunications, “Politehnica” University of Timișoara, Romania. He
received the Engineering Degree in applied electronics from “Politehnica”
University of Timișoara in 1986. For his work on “Optimization of methods and
electronic equipments for ultrasound investigation”, he received the Ph.D. degree
in electronics engineering from the “Politehnica” University of Timișoara in 2006.
His current research interests include methods and implementations for ultrasonic
measurement and testing, programmable logic systems, automatic test equipments
for automotive and avionics, hardware and software solutions for transit-time
ultrasonic flow meters, AMR (Automatic Meter Reading) and RFID.
SIMONA BOTA
Born on the 09th
of June 1982, graduate of the University of Medicine and
Pharmacy “Victor Babeș” from Timișoara, Romania in 2006. From 2007 she is a

v
fellow in Gastroenterology and Hepatology and from 2009 PhD student in the
field of Gastroenterology (ARFI elastography). She presented at National and
International Meetings, as first author or co-author, more than 200 abstracts. At
the EUROSON Meeting 2010 in Copenhagen, she received the fist prize for
poster presentention. Also, she won several bursaries to participate at International
Ultrasound and Gastroenterology Meetings. She published as first author or co-
author 11 articles related to elastography available in Pubmed.
JURCHIȘ ANA-ROXANA
Born on the 14th
of May 1985, graduate of the “Victor Babeș” University of
Medicine and Pharmacy from Timișoara, Romania in 2009. Starting from 2010
she is a fellow in Gastroenterology and from 2011 a PhD student in the field of
Gastroenterology (Tumor Elastography).

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 80’s 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 poorly
known 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

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

viii
PREFACE
Liver chronic diseases become more and more frequent in daily medical practice,
despite of medical progress in the treatment of chronic viral hepatitis. The
incidence of diseases such as non-alcoholic steato-hepatitis (NASH) or alcoholic
steato-hepatitis (ASH) increases in many regions of the world (especially in
Europe and the USA), but the evaluation of chronic hepatitis HCV or HBV still
represents a major challenge for the hepatologist, internal medicine or general
practitioner. The evaluation of cholestatic diseases, of autoimmune hepatitis or of
post-transplant patients is another field in which hepatologists try to find
solutions.
Traditionally, liver biopsy is used for chronic liver diseases staging and grading,
but this method is not very well accepted by patients and usually it is rarely
repeated during the follow-up. In the last years, non-invasive modalities for the
evaluation of chronic hepatopathies became more and more popular, especially in
Europe. Blood tests and elastographic methods for liver stiffness assessment
become part of routine evaluation of patients with chronic liver diseases.
Ultrasound based elastographic methods for the evaluation of liver stiffness
started with Transient Elastography, but in the last 2-3 years, other methods that
use ultrasound waves opened the door of hepatology. Acoustic Radiation Force
Impulse Elastography, Real Time Elastography or Shear Wave Elastography are
now available, trying to prove their value for liver stiffness assessment as a
marker for fibrosis or for the evaluation of liver masses in the liver.
Thus, so much new information concerning the non-invasive evaluation of liver
fibrosis or of liver masses, in such a short time, can make the practician to have
some problems concerning these methods, such as the types of waves used, or the
results of the examination, that can be expressed in kiloPascals or in
meters/second, with a large values spectrum.
In this eBook we try to clarify some notions regarding elastography, which we
think that will be useful for practitioners (fellows in training or specialists): what
is transient elastography or shear waves elastography, from physics point of view;

ix
how do different types of elastography work and which are the differences
between them; and, finally, which is their practical value (scientific proves)
methods. Surely, this field is a very dynamic one, and each month papers are
published showing new results of these methods.
Thus, the aim of this eBook is to show how ultrasound wave based elastographic
methods work and which their results in the field of hepatology are. We hope that
the level of presentation (especially information regarding the physics of
elastography) is adapted to the medical personnel, making this eBook useful for
daily practice of everyone interested in this field.
Ioan Sporea
Roxana Șirli
Department of Gastroenterology and Hepatology
“Victor Babeș” University of Medicine and Pharmacy Timișoara
Romania

x
List of Contributors
Simona Bota, MD, fellow in Gastroenterology, Department of Gastroenterology
and Hepatology, “Victor Babeș” University of Medicine and Pharmacy
Timișoara, Romania 10, Iosif Bulbuca Bv, 300736, Timișoara Romania
E-mail: bota_simona1982@yahoo.com
Ana Jurchiș, MD, fellow in Gastroenterology, Department of Gastroenterology
and Hepatology, “Victor Babeș” University of Medicine and Pharmacy
Timișoara, Romania 10, Iosif Bulbuca Bv, 300736, Timișoara Romania
E-mail: ana.jurchis@yahoo.com
Ioan Lie, PhD, Assoc. Prof., Applied Electronics Department, Electronics and
Telecomunications Faculty, “Politehnica” University Timișoara 2, Vasile Pârvan
Bv, 300223 Timișoara Romania
E-mail: ioan_lie@yahoo.com
Alina Popescu, MD, PhD, Assoc. Prof. of Gastroenterology, Department of
Gastroenterology and Hepatology, “Victor Babeș” University of Medicine and
Pharmacy Timișoara, Romania 10, Iosif Bulbuca Bv, 300736, Timișoara Romania
E-mail: alinamircea.popescu@gmail.com
Ioan Sporea, MD, PhD, Prof., Head of the Department of Gastroenterology and
Hepatology, “Victor Babeș” University of Medicine and Pharmacy Timișoara,
Romania 10, Iosif Bulbuca Bv, 300736, Timișoara Romania
E-mail: isporea@umft.ro
Roxana Șirli, MD, PhD, Assist. Prof. of Gastroenterology, Department of
Gastroenterology and Hepatology, “Victor Babeș” University of Medicine and
Pharmacy Timișoara, Romania 10, Iosif Bulbuca Bv, 300736, Timisoara Romania
E-mail: roxanasirli@gmail.com

Hepatic Elastography Using Ultrasound Waves, 2012, 3-24 3
Ioan Sporea and Roxana Șirli (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 Timișoara 2, Vasile Pârvan Bv, 300223 Timișoara
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 system’s 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 and
Telecommunications Faculty, “Politehnica” University Timișoara 2, Vasile Pârvan Bv, 300223 Timișoara
Romania; E-mail: ioan_lie@yahoo.com

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 system’s 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 target
volume 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 (60-100
dB). 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

Elastography: Physics Hepatic Elastography Using Ultrasound Waves 5
high 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

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 an
object 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 shape
and keep its volume, when mechanical stress is achieved by opposing
forces placed in parallel planes.
- The bulk modulus (K) - describes volumetric elasticity or an object’s
tendency to deform in all directions, when it supports mechanical
stress in all directions. It is defined as the ratio between the force per

unit 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.
Lamé's first parameter denoted by λ, expresses the relationship between the bulk
modulus and the shear modulus. The second parameter of Lamé, noted μ
(formerly G) is the shear modulus.
The relationship between the Young’s modulus E, the Poisson coefficient υ and
the Lamé parameters λ and μ, 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
λ >> μ leads to a value of Poisson ratio υ ≈ 0.5, which characterizes the quasi-
incompressible medium. In these conditions a simple relationship between
longitudinal and shear modules is established.

E = 3·G (2)
One way of assessing tissue elasticity is based on measuring the propagation
velocity 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 (ρ)
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
K
V

 (3a)
When the material is subjected to shear forces, shear waves will propagate
through it, which will produce material deformation perpendicular to the force’s
direction. Shear waves propagate at a speed given by the equation:
S
G
V

 (3b)
Because the elasticity module’s 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, ρ:
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.

The 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 dynamic
deformation, or
- By measuring the shear waves’ propagation velocity and indirect
determination 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 approaches strain elastography 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 as
compared to the rigid one. The rigid spring is mechanically less elastic; thereby
producing less displacement vis-à-vis the less rigid spring, which deforms more
due to the same force [5].

Elastography is an analogue to the spring example, tissues generally having
varying mechanical properties [2]. When subjected to similar forces, tissues with
higher elastic modulus deform less, as compared to tissues with lower elastic
modules.
Figure 2: Measurement of strain in a one-dimensional cascaded system of unequal spring
constants. a) Pre-compression state b) Post-compression state. The strain in the softer springs
depends on the presence of the stiff spring [6].
Using cross correlation function, one can measure such deformation (strain) and
knowing the applied force (stress), one can estimate the elastic modules. Fig. (3)
shows a schematic representation of the time delay and strain computation process.
Figure 3: Left: The principle of Elastography - The tissue is insonated a) before and b) after a
small uniform compression. In harder tissues (e.g. the circular lesion depicted) the echoes will be
less distorted than in the surrounding tissues, denoting thus smaller strain [7]; Right: A schematic
showing the process of computing the strain in a tissue segment. Congruent windowed segments

of 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 elastic
deformation 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 echo
signals 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 be
classified, 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

using optical techniques, ultrasound or magnetic resonance. The difficulty of the
method comes from the necessity of knowing the conditions at the border of the
investigated region. Dynamic methods consist of the application of time-varying
stresses, which are associated with wave propagation. This phenomenon is
described by a wave equation, which has a local differential form. Both static and
dynamic excitation is feasible using ultrasound radiation force.
Depending on the spatial characteristics, excitation methods can be external or
internal. When using external excitation, tissue deformation occurs due to the
action of a compressive force that is applied directly on the skin. The request is
produced using mechanical means such as a plate that holds down the skin (static
version) or a device for tissue vibration (dynamic version). Internal methods
consist of internal excitation, directly within the tissue region of interest. For
internal excitation, biological sources are often used, such as breathing or
cardiovascular pulsation. Deformation measurement is based on ultrasonic
methods using Doppler techniques or pulse echo measurement [7, 9].
After measuring the deformation, an image is generated, usually in color, which is a
relative assessment of tissue elasticity. Representation is based on the inverse
proportionality between stiffness and deformation: the larger the displacement, the softer
the tissue. Although highly useful in identifying structures in radiological techniques,
such methods do not allow the quantitative assessment of tissue stiffness [5].
5. BACKGROUND OF QUANTITATIVE (SHEAR WAVES)
ELASTOGRAPHY
Quantitative elastography is based on shear waves production, tracking and
detection. Biological environments allow propagation of two types of waves:
longitudinal and shearing. For longitudinal waves the direction of particles
oscillation coincides with the propagation direction of the wave front. In the case
of the shear wave, particle the oscillation occurs perpendicular to the direction of
propagation. According to the equation (4) to determine the elasticity modulus is
to measure the shear waves propagation velocity [3].
Quantitative elastography techniques provide high resolution quantitative
information about tissue elasticity, as an evaluation technique or often as a region

of interest. For this purpose, complex equipment is used, to generate shear waves
and to make high-resolution measurements of their propagation velocity.
Quantitative elastography techniques are divided into two groups according to
how the shear waves are generated: by mechanical vibration or using acoustic
radiation force. The shear wave frequency content may also be different:
harmonic or transient.
In transient elastography techniques, the shear wave results from a transient tissue
excitation. This type of excitation does not allow the occurrence of reflections or
interferences into the tissue. On the other hand, shear waves produced this way
transit the region of interest in tenths of a millisecond, which requires the use of
ultra-fast ultrasonic techniques for shear wave motion tracking through the
medium. Harmonic techniques using fixed frequency harmonic vibrations do not
impose these restrictions, but are susceptible to interference and reflections.
The steps in the estimation of Young’s modulus in shear wave elastography are [5]:
1. Induce shear waves;
2. Track shear wave’s propagation through the tissues;
3. Estimate Young’s modulus using the equation (4).
As the shear waves travel through the tissue, there is local tissue displacement.
The local displacements cause changes in the echo pattern with time, which may
be monitored using A-line correlation techniques.
The equipment used to track the shear waves must satisfy certain temporal
constraints. Thus if the investigation depth is 5 cm and the shear wave velocity
has a maximum value of 10 ms-1
, a propagation delay time of 5 ms results when
shear waves propagate in the direction of the US beam tracker. On the other hand,
for accurately tracking the shear wave position, the acquisition of several lines in
the same direction is required. If 20 lines are acquired, a period of line repetition
of 250uS or pulse repetition frequency (PRF) of 4000 Hz is needed. For elasticity
assessment only in one direction, these constraints are easy to meet, but to build
an image of several lines requires PRF values that cannot be obtained by

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 through
the 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.

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 symmetry
considerations 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 with
the 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].

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 of
tissue 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 by
conventional 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) US
beam 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

observe 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 of
elementary 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.

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).

A 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 wave’s 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 are
used 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].

Shear Wave Initiation
Shear waves induced in the region of interest must be ample enough so that their
propagation 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 from
multiple 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 waves
typically 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).

So 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

typical US pulse is made of 400 oscillations at 4.3 MHz. This corresponds to a
“pushing time” of 100 μs.
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 Young’s 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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Hepatic Elastography Using Ultrasound Waves, 2012, 25-51 25
Ioan Sporea and Roxana Șirli (Eds)
All rights reserved-© 2012 Bentham Science Publishers
CHAPTER 2
Transient Elastography (TE)
Ioan Sporea and Roxana Șirli*
Department of Gastroenterology and Hepatology, “Victor Babeș“ University of
Medicine and Pharmacy, 10, Iosif Bulbuca Bv, 300736, Timișoara, 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, the
difference 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
F≥2 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 AUROC’s 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 AUROC’s 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 Hooke’s law, which
characterizes a material’s 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 Șirli: Department of Gastroenterology and Hepatology, “Victor
Babeș“ University of Medicine and Pharmacy, 10, Iosif Bulbuca Bv, 300736, Timișoara, Romania;
E-mail: roxanasirli@gmail.com

26 Hepatic Elastography Using Ultrasound Waves Sporea and Șirli
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

TE Hepatic Elastography Using Ultrasound Waves 27
right 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 75th
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 considered failed if 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 the
training 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

>50 years (OR 4.0) and steatohepatitis (OR 3.4). Failure to obtain VM was not
operator dependent and was not associated with the patient’s 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

was 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 kPa
within 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 1–2 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 Lupşor et al., the univariant regression analysis
demonstrated that fibrosis (R
2
=0.610, p<0.0005), activity (R
2
=0.145, p<0.0005)
and steatosis (R
2
=0.037, p<0.002) were correlated with LS. In multiple regression
analysis, all three variable independently influenced LS: fibrosis (p<0.0005),
activity (p=0.039) and steatosis (p=0.025) [17].
Several studies investigated TE reproducibility. The intraobserver and
interobserver agreements were good, with intraclass correlation coefficients
generally above 90%; 0.98 in a study by Fraquelli et al. [18], 0.96 in the Nobili
study [19].
3. TE IN NORMAL SUBJECTS
In a study published by our group [20], 152 healthy subjects were evaluated. In 8
cases (5.3%), valid measurements (VM) could not be obtained. In the 144

subjects, in whom VMs were obtained, the mean LS value was 4.8±1.3 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 (4.6±1.2 kPa vs. 5.1±1.2 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 4.8±1.3 2.3 8.8
18-29 43 5±1.3 2.3 8.8
30-39 24 4.5±1.2 2.6 7.3
40-49 17 5±1.1 3.0 7.1
50-59 27 4.7±1.2 2.5 7.7
60-69 20 5±1.3 3.2 7.7
>70 13 4.7±1.4 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 5.49±1.59 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].

4. 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 method’s 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 6.8–7.6 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<0.001) between the severity of fibrosis and the LS by TE (r=0.57).
This study tried to establish cut-off values for LS that could differentiate between
various stages of fibrosis. Thus, the cut-off value of 7.5 kPa differentiates F0-1
from F2-4 with 67% sensitivity, 87% specificity, 86% PPV and 68% NPV, with a
diagnostic accuracy of 76%. Other studies [26-28] established cut-off values that
differentiate F0-1 from F2-4 ranging from 6.8-7.3 kPa.
As a practical approach, viremic patients with LS lower than 7 kPa should
undergo LB, in order to discover the ones with significant fibrosis underestimated
by FibroScan and who, otherwise, would not receive antiviral therapy. This
strategy is already used in France, a country in which non-invasive evaluation of
chronic C viral hepatitis is used more and more frequently.
TE is not accurate enough to differentiate among contiguous stages of fibrosis
(especially 0, 1 and 2), but is sensitive enough to differentiate between the absence
and mild fibrosis from significant fibrosis, essential for the decision regarding
treatment. At the same time, in the future we must find exactly if histological

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<0.0005), but also with steatosis (r=0.255, p<0.005),
necroinflammatory activity (r=0.378, p<0.0005) and hepatic iron deposition
(r=0.143, p=0.03). The conclusion of this study was that fibrosis is the main
predictor of LS, but that it is also influenced by disease activity and steatosis [17].
In a study by our group that included 407 naive patients with HCV chronic
hepatitis, in which LB and TE were performed in the same session, reliable LS
measurements were obtained in 96.8% of the patients. A significant direct
correlation of LS measurements with fibrosis was found: Spearman’s r=0.605,
P<0.0001. For a cut-off value of 6.8 kPa, LS had 58.9% sensitivity and 89.1
specificity (AUROC 0.760) for predicting significant fibrosis (at least F2
Metavir), while for a cut-off value of 12.6 kPa, the sensitivity was 92.1%, the
specificity 91.6% (AUROC 0.953) for predicting cirrhosis [30].
Considering all these data, TE evaluation of LS in patients with chronic HCV
hepatitis for decisions regarding therapy could be utilised. All these studies showed
that, by using cut-off values of 6.8–7.6 kPa, patients could be identified accurately
enough to decide those who should be treated (F≥2 METAVIR) versus those who
should not be treated (F<2 METAVIR), without performing a LB (Fig. 4).
Finally, several meta-analyses assessed LS measurements by TE as a predictor of
significant fibrosis in patients with HCV hepatitis [24, 25, 31, 32]. In the
Friedrich-Rust meta-analysis, based on 50 studies [25], the mean AUROC was
0.84, with a suggested optimal cut-off of 7.6 kPa. In the Tsochatzis meta-analysis,
the pooled cut-off for F≥2 Metavir was also 7.6 kPa (range 5.1–10.1), with 0.78
pooled sensitivity and 0.89 pooled specificity [32].
Combining FibroScan with serum fibrosis markers can further improve the
diagnostic accuracy of non-invasive liver fibrosis measurement [33-35] and
different algorithms have been suggested.

Figure 4: Correlation between liver fibrosis and TE measurements.
Several studies suggested that TE may be used for the evaluation of antiviral
therapy results in HCV patients. In a study published in 2011, Hezode et al.
prospectively evaluated 91 patients with chronic HCV hepatitis during the
antiviral therapy. LS was assessed by TE and compared with the virologic
responses at weeks 4, 12, 24, end of treatment and 12 and 24 weeks after. A
significant LS decrease was observed during therapy, which continued after
treatment, only in patients who achieved a sustained virologic response (SVR). In
this group, the median intra-patient decrease relative to baseline at the end of
follow-up was - 3.4 kPa, vs. - 1.8 kPa in the patients who did not achieve an SVR.
In multivariate analysis, only the SVR was associated with long-term LS
improvement (odds ratio: 3.10, p=0.019) [36].
A similar decrease in LS values by TE was observed in other studies performed in
the European [37] and Asian population [38, 39]. All these data support the
conclusion that fibrosis may be reversible in patients with HCV chronic hepatitis,
which achieve SVR following antiviral therapy.
b) TE in Chronic HBV Hepatitis
Published studies concerning the value of LS measurement by means of TE in
patients with HBV chronic hepatitis have shown conflicting results regarding the
cut-off values for different stages of fibrosis (Table 2).

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<0.001) correlated with METAVIR (r=0.65)
fibrosis stage (0.65). The AUROCs for F≥2, F≥3 and F=4 were 0.81, 0.93 and
0.93 respectively. Optimal LS cut-off values were 7.2 and 11.0 kPa for F≥2 and
F=4, respectively, by maximizing the sum of sensitivity and specificity, and 7.2
and 18.2 kPa by maximizing the diagnosis accuracy [41].
Several studies compared the LS values by TE in HCV and HBV patients. A
previously published study of our group [42], performed on a large cohort of
patients (140 subjects with HBV and 317 with HCV chronic hepatitis) showed
that the mean LS values were similar in both groups, for the same stage of fibrosis
(Table 2). A significant direct correlation of LS measurements with fibrosis was
found to exist in HCV patients (Spearman’s correlation coefficient r=0.578,
P<0.0001), as well as in HBV patients (r=0.408, P<0.0001). The correlation was
stronger in HCV than in HBV patients (Fisher’s Z-test, Z=2.210, P=0.0271).
Table 2: Mean LS values, according to fibrosis, in patients with HBV vs. HCV chronic hepatitis.
Category HBV HCV P
No. of
Cases
Mean Values of
LS (kPa)
No. of
Cases
Mean Values of
LS (kPa)
Total cases 140 8.1±4.2 317 8.9±5.2 0.395 (NS)
F=0 1 7.4 5 5.2±0.7 -
F=1 32 6.5±1.9 34 5.8±2.1 0.0889 (NS)
F=2 67 7.1±2 146 6.9±2.5 0.3369 (NS)
F=3 33 9.1±3.6 93 9.9±5 0.7038 (NS)
F=4 7 19.8±8.6 39 17.3±6.1 0.6574 (NS)
In this cohort of 140 chronic HBV infected patients, the mean values for F1, F2,
F3 and F4 were: 6.5 kPa, 7.1 kPa, 9.1 kPa and 19.8 kPa, respectively, similar to
those obtained in the study performed by Marcellin' s group [41].

A 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 F≥2 Metavir was 7 kPa (range 6.9–7.2,
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 F≥2 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

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 F≥2 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
Regarding HCV-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 fibrosis
stage (Kendall tau-b=0.48; P<0.0001). The AUROC of LS measurement was 0.72
for F≥2 (cut-off 5.4 kPa) and 0.97 for F=4 [47]. In the Vegara study, the AUROCs
were 0.87 for significant fibrosis (cut-off 7.2 kPa) and 0.95 for cirrhosis (cut-off 14.6
kPa). To diagnose significant liver fibrosis, a cut-off value of 7.2 kPa was associated
with a positive predictive value of 88% and a negative predictive value of 75% [48].
In a more recent Spanish study, the AUROCs of LS were 0.80 for F>2, 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<0.0001) and histological (0.79, P<0.0001) stages. These correlations were still
found when PBC and PSC patients were analyzed separately. Areas under ROC

curves were 0.92 for F≥2, 0.95 for F≥3 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; P<0.005), the
AUROCs being 0.89 for F>2 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 F≥2
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 can
be 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<0.0001). The AUROCs were: 0.927 for F≥1,
0.865 for F≥2, 0.904 for F≥3, and 0.991 for F4. Only fibrosis stage was correlated
significantly with LS measurement by multiple regression analysis. Lupşor et al.
[58] evaluated 72 consecutive NASH patients LS was correlated with fibrosis
(r=0.661; p<0.0001), steatosis (r=0.435, p<0.0001), ballooning (r=0.385;
p=0.001) and lobular inflammation (r=0.364; p=0.002). In multivariate analysis,
only fibrosis significantly correlated with LS (p<0.0001). Cut-off values were
calculated for predicting each fibrosis stage: 5.3 kPa (AUROC=0.879) for F1, 6.8
kPa (AUROC=0.789) for F2 and 10.4 kPa (AUROC=0.978) for F3. Wong et al.
evaluated TE as a predictor of fibrosis and cirrhosis in NAFLD patients and the
factors associated with discordance between TE and histology in 246 consecutive
patients, who had successful LS measurement and satisfactory liver biopsy
specimens [59]. The AUROCs of TE for F≥3 and F4 were 0.93 and 0.95,
respectively. At a cut-off value of 7.9 kPa, the sensitivity, specificity, and positive
and negative predictive values for F≥3 were 91%, 75%, 52%, and 97%,
respectively. LS was not affected by hepatic steatosis, necroinflammation or body
mass index. Discordance of at least two stages between TE and histology was

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
ρ=0.81, p<0.00001). AUROCs for the detection of >10% 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 observation
interval 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 <50 U/L. The conclusion of this study was that postponing
cirrhosis assessment by TE, during alcohol withdrawal, until GOT decreases to
<100 U/mL, significantly improves the diagnostic accuracy [63].

5. TE FOR THE DIAGNOSIS OF LIVER CIRRHOSIS
If the performances of TE for the differentiation of mild from significant fibrosis
are only moderate, its real value is for the diagnosis of cirrhosis. Data from 9
studies were evaluated by Talwalkar et al. [24] showing that TE has 87% pooled
sensitivity [95% confidence interval (CI): 84–90%)] and 91% pooled specificity
(95% CI: 89–92%) 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 15±4.1 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

<19 kPa are highly predictive for the absence of significant EV (≥ grade 2) [67].
Cut-off values for at least grade 2 EV range from 27.5 [67] to 47.2 kPa [68], while
for esophageal bleeding, one study reported a cut-off value of 62.7kPa [69]. In a
study from 2009, performed on 298 HCV patients (70 with cirrhosis; 25 with EV),
Castera concluded that TE cannot replace upper endoscopy for EV diagnosis,
even if it predicted their presence with 76% sensitivity and 78% specificity [70].
Nguyen-Khac et al. demonstrated that there are different cut-off LS values for
predicting at least grade 2 EV, according to the etiology of cirrhosis [69]. The cut-
offs for predicting significant EV were: 47.2 kPa in alcoholic cirrhosis (84.6%
sensitivity, 63.6% specificity, 44% positive predictive value and 92.5% negative
predictive value, AUROC=0.77) and 19.8 kPa in cirrhotic patients with viral
etiology (88.9% sensitivity, 55.1% specificity, 26.7% positive predictive value,
and 96.4% negative predictive value, AUROC=0.73).
Portal hypertension is best assessed by measuring the hepatic venous pressure
gradient (HVPG), an invasive procedure. In an Italian study on 61 patients, LS
cut-off values of 13.6 kPa and 17.6 kPa predicted significant HVPG of ≥10 and
≥12 mm Hg, with 97% and 94% sensitivity (AUROCs 0.99 and 0.92,
respectively). For predicting the presence of EV, the cut-off was 17.6 kPa, with
90% sensitivity (AUROC 0.76) [71].
The correlation between LS by TE and HVPG was also assessed in a French study
on 150 patients [72]. For a cut-off of 21 kPa, TE accurately predicted significant
portal hypertension (HVPG > 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 2
years 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].

Reiberger et 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 performances
of 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% and
71.3%, respectively, for a cut-off value of 31 kPa, chosen to maximize the sum of
sensitivity and 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: 49.60–60.23). 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 <40 kPa will have
significant EV (NPV 54.9%), and in these cases we recommend endoscopic
evaluation. In patients with LS <17.1 kPa, we cannot recommend endoscopic

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: 51.92±1.56 vs. 35.20±0.91kPa, p<0.0001. For a cut-off value of
50.7 kPa, LS had 53.33% sensitivity and 82.67% specificity, with 82.71% PPV
and 53.66% NPV (AUROC 0.7300, p<0.0001) for predicting esophageal bleeding
[76].
Hepatocellular carcinoma (HCC) is another feared complication of cirrhosis,
being one of the most common causes of death in these patients. Several studies
assessed the predictive value of LS by TE for the presence of HCC. In a study by
Foucher et al., the cut-off values for the presence of grade 2/3 EV, cirrhosis
Child-Pugh B or C, past history of ascites, HCC, and esophageal bleeding were
27.5, 37.5, 49.1, 53.7, and 62.7 kPa, respectively [68]. In a Japanese study LS
values in patients with HCC were significantly higher than in those without HCC
(24.9±19.5 kPa vs. 10.9±8.4 kPa; P<0.0001). Multivariate analysis identified LS
≥12.5 kPa, age ≥60 years, and serum total bilirubin ≥1.0 mg/dL, as significantly
correlated with development of HCC [77]. These data were similar to the ones
from another Japanese study, that proved a significant increase in the risk of
developing HCC that paralleled the increase of LS values, from 16.7 folds when
LS was 10.1-15 kPa, to 20.9 folds when LS was 15.1-20 kPa, to 25.6 folds when
LS was 20.1-25 kPa, and to 45.5 folds when LS was >25 kPa, as compared to
patients with LS values<10 kPa [78].
7. TE IN TRANSPLANTED PATIENTS
It is a known fact that recurrence of HCV infection is a rule in transplanted
patients, with cirrhosis developing in a few years. Several studies proved that TE
could be a valuable tool for assessing the severity of recurrent HCV hepatitis,
following liver transplantation, reducing the need for follow-up liver biopsies [79-
85]. Carrion et al. evaluated 124 transplanted HCV patients, who underwent 169
liver biopsies and LS measurements by TE. For a cut-off value of 8.5 kPa, TE had
90% sensitivity, 81% specificity, 79% negative predictive value, and 92% positive

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