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Elastografía Hepática

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Elastografía Hepática

  1. 1. 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
  2. 2. Bentham Science Publishers Executive Suite Y - 2 PO Box 7917, Saif Zone Sharjah, U.A.E. subscriptions@benthamscience.org Bentham Science Publishers P.O. Box 446 Oak Park, IL 60301-0446 USA subscriptions@benthamscience.org Bentham Science Publishers P.O. Box 294 1400 AG Bussum THE NETHERLANDS subscriptions@benthamscience.org Please read this license agreement carefully before using this eBook. Your use of this eBook/chapter constitutes your agreement to the terms and conditions set forth in this License Agreement. Bentham Science Publishers agrees to grant the user of this eBook/chapter, a non- exclusive, nontransferable license to download and use this eBook/chapter under the following terms and conditions: All content available in this eBook is licensed under the terms of the Creative Commons Attribution non-commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided that the work is properly cited. Warranty Disclaimer: The publisher does not guarantee that the information in this publication is error-free, or warrants that it will meet the users’ requirements or that the operation of the publication will be uninterrupted or error-free. This publication is provided "as is" without warranty of any kind, either express or implied or statutory, including, without limitation, implied warranties of merchantability and fitness for a particular purpose. The entire risk as to the results and performance of this publication is assumed by the user. In no event will the publisher be liable for any damages, including, without limitation, incidental and consequential damages and damages for lost data or profits arising out of the use or inability to use the publication. The entire liability of the publisher shall be limited to the amount actually paid by the user for the eBook or eBook license agreement. Limitation of Liability: Under no circumstances shall Bentham Science Publishers, its staff, editors and authors, be liable for any special or consequential damages that result from the use of, or the inability to use, the materials in this site. eBook Product Disclaimer: No responsibility is assumed by Bentham Science Publishers, its staff or members of the editorial board for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products instruction, advertisements or ideas contained in the publication purchased or read by the user(s). Any dispute will be governed exclusively by the laws of the U.A.E. and will be settled exclusively by the competent Court at the city of Dubai, U.A.E. You (the user) acknowledge that you have read this Agreement, and agree to be bound by its terms and conditions.
  3. 3. 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
  4. 4. 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
  5. 5. 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
  6. 6. 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.
  7. 7. 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
  8. 8. 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).
  9. 9. 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
  10. 10. 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
  11. 11. 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;
  12. 12. 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
  13. 13. 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
  14. 14. 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
  15. 15. 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
  16. 16. 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
  17. 17. 6 Hepatic Elastography Using Ultrasound Waves Ioan Lie standard US examination, although they are much more rigid than the tissues they are embedded into. In diffuse diseases such as liver cirrhosis, a significant increase in tissue stiffness is characteristic, but it may occur normally in a conventional US examination. Because tissue echogenity and stiffness are generally uncorrelated, it is expected that mapping tissue stiffness or elasticity, should provide new information on pathological tissues’ structure. 2. PHYSICAL FUNDAMENTALS OF ELASTOGRAPHY Elasticity is the physical property of materials to return to their original shape after removing the force that caused the deformation. For small deformations, most materials show linear elasticity, i.e. a linear dependence between stress (force per unit area) and relative deformation (relative change). This dependence is known as Hooke's law. A complementary concept of elasticity is stiffness, which is a measure of the resistance opposed by an elastic material to deformation. The elasticity modulus describes mathematical, elastic deformation tendency of an object or material. The elasticity modulus of a material is defined as a slope of the curve describing the dependence between mechanical stress and deformation, considering the elastic deformation region of the curve. As the material is more rigid, it will have a higher modulus. Depending on how the mechanical stress is applied and how the deformation is measured, several types of elasticity modules are defined. The most important are: - Young's modulus (E) - this describes the deformation tendency of 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
  18. 18. Elastography: Physics Hepatic Elastography Using Ultrasound Waves 7 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.
  19. 19. 8 Hepatic Elastography Using Ultrasound Waves Ioan Lie 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.
  20. 20. Elastography: Physics Hepatic Elastography Using Ultrasound Waves 9 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].
  21. 21. 10 Hepatic Elastography Using Ultrasound Waves Ioan Lie 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
  22. 22. Elastography: Physics Hepatic Elastography Using Ultrasound Waves 11 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
  23. 23. 12 Hepatic Elastography Using Ultrasound Waves Ioan Lie 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
  24. 24. Elastography: Physics Hepatic Elastography Using Ultrasound Waves 13 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
  25. 25. 14 Hepatic Elastography Using Ultrasound Waves Ioan Lie conventional systems. To solve this limitation, elastography dedicated hardware architectures have been designed. Depending on how shear waves are generated, three types of US elastography systems have been implemented. 6. INDUCTION OF SHEAR WAVES USING AN EXTERNAL ACTUATOR – TRANSIENT ELASTOGRAPHY This method uses an external actuator to produce low-frequency vibrations with frequencies in the 50-500 Hz range [9, 10]. The solution used in the "FibroScan" commercialized by Echosens, France, combines the actuator and the ultrasonic transducer in the same probe [4, 11-15]. Induced shear waves propagate 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.
  26. 26. 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 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].
  27. 27. 16 Hepatic Elastography Using Ultrasound Waves Ioan Lie The Siemens systems, Acuson S2000, implement both the strain and the shear wave elastography based on acoustic radiation force [21]. Principle of Acoustic Radiation Force Impulse ARFI imaging involves transmission of an initial ultrasonic pulse at diagnostic intensity levels, to obtain a baseline signal for later comparison. A short duration, high-intensity acoustic "pushing pulse" is then transmitted by the same transducer, followed by a series of diagnostic intensity pulses, which are used to track the displacement of the tissue caused by the pushing pulse [17, 22, 23]. The tissue response to the radiation force is observed using conventional B-mode imaging pulses, and it is possible to display the quantitative shear-wave velocity (Vs; m/s) of ARFI displacement. This velocity (m/s) is proportional to the square root 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
  28. 28. Elastography: Physics Hepatic Elastography Using Ultrasound Waves 17 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.
  29. 29. 18 Hepatic Elastography Using Ultrasound Waves Ioan Lie Figure 5: Virtual Touch Tissue Imaging utilizes acoustic push pulses (orange) and tracking beams (green arrow), sequenced across a user-defined region of interest, to generate an elastogram depicting the relative stiffness of tissue – from [21]. ARFI Elastography – Quantitative Approach ARFI technology allows a quantitative assessment of tissue elasticity based on shear wave velocity measurement. An appropriate application is "Virtual Touch Tissue Imaging" made by Siemens [21]. According to the equation (4) shear wave velocity is directly proportional to the square modulus of elasticity. Therefore, by measuring the shear wave velocity, we obtain a direct characterization of the elastic properties of the tissue. Shear waves are generated and propagate perpendicular to the disturbing pulse. Unlike longitudinal ultrasonic waves used in conventional investigation, shear waves do not interact with the transducer. They are attenuated more than 10,000 times faster than conventional waves and therefore require a more sensitive measurement. Displacements generated by the shear wave propagation through tissue can be detected using ultrasonic beams which scan the ROI. Shear wave velocity arises from the determination of the shear wave front position and its correlation with the time elapsed between consecutive measurements (Fig. 6).
  30. 30. Elastography: Physics Hepatic Elastography Using Ultrasound Waves 19 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].
  31. 31. 20 Hepatic Elastography Using Ultrasound Waves Ioan Lie Shear Wave Initiation Shear waves induced in the region of interest must be ample enough so that 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).
  32. 32. Elastography: Physics Hepatic Elastography Using Ultrasound Waves 21 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
  33. 33. 22 Hepatic Elastography Using Ultrasound Waves Ioan Lie typical US pulse is made of 400 oscillations at 4.3 MHz. This corresponds to a “pushing time” of 100 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.
  34. 34. Elastography: Physics Hepatic Elastography Using Ultrasound Waves 23 REFERENCES [1] Douglas C. Ultrasonic Bioinstrumentation John Wiley & Sons 1988. [2] Y C Fung Biomechanics. Circulation Second Edition Springer 1996. [3] Sandrin L, Oudry J, Bastard C, et al. Non-Invasive Assessment of Liver Fibrosis by Vibration-Controlled Transient Elastography (Fibroscan) Liver Biopsy, 2011; 7, pp. 293- 314. [4] Sarvazyan AP, Rudenko OV, Swanson SD, et al. Shear wave elasticity imaging: a new ultrasonic technology of medical diagnostics. Ultrasound Med Biol 1998; 24: 1419–35. [5] Hoskins PR. Principles of ultrasound elastography. Ultrasound 2012; 20: 8-15. [6] Ophir J, Cespedes I, Ponnekanti H, et al. A quantitative method for imaging the elasticity of biological tissues. Ultrasonic Imag 1991; 13: 111-134. [7] Konofagou EE, et al. Elastography: From theory to clinical applications, Summer Bioengineering Conference, June 25-29, Florida, 2003. [8] Ophir J, et al. Elastography: Imaging the Elastic Properties of Soft Tissues with Ultrasound. J Med Ultrasonics, Vol. 29, 2002. [9] Greenleaf, JF, et al. Selected Methods for Imaging Elastic Properties of Biological tissues, Ann Revi Biomed Eng, 2003; 5: 57-58. [10] Ophir J, Alam SK, Garra B, et al. Elastography: ultrasonic estimation and imaging of the elastic properties of tissues. J Eng Med 1999; 213: 203–233. [11] Sandrin L, Fourquet B, Hasquenoph JM, et al. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol 2003; 29: 1705-1713. [12] Ziol M, Handra-Luca A, Kettaneh A, et al. Non-invasive assessment of liver fibrosis by stiffness measurements: a prospective multicenter study in patients with chronic hepatitis C. Hepatology 2005; 41: 48-54. [13] Sandrin L, Tanter M, Catheline S. et al. Shear modulus imaging with 2D transient elastography, IEEE Trans Utrasoni Ferroelectr Freq Control 2002; 49: 426-435. [14] Sandrin L, Tanter M, Gennisson JL, et al. Shear elasticity probe for soft tissues with 1-D transient elastography, IEEE Trans Ultrason Ferroelectr Freq Control 2002; 49: 436-446. [15] Castera L, Vergniol J, Foucher J, et al. Prospective comparison of transient elastography, Fibrotest, APRI and liver biopsy for the assessement of fibrosis in chronic hepatitis C, Gastroenterology 2005; 128: 343-350. [16] Sandrin L, Cassereau D, Fink M. The role of the coupling term in transient elastography. J Acous Soc Am 2004; 115: 73-83. [17] Nightingale KR, Palmeri ML, Nightingale RW, et al. On the feasibility of remote palpation using acoustic radiation force. J Acoust Soc Am 2001; 110: 625–634. [18] Nightingale K, McAleavey S, Trahey G. Shear-wave generation using acoustic radiation force: in vivo and ex vivo results. Ultrasound Med Biol 2003; 29: 1715-1723. [19] Palmeri ML, Wang MH, Dahl JJ, et al. Quantifying hepatic shear modulus in vivo using acoustic radiation force. Ultrasound Med Biol 2008; 34: 546–558. [20] Bercoff J, Tanter M, Fink M. Supersonic shear imaging: A new technique for soft tissue elasticity mapping. IEEE Trans Ultrason Ferroelec Freq Control 2004; 51: 396–409. [21] Lazebnik RS. Tissue Strain Analytics Virtual Touch Tissue Imaging and Quantification, ACUSON S2000 Ultrasound System, Siemens Medical Solutions, USA, Inc., Ultrasound, Mountain View, CA USA, 2008.
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  36. 36. 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
  37. 37. 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
  38. 38. 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
  39. 39. 28 Hepatic Elastography Using Ultrasound Waves Sporea and Șirli >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
  40. 40. TE Hepatic Elastography Using Ultrasound Waves 29 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
  41. 41. 30 Hepatic Elastography Using Ultrasound Waves Sporea and Șirli 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].
  42. 42. TE Hepatic Elastography Using Ultrasound Waves 31 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
  43. 43. 32 Hepatic Elastography Using Ultrasound Waves Sporea and Șirli 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.
  44. 44. TE Hepatic Elastography Using Ultrasound Waves 33 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).
  45. 45. 34 Hepatic Elastography Using Ultrasound Waves Sporea and Șirli 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].
  46. 46. TE Hepatic Elastography Using Ultrasound Waves 35 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
  47. 47. 36 Hepatic Elastography Using Ultrasound Waves Sporea and Șirli 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
  48. 48. TE Hepatic Elastography Using Ultrasound Waves 37 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
  49. 49. 38 Hepatic Elastography Using Ultrasound Waves Sporea and Șirli 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].
  50. 50. TE Hepatic Elastography Using Ultrasound Waves 39 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
  51. 51. 40 Hepatic Elastography Using Ultrasound Waves Sporea and Șirli <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].
  52. 52. TE Hepatic Elastography Using Ultrasound Waves 41 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
  53. 53. 42 Hepatic Elastography Using Ultrasound Waves Sporea and Șirli 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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