无创肝纤维化检测技术_fibroscan

19 Non-Invasive Assessment of Liver Fibrosis by Vibration-Controlled Transient Elastography (Fibroscan®) Sandrin Laurent1, Oudry Jennifer1, Bastard Cécile1, Fournier Céline1, Miette Véronique1 and Mueller Sebastian2 1Echosens, 2University of Heidelberg, 1France 2Germany 1. Introduction Chronic liver diseases result in fibrosis ultimately leading to cirrhosis, a liver end stage disease with high mortality and life threatening complications such as hepatocellular carcinoma. Thus far, no treatment options exist to cure and stop fibrosis progression except organ replacement by liver transplantation. This clinically unsatisfactory situation justifies the enormous interest in quantifying and monitoring fibrosis progression. Though liver biopsy remains the gold standard for assessing liver fibrosis, non invasive procedures are being developed for many years to overcome its complications (Bravo et al. 2001), sampling error and interobserver variability (Abdi et al. 1979; Bedossa et al. 2003; Cadranel et al. 2001). Fibrosis and activity marker scores based on several blood parameters from a simple blood test have been developed to assess liver fibrosis and activity as obtained by liver biopsy Many efforts have been invested to identify serum markers that allow the diagnosis of cirrhosis from simple blood tests (Poynard et al. 2004). However those scores are indirect and reflect the fibrogenetic activity. Thus they do not correlate with the absolute amount of fibrotic tissue within the liver. It is now well established that fibrosis increases liver stiffness. Liver palpation (Fig. 1) is a routine medical practice that has been used since the beginning of medicine to assess liver stiffness. Though, palpation suffers from major limitations: it is highly subjective, very operator dependent and sometimes even impossible to perform. Recently, quantitative elastography emerged as a means to assess liver fibrosis non-invasively. Nowadays Vibration-Controlled Transient Elastography (VCTE™) is by far the most clinically validated quantitative elastography technique and VCTE™ based device, Fibroscan® (Echosens, France), has emerged as the reference tool for liver stiffness measurement. As a fact, Fibroscan® is more and more used in routine clinical practice as an alternative method to liver biopsy in patients with chronic liver diseases. The chapter is organized as follows: Section 2 covers quantitative elastography; the main quantitative elastography techniques are described with a strong focus on the most clinically validated technique: VCTE™. Fibroscan® device is described in Section 3; the examination www.intechopen.com Liver Biopsy 294 procedure is described. Advantages and limitations of the device are detailed. Applications of VCTE™ in hepatology are described in Section 4. The role of liver stiffness as a clinically relevant parameter will be pointed out. In Section 5, the pressure-stiffness-fibrosis sequence hypothesis is addressed. Eventually, discussion and conclusion are drawn in Section 6 and Section 7, respectively. Fig. 1. Liver hand palpation: “The living are soft and yielding; the dead are rigid and stiff”, Lao Tzu, (6th century BCE). 2. Quantitative elastography 2.1 Elastography techniques It was a matter of time to see the development and emergence of sophisticated techniques such as elastography to quantitatively and non-invasively measure liver stiffness. Elastography is a recent field of research that started in the 80s to propose a reproducible and operator-independent alternative technique to hand palpation. Elastography techniques may be divided into two groups: qualitative elastography and quantitative elastography. Qualitative elastography is now widely available on ultrasound scanners, it provides a qualitative color image that gives an interpretation of stiffness without providing any number. Basically, while the operator moves the ultrasound transducer at the skin surface of the body, the scanner measures the quasi static displacements within the tissues. A map representing the inverse of the displacement is displayed usually in color: the larger the displacement, the softer the tissue. While this technique may be helpful in radiology to identify focal lesions, it is definitively not adapted to quantify stiffness. Quantitative elastography techniques rely on the use of low frequency shear waves. Indeed the velocity of these mechanical waves is directly related to the stiffness. Thus all quantitative elastography techniques combine a means to generate shear waves and an imaging technique to measure the propagation of the generated shear waves. 2.2 Physics of elastography From a physical and mechanical point of view, stiffness can be defined as the shear modulus, µ, or the Young’s modulus, E. These moduli describe the mechanical response of a www.intechopen.com Non-Invasive Assessment of Liver Fibrosis by Vibration-Controlled Transient Elastography (Fibroscan®) 295 medium under shear stress and longitudinal stress, respectively. The theory of linear elasticity is based on this relationship between stress and strain and states that the deformation of a material is directly proportional to the applied stress, σ = Eε, where σ is the stress applied to the material, and ε is the strain induced in the material. The Young’s modulus E is expressed in kilopascals (kPa) and represents the resistance of material to deformation. This law, known as Hooke’s law, gives the relationship between the strain ε, the Young’s modulus and the stress σ. A rod, length L, of elastic material can be seen as a linear spring. Under a stress σ, it will experience an extension ΔL:   E LL E (2.1) The relationship between the Young’s modulus E, the Poisson coefficient υ and the Lamé coefficients λ and µ (also known as compression and shear moduli), is given by:   3 2 2           E (2.2) Biological tissues are mainly composed of water. The compression modulus λ is several Giga Pascal; it is thus very large compared to the shear modulus of soft biological tissues (several kilo Pascal) (Sarvazyan et al. 1995). With λ >> µ, it yields that υ ≈ 0.5 which is characteristic of a quasi-incompressible medium. Eventually, in soft medium, the Young‘s modulus E simplifies to: 3E µ (2.3) Interestingly, under some simplification hypothesis, the shear modulus can be deduced from the shear wave velocity, Vs, and the mass density, ρ: 2 2 3   S s V E V (2.5) Since the soft body tissues mass density is almost constant (1000 kg/m3), the Young‘s modulus E can be obtained by measuring the velocity of shear waves. Thus shear waves are the foundation of quantitative elastography techniques. 2.3 Background of quantitative elastography Quantitative elastography techniques, also called dynamic elastography techniques, have the advantage of allowing a quantitative imaging and better resolution than the static elastography techniques. However, they require more complex equipment for the generation of shear waves (monochromatic, transient) and imaging devices (ultrafast ultrasound, magnetic resonance imaging) able to measure shear wave induced displacement with a high resolution. There are basically two groups of quantitative elastography techniques depending on the shear wave generation method: remote generation using www.intechopen.com Liver Biopsy 296 radiation force and mechanical vibration. The shear wave frequency content may also be different: harmonic or transient. In transient elastography techniques, the propagating shear wave results from a transient (impulsive or short tone burst) excitation of the tissue. Indeed, an important feature of transient elastography techniques is that the vibration be transient to avoid reflections and interferences occurring within the tissues. The transient shear wave travels through the tissues within tens of milliseconds which implies that the ultrasound-based imaging modality be ultrafast to follow its propagation. Harmonic elastography techniques are using a continuous vibration at a fixed frequency. Several quantitative elastography techniques (see Table 1) were proposed to assess liver stiffness as a marker of pathological state. Advantages and limitations of quantitative elastography techniques are summarized in Table 2. Imaging modality Shear wave generation mode Frequency Vibration-Controlled Transient Elastography (VCTE™) Ultrasound Mechanical vibration Transient Fixed 50 Hz Magnetic Resonance Elastography (MRE) Magnetic resonance imaging Mechanical vibration Harmonic Fixed 60 Hz Acoustic Radiation Force Impulse (ARFI) Ultrasound Radiation force Transient Wideband Supersonic Shear Imaging (SSI) Ultrasound Radiation force Transient Wideband Table 1. Quantitative elastography techniques for liver stiffness measurement. Advantages Limitations Vibration-Controlled Transient Elastography (VCTE™) Ease of use Highly standardized Controlled shear frequency Transient shear wave Large clinical validation Ascites Magnetic Resonance Elastography (MRE) Controlled shear frequency Penetration depth 2D stiffness map Cost Acoustic Radiation Force Impulse (ARFI) Image guidance Transient shear wave Absence of shear wave control High intensity ultrasound Penetration depth Limited clinical validation Supersonic Shear Imaging (SSI) Image guidance Transient shear wave Absence of shear wave control High intensity ultrasound Penetration depth Absence of clinical validation Table 2. Advantages and limitations of quantitative elastography techniques. www.intechopen.com Non-Invasive Assessment of Liver Fibrosis by Vibration-Controlled Transient Elastography (Fibroscan®) 297 2.3.1 Radiation force based elastography Radiation force based elastography uses high intensity ultrasound beams to induce displacements and tissue heating inside the liver remotely. Acoustic radiation force is applied to absorbing and/or reflecting materials in the propagation path of acoustic waves. This phenomenon is caused by a transfer of momentum from the acoustic wave to the propagation medium. The spatial distribution of the radiation force field is determined by both the acoustic excitation parameters and the tissue properties. ARFI technique (Nightingale et al. 2003; Palmeri et al. 2008) involves the mechanical excitation of tissue using localized, focused, impulsive radiation force excitations. This results in shear-wave propagation away from the region of excitation. The mechanical excitation occurs along the acoustic wave propagation path and within the focal region of the acoustic beam. The resulting displacement response is ultrasonically tracked through time using an abdominal ultrasound transducer combined with a dedicated ultrasound scanner. Direct inversion methods are then applied to estimate the associated shear velocity. Supersonic shear imaging (Bercoff et al. 2004; Muller et al. 2009) relies on the use of radiation force and a high frame rate ultrasound scanner (Sandrin et al. 2002). The medium is illuminated by a supersonic Mach cone: ultrasounds are focused successively at different increasing depths. The different spherical waves generated by each focus then interfere along a Mach cone in which the source is spreading faster than the shear wave generated and creates a plane wave front in the imaging plane. The ultrasound imaging system is then used to visualize the entire imaging plane with a good temporal resolution in a single acquisition typically 5000 to 20000 frames per second. Maps of the Young’s modulus are estimated by inverse problems from the time of flight of the shear wave front. Generating shear waves within the liver using radiation force requires high intensity ultrasound beams which induce liver tissue heating. Thermal safety issues related to incident radiation force pulses have been studied (Fahey et al. 2006; Palmeri & Nightingale 2004). It required the development of special cooling time sequences to prevent overheating of liver tissues. As a consequence of the relative low energetic transfer efficacy, the amplitude of the remotely induced displacements remains low and the penetration depth of radiation force based elastography technique is thus limited. 2.3.2 Mechanical vibration based elastography Mechanical vibration based elastography techniques are using a mechanical vibrator to induce shear waves into the body. In Magnetic Resonance Elastography (MRE) (Muthupillai et al. 1995), a nuclear magnetic resonance imaging (MRI) method is used for quantitatively mapping the physical response of the tissues to an excitation of low frequency typically between 50 Hz and 80 Hz (Klatt et al. 2006; Rouviere et al. 2006). MRE showed promising results especially for 2D mapping of tissue stiffness. Vibration-Controlled Transient Elastography (Castera et al. 2005; Sandrin et al. 2003; Sandrin et al. 2002; Ziol et al. 2005) is based on a single ultrasound transducer mounted on the axis of a mechanical actuator (Fig. 2). The ultrasound transducer (3.5 MHz) is used in pulse-echo mode to measure the displacements induced in a medium by the propagation of a low-frequency (50 Hz) shear wave. Interestingly the low frequency shear wave and the ultrasound are generated by the same piston-like transducer. The ultrasound beam coincides with the vibrator axis. Under the assumption of homogeneity, the symmetry considerations impose that the displacements on the axis of the transducer be purely www.intechopen.com Liver Biopsy 298 longitudinal. Diffraction effects from the piston-like transducer result in longitudinally polarized shear wave on the axis of symmetry (Sandrin et al. 2004). The displacements induced by the shear wave in the medium are measured using cross-correlation of successive ultrasound lines acquired at high frame rate. A spatial-temporal strain map is computed from the recorded displacements. The shear wave speed is calculated based on the slope of the wave front visualized in the strain map. Fig. 2. 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). This technique is implemented in a standalone clinical device: Fibroscan®. It is the unique device that does not require integration into a conventional imaging system. Fibroscan® device is detailed in the next section. 2.4 The importance of the vibration control in quantitative elastography The proper use of shear wave velocity analysis for clinical diagnosis requires the control of various physical parameters and in particular the control of the vibration to ensure an accurate, reliable and reproducible assessment of tissue stiffness. The control must be done on the shape, frequency and amplitude of the vibration. Of course, in VCTE, the amplitude of the vibration may be adapted to the morphology of the patients to increase the penetration depth of the shear wave. Furthermore, as stiffness value depends on shear wave frequency, the shape of the vibration must be controlled to obtain a consistent measurement that can be used for diagnostic purposes whatever the mechanical properties of the organ under investigation or the etiology of the patient. Provided that the shape of the vibration be constant, a reference frequency is obtained and a comparison of the shear wave propagation parameters can be performed independently of the organ conditions, etiology, patient and operator. 2.5 The difficult process of liver stiffness measurement standardization The development and clinical validation of non-invasive methods for assessing liver fibrosis in patients with chronic liver diseases were eased by the fact that liver biopsy is not a perfect Mechanical actuator Ultrasound transducer Tissues Shear wave US beam www.intechopen.com Non-Invasive Assessment of Liver Fibrosis by Vibration-Controlled Transient Elastography (Fibroscan®) 299 gold standard. However, standardization of elastography procedures is a challenging aspect of the success of elastography in the medical field and more precisely in hepatology. Radiation force based elastography techniques such as ARFI and SSI are attractive techniques since they are intrinsically image-guided and do not require the use of an external vibrator. Actually these attractive aspects of the technology may result in significant loss of performances. As a matter of fact, using an image guided system in which the operator has a full freedom of choice of the region of measurement will increase the operator dependency of the technique. While VCTE™ may look less sophisticated, it is based on a highly standardized procedure that can be followed not only by physicians but also by nurses. A short training is required before using Fibroscan®. This standardization favors the consistency of the results obtained whatever the operator, the studied population and the etiology of the patients. Shear waves remotely generated using radiation force are wide band with frequencies ranging from 100 Hz to 500 Hz. Indeed with radiation force, the frequency of the shear waves can not be controlled precisely. Thus the frequency content of the generated shear wave will vary as a function of parameters such as the acoustic attenuation, the nature of reflecting materials, the mechanical properties of the tissues through which the ultrasound and shear waves travel, the depth of the region of measurement, etc. Some of these parameters are obviously etiology-dependent. As a consequence, measured stiffness will vary. Moreover, it is now well described that liver stiffness increases when the shear wave frequency increases (see Fig. 3). Thus, the higher the frequency is, the higher the measured stiffness will be. 0 100 200 300 400 0 2000 4000 6000 8000 10000 12000 Frequency (Hz) G ' (P a ) Fig. 3. Preliminary result: elastic modulus of a fresh pig liver sample as a function of frequency (courtesy of RheoLution inc). Eventually, though a direct conversion of liver stiffness values measured with transient elastography techniques based on radiation force and mechanical vibration is tempting, this task might be a very challenging task. Indeed, theoretically Young’s modulus as provided www.intechopen.com Liver Biopsy 300 by VCTE™ could be deduced from the shear velocity as measured by radiation force-based technique (ARFI, SSI, etc.). However, this relationship is only valid at a given frequency:    23 SE f V f (2.6) As a matter of fact, while shear wave frequency in VCTE™ is 50 Hz, shear wave frequency using radiation force is not controlled. Thus, as the frequencies may be significantly different with these techniques, a direct conversion of radiation-force-based shear wave velocity to VCTE™ Young’s modulus is not possible. The Young’s modulus obtained with VCTE™ and radiation-force based elastograhy will differ. Therefore liver stiffness thresholds used for clinical decision support will have to be reevaluated. The success of VCTE™ and the good performances reported in many studies all over the world is certainly due to its high standardization and high control of the shear wave shape. 3. Fibroscan® device In this Section, the Fibroscan® device is described from a technical point of view. The operating principle is detailed with appropriate figures. Tables are included to provide parameters of the differ