Noninvasive In Vivo Liver Fibrosis Evaluation Using Supersonic Shear Imaging: A Clinical Study on 113 Hepatitis C Virus Patients

Abstract

Supersonic shear imaging (SSI) has recently been demonstrated to be a repeatable and reproducible transient bidimensional elastography technique. We report a prospective clinical evaluation of the performances of SSI for liver fibrosis evaluation in 113 patients with hepatitis C virus (HCV) and a comparison with FibroScan (FS). Liver elasticity values using SSI and FS ranged from 4.50 kPa to 33.96 kPa and from 2.60 kPa to 46.50 kPa, respectively. Analysis of variance (ANOVA) shows a good agreement between fibrosis staging and elasticity assessment using SSI and FS (p < 10⁻⁵). The areas under receiver operating characteristic (ROC) curves for elasticity values assessed from SSI were 0.948, 0.962 and 0.968 for patients with predicted fibrosis levels F ≥ 2, F ≥ 3 and F = 4, respectively. These values are compared with FS area under the receiver operating characteristic curve (AUROC) of 0.846, 0.857 and 0.940, respectively. This comparison between ROC curves is particularly significant for mild and intermediate fibrosis levels. SSI appears to be a fast, simple and reliable method for noninvasive liver fibrosis evaluation.

Introduction

Liver fibrosis, which results from persistent hepatic inflammation, has serious long-term consequences for patient morbidity and mortality in relation to cirrhosis evolution (World Health Organization 2004). As a consequence, the assessment of liver fibrosis is of crucial clinical importance for the diagnosis and monitoring of chronic liver diseases at early stages (Beaugrand 2006) and treatment monitoring (Pinzani et al. 2005).

Liver biopsy (LB) is still considered as the “gold standard” examination to assess the liver fibrosis level, despite limitations (Afdahl 2003), such as patient refusal, patient discomfort, morbidity and even mortality (Cadranel et al., 2000, Friedman, 2003, Castéra et al., 1999, Bravo et al., 2001). The specificity and sensitivity of LB has also been questioned (Beaugrand, 2006, Bedossa et al., 2003, The French METAVIR Cooperative Study Group, 1994, Colloredo et al., 2003) because of the intraobserver and interobserver variability of the examination (Maharaj et al. 1986). These variabilities can be explained by sampling errors during punctures (Maharaj et al., 1986, Regev et al.,, fibrosis heterogeneities in the liver tissues and accentuated by the small length of liver samples (Maharaj et al., 1986, Ziol et al., 2005).

Such limitations led to the development of surrogate serum markers and noninvasive biochemical such as glycomics, fibrotest, fibrometer, hepascore, aspartate transaminase to platelet ratio (APRI), Fib 4 or Forn’s score and morphologic tests such as FibroScan (FS, Echosens, Paris, France) (Trinchet J-, 1995, Halfon et al., 2005, Wai et al., 2003, Forns et al., 2002, Imbert-Bismut et al., 2001, Ono et al., 1999, Sterling et al., 2006, Vallet-Pichard et al., 2007). Several studies reported that the combination of different blood markers and the assessment of tissue elasticity based on transient elastography by FibroScan (FS) has shown good results in liver fibrosis staging (Ziol et al., 2005, Fontana and Lok, 2002, Lackner et al., 2005, Castéra et al., 2005). Although being used in conjunction with FS, those blood indexes are reported to be not specific enough (Beaugrand, 2006, Bataller and Brenner, 2005, Stauber and Lackner, 2007 and could be influenced by extrahepatic diseases including hemolysis. Furthermore, the most important limitation of these fibrosis tests is the bad discrimination between intermediate stages of fibrosis (Stauber and Lackner, 2007, Parkes et al., 2006). As a consequence, there is a critical need for alternative fibrosis methods for liver fibrosis staging allowing high specificity and sensibility (Friedman, 2003, Stauber and Lackner, 2007) for intermediate more than for advanced stages of liver fibrosis to initiate treatments.

Elasticity imaging (Ophir et al., 1991, Sarvazyan et al., 1998) is now widely considered as a useful technique for biologic tissues characterization. Recently, several elasticity imaging techniques have been developed for the assessment of the mechanical properties of liver tissues (Yeh et al. 2002) and fibrosis level staging, using different imaging modalities, such as magnetic resonance elastography (Klatt et al. 2006); Muthupillai et al., 1995, Huwart et al., 2008), two-dimensional (2-D) static ultrasound elastography (Friedrich-Rust et al. 2007), one-dimensional (1-D) transient ultrasound elastography (Sandrin et al. (2003), supersonic shear imaging (SSI) (Muller et al. 2009), shearwave dispersion ultrasound vibrometry (SDUV) (Chen et al. 2009), spatially modulated ultrasound radiation force (SMURF) imaging (McAleavey et al. 2009), sonoelastography (Taylor et al. 2000) and acoustic radiation force impulse (ARFI imaging) (Fahey et al., 2008, Palmeri et al., 2008, Yoneda et al., 2010), which is already commercially implemented by Siemens company. All these methods are based on the same methodology: the liver is mechanically stressed and the induced tissue displacement in the organ is measured, allowing the estimation of the elastic properties in the liver, which are known to be related to the degree of hepatic fibrosis. Some of the procedures involve a static compression of the liver and do not allow quantitative estimation of the liver stiffness (Friedrich-Rust et al. 2007).

Supersonic shear imaging was already evaluated in the framework of breast cancer diagnosis (Athanasiou et al. 2010), muscular (Gennisson et al. 2010) and cornea (Tanter et al. (2009) stiffness assessments. In a recent paper (Muller et al. 2009), Muller et al. presented a feasibility study of the SSI and shear wave spectroscopy (SWS) for the quantitative mapping of human liver using a linear ultrasonic probe. This imaging technique is based on the combination of the acoustic radiation force imaging technique and an ultrafast echographic imaging approach, allowing the assessment a quantitative elasticity map of biological tissues in a single ultrasonic sequence (Muller et al., 2009, Bercoff et al., 2004a, Bercoff et al., 2004b, Tanter et al., 2008). This preliminary in vivo feasibility on 15 healthy volunteers (Muller et al. 2009) showed that the SSI technique is promising and that the liver stiffness estimation on a large area (10 cm²) using the SSI mode is fast (less than 1 s), repeatable (5.7% standard deviation) and reproducible (6.7% standard deviation). Moreover, it was shown in (Muller et al. 2009) that both elasticity and viscosity can be assessed using SSI. In many organs, tissue exhibit shear viscosity and signal processing of the shear wave propagation movie can be refined to study this more complex biomechanical behavior. Viscosity affects the shear wave propagation speed (Bercoff et al., 2004c, Deffieux et al., 2009). The time profile of the plane shear wave is progressively distorted and attenuated during propagation. This distortion is characterized by a frequency dependence of the shear wave speed and attenuation that fully describes the rheologic behavior of tissue (Deffieux et al. 2009) as already shown in breast cancer diagnosis (Tanter et al. 2008). Simple signal processing on acquired data enables to provide the dispersion curve of the shear wave phased speed.

The purpose of our clinical study was to determine the efficiency of this method for liver fibrosis level evaluation and prospectively compare the sensitivity and specificity of SSI with those of the FS for hepatic fibrosis levels in patients with hepatitis C virus (HCV). Our results demonstrate that SSI is feasible and appear to be at least as efficient as FS for intermediate levels.