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SOUND JUDGMENT SERIES
Shear Wave Elastography for Evaluation of Liver Fibrosis Giovanna Ferraioli, MD, Parth Parekh, MD, Alexander B. Levitov, MD, RDCS, Carlo Filice, MD
Invited paper
The Sound Judgment Series consists of invited articles highlighting the clinical value of using ultrasound first in specific clinical diagnoses where ultrasound has shown comparative or superior value. The series is meant to serve as an educational tool for medical and sonography students and clinical practitioners and may help integrate ultrasound into clinical practice.
Received August 19, 2013, from the Ultrasound Unit, Department of Infectious Diseases, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, University of Pavia Medical School, Pavia, Italy (G.F., C.F.); and Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, Virginia USA (P.P., A.B.L.). Revision requested September 3, 2013. Revised manuscript accepted for publication September 11, 2013. Drs Ferraioli and Filice received a research grant from Philips Healthcare (Bothell, WA). Address correspondence to Giovanna Ferraioli, MD, Ultrasound Unit, Department of Infectious Diseases, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, University of Pavia Medical School, Via Taramelli 5, 27100 Pavia, Italy. E-mail: [email protected] Abbreviations
SWE, ShearWave Elastography; VTTQ, Virtual Touch Tissue Quantification doi:10.7863/ultra.33.2.197
The prognosis and management of chronic viral hepatitis mainly depend on the extent of liver fibrosis, particularly in chronic hepatitis C. Liver histologic analysis is still considered the reference standard in the assessment of liver fibrosis despite the interobserver and interobserver variability in staging and some morbidity and mortality risks. Thus, noninvasive methods for assessing liver fibrosis are of great clinical interest. In the last decade, ultrasound-based techniques to estimate the stage of liver fibrosis have become commercially available. They all have the capability to noninvasively evaluate differences in the elastic properties of soft tissues by measuring tissue behavior when a mechanical stress is applied. Shear wave elastography relies on the generation of shear waves determined by the displacement of tissues induced by the force of a focused ultrasound beam or by an external push. This article reviews the results that have been obtained with shear wave elastography for assessment of liver fibrosis. Key Words—chronic hepatitis; elastography; fibrosis; gastrointestinal ultrasound; liver; ultrasound
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t is estimated that 500 million people are affected by chronic viral hepatitis worldwide, of which 1 million people will die of their illness every year, primarily from cirrhosis or hepatocellular carcinoma as a result of their infection.1 In the United States, more than 4 million people have this disease, with an annual mortality rate of 15,000 people.2 The prognosis and management of chronic viral hepatitis mainly depend on the extent of liver fibrosis, particularly in chronic hepatitis C. Long thought to be irreversible, recent studies have shown this idea to be false, even in its advanced stages, thus stressing the importance of early diagnosis.3 Liver histologic analysis is still considered the reference standard in the assessment of liver fibrosis despite the intraobserver and interobserver variability in staging.4 Regev et al4 found approximately 25% of patients (30 of 124) to have a difference of at least one grade and 33% (41 of 124) to have at least one stage difference between the right and left lobes. Ultimately, Regev et al4 found an underdiagnosis of cirrhosis in approximately 15% of patients. Moreover, liver biopsy is a painful technique that is not well accepted by patients, has morbidity and mortality risks, and is not an ideal method for following patients. Thus, noninvasive methods for assessing liver fibrosis are of great clinical interest. In the last decade, techniques to noninvasively estimate the stage of liver fibrosis have become commercially available. They all have the capability to evaluate differences in the elas-
©2014 by the American Institute of Ultrasound in Medicine | J Ultrasound Med 2014; 33:197–203 | 0278-4297 | www.aium.org
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tic properties of soft tissues by measuring tissue behavior when a mechanical stress is applied. Ultrasound and magnetic resonance have been used for elasticity imaging. Magnetic resonance elastography, even though promising, has some disadvantages. It cannot be performed in a liver with an iron overload because of signal-to-noise limitations, the examination time is longer with respect to ultrasound elastography, and it is a costly procedure.5 Shear wave elastography relies on the generation of shear waves determined by the displacement of tissues induced by the force of a focused ultrasound beam or by external pressure. The shear waves are lateral waves, with a motion perpendicular to the direction of the force that has generated them. They travel slowly (between 1 and 10 m/s) and are rapidly attenuated by tissue. The propagation velocity of the shear waves correlates with the elasticity of tissue; ie, it increases with increasing stiffness of the liver parenchyma.6 To correctly read the results, it should be kept in mind that elastography assesses liver elasticity that could be modified by factors other than fibrosis, such as edema, inflammation, extrahepatic cholestasis, and congestion.7–10 In fact, these factors may lead to overestimation of the liver stiffness for a sharp enlargement of the liver, which is covered by the Glisson capsule, a poor distensible envelope. Thus, the results obtained should always be interpreted in clinical settings. Examinations should be performed under fasting conditions because it has been demonstrated that food intake may produce false-positive results.11,12
Transient Elastography The pioneer technique has been transient elastography, which is performed with the FibroScan device (Echosens, Paris, France). A single-element ultrasound transducer operating at 5 MHz is built on the axis of a pistonlike vibrator.13 By pushing a button, low-frequency (50 Hz) transient vibrations are transmitted, and the elastic shear waves that are generated propagate through underlying tissues. Pulse-echo ultrasound acquisitions are used to follow the propagation of the shear wave and to measure its velocity.13 Transient elastography measures liver stiffness in a volume that approximates a cylinder 1 cm wide and 4 cm long between 25 and 65 mm below the skin surface. This volume is at least 100 times bigger than a biopsy sample and is therefore far more representative of the liver parenchyma.14 Transient elastography is performed on a patient lying supine with the right arm elevated to facilitate access to the right liver. The tip of the probe contacts the intercostal skin with coupling gel. The operator, assisted
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by a time-motion image, locates a liver portion at least 6 cm deep and free of large vascular structures (Figure 1). The device gives an estimate of the velocity of shear waves, which can be also expressed in kilopascals through the Young modulus: E = 3 (vs · ρ), where E is the Young modulus, vs is the shear wave velocity, and ρ is the density of tissue, assumed to be the same as water. The software of the device determines whether each measurement is successful. When a shot is unsuccessful, the machine does not give any value. The entire procedure is considered to have failed when no value is obtained after 10 shots. Successful measurements are validated by these criteria: (1) 10 valid shots; (2) a ratio of valid shots to the total number of shots of 60% or higher; and (3) variability of measurements less than 30% of the median value of liver stiffness measurements.15 Transient elastography has excellent intraobserver and interobserver reproducibility, with an intraclass correlation coefficient of 0.98 even though the interobserver agreement decreases in patients with a lower degree of liver fibrosis, with liver steatosis, or with an increased body mass index.16 In healthy blood donors, a mean normal liver stiffness ± SD of 4.9 ± 1.7 kPa (1.28 ± 0.75 m/s) has been found.16 Several studies and metaanalyses13–25 have examined the diagnostic performance of transient elastography in staging liver fibrosis in patients with different etiologies of chronic liver disease. Most of the studies have been conducted in patients with chronic hepatitis C and have shown high diagnostic accuracy of transient elastography in staging liver fibrosis. It should be pointed out, however, that a substantial overlap of liver stiffness values between adjacent stages of liver fibrosis, particFigure 1. Shear wave elastography with the FibroScan device: A, TMmode image; B, A-mode image; C, elastographic image. TM-mode and A-mode images are used to locate a liver portion suitable for the measurement. The slope of the white dotted line in C, which represents shear wave velocity, is a function of the fibrosis stage.
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ularly for lower fibrosis stages, has been observed. Transient elastography more accurately detects cirrhosis than significant fibrosis. Several meta-analyses have confirmed that transient elastography appears to be a reliable method for the diagnosis and exclusion of cirrhosis as opposed to predicting cirrhosis. For the diagnosis of cirrhosis, transient elastographic cutoff values have been found to be between 11.8 and 14.6 kPa (1.98 and 2.21 m/s). In clinical practice, liver stiffness values from 2.5 to 7.0 kPa (0.91–1.53 m/s) indicate mild or no fibrosis, and values greater than 12.5 kPa (2.04 m/s) are suggestive of cirrhosis.17 The European Association for the Study of the Liver has indicated that noninvasive methods can now be used instead of liver biopsy in patients with chronic hepatitis C to assess liver disease severity before therapy at a safe level of predictability.26 Transient elastography cannot technically be performed in patients with ascites and has a high rate of failure in patients with body mass indices greater than 30 kg/m2. The recent availability of the FibroScan XL probe has overcome this latter limitation.
of liver stiffness at a single location is obtained (Figures 2 and 3). They have been categorized as point–shear wave elastography.27 The SWE technique is based on an ultrafast ultrasound imaging approach that allows detailed monitoring of the shear waves in a large area of liver parenchyma with real-time color-coded elasticity imaging inside a sample box, and the measurement is obtained by placing a region of interest inside the sample box (Figure 4). This technique is 2-dimensional elastography.27 In all of the studies that have assessed the accuracy of the different devices in staging liver fibrosis, right intercostal access has been used. The patient is examined in the dorsal decubitus position with the right arm elevated above the head for optimal intercostal access in a resting respiraFigure 2. Shear wave elastography of the liver performed with the Siemens system through intercostal access. The measurement is given in meters per seconds.
Elastographic Techniques Based on Shear Waves Generated by the Acoustic Beam These techniques have the advantage of being integrated into ultrasound systems; thus, conventional sonography, which is advised every 6 to 12 months in patients with chronic liver disease, could also be performed. As of today, for the assessment of liver stiffness, these techniques are commercially available in high-end ultrasound systems made by Philips Healthcare (Bothell, WA; ElastPQ), Siemens Medical Solutions (Mountain View, CA; Virtual Touch Tissue Quantification [VTTQ]), and SuperSonic Imagine, SA (Aix-en-Provence, France; ShearWave Elastography [SWE]). These techniques generate shear waves inside the liver by using radiation force from a focused ultrasound beam. The shear waves are generated near the region of interest in the liver parenchyma and not on the surface of the body, as happens with external vibration devices. The ultrasound system monitors shear wave propagation using a Doppler-like ultrasound technique and measures its velocity. The shear wave velocity is displayed in meters per second or kilopascals through the Young modulus. Unlike transient elastography, the measurements are not limited by the presence of ascites because the ultrasound beam, which generates the shear waves, propagates through fluids. With the VTTQ and ElastPQ techniques, the readings of the shear wave speed are made by using a small sample box (usually 0.5 × 1 cm); thus, a quantitative estimate
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Figure 3. Shear wave elastography of the liver performed with the Philips system through intercostal access. The measurement is shown in kilopascals. In the bottom left corner, a scale shows the stiffness degree.
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tory position. Measurements are performed at least 1.5 to 2.0 cm beneath the Glisson capsule to avoid reverberation artifacts. In case of physical conditions affecting the signalto-noise ratio, the Philips and Siemens devices do not give any measurement. With the SuperSonic Imagine device, a measurement fails when no/little signals are obtained in the sample box for all of the acquisitions. Siemens Technique (VTTQ) The first one available was the Siemens technique, which is commonly referred to as acoustic radiation force impulse in the literature, which is technically the same force that generates shear waves for all 3 available techniques.27 Moreover, the term acoustic radiation force impulse is rather generic and does not identify shear wave–based methods. In fact, acoustic radiation force impulse push pulses are also used in strain imaging of other organs, such as the breast and thyroid. In recent years, the diagnostic accuracy of the VTTQ technology for quantification of liver stiffness, mainly in patients with chronic hepatitis C, has been investigated in several studies and a meta-analysis.28–34 The technology has shown high interobserver agreement, with an intraclass correlation coefficient of 0.86.35 Operator training does not seem to be required.28 The cutoff values obtained in a large meta-analysis were 1.34, 1.55, and 1.80 m/s for significant fibrosis (METAVIR fibrosis score of F2 or greater), severe fibrosis (METAVIR fibrosis score of F3 or greater), and cirrhosis (METAVIR fibrosis score of F4), respectively.34 In this meta-analysis, which included patients with several etiologies of chronic liver
Figure 4. Shear wave elastography of the liver performed with the SuperSonic Imagine system through intercostal access. The shade of blue in the box is related to the speed of the shear waves. The velocity range (in kilopascals) is shown in the vertical bar on the right: the colors go from dark blue (soft tissues) to red (hard tissues).
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disease, the diagnostic accuracy was comparable with that of transient elastography for the assessment of severe fibrosis, whereas higher performance of transient elastography was seen for significant fibrosis and liver cirrhosis. In a study by Rizzo et al,33 the technique was significantly more accurate than transient elastography for diagnosing significant and severe fibrosis, whereas this difference was only marginal for cirrhosis.
SuperSonic Imagine Technique (SWE) The reproducibility of the SWE method is very high, with intraobserver intraclass correlation coefficients of 0.95 and 0.93 for an expert and a novice operator, respectively, and interobserver agreement of 0.88.36 As for conventional sonography, it is user dependent; thus, it is recommended that at least 50 supervised scans and measurements should be performed by a novice operator to obtain consistent measurements. Values obtained in a small series of healthy participants ranged from 4.92 kPa (1.28 m/s) to 5.39 kPa (1.34 m/s).36 In a pilot study conducted on 121 patients with chronic hepatitis C undergoing liver biopsy, the optimal cutoff values were 7.1 kPa (1.54 m/s) for significant fibrosis (METAVIR fibrosis score of F2 or greater), 8.7 kPa (1.70 m/s) for advanced fibrosis (METAVIR fibrosis score of F3 or greater), and 10.4 kPa (1.86 m/s) for cirrhosis (METAVIR fibrosis score of F4), and the technique was more accurate than transient elastography in assessing significant fibrosis.37 In another study, with respect to transient elastography, the technique showed higher accuracy in assessing mild and intermediate stages of fibrosis.38
Philips Technique (ElastPQ) The ElastPQ technique was the most recent to enter the market; thus, only a few studies have been published so far. With this technique, liver stiffness values in healthy volunteers have been reported to be less than 4.0 kPa (1.15 m/s).39,40 Ling et al39 found that men had higher values than women (3.8 ± 0.7 versus 3.5 ± 0.4 kPa, or 1.13 ± 0.48 versus 1.08 ± 0.37 m/s) and liver stiffness was comparable with different probe positions, examiners, and age groups. In a series that comprised 88 patients with chronic viral hepatitis and 33 healthy volunteers, the technique compared favorably with transient elastography in staging liver fibrosis, and healthy volunteers showed significantly lower values than patients with nonsignificant fibrosis.40
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Limitations and Pitfalls Working on phantoms, the Quantitative Imaging Biomarker Alliance created by the Radiological Society of North America has shown that a limitation of the technique is that there is a statistically significant difference in the shear wave velocity estimates among systems and with depth into the phantom, which was shown with all imaging systems, whereas no statistically significant differences were found among appraisers using the same or equivalent systems.41 Because most studies have been conducted in patients with chronic hepatitis C, the cutoffs need to be further validated for other etiologies of diffuse liver disease. In acute hepatitis, values could be very high even in the absence of fibrosis, and there is a progressive normalization of stiffness values in parallel with the decrease in aminotransferase levels. In a study by Coco et al,8 the values of liver stiffness assessed by transient elastography were correlated with aminotransferase levels at the onset of acute viral hepatitis, when the presence of tissue inflammation and edema is likely to be maximal. In patients with congestive heart failure, it has been shown that liver stiffness directly depends on venous pressure. The stiffness increase could be due to the congestion of the liver with dilatation of both venae cavae and hepatic veins that causes enlargement of the liver, which is enveloped by the Glisson capsule.9 Moreover, it has been reported that cholestasis represents a confounding factor in liver stiffness measurement.10 Transient elastography cannot be performed in patients with ascites. Failure to obtain any measurement with transient elastography has been observed in 4% of examinations, and unreliable results were obtained in 17%;
both were associated with obesity or limited operator experience.42 Measurement failure with elastographic techniques based on shear waves generated by the acoustic beam has been reported in less than 3% of patients.34–37
Clinical Cases Case 1 A 43-year-old man has been infected with chronic hepatitis C for 20 years. He has had transiently elevated serum aminotransferase levels in the past but has had normal values at follow-up for 2 years. To start an antiviral treatment, he has been scheduled for liver biopsy by the referring physician. Biochemical test results obtained the day before liver biopsy are within the normal range. Two shear wave elastographic techniques are performed on the same day as liver biopsy (Figure 5). The results of the noninvasive methods are discordant with that of liver biopsy. In fact, both techniques give values of advanced fibrosis, whereas liver histologic analysis shows METAVIR stage F1 (nonsignificant fibrosis). On the basis of the concordance between the two noninvasive methods the physician has decided to start antiviral therapy, and the patient is now receiving treatment. Considering that liver biopsy is not a perfect reference standard, these different results could be due to a failure of liver biopsy in correctly assessing liver fibrosis and could be explained by the uneven distribution of fibrosis. In fact, histologic staging is based on a biopsy specimen that represents at most 1/50,000 of the total liver mass. In this regard, the sample size of elastographic techniques is more representative of liver tissue than a liver biopsy specimen, and the evaluation could be done in several areas of the liver parenchyma. On the other hand, even when an expe-
Figure 5. Images from 43-year-old man infected with chronic hepatitis C for 20 years. Shear wave elastography of the liver performed with the Philips system (A) and the SuperSonic Imagine system (B) show advanced fibrosis. A
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B
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rienced physician performs a liver biopsy and an expert pathologist interprets the results, liver biopsy has a sampling error in diffuse liver disease staging.4,43 Case 2 A 57-year-old woman has been infected with chronic hepatitis C for 28 years. Biochemical test results are within the normal range. She has had follow-up with sonography every 6 months. Sonographic findings are normal, whereas elastography gives a value compatible with liver cirrhosis (Figure 6), which is confirmed by a liver biopsy performed 3 weeks later. Sonography is a noninvasive and inexpensive procedure for diagnosis of diffuse liver disease; however, the value of sonography for distinguishing a low degree of liver fibrosis from cirrhosis is limited. In a study by Colli et al,44 28 of 107 patients with severe fibrosis or definite cirrhosis (26%) had negative results for liver surface nodularity and caudate lobe hypertrophy and had normal hepatic venous flow. In this regard, elastography integrated into ultrasound systems is an effective adjunctive tool for quantifying liver fibrosis.
allows one to choose an area of liver parenchyma better suited for stiffness assessment (ie, free of large vessels and focal lesions). These methods are all valid when information about fibrosis is needed. Liver biopsy should still be performed when biochemical tests and imaging studies are inconclusive or information other than liver fibrosis is required.
References 1.
2.
3.
4.
5.
Conclusions In patients with chronic viral hepatitis, particularly in patients with hepatitis C virus infection, all noninvasive methods are ready to be used for detecting and staging liver fibrosis before therapy at a safe level of predictability. As with transient elastography, elastographic techniques based on shear waves generated by the acoustic beam are more accurate in detecting cirrhosis than significant fibrosis. They have the advantage of B-mode guidance, which
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9. Figure 6. Image from a 57-year-old woman infected with chronic hepatitis C for 28 years. Elastography gives a value indicating liver cirrhosis.
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13. 14.
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15. Castéra L, Vergniol J, Foucher J, et al. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology 2005; 128:343–350. 16. Fraquelli M, Rigamonti C, Casazza G, et al. Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic liver disease. Gut 2007; 56:968–973. 17. Colombo S, Belloli L, Zaccanelli M, et al. Normal liver stiffness and its determinants in healthy blood donors. Dig Liver Dis 2011; 43:231–236. 18. Ziol M, Handra-Luca A, Kettaneh A, et al. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C. Hepatology 2005; 41:48–54. 19. Castéra L. Transient elastography and other noninvasive tests to assess hepatic fibrosis in patients with viral hepatitis. J Viral Hepat 2009; 16:300– 314. 20. Arena U, Vizzutti F, Abraldes JG, et al. Reliability of transient elastography for the diagnosis of advanced fibrosis in chronic hepatitis C. Gut2008; 57:1288–1293. 21. Ferraioli G, Tinelli C, Dal Bello B, et al. Performance of liver stiffness measurements by transient elastography in chronic hepatitis. World J Gastroenterol 2013; 19:49–56. 22. Friedrich-Rust M, Ong MF, Martens S, et al. Performance of transient elastography for the staging of liver fibrosis: a meta-analysis. Gastroenterology 2008; 134:960–974. 23. Shaheen AA, Wan AF, Myers RP. FibroTest and FibroScan for the prediction of hepatitis C-related fibrosis: a systematic review of diagnostic test accuracy. Am J Gastroenterol 2007; 102:2589–2600. 24. Tsochatzis EA, Gurusamy KS, Ntaoula S, Cholongitas E, Davidson BR, Burroughs AK. Elastography for the diagnosis of severity of fibrosis in chronic liver disease: a meta-analysis of diagnostic accuracy. J Hepatol 2011; 54:650–659. 25. Talwalkar JA, Kurtz DM, Schoenleber SJ, West CP, Montori VM. Ultrasound-based transient elastography for the detection of hepatic fibrosis: systematic review and meta-analysis. Clin Gastroenterol Hepatol 2007; 5:1214–1220. 26. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol 2011; 55:245–264. 27. Bamber J, Cosgrove D, Dietrich CF, et al. EFSUMB guidelines and recommendations on the clinical use of ultrasound elastography, part 1: basic principles and technology. Ultraschall Med 2013; 34:169–184. 28. Boursier J, Isselin G, Fouchard-Hubert I, et al. Acoustic radiation force impulse: a new ultrasonographic technology for the widespread noninvasive diagnosis of liver fibrosis. Eur J Gastroenterol Hepatol 2010; 22:1074– 1084. 29. Friedrich-Rust M, Wunder K, Kriener S, et al. Liver fibrosis in viral hepatitis: noninvasive assessment with acoustic radiation force impulse imaging versus transient elastography. Radiology 2009; 252:595–604. 30. Takahashi H, Ono N, Eguchi Y, et al. Evaluation of acoustic radiation force impulse elastography for fibrosis staging of chronic liver disease: a pilot study. Liver Int 2010; 30:538–545.
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31. Palmeri ML, Wang MH, Rouze NC, et al. Noninvasive evaluation of hepatic fibrosis using acoustic radiation force-based shear stiffness in patients with nonalcoholic fatty liver disease. J Hepatol 2011; 55:666–672. 32. Crespo G, Fernández-Varo G, Mariño Z, et al. ARFI, FibroScan®, ELF, and their combinations in the assessment of liver fibrosis: a prospective study. J Hepatol 2012; 57:281–287. 33. Rizzo L, Calvaruso V, Cacopardo B, et al. Comparison of transient elastography and acoustic radiation force impulse for non-invasive staging of liver fibrosis in patients with chronic hepatitis C. Am J Gastroenterol 2011; 106:2112–2120. 34. Friedrich-Rust M, Nierhoff J, Lupsor M, et al. Performance of Acoustic Radiation Force Impulse imaging for the staging of liver fibrosis: a pooled meta-analysis. J Viral Hepat 2012; 19:e212–e219. 35. Guzmán-Aroca F, Reus M, Berná-Serna JD, et al. Reproducibility of shear wave velocity measurements by acoustic radiation force impulse imaging of the liver: a study in healthy volunteers. J Ultrasound Med 2011; 30:975– 979. 36. Ferraioli G, Tinelli C, Zicchetti M, et al. Precision of real-time shear wave elastography in the evaluation of liver elasticity. Eur J Radiol 2012; 81:3102–3106. 37. Ferraioli G, Tinelli C, Dal Bello B, Zicchetti M, Filice G, Filice C; Liver Fibrosis Study Group. Accuracy of real-time shear wave elastography for assessing liver fibrosis in chronic hepatitis C: a pilot study. Hepatology 2012; 56:2125–2133. 38. Bavu E, Gennisson JL, Couade M, et al. Noninvasive in vivo liver fibrosis evaluation using supersonic shear imaging: a clinical study on 113 hepatitis C virus patients. Ultrasound Med Biol 2011; 37:1361–1373. 39. Ling W, Lu Q, Quan J, Ma L, Luo Y. Assessment of impact factors on shear wave based liver stiffness measurement. Eur J Radiol 2013; 82:335– 341. 40. Ferraioli G, Tinelli C, Lissandrin R, Zicchetti M, Dal Bello B, Filice C. Performance of ElastPQ® shear wave elastography technique for assessing fibrosis in chronic viral hepatitis [abstract]. J Hepatol2013; 58(suppl 1):S7. 41. Hall TJ, Milkowski A, Garra B, et al. RSNA/QIBA: shear wave speed as a biomarker for liver fibrosis staging. Paper presented at: IEEE International Ultrasonics Symposium; July 21–25, 2013; Prague, Czech Republic. 42. Castéra L, Foucher J, Bernard PH, et al. Pitfalls of liver stiffness measurement: a 5-year prospective study of 13,369 examinations. Hepatology 2010; 51:828–835. 43. Bedossa P, Dargere D, Paradise V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology 2003; 38:1449–1457. 44. Colli A, Fraquelli M, Andreoletti M, Marino B, Zuccoli E, Conte D. Severe liver fibrosis or cirrhosis: accuracy of US for detection—analysis of 300 cases. Radiology 2003; 227:89–94.
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SOUND JUDGMENT SERIES
Shear Wave Elastography for Evaluation of Liver Fibrosis Giovanna Ferraioli, MD, Parth Parekh, MD, Alexander B. Levitov, MD, RDCS, Carlo Filice, MD
Invited paper
The Sound Judgment Series consists of invited articles highlighting the clinical value of using ultrasound first in specific clinical diagnoses where ultrasound has shown comparative or superior value. The series is meant to serve as an educational tool for medical and sonography students and clinical practitioners and may help integrate ultrasound into clinical practice.
Received August 19, 2013, from the Ultrasound Unit, Department of Infectious Diseases, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, University of Pavia Medical School, Pavia, Italy (G.F., C.F.); and Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, Virginia USA (P.P., A.B.L.). Revision requested September 3, 2013. Revised manuscript accepted for publication September 11, 2013. Drs Ferraioli and Filice received a research grant from Philips Healthcare (Bothell, WA). Address correspondence to Giovanna Ferraioli, MD, Ultrasound Unit, Department of Infectious Diseases, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, University of Pavia Medical School, Via Taramelli 5, 27100 Pavia, Italy. E-mail: [email protected] Abbreviations
SWE, ShearWave Elastography; VTTQ, Virtual Touch Tissue Quantification doi:10.7863/ultra.33.2.197
The prognosis and management of chronic viral hepatitis mainly depend on the extent of liver fibrosis, particularly in chronic hepatitis C. Liver histologic analysis is still considered the reference standard in the assessment of liver fibrosis despite the interobserver and interobserver variability in staging and some morbidity and mortality risks. Thus, noninvasive methods for assessing liver fibrosis are of great clinical interest. In the last decade, ultrasound-based techniques to estimate the stage of liver fibrosis have become commercially available. They all have the capability to noninvasively evaluate differences in the elastic properties of soft tissues by measuring tissue behavior when a mechanical stress is applied. Shear wave elastography relies on the generation of shear waves determined by the displacement of tissues induced by the force of a focused ultrasound beam or by an external push. This article reviews the results that have been obtained with shear wave elastography for assessment of liver fibrosis. Key Words—chronic hepatitis; elastography; fibrosis; gastrointestinal ultrasound; liver; ultrasound
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t is estimated that 500 million people are affected by chronic viral hepatitis worldwide, of which 1 million people will die of their illness every year, primarily from cirrhosis or hepatocellular carcinoma as a result of their infection.1 In the United States, more than 4 million people have this disease, with an annual mortality rate of 15,000 people.2 The prognosis and management of chronic viral hepatitis mainly depend on the extent of liver fibrosis, particularly in chronic hepatitis C. Long thought to be irreversible, recent studies have shown this idea to be false, even in its advanced stages, thus stressing the importance of early diagnosis.3 Liver histologic analysis is still considered the reference standard in the assessment of liver fibrosis despite the intraobserver and interobserver variability in staging.4 Regev et al4 found approximately 25% of patients (30 of 124) to have a difference of at least one grade and 33% (41 of 124) to have at least one stage difference between the right and left lobes. Ultimately, Regev et al4 found an underdiagnosis of cirrhosis in approximately 15% of patients. Moreover, liver biopsy is a painful technique that is not well accepted by patients, has morbidity and mortality risks, and is not an ideal method for following patients. Thus, noninvasive methods for assessing liver fibrosis are of great clinical interest. In the last decade, techniques to noninvasively estimate the stage of liver fibrosis have become commercially available. They all have the capability to evaluate differences in the elas-
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tic properties of soft tissues by measuring tissue behavior when a mechanical stress is applied. Ultrasound and magnetic resonance have been used for elasticity imaging. Magnetic resonance elastography, even though promising, has some disadvantages. It cannot be performed in a liver with an iron overload because of signal-to-noise limitations, the examination time is longer with respect to ultrasound elastography, and it is a costly procedure.5 Shear wave elastography relies on the generation of shear waves determined by the displacement of tissues induced by the force of a focused ultrasound beam or by external pressure. The shear waves are lateral waves, with a motion perpendicular to the direction of the force that has generated them. They travel slowly (between 1 and 10 m/s) and are rapidly attenuated by tissue. The propagation velocity of the shear waves correlates with the elasticity of tissue; ie, it increases with increasing stiffness of the liver parenchyma.6 To correctly read the results, it should be kept in mind that elastography assesses liver elasticity that could be modified by factors other than fibrosis, such as edema, inflammation, extrahepatic cholestasis, and congestion.7–10 In fact, these factors may lead to overestimation of the liver stiffness for a sharp enlargement of the liver, which is covered by the Glisson capsule, a poor distensible envelope. Thus, the results obtained should always be interpreted in clinical settings. Examinations should be performed under fasting conditions because it has been demonstrated that food intake may produce false-positive results.11,12
Transient Elastography The pioneer technique has been transient elastography, which is performed with the FibroScan device (Echosens, Paris, France). A single-element ultrasound transducer operating at 5 MHz is built on the axis of a pistonlike vibrator.13 By pushing a button, low-frequency (50 Hz) transient vibrations are transmitted, and the elastic shear waves that are generated propagate through underlying tissues. Pulse-echo ultrasound acquisitions are used to follow the propagation of the shear wave and to measure its velocity.13 Transient elastography measures liver stiffness in a volume that approximates a cylinder 1 cm wide and 4 cm long between 25 and 65 mm below the skin surface. This volume is at least 100 times bigger than a biopsy sample and is therefore far more representative of the liver parenchyma.14 Transient elastography is performed on a patient lying supine with the right arm elevated to facilitate access to the right liver. The tip of the probe contacts the intercostal skin with coupling gel. The operator, assisted
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by a time-motion image, locates a liver portion at least 6 cm deep and free of large vascular structures (Figure 1). The device gives an estimate of the velocity of shear waves, which can be also expressed in kilopascals through the Young modulus: E = 3 (vs · ρ), where E is the Young modulus, vs is the shear wave velocity, and ρ is the density of tissue, assumed to be the same as water. The software of the device determines whether each measurement is successful. When a shot is unsuccessful, the machine does not give any value. The entire procedure is considered to have failed when no value is obtained after 10 shots. Successful measurements are validated by these criteria: (1) 10 valid shots; (2) a ratio of valid shots to the total number of shots of 60% or higher; and (3) variability of measurements less than 30% of the median value of liver stiffness measurements.15 Transient elastography has excellent intraobserver and interobserver reproducibility, with an intraclass correlation coefficient of 0.98 even though the interobserver agreement decreases in patients with a lower degree of liver fibrosis, with liver steatosis, or with an increased body mass index.16 In healthy blood donors, a mean normal liver stiffness ± SD of 4.9 ± 1.7 kPa (1.28 ± 0.75 m/s) has been found.16 Several studies and metaanalyses13–25 have examined the diagnostic performance of transient elastography in staging liver fibrosis in patients with different etiologies of chronic liver disease. Most of the studies have been conducted in patients with chronic hepatitis C and have shown high diagnostic accuracy of transient elastography in staging liver fibrosis. It should be pointed out, however, that a substantial overlap of liver stiffness values between adjacent stages of liver fibrosis, particFigure 1. Shear wave elastography with the FibroScan device: A, TMmode image; B, A-mode image; C, elastographic image. TM-mode and A-mode images are used to locate a liver portion suitable for the measurement. The slope of the white dotted line in C, which represents shear wave velocity, is a function of the fibrosis stage.
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ularly for lower fibrosis stages, has been observed. Transient elastography more accurately detects cirrhosis than significant fibrosis. Several meta-analyses have confirmed that transient elastography appears to be a reliable method for the diagnosis and exclusion of cirrhosis as opposed to predicting cirrhosis. For the diagnosis of cirrhosis, transient elastographic cutoff values have been found to be between 11.8 and 14.6 kPa (1.98 and 2.21 m/s). In clinical practice, liver stiffness values from 2.5 to 7.0 kPa (0.91–1.53 m/s) indicate mild or no fibrosis, and values greater than 12.5 kPa (2.04 m/s) are suggestive of cirrhosis.17 The European Association for the Study of the Liver has indicated that noninvasive methods can now be used instead of liver biopsy in patients with chronic hepatitis C to assess liver disease severity before therapy at a safe level of predictability.26 Transient elastography cannot technically be performed in patients with ascites and has a high rate of failure in patients with body mass indices greater than 30 kg/m2. The recent availability of the FibroScan XL probe has overcome this latter limitation.
of liver stiffness at a single location is obtained (Figures 2 and 3). They have been categorized as point–shear wave elastography.27 The SWE technique is based on an ultrafast ultrasound imaging approach that allows detailed monitoring of the shear waves in a large area of liver parenchyma with real-time color-coded elasticity imaging inside a sample box, and the measurement is obtained by placing a region of interest inside the sample box (Figure 4). This technique is 2-dimensional elastography.27 In all of the studies that have assessed the accuracy of the different devices in staging liver fibrosis, right intercostal access has been used. The patient is examined in the dorsal decubitus position with the right arm elevated above the head for optimal intercostal access in a resting respiraFigure 2. Shear wave elastography of the liver performed with the Siemens system through intercostal access. The measurement is given in meters per seconds.
Elastographic Techniques Based on Shear Waves Generated by the Acoustic Beam These techniques have the advantage of being integrated into ultrasound systems; thus, conventional sonography, which is advised every 6 to 12 months in patients with chronic liver disease, could also be performed. As of today, for the assessment of liver stiffness, these techniques are commercially available in high-end ultrasound systems made by Philips Healthcare (Bothell, WA; ElastPQ), Siemens Medical Solutions (Mountain View, CA; Virtual Touch Tissue Quantification [VTTQ]), and SuperSonic Imagine, SA (Aix-en-Provence, France; ShearWave Elastography [SWE]). These techniques generate shear waves inside the liver by using radiation force from a focused ultrasound beam. The shear waves are generated near the region of interest in the liver parenchyma and not on the surface of the body, as happens with external vibration devices. The ultrasound system monitors shear wave propagation using a Doppler-like ultrasound technique and measures its velocity. The shear wave velocity is displayed in meters per second or kilopascals through the Young modulus. Unlike transient elastography, the measurements are not limited by the presence of ascites because the ultrasound beam, which generates the shear waves, propagates through fluids. With the VTTQ and ElastPQ techniques, the readings of the shear wave speed are made by using a small sample box (usually 0.5 × 1 cm); thus, a quantitative estimate
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Figure 3. Shear wave elastography of the liver performed with the Philips system through intercostal access. The measurement is shown in kilopascals. In the bottom left corner, a scale shows the stiffness degree.
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tory position. Measurements are performed at least 1.5 to 2.0 cm beneath the Glisson capsule to avoid reverberation artifacts. In case of physical conditions affecting the signalto-noise ratio, the Philips and Siemens devices do not give any measurement. With the SuperSonic Imagine device, a measurement fails when no/little signals are obtained in the sample box for all of the acquisitions. Siemens Technique (VTTQ) The first one available was the Siemens technique, which is commonly referred to as acoustic radiation force impulse in the literature, which is technically the same force that generates shear waves for all 3 available techniques.27 Moreover, the term acoustic radiation force impulse is rather generic and does not identify shear wave–based methods. In fact, acoustic radiation force impulse push pulses are also used in strain imaging of other organs, such as the breast and thyroid. In recent years, the diagnostic accuracy of the VTTQ technology for quantification of liver stiffness, mainly in patients with chronic hepatitis C, has been investigated in several studies and a meta-analysis.28–34 The technology has shown high interobserver agreement, with an intraclass correlation coefficient of 0.86.35 Operator training does not seem to be required.28 The cutoff values obtained in a large meta-analysis were 1.34, 1.55, and 1.80 m/s for significant fibrosis (METAVIR fibrosis score of F2 or greater), severe fibrosis (METAVIR fibrosis score of F3 or greater), and cirrhosis (METAVIR fibrosis score of F4), respectively.34 In this meta-analysis, which included patients with several etiologies of chronic liver
Figure 4. Shear wave elastography of the liver performed with the SuperSonic Imagine system through intercostal access. The shade of blue in the box is related to the speed of the shear waves. The velocity range (in kilopascals) is shown in the vertical bar on the right: the colors go from dark blue (soft tissues) to red (hard tissues).
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disease, the diagnostic accuracy was comparable with that of transient elastography for the assessment of severe fibrosis, whereas higher performance of transient elastography was seen for significant fibrosis and liver cirrhosis. In a study by Rizzo et al,33 the technique was significantly more accurate than transient elastography for diagnosing significant and severe fibrosis, whereas this difference was only marginal for cirrhosis.
SuperSonic Imagine Technique (SWE) The reproducibility of the SWE method is very high, with intraobserver intraclass correlation coefficients of 0.95 and 0.93 for an expert and a novice operator, respectively, and interobserver agreement of 0.88.36 As for conventional sonography, it is user dependent; thus, it is recommended that at least 50 supervised scans and measurements should be performed by a novice operator to obtain consistent measurements. Values obtained in a small series of healthy participants ranged from 4.92 kPa (1.28 m/s) to 5.39 kPa (1.34 m/s).36 In a pilot study conducted on 121 patients with chronic hepatitis C undergoing liver biopsy, the optimal cutoff values were 7.1 kPa (1.54 m/s) for significant fibrosis (METAVIR fibrosis score of F2 or greater), 8.7 kPa (1.70 m/s) for advanced fibrosis (METAVIR fibrosis score of F3 or greater), and 10.4 kPa (1.86 m/s) for cirrhosis (METAVIR fibrosis score of F4), and the technique was more accurate than transient elastography in assessing significant fibrosis.37 In another study, with respect to transient elastography, the technique showed higher accuracy in assessing mild and intermediate stages of fibrosis.38
Philips Technique (ElastPQ) The ElastPQ technique was the most recent to enter the market; thus, only a few studies have been published so far. With this technique, liver stiffness values in healthy volunteers have been reported to be less than 4.0 kPa (1.15 m/s).39,40 Ling et al39 found that men had higher values than women (3.8 ± 0.7 versus 3.5 ± 0.4 kPa, or 1.13 ± 0.48 versus 1.08 ± 0.37 m/s) and liver stiffness was comparable with different probe positions, examiners, and age groups. In a series that comprised 88 patients with chronic viral hepatitis and 33 healthy volunteers, the technique compared favorably with transient elastography in staging liver fibrosis, and healthy volunteers showed significantly lower values than patients with nonsignificant fibrosis.40
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Limitations and Pitfalls Working on phantoms, the Quantitative Imaging Biomarker Alliance created by the Radiological Society of North America has shown that a limitation of the technique is that there is a statistically significant difference in the shear wave velocity estimates among systems and with depth into the phantom, which was shown with all imaging systems, whereas no statistically significant differences were found among appraisers using the same or equivalent systems.41 Because most studies have been conducted in patients with chronic hepatitis C, the cutoffs need to be further validated for other etiologies of diffuse liver disease. In acute hepatitis, values could be very high even in the absence of fibrosis, and there is a progressive normalization of stiffness values in parallel with the decrease in aminotransferase levels. In a study by Coco et al,8 the values of liver stiffness assessed by transient elastography were correlated with aminotransferase levels at the onset of acute viral hepatitis, when the presence of tissue inflammation and edema is likely to be maximal. In patients with congestive heart failure, it has been shown that liver stiffness directly depends on venous pressure. The stiffness increase could be due to the congestion of the liver with dilatation of both venae cavae and hepatic veins that causes enlargement of the liver, which is enveloped by the Glisson capsule.9 Moreover, it has been reported that cholestasis represents a confounding factor in liver stiffness measurement.10 Transient elastography cannot be performed in patients with ascites. Failure to obtain any measurement with transient elastography has been observed in 4% of examinations, and unreliable results were obtained in 17%;
both were associated with obesity or limited operator experience.42 Measurement failure with elastographic techniques based on shear waves generated by the acoustic beam has been reported in less than 3% of patients.34–37
Clinical Cases Case 1 A 43-year-old man has been infected with chronic hepatitis C for 20 years. He has had transiently elevated serum aminotransferase levels in the past but has had normal values at follow-up for 2 years. To start an antiviral treatment, he has been scheduled for liver biopsy by the referring physician. Biochemical test results obtained the day before liver biopsy are within the normal range. Two shear wave elastographic techniques are performed on the same day as liver biopsy (Figure 5). The results of the noninvasive methods are discordant with that of liver biopsy. In fact, both techniques give values of advanced fibrosis, whereas liver histologic analysis shows METAVIR stage F1 (nonsignificant fibrosis). On the basis of the concordance between the two noninvasive methods the physician has decided to start antiviral therapy, and the patient is now receiving treatment. Considering that liver biopsy is not a perfect reference standard, these different results could be due to a failure of liver biopsy in correctly assessing liver fibrosis and could be explained by the uneven distribution of fibrosis. In fact, histologic staging is based on a biopsy specimen that represents at most 1/50,000 of the total liver mass. In this regard, the sample size of elastographic techniques is more representative of liver tissue than a liver biopsy specimen, and the evaluation could be done in several areas of the liver parenchyma. On the other hand, even when an expe-
Figure 5. Images from 43-year-old man infected with chronic hepatitis C for 20 years. Shear wave elastography of the liver performed with the Philips system (A) and the SuperSonic Imagine system (B) show advanced fibrosis. A
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B
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rienced physician performs a liver biopsy and an expert pathologist interprets the results, liver biopsy has a sampling error in diffuse liver disease staging.4,43 Case 2 A 57-year-old woman has been infected with chronic hepatitis C for 28 years. Biochemical test results are within the normal range. She has had follow-up with sonography every 6 months. Sonographic findings are normal, whereas elastography gives a value compatible with liver cirrhosis (Figure 6), which is confirmed by a liver biopsy performed 3 weeks later. Sonography is a noninvasive and inexpensive procedure for diagnosis of diffuse liver disease; however, the value of sonography for distinguishing a low degree of liver fibrosis from cirrhosis is limited. In a study by Colli et al,44 28 of 107 patients with severe fibrosis or definite cirrhosis (26%) had negative results for liver surface nodularity and caudate lobe hypertrophy and had normal hepatic venous flow. In this regard, elastography integrated into ultrasound systems is an effective adjunctive tool for quantifying liver fibrosis.
allows one to choose an area of liver parenchyma better suited for stiffness assessment (ie, free of large vessels and focal lesions). These methods are all valid when information about fibrosis is needed. Liver biopsy should still be performed when biochemical tests and imaging studies are inconclusive or information other than liver fibrosis is required.
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2.
3.
4.
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Conclusions In patients with chronic viral hepatitis, particularly in patients with hepatitis C virus infection, all noninvasive methods are ready to be used for detecting and staging liver fibrosis before therapy at a safe level of predictability. As with transient elastography, elastographic techniques based on shear waves generated by the acoustic beam are more accurate in detecting cirrhosis than significant fibrosis. They have the advantage of B-mode guidance, which
6.
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9. Figure 6. Image from a 57-year-old woman infected with chronic hepatitis C for 28 years. Elastography gives a value indicating liver cirrhosis.
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