- Email: [email protected]
Update on ultrasound imaging of liver fibrosis
Hepatology Snapshot
Update on ultrasound imaging of liver fibrosis Annalisa Berzigotti1,2, Laurent Castera3,4,* 1
Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Institut d’Investigacións Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; 2Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), University of Barcelona, Barcelona, Spain; 3Department of Hepatology, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Université Denis Diderot Paris-7, Clichy, France; 4INSERM U773 CRB3, Clichy, France *Corresponding author. Address: Department of Hepatology, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, 100 Bd du Général Leclerc, Clichy, France. *E-mail address: [email protected]
Well validated techniques
New techniques - need validation
Bidimensional grey-scale ultrasound
A
High-frequency grey-scale ultrasound
B
C
Colour and power Doppler ultrasound
E
D
Liver surface evaluation • digital analysis • qualitative and quantitative data
Liver and spleen morphologic features • qualitative and quantitative data
Acoustic structure quantification
Ultrasound texture features • digital analysis • quantitative data
Dynamic contrast-enhanced ultrasound
F
G
H
Hepatic vasculature morphology and patency • qualitative and semi-quantitative data
Microvascular derangement • dynamic quantitative data on hepatic transit time and perfusion by microbubbles, kinetics digitally assessed
Pulse-wave Doppler ultrasound
Sonoelastographic techniques
Liver stiffness estimation indirectly derived by blood flow velocity tracing • quantitative and semi-quantitative data
I
K
L
Transient elastography Liver stiffness quantification • M-mode visualization of the region of interest (ROI) • quantitative data
J
Elasticity/stiffness of the tissue • ROI placed on direct B-mode visualization in real-time (liver, spleen) • quantitative data
accepted 28 December 2012
Journal of Hepatology 2013 vol 58 | 180-182
M
Hepatology Snapshot Table 1. Respective advantages and disadvantages of currently available US-based techniques for measuring liver stiffness.
Transient elastography (TE) Advantages
Disadvantages
• Reference standard to be beaten • User-friendly (performed at bedside; rapid, short learning curve) • Good reproducibility • High range of values (2-75 kPa) • Quality criteria well defined • High performance for cirrhosis (AUROC >0.9) • Prognostic value in cirrhosis • Requires a dedicated device • Region of Interest (ROI) cannot be chosen • Unable to discriminate between intermediate stages of fibrosis • Low applicability 80% (obesity, ascites, limited operator experience) • False positive in case of acute hepatitis, extra-hepatic cholestasis and congestion
Acoustic radiation force impulse imaging (ARFI) • Can be implemented on a regular US machine • ROI smaller than TE but chosen by the operator • Higher applicability than TE (ascites and obesity) • Performance likely equivalent to that of TE for significant fibrosis and cirrhosis • Ongoing validation • Unable to discriminate between intermediate stages of fibrosis • Units (m/sec) different from that of TE (kPa) • Narrow range of values (0.5-4.4 m/sec) • Quality criteria not well defined • Influence of inflammation? • Prognostic value in cirrhosis?
ShearWave elastography (SWE) • Can be implemented on a regular US machine • ROI can be adjusted in size and location and chosen by the operator • Measures liver stiffness in real-time • High range of values (2-150 kPa) • Good applicability • Performance may be higher than TE for significant fibrosis • Further validation warranted • Unable to discriminate between intermediate stages of fibrosis • Limited data on reproducibility • Learning curve? • Quality criteria? • Influence of inflammation?
Introduction
US techniques to assess the hepatic vasculature
Staging of liver fibrosis is crucial in the management of patients with chronic liver diseases (CLD) since fibrosis severity influences the prognosis and treatment options. An early diagnosis of cirrhosis is particularly important in patients with compensated CLD, because it triggers screening for portal hypertension and hepatocellular carcinoma. Liver biopsy has been considered the reference technique for staging liver fibrosis, but has well known limitations, including invasiveness and sampling errors, which have led to explore non-invasive surrogates [1]. Ultrasound has been used for many years for the work-up of patients with CLD because of its ease of use and wide availability. Recent technological advances have allowed liver fibrosis staging using a variety of US-based techniques (Fig. 1).
Liver fibrosis induces a progressive distortion of the intrahepatic vasculature and is accompanied by angiogenesis, concurring to portal hypertension in cirrhosis. Colour (CDUS) and Power Doppler US are accurate in assessing liver macrovascular anatomy and its changes secondary to portal hypertension [5], but no sign is observed before cirrhosis develops. Conversely, contrast-enhanced US (CEUS) allows the study of the microvascular component of hepatic circulation. The interval between the appearance of contrast microbubbles (purely intravascular) in the portal vein (or hepatic artery) and hepatic veins, known as hepatic transit time (HTT), shortens progressively as liver fibrosis progresses [6], due to intrahepatic arteriovenous shunting and arterialization of the liver vasculature. Even if HTT accuracy in diagnosing mild or moderate fibrosis remains unsatisfactory, preliminary data indicate a better performance in diagnosing cirrhosis. CEUS can also be used to assess regional hepatic perfusion, which correlates with the severity of liver failure and circulatory abnormalities in cirrhosis [5].
US techniques to assess liver and spleen morphologic features Ultrasound is inaccurate in detecting mild fibrosis. Indeed, liver morphology is normal in patients with mild fibrosis, while significant liver fibrosis deposition progressively induces changes in liver (and spleen) anatomy, which can be characterized by conventional grey-scale Bmode ultrasound (US). Among them, liver surface irregularity, heterogeneity of liver echotexture and increase in spleen size are often seen in patients with significant fibrosis and early cirrhosis, and left-to-right liver volume redistribution (left liver lobe and caudate lobe often increase in size in cirrhosis) can become evident in established cirrhosis [2]. Even if none of these signs are accurate enough for distinguishing mild to moderate/severe fibrosis, their combination improves the performance of US to detect cirrhosis, reaching an accuracy of over 80% [2]. A closer look to morphology can be obtained by the digital analysis of US images of the liver parenchyma (quantification of the heterogeneity of echotexture, Acoustic Structure Quantification, Toshiba Medical Systems [3]) and of liver surface studied by high frequency ultrasound (nodularity quantification [4]).
US techniques to estimate liver stiffness Spectral analysis of hepatic blood flow tracings by Pulsed-Doppler US was used in the 90s and early 2000s as surrogate measurement of liver and spleen stiffness. Portal vein velocity decreases, hepatic and splenic artery resistance and pulsatility index (PI) increase, and hepatic veins tracing flattens, as fibrosis progresses and as portal pressure increases [5]. Splenic artery PI has shown a good accuracy for the prediction of significant fibrosis (AUROC 0.87; diagnostic accuracy of 79% using 1.10 as cut-off value) and cirrhosis (AUROC 0.90; diagnostic accuracy of 90% using 1.40 as cut-off value) in HCV patients [7]. However, Doppler resistance varies according to several factors unrelated to liver fibrosis, and its routine measurement is not recommended [5]. A major advance in the measurement of stiffness (or elasticity) was further brought in by the development of liver elasticity-based US techniques. Their respective advantages and disadvantages are summarized in the Table 1.
Fig. 1. Update on ultrasound imaging of liver fibrosis. Morphologic features of the (A) liver and (B) spleen on grey-scale ultrasound can suggest the presence of significant fibrosis and are the mainstay of the US diagnosis of cirrhosis, but are inaccurate for discriminating mild to moderate/severe fibrosis. (C) High frequency ultrasound of the liver surface and (D) acoustic structure quantification allow a digital analysis of the two most important US aspects related to fibrosis deposition, namely irregularity of liver profile and heterogeneity of its echotexture. Changes in the anatomy of hepatic vessels can be studied by Colour- and Power-Doppler US (E and F) and are useful to depict the presence of signs of portal hypertension when cirrhosis has already developed. On the other hand, in pre-cirrhotic phases, when macrovasculature is normal, changes in the hepatic microvasculature can already be found and can be studied by contrast-enhanced ultrasound techniques, such as hepatic transit time (interval occurring between the arrival of microbubbles in the portal vein and hepatic veins: G and H), which shortens as liver fibrosis amount increases. Liver stiffness measurement has been indirectly evaluated by calculating hepatic artery resistance and pulsatility index derived from blood flow velocity tracing on pulsed US-Doppler (I) with inaccurate results. Transient elastography (FibroScan®, Echosens, Paris, France) (J) was the first technique assessing stiffness and is well validated and accurate for the quantitative, non-invasive measurement of liver fibrosis; a limitation of this technique depends on the lack of direct visualization of the region of interest where the measurement is done, since the machine only allows it in monodimensional (M)-mode. Newer proposed sonographic techniques overcoming this limitation include real-time elastography (Hitachi Medical Systems) (K), based on measurement of elastic strain ratio, and shear-wave elastography, which is already available on different ultrasound equipments: Acoustic Radiation Force Impulse imaging (Acuson 2000 Virtual TouchTM Tissue Quantification, Siemens Healthcare, Erlangen, Germany) (L); shear-wave elastography (Aixplorer®, Supersonic Imagine, Aix en Provence, France) (M).
Journal of Hepatology 2013 vol 58 | 180-182
181
Monodimensional ultrasound transient elastography, (TE, FibroScan®, Echosens, Paris, France), was the first introduced technique in the early 2000s. Its principle relies on the measurement of the velocity of a low-frequency (50 Hz) elastic shear wave propagating through the liver, that is directly related to tissue stiffness, called the elastic modulus (expressed as E = 3ρv2, where v is the shear velocity and ρ is the density of tissue, assumed to be constant) [8]. The stiffer the tissue, the faster the shear wave propagates. TE measures liver stiffness in a volume that approximates a cylinder (10-mm wide, 40-mm long), 25–65 mm below skin surface; this region is only visualized in M-mode. Its results are expressed in kilopascals (kPa), and range from 2.5 to 75 kPa, with normal value around 5 kPa. Accurate results require careful interpretation of data, based on at least 10 validated measurements, a success rate (the ratio of valid measurements to the total number of measurement) >60%, and an interquartile range (IQR, reflects variations among measurements) <30% of the median value (IQR/LSM ≤30%) [9]. TE is currently the most widely used and best validated technique for noninvasive assessment of liver fibrosis worldwide, mainly in viral hepatitis [1]. Its diagnostic performance is better for cirrhosis than for significant fibrosis, with mean AUROC values of 0.94 and 0.84, respectively [10]. The main limitation of TE in clinical practice is its limited applicability (80%), mostly due to obesity, ascites or limited operator experience [11]. Recently, the XL-probe has been proposed in order to increase the applicability of TE in obese subjects, but its validation is still ongoing. Also hepatic inflammation, extrahepatic cholestasis, or congestion can lead to overestimation of liver stiffness, independently of fibrosis [1]. More recently, 2D-elastography techniques incorporated into conventional US machines (sonoelastography), hence allowing the examiner visually choosing a region of interest in B-mode, have been introduced and are currently under investigation. Real-time elastography (RTE, Hitachi Medical Systems) is based on strain imaging induced by slight manual compression; it is less accurate in staging liver fibrosis than TE [12]. Other techniques are based on the measurement of the velocity of shear waves generated by mechanically exciting liver tissue by ultrasound pushes. The first one to be described was acoustic radiation force impulse imaging (ARFI, Acuson 2000 Virtual TouchTM Tissue Quantification, Siemens Healthcare, Erlangen, Germany). The shear-wave velocity is measured in a region of interest 6-mm wide, 10-mm long, and in contrast to TE, results are not expressed in kPa and have a narrower range (range: 0.5–4.4 m/ sec) that may represent a limitation for definition of clinically relevant cut-offs. ARFI applicability is high [13], and its accuracy is likely similar to that of TE (AUROC 0.87 for diagnosis of significant fibrosis and 0.93 for cirrhosis) [14], but validation is still ongoing and its place remains to be defined in clinical practice. Sonoelastography techniques have the added advantage of improving the applicability of measurement of spleen stiffness, which is emerging as a novel non-invasive parameter closely correlating with portal pressure in cirrhosis [15]. Shear-Wave elastography (SWE, Aixplorer®, Supersonic Imagine, Aix en Provence, France) has the advantage of being able to image liver stiffness in real time. Preliminary results suggest that SWE may have better performance than TE for diagnosing significant fibrosis in HCV patients [16], but further validation is warranted. © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
182
Financial support CIBERehd is funded by Instituto de Salud Carlos III. Conflict of interest The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Reference [1] Castera L. Noninvasive methods to assess liver disease in patients with hepatitis B or C. Gastroenterology 2012;142:1293-1302 e1294. [2] Arguedas MR, Heudebert GR, Eloubeidi MA, Abrams GA, Fallon MB. Cost-effectiveness of screening, surveillance, and primary prophylaxis strategies for esophageal varices. Am J Gastroenterol 2002;97:2441-2452. [3] Toyoda H, Kumada T, Kamiyama N, Shiraki K, Takase K, Yamaguchi T, et al. B-mode ultrasound with algorithm based on statistical analysis of signals: evaluation of liver fibrosis in patients with chronic hepatitis C. AJR Am J Roentgenol 2009;193:1037-1043. [4] Berzigotti A, Abraldes JG, Tandon P, Erice E, Gilabert R, Garcia-Pagan JC, et al. Ultrasonographic evaluation of liver surface and transient elastography in clinically doubtful cirrhosis. J Hepatol 2010;52:846-853. [5] Berzigotti A, Piscaglia F. Ultrasound in portal hypertension--part 2--and EFSUMB recommendations for the performance and reporting of ultrasound examinations in portal hypertension. Ultraschall Med;33:8-32; quiz 30-31. [6] Staub F, Tournoux-Facon C, Roumy J, Chaigneau C, Morichaut-Beauchant M, Levillain P, et al. Liver fibrosis staging with contrast-enhanced ultrasonography: prospective multicenter study compared with METAVIR scoring. Eur Radiol 2009;19:1991-1997. [7] Liu CH, Hsu SJ, Lin JW, Hwang JJ, Liu CJ, Yang PM, et al. Noninvasive diagnosis of hepatic fibrosis in patients with chronic hepatitis C by splenic Doppler impedance index. Clin Gastroenterol Hepatol 2007;5:1199-1206 e1191. [8] Sandrin L, Fourquet B, Hasquenoph JM, Yon S, Fournier C, Mal F, et al. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol 2003;29:1705-1713. [9] Castera L, Forns X, Alberti A. Non-invasive evaluation of liver fibrosis using transient elastography. J Hepatol 2008;48:835-847. [10] Friedrich-Rust M, Ong MF, Martens S, Sarrazin C, Bojunga J, Zeuzem S, et al. Performance of transient elastography for the staging of liver fibrosis: a meta-analysis. Gastroenterology 2008;134:960-974. [11] Castera L, Foucher J, Bernard PH, Carvalho F, Allaix D, Merrouche W, et al. Pitfalls of liver stiffness measurement: A 5-year prospective study of 13,369 examinations. Hepatology 2010;51:828-835. [12] Friedrich-Rust M, Schwarz A, Ong M, Dries V, Schirmacher P, Herrmann E, et al. Real-time tissue elastography versus FibroScan for noninvasive assessment of liver fibrosis in chronic liver disease. Ultraschall Med 2009;30:478-484. [13] Nightingale K, Soo MS, Nightingale R, Trahey G. Acoustic radiation force impulse imaging: in vivo demonstration of clinical feasibility. Ultrasound Med Biol 2002;28:227-235. [14] Friedrich-Rust M, Nierhoff J, Lupsor M, Sporea I, Fierbinteanu-Braticevici C, Strobel D, et al. Performance of Acoustic Radiation Force Impulse imaging for the staging of liver fibrosis: a pooled meta-analysis. J Viral Hepat 2011;19:e212-e219. [15] Castera L, Garcia-Tsao G. When the Spleen Gets Tough, the Varices Get Going. Gastroenterology 2013;144:19-22. [16] Ferraioli G, Tinelli C, Dal Bello B, Zicchetti M, Filice G, Filice C. Accuracy of realtime shear wave elastography for assessing liver fibrosis in chronic hepatitis C: A pilot study. Hepatology 2012;56:2125-2133.
Journal of Hepatology 2013 vol 58 | 180-182
Update on ultrasound imaging of liver fibrosis Annalisa Berzigotti1,2, Laurent Castera3,4,* 1
Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Institut d’Investigacións Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; 2Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), University of Barcelona, Barcelona, Spain; 3Department of Hepatology, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Université Denis Diderot Paris-7, Clichy, France; 4INSERM U773 CRB3, Clichy, France *Corresponding author. Address: Department of Hepatology, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, 100 Bd du Général Leclerc, Clichy, France. *E-mail address: [email protected]
Well validated techniques
New techniques - need validation
Bidimensional grey-scale ultrasound
A
High-frequency grey-scale ultrasound
B
C
Colour and power Doppler ultrasound
E
D
Liver surface evaluation • digital analysis • qualitative and quantitative data
Liver and spleen morphologic features • qualitative and quantitative data
Acoustic structure quantification
Ultrasound texture features • digital analysis • quantitative data
Dynamic contrast-enhanced ultrasound
F
G
H
Hepatic vasculature morphology and patency • qualitative and semi-quantitative data
Microvascular derangement • dynamic quantitative data on hepatic transit time and perfusion by microbubbles, kinetics digitally assessed
Pulse-wave Doppler ultrasound
Sonoelastographic techniques
Liver stiffness estimation indirectly derived by blood flow velocity tracing • quantitative and semi-quantitative data
I
K
L
Transient elastography Liver stiffness quantification • M-mode visualization of the region of interest (ROI) • quantitative data
J
Elasticity/stiffness of the tissue • ROI placed on direct B-mode visualization in real-time (liver, spleen) • quantitative data
accepted 28 December 2012
Journal of Hepatology 2013 vol 58 | 180-182
M
Hepatology Snapshot Table 1. Respective advantages and disadvantages of currently available US-based techniques for measuring liver stiffness.
Transient elastography (TE) Advantages
Disadvantages
• Reference standard to be beaten • User-friendly (performed at bedside; rapid, short learning curve) • Good reproducibility • High range of values (2-75 kPa) • Quality criteria well defined • High performance for cirrhosis (AUROC >0.9) • Prognostic value in cirrhosis • Requires a dedicated device • Region of Interest (ROI) cannot be chosen • Unable to discriminate between intermediate stages of fibrosis • Low applicability 80% (obesity, ascites, limited operator experience) • False positive in case of acute hepatitis, extra-hepatic cholestasis and congestion
Acoustic radiation force impulse imaging (ARFI) • Can be implemented on a regular US machine • ROI smaller than TE but chosen by the operator • Higher applicability than TE (ascites and obesity) • Performance likely equivalent to that of TE for significant fibrosis and cirrhosis • Ongoing validation • Unable to discriminate between intermediate stages of fibrosis • Units (m/sec) different from that of TE (kPa) • Narrow range of values (0.5-4.4 m/sec) • Quality criteria not well defined • Influence of inflammation? • Prognostic value in cirrhosis?
ShearWave elastography (SWE) • Can be implemented on a regular US machine • ROI can be adjusted in size and location and chosen by the operator • Measures liver stiffness in real-time • High range of values (2-150 kPa) • Good applicability • Performance may be higher than TE for significant fibrosis • Further validation warranted • Unable to discriminate between intermediate stages of fibrosis • Limited data on reproducibility • Learning curve? • Quality criteria? • Influence of inflammation?
Introduction
US techniques to assess the hepatic vasculature
Staging of liver fibrosis is crucial in the management of patients with chronic liver diseases (CLD) since fibrosis severity influences the prognosis and treatment options. An early diagnosis of cirrhosis is particularly important in patients with compensated CLD, because it triggers screening for portal hypertension and hepatocellular carcinoma. Liver biopsy has been considered the reference technique for staging liver fibrosis, but has well known limitations, including invasiveness and sampling errors, which have led to explore non-invasive surrogates [1]. Ultrasound has been used for many years for the work-up of patients with CLD because of its ease of use and wide availability. Recent technological advances have allowed liver fibrosis staging using a variety of US-based techniques (Fig. 1).
Liver fibrosis induces a progressive distortion of the intrahepatic vasculature and is accompanied by angiogenesis, concurring to portal hypertension in cirrhosis. Colour (CDUS) and Power Doppler US are accurate in assessing liver macrovascular anatomy and its changes secondary to portal hypertension [5], but no sign is observed before cirrhosis develops. Conversely, contrast-enhanced US (CEUS) allows the study of the microvascular component of hepatic circulation. The interval between the appearance of contrast microbubbles (purely intravascular) in the portal vein (or hepatic artery) and hepatic veins, known as hepatic transit time (HTT), shortens progressively as liver fibrosis progresses [6], due to intrahepatic arteriovenous shunting and arterialization of the liver vasculature. Even if HTT accuracy in diagnosing mild or moderate fibrosis remains unsatisfactory, preliminary data indicate a better performance in diagnosing cirrhosis. CEUS can also be used to assess regional hepatic perfusion, which correlates with the severity of liver failure and circulatory abnormalities in cirrhosis [5].
US techniques to assess liver and spleen morphologic features Ultrasound is inaccurate in detecting mild fibrosis. Indeed, liver morphology is normal in patients with mild fibrosis, while significant liver fibrosis deposition progressively induces changes in liver (and spleen) anatomy, which can be characterized by conventional grey-scale Bmode ultrasound (US). Among them, liver surface irregularity, heterogeneity of liver echotexture and increase in spleen size are often seen in patients with significant fibrosis and early cirrhosis, and left-to-right liver volume redistribution (left liver lobe and caudate lobe often increase in size in cirrhosis) can become evident in established cirrhosis [2]. Even if none of these signs are accurate enough for distinguishing mild to moderate/severe fibrosis, their combination improves the performance of US to detect cirrhosis, reaching an accuracy of over 80% [2]. A closer look to morphology can be obtained by the digital analysis of US images of the liver parenchyma (quantification of the heterogeneity of echotexture, Acoustic Structure Quantification, Toshiba Medical Systems [3]) and of liver surface studied by high frequency ultrasound (nodularity quantification [4]).
US techniques to estimate liver stiffness Spectral analysis of hepatic blood flow tracings by Pulsed-Doppler US was used in the 90s and early 2000s as surrogate measurement of liver and spleen stiffness. Portal vein velocity decreases, hepatic and splenic artery resistance and pulsatility index (PI) increase, and hepatic veins tracing flattens, as fibrosis progresses and as portal pressure increases [5]. Splenic artery PI has shown a good accuracy for the prediction of significant fibrosis (AUROC 0.87; diagnostic accuracy of 79% using 1.10 as cut-off value) and cirrhosis (AUROC 0.90; diagnostic accuracy of 90% using 1.40 as cut-off value) in HCV patients [7]. However, Doppler resistance varies according to several factors unrelated to liver fibrosis, and its routine measurement is not recommended [5]. A major advance in the measurement of stiffness (or elasticity) was further brought in by the development of liver elasticity-based US techniques. Their respective advantages and disadvantages are summarized in the Table 1.
Fig. 1. Update on ultrasound imaging of liver fibrosis. Morphologic features of the (A) liver and (B) spleen on grey-scale ultrasound can suggest the presence of significant fibrosis and are the mainstay of the US diagnosis of cirrhosis, but are inaccurate for discriminating mild to moderate/severe fibrosis. (C) High frequency ultrasound of the liver surface and (D) acoustic structure quantification allow a digital analysis of the two most important US aspects related to fibrosis deposition, namely irregularity of liver profile and heterogeneity of its echotexture. Changes in the anatomy of hepatic vessels can be studied by Colour- and Power-Doppler US (E and F) and are useful to depict the presence of signs of portal hypertension when cirrhosis has already developed. On the other hand, in pre-cirrhotic phases, when macrovasculature is normal, changes in the hepatic microvasculature can already be found and can be studied by contrast-enhanced ultrasound techniques, such as hepatic transit time (interval occurring between the arrival of microbubbles in the portal vein and hepatic veins: G and H), which shortens as liver fibrosis amount increases. Liver stiffness measurement has been indirectly evaluated by calculating hepatic artery resistance and pulsatility index derived from blood flow velocity tracing on pulsed US-Doppler (I) with inaccurate results. Transient elastography (FibroScan®, Echosens, Paris, France) (J) was the first technique assessing stiffness and is well validated and accurate for the quantitative, non-invasive measurement of liver fibrosis; a limitation of this technique depends on the lack of direct visualization of the region of interest where the measurement is done, since the machine only allows it in monodimensional (M)-mode. Newer proposed sonographic techniques overcoming this limitation include real-time elastography (Hitachi Medical Systems) (K), based on measurement of elastic strain ratio, and shear-wave elastography, which is already available on different ultrasound equipments: Acoustic Radiation Force Impulse imaging (Acuson 2000 Virtual TouchTM Tissue Quantification, Siemens Healthcare, Erlangen, Germany) (L); shear-wave elastography (Aixplorer®, Supersonic Imagine, Aix en Provence, France) (M).
Journal of Hepatology 2013 vol 58 | 180-182
181
Monodimensional ultrasound transient elastography, (TE, FibroScan®, Echosens, Paris, France), was the first introduced technique in the early 2000s. Its principle relies on the measurement of the velocity of a low-frequency (50 Hz) elastic shear wave propagating through the liver, that is directly related to tissue stiffness, called the elastic modulus (expressed as E = 3ρv2, where v is the shear velocity and ρ is the density of tissue, assumed to be constant) [8]. The stiffer the tissue, the faster the shear wave propagates. TE measures liver stiffness in a volume that approximates a cylinder (10-mm wide, 40-mm long), 25–65 mm below skin surface; this region is only visualized in M-mode. Its results are expressed in kilopascals (kPa), and range from 2.5 to 75 kPa, with normal value around 5 kPa. Accurate results require careful interpretation of data, based on at least 10 validated measurements, a success rate (the ratio of valid measurements to the total number of measurement) >60%, and an interquartile range (IQR, reflects variations among measurements) <30% of the median value (IQR/LSM ≤30%) [9]. TE is currently the most widely used and best validated technique for noninvasive assessment of liver fibrosis worldwide, mainly in viral hepatitis [1]. Its diagnostic performance is better for cirrhosis than for significant fibrosis, with mean AUROC values of 0.94 and 0.84, respectively [10]. The main limitation of TE in clinical practice is its limited applicability (80%), mostly due to obesity, ascites or limited operator experience [11]. Recently, the XL-probe has been proposed in order to increase the applicability of TE in obese subjects, but its validation is still ongoing. Also hepatic inflammation, extrahepatic cholestasis, or congestion can lead to overestimation of liver stiffness, independently of fibrosis [1]. More recently, 2D-elastography techniques incorporated into conventional US machines (sonoelastography), hence allowing the examiner visually choosing a region of interest in B-mode, have been introduced and are currently under investigation. Real-time elastography (RTE, Hitachi Medical Systems) is based on strain imaging induced by slight manual compression; it is less accurate in staging liver fibrosis than TE [12]. Other techniques are based on the measurement of the velocity of shear waves generated by mechanically exciting liver tissue by ultrasound pushes. The first one to be described was acoustic radiation force impulse imaging (ARFI, Acuson 2000 Virtual TouchTM Tissue Quantification, Siemens Healthcare, Erlangen, Germany). The shear-wave velocity is measured in a region of interest 6-mm wide, 10-mm long, and in contrast to TE, results are not expressed in kPa and have a narrower range (range: 0.5–4.4 m/ sec) that may represent a limitation for definition of clinically relevant cut-offs. ARFI applicability is high [13], and its accuracy is likely similar to that of TE (AUROC 0.87 for diagnosis of significant fibrosis and 0.93 for cirrhosis) [14], but validation is still ongoing and its place remains to be defined in clinical practice. Sonoelastography techniques have the added advantage of improving the applicability of measurement of spleen stiffness, which is emerging as a novel non-invasive parameter closely correlating with portal pressure in cirrhosis [15]. Shear-Wave elastography (SWE, Aixplorer®, Supersonic Imagine, Aix en Provence, France) has the advantage of being able to image liver stiffness in real time. Preliminary results suggest that SWE may have better performance than TE for diagnosing significant fibrosis in HCV patients [16], but further validation is warranted. © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
182
Financial support CIBERehd is funded by Instituto de Salud Carlos III. Conflict of interest The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Reference [1] Castera L. Noninvasive methods to assess liver disease in patients with hepatitis B or C. Gastroenterology 2012;142:1293-1302 e1294. [2] Arguedas MR, Heudebert GR, Eloubeidi MA, Abrams GA, Fallon MB. Cost-effectiveness of screening, surveillance, and primary prophylaxis strategies for esophageal varices. Am J Gastroenterol 2002;97:2441-2452. [3] Toyoda H, Kumada T, Kamiyama N, Shiraki K, Takase K, Yamaguchi T, et al. B-mode ultrasound with algorithm based on statistical analysis of signals: evaluation of liver fibrosis in patients with chronic hepatitis C. AJR Am J Roentgenol 2009;193:1037-1043. [4] Berzigotti A, Abraldes JG, Tandon P, Erice E, Gilabert R, Garcia-Pagan JC, et al. Ultrasonographic evaluation of liver surface and transient elastography in clinically doubtful cirrhosis. J Hepatol 2010;52:846-853. [5] Berzigotti A, Piscaglia F. Ultrasound in portal hypertension--part 2--and EFSUMB recommendations for the performance and reporting of ultrasound examinations in portal hypertension. Ultraschall Med;33:8-32; quiz 30-31. [6] Staub F, Tournoux-Facon C, Roumy J, Chaigneau C, Morichaut-Beauchant M, Levillain P, et al. Liver fibrosis staging with contrast-enhanced ultrasonography: prospective multicenter study compared with METAVIR scoring. Eur Radiol 2009;19:1991-1997. [7] Liu CH, Hsu SJ, Lin JW, Hwang JJ, Liu CJ, Yang PM, et al. Noninvasive diagnosis of hepatic fibrosis in patients with chronic hepatitis C by splenic Doppler impedance index. Clin Gastroenterol Hepatol 2007;5:1199-1206 e1191. [8] Sandrin L, Fourquet B, Hasquenoph JM, Yon S, Fournier C, Mal F, et al. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol 2003;29:1705-1713. [9] Castera L, Forns X, Alberti A. Non-invasive evaluation of liver fibrosis using transient elastography. J Hepatol 2008;48:835-847. [10] Friedrich-Rust M, Ong MF, Martens S, Sarrazin C, Bojunga J, Zeuzem S, et al. Performance of transient elastography for the staging of liver fibrosis: a meta-analysis. Gastroenterology 2008;134:960-974. [11] Castera L, Foucher J, Bernard PH, Carvalho F, Allaix D, Merrouche W, et al. Pitfalls of liver stiffness measurement: A 5-year prospective study of 13,369 examinations. Hepatology 2010;51:828-835. [12] Friedrich-Rust M, Schwarz A, Ong M, Dries V, Schirmacher P, Herrmann E, et al. Real-time tissue elastography versus FibroScan for noninvasive assessment of liver fibrosis in chronic liver disease. Ultraschall Med 2009;30:478-484. [13] Nightingale K, Soo MS, Nightingale R, Trahey G. Acoustic radiation force impulse imaging: in vivo demonstration of clinical feasibility. Ultrasound Med Biol 2002;28:227-235. [14] Friedrich-Rust M, Nierhoff J, Lupsor M, Sporea I, Fierbinteanu-Braticevici C, Strobel D, et al. Performance of Acoustic Radiation Force Impulse imaging for the staging of liver fibrosis: a pooled meta-analysis. J Viral Hepat 2011;19:e212-e219. [15] Castera L, Garcia-Tsao G. When the Spleen Gets Tough, the Varices Get Going. Gastroenterology 2013;144:19-22. [16] Ferraioli G, Tinelli C, Dal Bello B, Zicchetti M, Filice G, Filice C. Accuracy of realtime shear wave elastography for assessing liver fibrosis in chronic hepatitis C: A pilot study. Hepatology 2012;56:2125-2133.
Journal of Hepatology 2013 vol 58 | 180-182