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WFUMB Guidelines and Recommendations for Clinical Use of Ultrasound Elastography: Part 3: Liver

Open AccessPublished:March 20, 2015DOI:https://doi.org/10.1016/j.ultrasmedbio.2015.03.007

      Abstract

      The World Federation for Ultrasound in Medicine and Biology (WFUMB) has produced these guidelines for the use of elastography techniques in liver disease. For each available technique, the reproducibility, results, and limitations are analyzed, and recommendations are given. Finally, recommendations based on the international literature and the findings of the WFUMB expert group are established as answers to common questions. The document has a clinical perspective and is aimed at assessing the usefulness of elastography in the management of liver diseases.

      Key words

      Introduction

      Diffuse liver disease is a major health problem worldwide. A wide range of liver insults (chronic viral hepatitis, alcoholic and non-alcoholic fatty liver disease, autoimmune hepatitis drug-induced liver injury, primary biliary cirrhosis and several rarer causes) set up a common pathway of fibrosis, which, if the damage continues, progresses and leads to cirrhosis which may be complicated by portal hypertension, liver failure and the development of hepatocellular carcinoma.
      Accurate staging of the degree of fibrosis is essential in planning therapy (including antiviral therapy) and predicting response to treatment and malignant potential. Although liver biopsy has long been the gold standard, it is an invasive procedure with potential complications such as bleeding and severe pain (
      • Bravo A.A.
      • Sheth S.G.
      • Chopra S.
      Liver biopsy.
      ,
      • Cadranel J.F.
      • Rufat P.
      • Degos F.
      Practices of liver biopsy in France: results of a prospective nationwide survey. For the Group of Epidemiology of the French Association for the Study of the Liver (AFEF).
      ). In addition, sampling error is an intrinsic problem because of the small sample size taken from a heterogeneous organ (
      • Cholongitas E.
      • Senzolo M.
      • Standish R.
      • Marelli L.
      • Quaglia A.
      • Patch D.
      • Dhillon A.P.
      • Burroughs A.K.
      A systematic review of the quality of liver biopsy specimens.
      ), and diagnostic consistency may be influenced by interobserver variability (
      • Maharaj B.
      • Maharaji R.J.
      • Leary W.P.
      • Cooppan R.M.
      • Naran A.D.
      • Pirie D.
      • Pudifin D.J.
      Sampling variability and its influence on the diagnostic yield of percutaneous needle biopsy of the liver.
      ,
      • Bedossa P.
      • Dargère D.
      • Paradis V.
      Sampling variability of liver fibrosis in chronic hepatitis C.
      ,
      • Regev A.
      • Berho M.
      • Jeffers L.J.
      • Milikowski C.
      • Molina E.G.
      • Pyrsopoulos N.T.
      • Feng Z.Z.
      • Reddy K.R.
      • Schiff E.R.
      Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection.
      ).
      Therefore, there has been great interest in the development of noninvasive techniques for the diagnosis of liver fibrosis. There are many reports on the use of blood markers for liver fibrosis, such as platelets, hyaluronic acid, type IV collagen, aminotransferase/platelet ratio index (APRI), and algorithm-based serum models (such as Fibro Index, FIB-4, and Fibro Test) (
      • Martinez S.
      • Crespo G.
      • Navasa M.
      • Forns X.
      Noninvasive assessment of liver fibrosis.
      ). However, these methods can be affected by factors unrelated to the liver.
      As chronic liver damage results in hepatic fibrosis characterized by an increase of extracellular matrix produced by fibroblast-like cells, the liver becomes stiffer than normal.
      Elastography can be used to assess liver stiffness noninvasively. It measures tissue behavior when a mechanical stress is applied using ultrasound (US) or magnetic resonance imaging.
      Several US-based elastography techniques are available and have been extensively described in Part 1. Table 1 lists those that are in clinical use. They differ in the physical properties used.
      Table 1Elastography methods in clinical use for the liver
      1- Shear wave speed techniquesTransient elastography

      Point shear wave speed measurement

      Shear wave speed imaging
      2- Strain/displacement techniquesStrain elastography
      SHEAR WAVE-BASED techniques measure the speed of shear waves in tissues. The shear waves can be generated by an external push (transient elastography) or by ultrasound radiation force enabling a single measurement (point shear wave speed measurement) or an image (shear wave speed imaging). The main difference between these techniques is that shear wave speed, being linked with stiffness, can be measured and converted into kPa, the unit of Young’s modulus whereas strain elastography gives relative estimates only.
      STRAIN IGING measures the deformation of tissue.
      The European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) has recently issued guidelines and recommendations on the clinical use of ultrasound elastography (
      • Bamber J.
      • Cosgrove D.
      • Dietrich C.F.
      • Fromageau J.
      • Bojunga J.
      • Calliada F.
      • Cantisani V.
      • Correas J.M.
      • D'Onofrio M.
      • Drakonaki E.E.
      • Fink M.
      • Friedrich-Rust M.
      • Gilja O.H.
      • Havre R.F.
      • Jenssen C.
      • Klauser A.S.
      • Ohlinger R.
      • Saftoiu A.
      • Schaefer F.
      • Sporea I.
      • Piscaglia F.
      EFSUMB guidelines and recommendations on the clinical use of ultrasound elastography. Part 1: Basic principles and technology.
      ,
      • Cosgrove D.
      • Piscaglia F.
      • Bamber J.
      • Bojunga J.
      • Correas J.M.
      • Gilja O.H.
      • Klauser A.S.
      • Sporea I.
      • Calliada F.
      • Cantisani V.
      • D'Onofrio M.
      • Drakonaki E.E.
      • Fink M.
      • Friedrich-Rust M.
      • Fromageau J.
      • Havre R.F.
      • Jenssen C.
      • Ohlinger R.
      • Săftoiu A.
      • Schaefer F.
      • Dietrich C.F.
      EFSUMB guidelines and recommendations on the clinical use of ultrasound elastography. Part 2: Clinical applications.
      ). Accordingly, our objectives are to determine based on the evidence whether elastography is useful and reproducible in the evaluation of diffuse liver disease, in particular, in terms of the accuracy and limitations of the available techniques depending on the indications and etiologies. The impact of elastography on liver biopsy (reduction and/or replacement) for diffuse liver disease will be discussed. Finally, we discuss the potential role of elastography in the characterization of focal liver diseases.

      Transient Elastography

      Procedure

      Transient elastography (TE) is performed on a patient lying supine, with the right arm elevated to facilitate access to the right liver. The tip of the probe is in contact with the intercostal skin through a coupling gel in the 9th to 11th intercostal space at the level where a liver biopsy would be performed. The operator, assisted by a time-motion image, locates a liver portion at least 6 cm deep and free of large vascular structures. The operator then presses the probe button to start the measurements (“shots”). TE measures the liver stiffness in a volume that approximates a cylinder 1 cm wide and 4 cm long, between 25 mm and 65 mm below the skin surface (Figure 1). The software determines whether each measurement is successful or not. When a shot is unsuccessful, the instrument does not return a value. The entire procedure is considered to have failed when no values are obtained after ten shots. Successful measurements are validated using the following criteria: 1) number of valid shots ≥ 10; 2) ratio of valid shots to the total number of shots ≥ 60%; and 3) interquartile range (IQR, reflecting the variability of measurements) less than 30% of the median liver stiffness measurement (LSM) value (IQR/LSM ≤30%) (
      • Castera L.
      • Forns X.
      • Alberti A.
      Non-invasive evaluation of liver fibrosis using transient elastography.
      ).
      Figure thumbnail gr1
      Figure 1(Adapted from
      • Castera L.
      • Forns X.
      • Alberti A.
      Non-invasive evaluation of liver fibrosis using transient elastography.
      ).
      a. Position of probe and explored volume (Imaging from Echosens).
      b. Shear wave propagation according to the severity of hepatic fibrosis (Metavir score). The elastic modulus E expressed as E = 3ρV2, where V is the shear velocity and ρ is the mass density (constant and close to 1 kg/m3 for tissue): the stiffer the tissue, the faster the shear wave propagates. In the absence of fibrosis (F0), the velocity is 1.0 m/s and elasticity is 3 kPa whereas with cirrhosis (F4), the velocity is 3.0 m/s and elasticity is 27 kPa.
      TE is a user-friendly procedure: it only requires a short time (<5 minutes) and can be performed at the bedside or in an outpatient clinic. The results, expressed in kilopascals (kPa) and ranging from 2.5 to 75 kPa, are available immediately. Finally, it is not a difficult procedure to learn and can be performed by a nurse after minimal training (about 100 examinations) (
      • Boursier J.
      • Konate A.
      • Guilluy M.
      • Gorea G.
      • Sawadogo A.
      • Quemener E.
      • Oberti F.
      • Reaud S.
      • Hubert-Fouchard I.
      • Dib N.
      • Cales P.
      Learning curve and interobserver reproducibility evaluation of liver stiffness measurement by transient elastography.
      ). Nevertheless, the clinical interpretation of TE results should be always in the hands of an expert clinician and should be made with full knowledge of the patient demographics, disease etiology and essential laboratory parameters.

      Reproducibility

      Two independent groups (
      • Boursier J.
      • Konate A.
      • Gorea G.
      • Reaud S.
      • Quemener E.
      • Oberti F.
      • Hubert-Fouchard I.
      • Dib N.
      • Cales P.
      Reproducibility of liver stiffness measurement by ultrasonographic elastometry.
      ,
      • Fraquelli M.
      • Rigamonti C.
      • Casazza G.
      • Conte D.
      • Donato M.F.
      • Ronchi G.
      • Colombo M.
      Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic liver disease.
      ) have evaluated its reproducibility. In the earlier study (
      • Fraquelli M.
      • Rigamonti C.
      • Casazza G.
      • Conte D.
      • Donato M.F.
      • Ronchi G.
      • Colombo M.
      Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic liver disease.
      ), the reproducibility of TE was excellent for both inter-observer and intra-observer agreement, with an intraclass correlation coefficient (ICC) of 0.98. However, interobserver agreement was significantly lower in patients with lower degrees of hepatic fibrosis (ICC for F0-F1 0.60 vs. 0.99 for F ≥ 2), with hepatic steatosis (ICC for steatosis ≥ 25% of hepatocytes 0.90 vs. 0.98 for <25%) and those with increased body mass index (ICC for BMI ≥ 25 kg/m² 0.94 vs. 0.98 for <25 kg/m²). Consistent results were reported by
      • Boursier J.
      • Konate A.
      • Guilluy M.
      • Gorea G.
      • Sawadogo A.
      • Quemener E.
      • Oberti F.
      • Reaud S.
      • Hubert-Fouchard I.
      • Dib N.
      • Cales P.
      Learning curve and interobserver reproducibility evaluation of liver stiffness measurement by transient elastography.
      in a series of 46 patients examined by 4 different operators, suggesting that the ideal candidate for TE is a lean patient with severe fibrosis.

      Normal values

      “Normal” liver stiffness values have been examined in 429 healthy subjects without overt causes of liver disease and normal liver enzymes, who were undergoing a medical check-up (
      • Roulot D.
      • Czernichow S.
      • Le Clesiau H.
      • Costes J.L.
      • Vergnaud A.C.
      • Beaugrand M.
      Liver stiffness values in apparently healthy subjects: Influence of gender and metabolic syndrome.
      ). The mean liver stiffness value in these patients was 5.5±1.6 kPa. Age had no influence but, as suggested previously (
      • Corpechot C.
      • El Naggar A.
      • Poupon R.
      Gender and liver: is the liver stiffness weaker in weaker sex?.
      ), liver stiffness values were higher in men than in women (5.8±1.5 vs. 5.2±1.6 kPa, p=0.0002) and in subjects with BMI>30 kg/m2 (6.3±1.9 vs. 5.4±1.5 kPa, p=0.0003). However, even after adjustment for gender and BMI, liver stiffness values remained higher in 59 subjects with the metabolic syndrome (6.5±1.6 vs. 5.3±1.5 kPa, p<0.0001). In a more recent study of 746 Italian subjects analyzed according to the absence (602) or presence of fatty liver (144) at ultrasonography, liver stiffness was significantly lower in normal livers without steatosis than in fatty livers (median 4.4 vs. 5.3 kPa, p<0.001), and male gender was associated with increased liver stiffness (
      • Colombo S.
      • Belloli L.
      • Zaccanelli M.
      • Badia E.
      • Jamoletti C.
      • Buonocore M.
      • Del Poggio P.
      Normal liver stiffness and its determinants in healthy blood donors.
      ). However, all these studies were conducted in developed countries. Recent data from India, using a populations-based approach in 437 healthy subjects, suggest that in healthy individuals, undernutrition and leanness (lower BMI), increase liver stiffness values in a similar way to obesity, providing a U-shaped distribution of normal liver stiffness values (
      • Das K.
      • Sarkar R.
      • Ahmed S.M.
      • Mridha A.R.
      • Mukherjee P.S.
      • Dhali G.K.
      • Santra A.
      • Chowdhury A.
      “Normal” liver stiffness measure (LSM) values are higher in both lean and obese individuals: a population-based study from a developing country.
      ).

      Results

      Diagnostic performances for staging liver fibrosis

      Viral hepatitis and HIV coinfection

      Two index studies suggest the value of TE in the assessment of liver fibrosis in patients with chronic hepatitis C (
      • Castera L.
      • Vergniol J.
      • Foucher J.
      • Le Bail B.
      • Chanteloup E.
      • Haaser M.
      • Darriet M.
      • Couzigou P.
      • De Ledinghen V.
      Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C.
      ,
      • Ziol M.
      • Handra-Luca A.
      • Kettaneh A.
      • Christidis C.
      • Mal F.
      • Kazemi F.
      • de Ledinghen V.
      • Marcellin P.
      • Dhumeaux D.
      • Trinchet J.C.
      • Beaugrand M.
      Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C.
      ). Liver stiffness values correlated strongly with Metavir fibrosis stages. However, despite high area under the receiver operator characteristic curve (AUROC) values, a substantial overlap in liver stiffness between adjacent stages of hepatic fibrosis was observed, particularly for lower stages. Many other groups have confirmed these results (
      • Arena U.
      • Vizzutti F.
      • Abraldes J.G.
      • Corti G.
      • Stasi C.
      • Moscarella S.
      • Milani S.
      • Lorefice E.
      • Petrarca A.
      • Romanelli R.G.
      • Laffi G.
      • Bosch J.
      • Marra F.
      • Pinzani M.
      Reliability of transient elastography for the diagnosis of advanced fibrosis in chronic hepatitis C.
      ;
      • Degos F.
      • Perez P.
      • Roche B.
      • Mahmoudi A.
      • Asselineau J.
      • Voitot H.
      • Bedossa P.
      Diagnostic accuracy of FibroScan and comparison to liver fibrosis biomarkers in chronic viral hepatitis: A multicenter prospective study (the FIBROSTIC study).
      ,
      • Lupsor M.
      • Badea R.
      • Stefănescu H.
      • Grigorescu M.
      • Serban A.
      • Radu C.
      • Crişan D.
      • Sparchez Z.
      • Iancu S.
      • Maniu A.
      Analysis of histopathological changes that influence liver stiffness in chronic hepatitis C. Results from a cohort of 324 patients.
      ,
      • Zarski J.P.
      • Sturm N.
      • Guechot J.
      • Paris A.
      • Zafrani E.S.
      • Asselah T.
      • Boisson R.C.
      • Bosson J.L.
      • Guyader D.
      • Renversez J.C.
      • Bronowicki J.P.
      • Gelineau M.C.
      • Tran A.
      • Trocme C.
      • Ledinghen V.D.
      • Lasnier E.
      • Poujol-Robert A.
      • Ziegler F.
      • Bourliere M.
      • Voitot H.
      • Larrey D.
      • Rosenthal-Allieri M.A.
      • Fouchard Hubert I.
      • Bailly F.
      • Vaubourdolle M.
      Comparison of nine blood tests and transient elastography for liver fibrosis in chronic hepatitis C: The ANRS HCEP-23 study.
      ), also in hepatitis B (
      • Chan H.L.
      • Wong G.L.
      • Choi P.C.
      • Chan A.W.
      • Chim A.M.
      • Yiu K.K.
      • Chan F.K.
      • Sung J.J.
      • Wong V.W.
      Alanine aminotransferase-based algorithms of liver stiffness measurement by transient elastography (Fibroscan) for liver fibrosis in chronic hepatitis B.
      ,
      • Coco B.
      • Oliveri F.
      • Maina A.M.
      • Ciccorossi P.
      • Sacco R.
      • Colombatto P.
      • Bonino F.
      • Brunetto M.R.
      Transient elastography: a new surrogate marker of liver fibrosis influenced by major changes of transaminases.
      ,
      • Degos F.
      • Perez P.
      • Roche B.
      • Mahmoudi A.
      • Asselineau J.
      • Voitot H.
      • Bedossa P.
      Diagnostic accuracy of FibroScan and comparison to liver fibrosis biomarkers in chronic viral hepatitis: A multicenter prospective study (the FIBROSTIC study).
      ,
      • Marcellin P.
      • Ziol M.
      • Bedossa P.
      • Douvin C.
      • Poupon R.
      • de Ledinghen V.
      • Beaugrand M.
      Non-invasive assessment of liver fibrosis by stiffness measurement in patients with chronic hepatitis B.
      ,
      • Oliveri F.
      • Coco B.
      • Ciccorossi P.
      • Colombatto P.
      • Romagnoli V.
      • Cherubini B.
      • Bonino F.
      • Brunetto M.R.
      Liver stiffness in the hepatitis B virus carrier: a non-invasive marker of liver disease influenced by the pattern of transaminases.
      ) and HIV-HCV coinfection (
      • de Ledinghen V.
      • Douvin C.
      • Kettaneh A.
      • Ziol M.
      • Roulot D.
      • Marcellin P.
      • Dhumeaux D.
      • Beaugrand M.
      Diagnosis of hepatic fibrosis and cirrhosis by transient elastography in HIV/hepatitis C virus-coinfected patients.
      ,
      • Kirk G.D.
      • Astemborski J.
      • Mehta S.H.
      • Spoler C.
      • Fisher C.
      • Allen D.
      • Higgins Y.
      • Moore R.D.
      • Afdhal N.
      • Torbenson M.
      • Sulkowski M.
      • Thomas D.L.
      Assessment of liver fibrosis by transient elastography in persons with hepatitis C virus infection or HIV-hepatitis C virus coinfection.
      ,
      • Pineda J.A.
      • Recio E.
      • Camacho A.
      • Macias J.
      • Almodovar C.
      • Gonzalez-Serrano M.
      • Merino D.
      • Tellez F.
      • Rios M.J.
      • Rivero A.
      Liver stiffness as a predictor of esophageal varices requiring therapy in HIV/hepatitis C virus-coinfected patients with cirrhosis.
      ,
      • Vergara S.
      • Macias J.
      • Rivero A.
      • Gutierrez-Valencia A.
      • Gonzalez-Serrano M.
      • Merino D.
      • Rios M.J.
      • Garcia-Garcia J.A.
      • Camacho A.
      • Lopez-Cortes L.
      • Ruiz J.
      • de la Torre J.
      • Viciana P.
      • Pineda J.A.
      The use of transient elastometry for assessing liver fibrosis in patients with HIV and hepatitis C virus coinfection.
      ).
      TE accurately discriminates cirrhosis from significant fibrosis (AUROC 0.87–0.98; correct classification 85% to 94%) (AUROC 0.75–0.93; correct classification from 57% to 90%). Several meta-analyses (
      • Friedrich-Rust M.
      • Ong M.F.
      • Martens S.
      • Sarrazin C.
      • Bojunga J.
      • Zeuzem S.
      • Herrmann E.
      Performance of transient elastography for the staging of liver fibrosis: a meta-analysis.
      ,
      • Shaheen A.A.
      • Wan A.F.
      • Myers R.P.
      FibroTest and FibroScan for the prediction of hepatitis C-related fibrosis: a systematic review of diagnostic test accuracy.
      ,
      • Talwalkar J.A.
      • Kurtz D.M.
      • Schoenleber S.J.
      • West C.P.
      • Montori V.M.
      Ultrasound-Based Transient Elastography for the Detection of Hepatic Fibrosis: Systematic Review and Meta-analysis.
      ,
      • Tsochatzis E.A.
      • Gurusamy K.S.
      • Ntaoula S.
      • Cholongitas E.
      • Davidson B.R.
      • Burroughs A.K.
      Elastography for the diagnosis of severity of fibrosis in chronic liver disease: a meta-analysis of diagnostic accuracy.
      ) have confirmed the better diagnostic performance of TE for cirrhosis than for fibrosis, with mean AUROC values of 0.94 and 0.84, respectively (
      • Friedrich-Rust M.
      • Ong M.F.
      • Martens S.
      • Sarrazin C.
      • Bojunga J.
      • Zeuzem S.
      • Herrmann E.
      Performance of transient elastography for the staging of liver fibrosis: a meta-analysis.
      ). In a meta-analysis of 40 studies (32 papers and 8 abstracts), sensitivity and specificity values were 0.83 and 0.89 for patients with cirrhosis and 0.79 and 0.78 for patients with significant fibrosis. However, only 9 studies (1364 patients) had acceptable standards for both liver biopsy and TE, which limits the conclusions (
      • Tsochatzis E.A.
      • Gurusamy K.S.
      • Ntaoula S.
      • Cholongitas E.
      • Davidson B.R.
      • Burroughs A.K.
      Elastography for the diagnosis of severity of fibrosis in chronic liver disease: a meta-analysis of diagnostic accuracy.
      ).
      The performance of TE is similar in patients with HBV and HCV infection (
      • Cardoso A.C.
      • Carvalho-Filho R.J.
      • Stern C.
      • Dipumpo A.
      • Giuily N.
      • Ripault M.P.
      • Asselah T.
      • Boyer N.
      • Lada O.
      • Castelnau C.
      • Martinot-Peignoux M.
      • Valla D.C.
      • Bedossa P.
      • Marcellin P.
      Direct comparison of diagnostic performance of transient elastography in patients with chronic hepatitis B and chronic hepatitis C.
      ).
      In the metanalysis of
      • Chon Y.E.
      • Choi E.H.
      • Song K.J.
      • Park J.Y.
      • Kim do Y.
      • Han K.H.
      • Chon C.Y.
      • Ahn S.H.
      • Kim S.U.
      Performance of transient elastography for the staging of liver fibrosis in patients with chronic hepatitis B: a meta-analysis.
      , 18 studies comprising 2,772 patients with chronic hepatitis B were analyzed. The mean AUROC values for the diagnosis of significant fibrosis, severe fibrosis, and cirrhosis were 0.86, 0.89, and 0.93, respectively. The estimated cutoffs for F2, F3 and F4 were 7.9 kPa (sensitivity, 74.3%; specificity, 78.3%), 8.8 kPa (sensitivity, 74.0%; specificity, 63.8%), and 11.7 kPa (sensitivity, 84.6%; specificity, 81.5%), respectively.
      Serum aminotransferases should be considered in interpreting the results from TE in patients with hepatitis B because elevated enzymes are associated with increased stiffness readings (
      • Fraquelli M.
      • Rigamonti C.
      • Casazza G.
      • Donato M.F.
      • Ronchi G.
      • Conte D.
      • Rumi M.
      • Lampertico P.
      • Colombo M.
      Etiology-related determinants of liver stiffness values in chronic viral hepatitis B or C.
      ). To avoid false positive results, some authors have proposed using modified TE cut-offs based on ALT levels (
      • Chan H.L.
      • Wong G.L.
      • Choi P.C.
      • Chan A.W.
      • Chim A.M.
      • Yiu K.K.
      • Chan F.K.
      • Sung J.J.
      • Wong V.W.
      Alanine aminotransferase-based algorithms of liver stiffness measurement by transient elastography (Fibroscan) for liver fibrosis in chronic hepatitis B.
      ) - a strategy that might not apply to patients with fluctuating levels of ALT or hepatitis flares. Conversely, in hepatitis B e antigen negative patients with normal ALT levels, non-invasive methods, particularly TE, could be used as adjuncts to HBV DNA measurements, to follow inactive carriers or better identify patients who require liver biopsy (those with ongoing disease activity or significant fibrosis, despite normal ALT levels) (
      • Castera L.
      • Bernard P.H.
      • Le Bail B.
      • Foucher J.
      • Trimoulet P.
      • Merrouche W.
      • Couzigou P.
      • de Ledinghen V.
      Transient elastography and biomarkers for liver fibrosis assessment and follow-up of inactive hepatitis B carriers.
      ,
      • Maimone S.
      • Calvaruso V.
      • Pleguezuelo M.
      • Squadrito G.
      • Amaddeo G.
      • Jacobs M.
      • Khanna P.
      • Raimondo G.
      • Dusheiko G.
      An evaluation of transient elastography in the discrimination of HBeAg-negative disease from inactive hepatitis B carriers.
      ,
      • Ngo Y.
      • Benhamou Y.
      • Thibault V.
      • Ingiliz P.
      • Munteanu M.
      • Lebray P.
      • Thabut D.
      • Morra R.
      • Messous D.
      • Charlotte F.
      • Imbert-Bismut F.
      • Bonnefont-Rousselot D.
      • Moussalli J.
      • Ratziu V.
      • Poynard T.
      An accurate definition of the status of inactive hepatitis B virus carrier by a combination of biomarkers (FibroTest-ActiTest) and viral load.
      ,
      • Oliveri F.
      • Coco B.
      • Ciccorossi P.
      • Colombatto P.
      • Romagnoli V.
      • Cherubini B.
      • Bonino F.
      • Brunetto M.R.
      Liver stiffness in the hepatitis B virus carrier: a non-invasive marker of liver disease influenced by the pattern of transaminases.
      ).

      NAFLD

      So far, the number of studies that have investigated TE in NAFLD patients remains limited (
      • Gaia S.
      • Carenzi S.
      • Barilli A.L.
      • Bugianesi E.
      • Smedile A.
      • Brunello F.
      • Marzano A.
      • Rizzetto M.
      Reliability of transient elastography for the detection of fibrosis in non-alcoholic fatty liver disease and chronic viral hepatitis.
      ,
      • Nobili V.
      • Vizzutti F.
      • Arena U.
      • Abraldes J.G.
      • Marra F.
      • Pietrobattista A.
      • Fruhwirth R.
      • Marcellini M.
      • Pinzani M.
      Accuracy and reproducibility of transient elastography for the diagnosis of fibrosis in pediatric nonalcoholic steatohepatitis.
      ,
      • Petta S.
      • Di Marco V.
      • Camma C.
      • Butera G.
      • Cabibi D.
      • Craxi A.
      Reliability of liver stiffness measurement in non-alcoholic fatty liver disease: the effects of body mass index.
      ,
      • Wong V.W.
      • Vergniol J.
      • Wong G.L.
      • Foucher J.
      • Chan H.L.
      • Le Bail B.
      • Choi P.C.
      • Kowo M.
      • Chan A.W.
      • Merrouche W.
      • Sung J.J.
      • de Ledinghen V.
      Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease.
      ,
      • Yoneda M.
      • Yoneda M.
      • Mawatari H.
      • Fujita K.
      • Endo H.
      • Iida H.
      • Nozaki Y.
      • Yonemitsu K.
      • Higurashi T.
      • Takahashi H.
      • Kobayashi N.
      • Kirikoshi H.
      • Abe Y.
      • Inamori M.
      • Kubota K.
      • Saito S.
      • Tamano M.
      • Hiraishi H.
      • Maeyama S.
      • Yamaguchi N.
      • Togo S.
      • Nakajima A.
      Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with nonalcoholic fatty liver disease (NAFLD).
      ,
      • Wong V.W.
      • Vergniol J.
      • Wong G.L.
      • Foucher J.
      • Chan A.W.
      • Chermak F.
      • Choi P.C.
      • Merrouche W.
      • Chu S.H.
      • Pesque S.
      • Chan H.L.
      • de Lédinghen V.
      Liver stiffness measurement using XL probe in patients with nonalcoholic fatty liver disease.
      ,
      • Kumar R.
      • Rastogi A.
      • Sharma M.K.
      • Bhatia V.
      • Tyagi P.
      • Sharma P.
      • Garg H.
      • Chandan Kumar K.N.
      • Bihari C.
      • Sarin S.K.
      Liver stiffness measurements in patients with different stages of nonalcoholic fatty liver disease: diagnostic performance and clinicopathological correlation.
      ). TE results should be interpreted with caution because these studies have been conducted either in particular populations (Asian with low BMI or pediatric population) or with small sample size. Nevertheless, TE could be useful to confidently exclude severe fibrosis and cirrhosis with a high negative predictive value (approximately 90%) in these patients (
      • Wong V.W.
      • Vergniol J.
      • Wong G.L.
      • Foucher J.
      • Chan H.L.
      • Le Bail B.
      • Choi P.C.
      • Kowo M.
      • Chan A.W.
      • Merrouche W.
      • Sung J.J.
      • de Ledinghen V.
      Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease.
      ). In a very recent meta-analysis, 9 studies including 1,047 NAFLD patients were compared. The analysis was performed only on the data obtained with the M probe in 854 patients. The overall results suggest that TE is good in diagnosing F ≥ 3 (sensitivity, 85%; specificity, 82%) and F=4 (sensitivity, 92%; specificity, 92%) and has moderate accuracy for F ≥ 2, (sensitivity, 79%; specificity 75%) (
      • Kwok R.
      • Tse Y.K.
      • Wong G.L.
      • Ha Y.
      • Lee A.U.
      • Ngu M.C.
      • Chan H.L.
      • Wong V.W.
      Systematic review with meta-analysis: non-invasive assessment of non-alcoholic fatty liver disease–the role of transient elastography and plasma cytokeratin-18 fragments.
      ).

      Other liver diseases

      TE has also been evaluated in cholestatic liver diseases (
      • Corpechot C.
      • Carrat F.
      • Poujol-Robert A.
      • Gaouar F.
      • Wendum D.
      • Chazouilleres O.
      • Poupon R.
      Noninvasive elastography-based assessment of liver fibrosis progression and prognosis in primary biliary cirrhosis.
      ,
      • Corpechot C.
      • El Naggar A.
      • Poujol-Robert A.
      • Ziol M.
      • Wendum D.
      • Chazouilleres O.
      • de Ledinghen V.
      • Dhumeaux D.
      • Marcellin P.
      • Beaugrand M.
      • Poupon R.
      Assessment of biliary fibrosis by transient elastography in patients with PBC and PSC.
      ), in a variety of chronic liver diseases (
      • Foucher J.
      • Chanteloup E.
      • Vergniol J.
      • Castera L.
      • Le Bail B.
      • Adhoute X.
      • Bertet J.
      • Couzigou P.
      • de Ledinghen V.
      Diagnosis of cirrhosis by transient elastography (FibroScan): a prospective study.
      ;
      • Fraquelli M.
      • Rigamonti C.
      • Casazza G.
      • Conte D.
      • Donato M.F.
      • Ronchi G.
      • Colombo M.
      Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic liver disease.
      ,
      • Ganne-Carrie N.
      • Ziol M.
      • de Ledinghen V.
      • Douvin C.
      • Marcellin P.
      • Castera L.
      • Dhumeaux D.
      • Trinchet J.C.
      • Beaugrand M.
      Accuracy of liver stiffness measurement for the diagnosis of cirrhosis in patients with chronic liver diseases.
      ) as well as in alcoholic liver disease (
      • Nahon P.
      • Kettaneh A.
      • Tengher-Barna I.
      • Ziol M.
      • de Ledinghen V.
      • Douvin C.
      • Marcellin P.
      • Ganne-Carrie N.
      • Trinchet J.C.
      • Beaugrand M.
      Assessment of liver fibrosis using transient elastography in patients with alcoholic liver disease.
      ,

      Nguyen-Khac E, Chatelain D, Tramier B, Decrombecque C, Robert B, Joly JP, Brevet M, Grignon P, Lion S, L LEP, Dupas JL. Assessment of asymptomatic liver fibrosis in alcoholic patients using fibroscan: prospective comparison with 7 non-invasive laboratory tests. Aliment Pharmacol Ther 2008:1188-98.

      ). In the study of
      • Corpechot C.
      • Carrat F.
      • Poujol-Robert A.
      • Gaouar F.
      • Wendum D.
      • Chazouilleres O.
      • Poupon R.
      Noninvasive elastography-based assessment of liver fibrosis progression and prognosis in primary biliary cirrhosis.
      , there was a significant association between TE and histological fibrosis stage (P < 0.0001), but no correlation with necroinflammatory activity grade or the presence of ductopenia. It has been suggested by several groups that the presence of alcoholic hepatitis may influence the liver stiffness results (
      • Bardou-Jacquet E.
      • Legros L.
      • Soro D.
      • Latournerie M.
      • Guillygomarc'h A.
      • Le Lan C.
      • Brissot P.
      • Guyader D.
      • Moirand R.
      Effect of alcohol consumption on liver stiffness measured by transient elastography.
      ,
      • Mueller S.
      • Millonig G.
      • Sarovska L.
      • Friedrich S.
      • Reimann F.M.
      • Pritsch M.
      • Eisele S.
      • Stickel F.
      • Longerich T.
      • Schirmacher P.
      • Seitz H.K.
      Increased liver stiffness in alcoholic liver disease: differentiating fibrosis from steatohepatitis.
      ,
      • Trabut J.B.
      • Thepot V.
      • Nalpas B.
      • Lavielle B.
      • Cosconea S.
      • Corouge M.
      • Vallet-Pichard A.
      • Fontaine H.
      • Mallet V.
      • Sogni P.
      • Pol S.
      Rapid decline of liver stiffness following alcohol withdrawal in heavy drinkers.
      ) and thus TE should be performed after alcohol withdrawal to improve accuracy.

      Cut-offs

      TE appears as a reliable method for the diagnosis of cirrhosis, better at excluding than at predicting cirrhosis. For instance, in a population of 1,007 patients with different chronic liver diseases, a cut-off value of 14.6 kPa yielded positive and negative predictive values of 74% and 96%, respectively (
      • Ganne-Carrie N.
      • Ziol M.
      • de Ledinghen V.
      • Douvin C.
      • Marcellin P.
      • Castera L.
      • Dhumeaux D.
      • Trinchet J.C.
      • Beaugrand M.
      Accuracy of liver stiffness measurement for the diagnosis of cirrhosis in patients with chronic liver diseases.
      ). Interestingly, proposed cut-off values for cirrhosis ranged from 11 kPa in patients with hepatitis B to 22.7 kPa in patients with alcoholic liver disease. Some researchers have proposed cut-off values based on the causes of liver disease (
      • Ganne-Carrie N.
      • Ziol M.
      • de Ledinghen V.
      • Douvin C.
      • Marcellin P.
      • Castera L.
      • Dhumeaux D.
      • Trinchet J.C.
      • Beaugrand M.
      Accuracy of liver stiffness measurement for the diagnosis of cirrhosis in patients with chronic liver diseases.
      ). However, differences among cut-off values could result from differences in the prevalence of cirrhosis among the study populations (ranging from 8% to 25%). A cut-off value for one population might not be applicable to another with a different prevalence of disease. Most studies used single cut-off values for patients with cirrhosis or advanced fibrosis, but more information can be obtained when values are interpreted as a continuum. For example, when liver stiffness values range from 2.5 to 7 kPa, fibrosis is likely mild or absent, whereas when values are above 12.5 kPa, cirrhosis is likely (
      • Castera L.
      • Forns X.
      • Alberti A.
      Non-invasive evaluation of liver fibrosis using transient elastography.
      ) (Figure 2).
      Figure thumbnail gr2
      Figure 2(Adapted from
      • Castera L.
      • Forns X.
      • Alberti A.
      Non-invasive evaluation of liver fibrosis using transient elastography.
      ). Clinical significance of liver stiffness cut-offs in chronic liver diseases. When liver stiffness values range between 2.5 and 7.0 kPa, mild or no fibrosis is likely, whereas when liver stiffness values are greater than 12.5 kPa, cirrhosis is likely.

      Monitoring disease progression and prognosis

      Portal hypertension

      TE results can identify patients most likely to develop clinically significant portal hypertension, but are not able to identify patients with esophageal varices (
      • Castera L.
      • Pinzani M.
      • Bosch J.
      Non invasive evaluation of portal hypertension using transient elastography.
      ). Given its likely prognostic value for patients with cirrhosis, TE could be used to discriminate among patients at different stages of progression of compensated cirrhosis, and stratify them in different risk categories.
      TE has recently been used to evaluate the stiffness of the spleen.
      • Colecchia A.
      • Montrone L.
      • Scaioli E.
      • Bacchi-Reggiani M.L.
      • Colli A.
      • Casazza G.
      • Schiumerini R.
      • Turco L.
      • Di Biase A.R.
      • Mazzella G.
      • Marzi L.
      • Arena U.
      • Pinzani M.
      • Festi D.
      Measurement of spleen stiffness to evaluate portal hypertension and the presence of esophageal varices in patients with HCV-related cirrhosis.
      have reported that in patients with compensated liver cirrhosis spleen stiffness correlates with portal pressure gradient and is accurate in predicting esophageal varices. However, the accuracy of spleen stiffness in ruling in or ruling out clinically significant portal hypertension or esophageal varices needs to be validated. A recent meta-analysis including 12 studies performed with either TE, PSWSM or magnetic resonance elastography, has concluded that the accuracy is still limited to allow its use in clinical practice (
      • Singh S.
      • Eaton J.E.
      • Murad M.H.
      • Tanaka H.
      • Iijima H.
      • Talwalkar J.A.
      Accuracy of spleen stiffness measurement in detection of esophageal varices in patients with chronic liver disease: systematic review and meta-analysis.
      ).

      Hepatocellular carcinoma

      Large, prospective cohort studies in Asia of patients with hepatitis B or C correlated liver stiffness values with HCC occurrence (
      • Fung J.
      • Lai C.L.
      • Seto W.K.
      • Wong D.K.
      • Yuen M.F.
      Prognostic significance of liver stiffness for hepatocellular carcinoma and mortality in HBeAg-negative chronic hepatitis B.
      ;
      • Jung K.S.
      • Kim S.U.
      • Ahn S.H.
      • Park Y.N.
      • Kim do Y.
      • Park J.Y.
      • Chon C.Y.
      • Choi E.H.
      • Han K.H.
      Risk assessment of hepatitis B virus-related hepatocellular carcinoma development using liver stiffness measurement (FibroScan).
      ,
      • Masuzaki R.
      • Tateishi R.
      • Yoshida H.
      • Goto E.
      • Sato T.
      • Ohki T.
      • Imamura J.
      • Goto T.
      • Kanai F.
      • Kato N.
      • Ikeda H.
      • Shiina S.
      • Kawabe T.
      • Omata M.
      Prospective risk assessment for hepatocellular carcinoma development in patients with chronic hepatitis C by transient elastography.
      ). Among 866 Japanese patients with HCV infection, the cumulative incidence of HCC within 3 years was as high as 38.5% among those with baseline liver stiffness values >25 kPa, compared with 0.4% among subjects with values ≤10 kPa (
      • Masuzaki R.
      • Tateishi R.
      • Yoshida H.
      • Goto E.
      • Sato T.
      • Ohki T.
      • Imamura J.
      • Goto T.
      • Kanai F.
      • Kato N.
      • Ikeda H.
      • Shiina S.
      • Kawabe T.
      • Omata M.
      Prospective risk assessment for hepatocellular carcinoma development in patients with chronic hepatitis C by transient elastography.
      ). Although the measurements of liver stiffness could be used to identify patients at risk of developing HCC, more data are needed before they can be integrated into a HCC surveillance program.

      Prognosis and survival

      Recently, it has been suggested that TE could be used to predict the prognosis of patients with chronic liver disease related to viral hepatitis or other causes (
      • Robic M.A.
      • Procopet B.
      • Metivier S.
      • Peron J.M.
      • Selves J.
      • Vinel J.P.
      • Bureau C.
      Liver stiffness accurately predicts portal hypertension related complications in patients with chronic liver disease: A prospective study.
      ,
      • Vergniol J.
      • Foucher J.
      • Terrebonne E.
      • Bernard P.H.
      • le Bail B.
      • Merrouche W.
      • Couzigou P.
      • de Ledinghen V.
      Noninvasive tests for fibrosis and liver stiffness predict 5-year outcomes of patients with chronic hepatitis C.
      ;
      • Merchante N.
      • Rivero-Juárez A.
      • Téllez F.
      • Merino D.
      • José Ríos-Villegas M.
      • Márquez-Solero M.
      • Omar M.
      • Macías J.
      • Camacho A.
      • Pérez-Pérez M.
      • Gómez-Mateos J.
      • Rivero A.
      • Antonio Pineda J.
      Grupo Andaluz para el Estudio de las Hepatitis Víricas (HEPAVIR) de la Sociedad Andaluza de Enfermedades Infecciosas (SAEI)
      Liver stiffness predicts clinical outcome in human immunodeficiency virus/hepatitis C virus-coinfected patients with compensated liver cirrhosis.
      ). When compared with serum biomarkers, TE had the highest 5-year predictive value to predict survival and liver-related death in 1,457 patients with HCV infection, and this did not change after adjustment for treatment response, patient age, or estimates of necroinflammatory grade (
      • Vergniol J.
      • Foucher J.
      • Terrebonne E.
      • Bernard P.H.
      • le Bail B.
      • Merrouche W.
      • Couzigou P.
      • de Ledinghen V.
      Noninvasive tests for fibrosis and liver stiffness predict 5-year outcomes of patients with chronic hepatitis C.
      ). Similarly, in a cohort of 600 patients with chronic hepatitis B, the 5-year overall survival was 97.1% in patients with liver stiffness <9 kPa, and 61.5% in patients with liver stiffness >20 kPa. At 5 years, no liver-related death was observed in inactive carriers, and the association of liver stiffness with survival persisted after adjustment for potential confounders (age, treatment, and estimate of necroinflammatory activity) (
      • de Lédinghen V.
      • Vergniol J.
      • Barthe C.
      • Foucher J.
      • Chermak F.
      • Le Bail B.
      • Merrouche W.
      • Bernard P.H.
      Non-invasive tests for fibrosis and liver stiffness predict 5-year survival of patients chronically infected with hepatitis B virus.
      ).

      Monitoring the response to antiviral treatment

      In patients already receiving antiviral therapy, TE can be used to monitor the response and evaluate the regression of fibrosis. Significant histologic improvements have been documented in studies of paired liver biopsies from patients with chronic hepatitis C who achieved sustained viral eradication (
      • Poynard T.
      • McHutchison J.
      • Manns M.
      • Trepo C.
      • Lindsay K.
      • Goodman Z.
      • Ling M.H.
      • Albrecht J.
      Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C.
      ,
      • Shiratori Y.
      • Imazeki F.
      • Moriyama M.
      • Yano M.
      • Arakawa Y.
      • Yokosuka O.
      • Kuroki T.
      • Nishiguchi S.
      • Sata M.
      • Yamada G.
      • Fujiyama S.
      • Yoshida H.
      • Omata M.
      Histologic improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy.
      ) and patients with chronic hepatitis B who received long-term antiviral therapy (
      • Chang T.T.
      • Liaw Y.F.
      • Wu S.S.
      • Schiff E.
      • Han K.H.
      • Lai C.L.
      • Safadi R.
      • Lee S.S.
      • Halota W.
      • Goodman Z.
      • Chi Y.C.
      • Zhang H.
      • Hindes R.
      • Iloeje U.
      • Beebe S.
      • Kreter B.
      Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B.
      ,
      • Hadziyannis S.J.
      • Tassopoulos N.C.
      • Heathcote E.J.
      • Chang T.T.
      • Kitis G.
      • Rizzetto M.
      • Marcellin P.
      • Lim S.G.
      • Goodman Z.
      • Ma J.
      • Brosgart C.L.
      • Borroto-Esoda K.
      • Arterburn S.
      • Chuck S.L.
      Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years.
      ). Several studies reported a significant decrease in liver stiffness values, compared with baseline values, in patients with HCV who achieved sustained viral eradication (Fontana et al. 2009;
      • Hezode C.
      • Castera L.
      • Roudot-Thoraval F.
      • Bouvier-Alias M.
      • Rosa I.
      • Roulot D.
      • Leroy V.
      • Mallat A.
      • Pawlotsky J.M.
      Liver stiffness diminishes with antiviral response in chronic hepatitis C.
      ,
      • Martinez S.M.
      • Fernandez-Varo G.
      • Gonzalez P.
      • Sampson E.
      • Bruguera M.
      • Navasa M.
      • Jimenez W.
      • Sanchez-Tapias J.M.
      • Forns X.
      Assessment of liver fibrosis before and after antiviral therapy by different serum marker panels in patients with chronic hepatitis C.
      ,
      • Ogawa E.
      • Furusyo N.
      • Toyoda K.
      • Takeoka H.
      • Maeda S.
      • Hayashi J.
      The longitudinal quantitative assessment by transient elastography of chronic hepatitis C patients treated with pegylated interferon alpha-2b and ribavirin.
      ,
      • Vergniol J.
      • Foucher J.
      • Castera L.
      • Bernard P.H.
      • Tournan R.
      • Terrebonne E.
      • Chanteloup E.
      • Merrouche W.
      • Couzigou P.
      • de Ledinghen V.
      Changes of non-invasive markers and FibroScan values during HCV treatment.
      ,
      • Stasi C.
      • Arena U.
      • Zignego A.L.
      • Corti G.
      • Monti M.
      • Triboli E.
      • Pellegrini E.
      • Renzo S.
      • Leoncini L.
      • Marra F.
      • Laffi G.
      • Milani S.
      • Pinzani M.
      Longitudinal assessment of liver stiffness in patients undergoing antiviral treatment for hepatitis C.
      ,
      • Casado J.L.
      • Quereda C.
      • Moreno A.
      • Pérez-Elías M.J.
      • Martí-Belda P.
      • Moreno S.
      Regression of liver fibrosis is progressive after sustained virological response to HCV therapy in patients with hepatitis C and HIV coinfection.
      ), as well as in HBV-infected patients treated with nucleoside analog drugs (
      • Enomoto M.
      • Mori M.
      • Ogawa T.
      • Fujii H.
      • Kobayashi S.
      • Iwai S.
      • Morikawa H.
      • Tamori A.
      • Sakaguchi H.
      • Sawada A.
      • Takeda S.
      • Habu D.
      • Shiomi S.
      • Kawada N.
      Usefulness of transient elastography for assessment of liver fibrosis in chronic hepatitis B: Regression of liver stiffness during entecavir therapy.
      ,
      • Fung J.
      • Lai C.L.
      • Wong D.K.
      • Seto W.K.
      • Hung I.
      • Yuen M.F.
      Significant changes in liver stiffness measurements in patients with chronic hepatitis B: 3-year follow-up study.
      ,
      • Lim S.G.
      • Cho S.W.
      • Lee Y.C.
      • Jeon S.J.
      • Lee M.H.
      • Cho Y.J.
      • Kim S.S.
      • Kim Y.B.
      • Seok J.Y.
      • Cheong J.Y.
      • Kim J.H.
      Changes in liver stiffness measurement during antiviral therapy in patients with chronic hepatitis B.
      ,
      • Ogawa E.
      • Furusyo N.
      • Murata M.
      • Ohnishi H.
      • Toyoda K.
      • Taniai H.
      • Ihara T.
      • Ikezaki H.
      • Hayashi T.
      • Kainuma M.
      • Hayashi J.
      Longitudinal assessment of liver stiffness by transient elastography for chronic hepatitis B patients treated with nucleoside analog.
      ,
      • Osakabe K.
      • Ichino N.
      • Nishikawa T.
      • Sugiyama H.
      • Kato M.
      • Kitahara S.
      • Hashimoto S.
      • Kawabe N.
      • Harata M.
      • Nitta Y.
      • Murao M.
      • Nakano T.
      • Shimazaki H.
      • Arima Y.
      • Suzuki K.
      • Yoshioka K.
      Reduction of liver stiffness by antiviral therapy in chronic hepatitis B.
      ;
      • Wong G.L.
      • Wong V.W.
      • Choi P.C.
      • Chan A.W.
      • Chim A.M.
      • Yiu K.K.
      • Chu S.H.
      • Chan F.K.
      • Sung J.J.
      • Chan H.L.
      On-treatment monitoring of liver fibrosis with transient elastography in chronic hepatitis B patients.
      ;
      • Kim M.N.
      • Kim S.U.
      • Kim B.K.
      • Park J.Y.
      • Kim D.Y.
      • Ahn S.H.
      • Han K.H.
      Long-term changes of liver stiffness values assessed using transient elastography in patients with chronic hepatitis B receiving entecavir.
      ;
      • Kuo Y.H.
      • Lu S.N.
      • Chen C.H.
      • Chang K.C.
      • Hung C.H.
      • Tai W.C.
      • Tsai M.C.
      • Tseng P.L.
      • Hu T.H.
      • Wang J.H.
      The changes of liver stiffness and its associated factors for chronic hepatitis B patients with entecavir therapy.
      ).
      Despite these encouraging results, following the progress of treated patients with TE can be confounded by changing levels of ALT and inflammation. Similarly, a decrease in liver stiffness could result from reductions in inflammatory activity, rather than fibrosis. However, in the only study (
      • Hezode C.
      • Castera L.
      • Roudot-Thoraval F.
      • Bouvier-Alias M.
      • Rosa I.
      • Roulot D.
      • Leroy V.
      • Mallat A.
      • Pawlotsky J.M.
      Liver stiffness diminishes with antiviral response in chronic hepatitis C.
      ) that assessed liver stiffness kinetics at multiple time points during (weeks 4 and 12) and after therapy (week 24), liver stiffness decreased significantly with treatment among all patients but only continued to decrease significantly after the end of treatment in those patients with sustained viral eradication.

      Limitations

      Applicability: failure and unreliable results

      TE can be difficult in obese patients or those with narrow intercostal space and cannot technically be performed in patients with ascites (
      • Sandrin L.
      • Fourquet B.
      • Hasquenoph J.M.
      • Yon S.
      • Fournier C.
      • Mal F.
      • Christidis C.
      • Ziol M.
      • Poulet B.
      • Kazemi F.
      • Beaugrand M.
      • Palau R.
      Transient elastography: a new noninvasive method for assessment of hepatic fibrosis.
      ).
      In an initial trial of 2114 examinations, failure occurred in 4.5% of cases (
      • Foucher J.
      • Castera L.
      • Bernard P.H.
      • Adhoute X.
      • Laharie D.
      • Bertet J.
      • Couzigou P.
      • de Ledinghen V.
      Prevalence and factors associated with failure of liver stiffness measurement using FibroScan in a prospective study of 2114 examinations.
      ). In a multivariate analysis, the only factor associated with failure was obesity (body mass index > 28 kg/m2 (OR 10.0 (95% CI 5.7-17.9), p=0.001). Updating this experience with more than 13,000 examinations in 7,261 patients seen over a 5 years period, failure to obtain any measurement was observed in 4% of examinations and unreliable results in 17% (
      • Castera L.
      • Foucher J.
      • Bernard P.H.
      • Carvalho F.
      • Allaix D.
      • Merrouche W.
      • Couzigou P.
      • de Ledinghen V.
      Pitfalls of liver stiffness measurement: A 5-year prospective study of 13,369 examinations.
      ). Thus, TE was not successful in almost 20% of cases. In the multivariate analysis, failure and unreliable results were associated with obesity and limited operator experience. However, a fatty thoracic belt, not a fatty mass index, was a limiting factor for the success rate. Indeed, when metabolic syndrome and waist circumference were taken into account in a subgroup of 2,835 patients, waist circumference was the most important determinant of unreliable results and LSM failure.
      Whether unreliable results translate into decreased accuracy is an important question in clinical practice. It has been suggested that among the recommendations, the IQR/LSM >30% is the most important for good diagnostic accuracy (
      • Lucidarme D.
      • Foucher J.
      • Le Bail B.
      • Vergniol J.
      • Castera L.
      • Duburque C.
      • Forzy G.
      • Filoche B.
      • Couzigou P.
      • de Ledinghen V.
      Factors of accuracy of transient elastography (fibroscan) for the diagnosis of liver fibrosis in chronic hepatitis C.
      ,
      • Myers R.P.
      • Crotty P.
      • Pomier-Layrargues G.
      • Ma M.
      • Urbanski S.J.
      • Elkashab M.
      Prevalence, risk factors and causes of discordance in fibrosis staging by transient elastography and liver biopsy.
      ). In 1165 patients with chronic liver diseases (798 with chronic hepatitis C),
      • Boursier J.
      • Zarski J.P.
      • de Ledinghen V.
      • Rousselet M.C.
      • Sturm N.
      • Lebail B.
      • Fouchard-Hubert I.
      • Gallois Y.
      • Oberti F.
      • Bertrais S.
      • Cales P.
      Determination of reliability criteria for liver stiffness evaluation by transient elastography.
      found no difference in the overall diagnostic accuracy. In a multivariate analysis, they found that fibrosis staging was independently associated with the median liver stiffness and IQR/LSM for all stages and proposed new reliability criteria: very reliable: IQR/M < 0.10; reliable: IQR/M 0.10–0.30 or IQR/M >0.30 and median liver stiffness <7.1 kPa; and poorly reliable: IQR/M >0.30 and median liver stiffness >7.1 kPa. Using these new criteria, only 9.1% of the examinations were unreliable. These results warrant further validation.

      Confounding factors

      The liver is encapsulated in a distensible but stiff envelope (Glisson’s capsule), such that additional space-occupying changes, such as edema, inflammation, extra-hepatic cholestasis, or congestion, can increase its stiffness and elevate the measurements, independently of fibrosis. The extent of necro-inflammatory activity has been shown to influence TE measurements in patients with viral hepatitis, with a steady increase of liver values in parallel with the degree of histological activity (
      • Arena U.
      • Vizzutti F.
      • Corti G.
      • Ambu S.
      • Stasi C.
      • Bresci S.
      • Moscarella S.
      • Boddi V.
      • Petrarca A.
      • Laffi G.
      • Marra F.
      • Pinzani M.
      Acute viral hepatitis increases liver stiffness values measured by transient elastography.
      ,
      • Chan H.L.
      • Wong G.L.
      • Choi P.C.
      • Chan A.W.
      • Chim A.M.
      • Yiu K.K.
      • Chan F.K.
      • Sung J.J.
      • Wong V.W.
      Alanine aminotransferase-based algorithms of liver stiffness measurement by transient elastography (Fibroscan) for liver fibrosis in chronic hepatitis B.
      ,
      • Fraquelli M.
      • Rigamonti C.
      • Casazza G.
      • Conte D.
      • Donato M.F.
      • Ronchi G.
      • Colombo M.
      Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic liver disease.
      ). Consistent with these results, overestimation of liver stiffness has been reported during ALT flares in patients with acute viral hepatitis or chronic hepatitis B (
      • Arena U.
      • Vizzutti F.
      • Corti G.
      • Ambu S.
      • Stasi C.
      • Bresci S.
      • Moscarella S.
      • Boddi V.
      • Petrarca A.
      • Laffi G.
      • Marra F.
      • Pinzani M.
      Acute viral hepatitis increases liver stiffness values measured by transient elastography.
      ,
      • Coco B.
      • Oliveri F.
      • Maina A.M.
      • Ciccorossi P.
      • Sacco R.
      • Colombatto P.
      • Bonino F.
      • Brunetto M.R.
      Transient elastography: a new surrogate marker of liver fibrosis influenced by major changes of transaminases.
      ; Sagir et al. 2007) as well as in cases of extrahepatic cholestasis (
      • Millonig G.
      • Reimann F.M.
      • Friedrich S.
      • Fonouni H.
      • Mehrabi A.
      • Buchler M.W.
      • Seitz H.K.
      • Mueller S.
      Extrahepatic cholestasis increases liver stiffness (FibroScan) irrespective of fibrosis.
      ) or congestive heart failure (
      • Millonig G.
      • Friedrich S.
      • Adolf S.
      • Fonouni H.
      • Golriz M.
      • Mehrabi A.
      • Stiefel P.
      • Poschl G.
      • Buchler M.W.
      • Seitz H.K.
      • Mueller S.
      Liver stiffness is directly influenced by central venous pressure.
      ). The influence of steatosis is still a matter of debate because of conflicting results: some studies suggest a detrimental effect (
      • Gaia S.
      • Carenzi S.
      • Barilli A.L.
      • Bugianesi E.
      • Smedile A.
      • Brunello F.
      • Marzano A.
      • Rizzetto M.
      Reliability of transient elastography for the detection of fibrosis in non-alcoholic fatty liver disease and chronic viral hepatitis.
      ) whereas others do not (
      • Wong V.W.
      • Vergniol J.
      • Wong G.L.
      • Foucher J.
      • Chan H.L.
      • Le Bail B.
      • Choi P.C.
      • Kowo M.
      • Chan A.W.
      • Merrouche W.
      • Sung J.J.
      • de Ledinghen V.
      Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease.
      ).

      Influence of food intake

      Food intake increased liver stiffness values in patients with cirrhosis and portal hypertension, and in healthy controls (
      • Mederacke I.
      • Wursthorn K.
      • Kirschner J.
      • Rifai K.
      • Manns M.P.
      • Wedemeyer H.
      • Bahr M.J.
      Food intake increases liver stiffness in patients with chronic or resolved hepatitis C virus infection.
      ,
      • Arena U.
      • Platon M.L.
      • Stasi C.
      • Moscarella S.
      • Assarat A.
      • Bedogni G.
      • Piazzolla V.
      • Badea R.
      • Laffi G.
      • Marra F.
      • Mangia A.
      • Pinzani M.
      Liver stiffness is influenced by a standardized meal in patients with chronic HCV hepatitis at different stages of fibrotic evolution.
      ,
      • Berzigotti A.
      • De Gottardi A.
      • Vukotic R.
      • Siramolpiwat S.
      • Abraldes J.G.
      • García-Pagan J.C.
      • Bosch J.
      Effect of meal ingestion on liver stiffness in patients with cirrhosis and portal hypertension.
      ), thus patients should fast before TE (and all liver elastography) examinations.

      Recommendations

      • The interpretation of TE results should always be in the hands of an expert clinician and should be made in light of the patient demographics, disease etiology and key laboratory findings, as well as according to the manufacturer’s recommendations, particularly the IQR/M ratio, which should be less than 30%.
      • The main limitation to the use of TE in clinical practice is its limited applicability in obese patients. The use of the XL probe reduces the failure rate in obese patients but results in a high rate of unreliable results (approximately 25%). The clinical value of unreliable results remains a matter of debate.
      • TE cannot be performed in patients with ascites.
      • Several factors, including acute hepatitis, cholestasis, liver congestion, and food intake, increase the liver stiffness. Therefore, TE should be performed in fasting patients, and avoided or interpreted cautiously in patients with elevated transaminases (>5 x upper limit of normal), cholestasis, congestive cardiac failure, ongoing alcohol intake or alcoholic hepatitis.
      • TE has been well validated in chronic viral hepatitis (C better than B) and can confidently be used as first line method for staging liver fibrosis. This strategy remains to be validated for other liver diseases.
      • Combining TE with serum biomarkers of fibrosis increases the diagnostic accuracy for significant fibrosis in patients with chronic hepatitis C, a strategy that needs to be validated for other liver diseases, such as hepatitis B or NAFLD.
      • TE offers better performance for detecting cirrhosis than significant fibrosis and is currently the standard among non-invasive methods.
      • In patients with cirrhosis, liver stiffness has a prognostic value for the occurrence of portal hypertension. However, TE cannot replace upper GI endoscopy for the detection of esophageal varices.
      • Current evidence suggests that TE could be used for monitoring the response to antiviral treatment and for predicting the prognosis of patients with chronic liver disease.

      Point Shear Wave Speed Measurement (PSWSM) and Shear Wave Speed Imaging (SWSI)

      Procedure

      All technologies are implemented in a conventional US system under direct visualization using a curved array broadband transducer. A sample box is positioned on B-mode image of the liver and elastography measurements are obtained by pressing a button.
      Optimal conditions include:
      • Fasting;
      • Dorsal decubitus position, with the right arm elevated above the head for optimal intercostal access;
      • Resting respiratory position (breath-hold without deep inspiration);
      • ROI placement beneath Glisson’s capsule by 1.5-2.0 cm to avoid reverberation artifacts and increased subcapsular stiffness;
      • ROI placement to avoid large liver vessels;
      • The median value of 5-10 measurements is considered with PSWSM, and the mean value of 4 measurements with SWSI.
      Specific recommendations include:
      • For SWSI, the sample box size should be large enough to reduce the variation between measurements. This provides a cumulative value that is the average of stiffness at several points, thus being more representative of the heterogeneous stiffness in abnormal and normal livers.
      • For PSWSM, the ROI should be placed perpendicular to the center of the transducer surface as the angle of insonation may have a slight but significant influence on the result.

      Results

      Point Shear Wave Speed Measurement

      As of today, there are two techniques: Virtual Touch Tissue Quantification (VTTQ®) technique that expresses the results in m/sec (Figure 3) and ElastPQ® that gives the results in m/sec or in kPa (Figure 4). There are numerous reports of studies performed using the VTTQ® technique, which has been commercially available since 2009, but only a few using ElastPQ®, which was introduced in 2012.
      Figure thumbnail gr3
      Figure 3VTTQ technique in a healthy subject. Measurements of liver stiffness are given in m/sec; the sample box is shown.
      Figure thumbnail gr4
      Figure 4ElastPQ in a patient with chronic hepatitis C of F4 Metavir stage on liver histology. The values of liver stiffness are expressed in kPa. Bottom left corner of the image: the stiffness is estimated and displayed by using a scale that ranges from soft to hard.
      The reproducibility of the VTTQ® technique is excellent, with an intraclass correlation coefficient ranging from 0.84 to 0.87 (
      • Bota S.
      • Sporea I.
      • Sirli R.
      • Popescu A.
      • Danila M.
      • Costachescu D.
      Intra and inter-operator reproducibility of Acoustic Radiation Force Impulse (ARFI) elastography – preliminary results.
      ,
      • Boursier J.
      • Isselin G.
      • Fouchard-Hubert I.
      • Oberti F.
      • Dib N.
      • Lebigot J.
      • Bertrais S.
      • Gallois Y.
      • Calès P.
      • Aubé C.
      Acoustic radiation force impulse: a new ultrasonographic technology for the widespread noninvasive diagnosis of liver fibrosis.
      ;
      • D'Onofrio M.
      • Gallotti A.
      • Mucelli R.P.
      Tissue quantification with acoustic radiation force impulse imaging: Measurement repeatability and normal values in the healthy liver.
      ;
      • Guzmán-Aroca F.
      • Reus M.
      • Berná-Serna J.D.
      • Serrano L.
      • Serrano C.
      • Gilabert A.
      • Cepero A.
      Reproducibility of shear wave velocity measurements by acoustic radiation force impulse imaging of the liver: a study in healthy volunteers.
      ). Operator training does not appear to be necessary (
      • Boursier J.
      • Isselin G.
      • Fouchard-Hubert I.
      • Oberti F.
      • Dib N.
      • Lebigot J.
      • Bertrais S.
      • Gallois Y.
      • Calès P.
      • Aubé C.
      Acoustic radiation force impulse: a new ultrasonographic technology for the widespread noninvasive diagnosis of liver fibrosis.
      ). Similarly, the ElastPQ® technique is highly reproducible, with an interobserver agreement ranging from 0.83 for comparison of single measurements to 0.93 for the median value of 10 measurements (
      • Ferraioli G.
      • Tinelli C.
      • Lissandrin R.
      • Zicchetti M.
      • Dal Bello B.
      • Filice G.
      • Filice C.
      Point shear wave elastography method for assessing liver stiffness.
      ).
      In healthy volunteers, the values of PSWSM performed with VTTQ are available in several publications (
      • D'Onofrio M.
      • Gallotti A.
      • Mucelli R.P.
      Tissue quantification with acoustic radiation force impulse imaging: Measurement repeatability and normal values in the healthy liver.
      ;
      • Friedrich-Rust M.
      • Wunder K.
      • Kriener S.
      • Kriener S.
      • Sotoudeh F.
      • Richter S.
      • Bojunga J.
      • Herrmann E.
      • Poynard T.
      • Dietrich C.F.
      • Vermehren J.
      • Zeuzem S.
      • Sarrazin C.
      Liver fibrosis in viral hepatitis: noninvasive assessment with acoustic radiation force impulse imaging versus transient elastography.
      ;
      • Goertz R.S.
      • Egger C.
      • Neurath M.F.
      • Strobel D.
      Impact of food intake, ultrasound transducer, breathing maneuvers and body position on acoustic radiation force impulse (ARFI) elastometry of the liver.
      ,
      • Grgurevic I.
      • Cikara I.
      • Horvat J.
      • Lukic I.K.
      • Heinzl R.
      • Banic M.
      • Kujundzic M.
      • Brkljacic B.
      Noninvasive assessment of liver fibrosis with acoustic radiation force impulse imaging: increased liver and splenic stiffness in patients with liver fibrosis and cirrhosis.
      ;
      • Kaminuma C.
      • Tsushima Y.
      • Matsumoto N.
      • Kurabayashi T.
      • Taketomi-Takahashi A.
      • Endo K.
      Reliable measurement procedure of virtual touch tissue quantification with acoustic radiation force impulse imaging.
      ;
      • Karlas T.
      • Pfrepper C.
      • Wiegand J.
      • Wittekind C.
      • Neuschulz M.
      • Mössner J.
      • Berg T.
      • Tröltzsch M.
      • Keim V.
      Acoustic radiation force impulse imaging (ARFI) for non-invasive detection of liver fibrosis: examination standards and evaluation of interlobe differences in healthy subjects and chronic liver disease.
      ;
      • Kim J.E.
      • Lee J.Y.
      • Kim Y.J.
      • Yoon J.H.
      • Kim S.H.
      • Lee J.M.
      • Han J.K.
      • Choi B.I.
      Acoustic radiation force impulse elastography for chronic liver disease: comparison with ultrasound-based scores of experienced radiologists, Child- Pugh scores and liver function tests.
      ;
      • Kircheis G.
      • Sagir A.
      • Vogt C.
      • Vom Dahl S.
      • Kubitz R.
      • Häussinger D.
      Evaluation of acoustic radiation force impulse imaging for determination of liver stiffness using transient elastography as a reference.
      ;
      • Osaki A.
      • Kubota T.
      • Suda T.
      • Igarashi M.
      • Nagasaki K.
      • Tsuchiya A.
      • Yano M.
      • Tamura Y.
      • Takamura M.
      • Kawai H.
      • Yamagiwa S.
      • Kikuchi T.
      • Nomoto M.
      • Aoyagi Y.
      Shear wave velocity is a useful marker for managing nonalcoholic steatohepatitis.
      ;
      • Piscaglia F.
      • Salvatore V.
      • Di Donato R.
      • D'Onofrio M.
      • Gualandi S.
      • Gallotti A.
      • Peri E.
      • Borghi A.
      • Conti F.
      • Fattovich G.
      • Sagrini E.
      • Cucchetti A.
      • Andreone P.
      • Bolondi L.
      Accuracy of VirtualTouch Acoustic Radiation Force Impulse (ARFI) imaging for the diagnosis of cirrhosis during liver ultrasonography.
      ;
      • Rifai K.
      • Cornberg J.
      • Mederacke I.
      • Bahr M.J.
      • Wedemeyer H.
      • Malinski P.
      • Bantel H.
      • Boozari B.
      • Potthoff A.
      • Manns M.P.
      • Gebel M.
      Clinical feasibility of liver elastography by acoustic radiation force impulse imaging (ARFI).
      ;
      • Rizzo L.
      • Calvaruso V.
      • Cacopardo B.
      • Alessi N.
      • Attanasio M.
      • Petta S.
      • Fatuzzo F.
      • Montineri A.
      • Mazzola A.
      • L'abbate L.
      • Nunnari G.
      • Bronte F.
      • Di Marco V.
      • Craxì A.
      • Cammà C.
      Comparison of transient elastography and acoustic radiation force impulse for non-invasive staging of liver fibrosis in patients with chronic hepatitis.
      ,
      • Son C.Y.
      • Kim S.U.
      • Han W.K.
      • Choi G.H.
      • Park H.
      • Yang S.C.
      • Choi J.S.
      • Park J.Y.
      • Kim do Y.
      • Ahn S.H.
      • Chon C.Y.
      • Han K.H.
      Normal liver elasticity values using acoustic radiation force impulse imaging: a prospective study in healthy living liver and kidney donors.
      ,
      • Sporea I.
      • Sirli R.L.
      • Deleanu A.
      Acoustic radiation force impulse elastography as compared to transient elastography and liver biopsy in patients with chronic hepatopathies.
      ,
      • Takahashi H.
      • Ono N.
      • Eguchi Y.
      • Eguchi T.
      • Kitajima Y.
      • Kawaguchi Y.
      • Nakashita S.
      • Ozaki I.
      • Mizuta T.
      • Toda S.
      • Kudo S.
      • Miyoshi A.
      • Miyazaki K.
      • Fujimoto K.
      Evaluation of acoustic radiation force impulse elastography for fibrosis staging of chronic liver disease: a pilot study.
      ). In all studies, the values were lower (< 1.2 m/sec) than in patients with chronic hepatitis. Food intake significantly increases the liver stiffness values (
      • Goertz R.S.
      • Egger C.
      • Neurath M.F.
      • Strobel D.
      Impact of food intake, ultrasound transducer, breathing maneuvers and body position on acoustic radiation force impulse (ARFI) elastometry of the liver.
      ;
      • Popescu A.
      • Bota S.
      • Sporea I.
      • Sirli R.
      • Danila M.
      • Racean S.
      • Suseanu D.
      • Gradinaru O.
      • Ivascu Siegfried C.
      The influence of food intake on liver stiffness values assessed by acoustic radiation force impulse elastography-preliminary results.
      ).
      The median value of PSWSM obtained with ElastPQ in healthy volunteers is 3.5 kPa (
      • Ling W.
      • Lu Q.
      • Quan J.
      • Ma L.
      • Luo Y.
      Assessment of impact factors on shear wave based liver stiffness measurement.
      ,
      • Ferraioli G.
      • Tinelli C.
      • Lissandrin R.
      • Zicchetti M.
      • Dal Bello B.
      • Filice G.
      • Filice C.
      Point shear wave elastography method for assessing liver stiffness.
      ).

      Chronic viral hepatitis

      The range of cut-offs for each fibrosis stage is quite large with overlap between consecutive stages. The range of cut-offs for the fibrosis stage ranges from 1.13 to 1.55 m/sec for F>2; from 1.43 to 1.81 m/sec for F>3; and from 1.36 to 2.13 m/sec for F4. The largest series comprises more than 600 patients with mixed etiologies of chronic liver disease (
      • Kircheis G.
      • Sagir A.
      • Vogt C.
      • Vom Dahl S.
      • Kubitz R.
      • Häussinger D.
      Evaluation of acoustic radiation force impulse imaging for determination of liver stiffness using transient elastography as a reference.
      ). Using TE as the reference method, the investigators obtained cut-off values of 1.32 m/sec for F2 and 1.62 m/sec for F4. Similar cut-offs were obtained in the meta-analysis of
      • Friedrich-Rust M.
      • Nierhoff J.
      • Lupsor M.
      • Sporea I.
      • Fierbinteanu-Braticevici C.
      • Strobel D.
      • Takahashi H.
      • Yoneda M.
      • Suda T.
      • Zeuzem S.
      • Herrmann E.
      Performance of Acoustic Radiation Force Impulse imaging for the staging of liver fibrosis: a pooled meta-analysis.
      , in which nine studies were analyzed. Patients with chronic liver disease of several etiologies were included, and the cut-off values were 1.34, 1.55 and 1.80 m/sec, for significant fibrosis, severe fibrosis and cirrhosis, respectively. PSWSM showed accuracy similar to that of TE for the diagnosis of severe fibrosis, whereas a slightly but significantly higher diagnostic accuracy of TE with respect to PSWSM was found for the diagnosis of significant fibrosis and liver cirrhosis. In the more recent meta-analysis of
      • Bota S.
      • Herkner H.
      • Sporea I.
      • Salzl P.
      • Sirli R.
      • Neghina A.M.
      • Peck-Radosavljevic M.
      Meta-analysis: ARFI elastography versus transient elastography for the evaluation of liver fibrosis.
      , in which thirteen studies were included, PSWSM showed a predictive value similar to TE for significant fibrosis and cirrhosis.
      In an international multicenter study comprising 1,095 patients (181 with chronic hepatitis B and 914 with chronic hepatitis C), the correlation of PSWSM with histological fibrosis was significantly higher in patients with chronic hepatitis C compared with those with chronic hepatitis B (r=0.653 vs. r=0.511, p=0.007), whereas both groups showed similar PSWSM values for each fibrosis stage (
      • Sporea I.
      • Bota S.
      • Peck-Radosavljevic M.
      • Sirli R.
      • Tanaka H.
      • Iijima H.
      • Badea R.
      • Lupsor M.
      • Fierbinteanu-Braticevici C.
      • Petrisor A.
      • Saito H.
      • Ebinuma H.
      • Friedrich-Rust M.
      • Sarrazin C.
      • Takahashi H.
      • Ono N.
      • Piscaglia F.
      • Borghi A.
      • D'Onofrio M.
      • Gallotti A.
      • Ferlitsch A.
      • Popescu A.
      • Danila M.
      Acoustic Radiation Force Impulse elastography for fibrosis evaluation in patients with chronic hepatitis C: an international multicenter study.
      ).
      In the study of
      • Rizzo L.
      • Calvaruso V.
      • Cacopardo B.
      • Alessi N.
      • Attanasio M.
      • Petta S.
      • Fatuzzo F.
      • Montineri A.
      • Mazzola A.
      • L'abbate L.
      • Nunnari G.
      • Bronte F.
      • Di Marco V.
      • Craxì A.
      • Cammà C.
      Comparison of transient elastography and acoustic radiation force impulse for non-invasive staging of liver fibrosis in patients with chronic hepatitis.
      , using the PSWSM cut-offs of 1.3 m/sec for the diagnosis of significant fibrosis (F ≥ 2), 1.7 m/s for severe fibrosis (F ≥ 3), and 2.0 m/sec for cirrhosis (F = 4), the highest concordance was obtained for the diagnosis of mild fibrosis. TE may overestimate the fibrosis stage in cases with severe liver inflammation (
      • Sagir A.
      • Erhardt A.
      • Schmitt M.
      • Sagir A.
      • Erhardt A.
      • Schmitt M.
      Transient elastography is unreliable for detection of cirrhosis in patients with acute liver damage.
      ,
      • Arena U.
      • Vizzutti F.
      • Abraldes J.G.
      • Corti G.
      • Stasi C.
      • Moscarella S.
      • Milani S.
      • Lorefice E.
      • Petrarca A.
      • Romanelli R.G.
      • Laffi G.
      • Bosch J.
      • Marra F.
      • Pinzani M.
      Reliability of transient elastography for the diagnosis of advanced fibrosis in chronic hepatitis C.
      ). The same limitation has been observed in some studies with PSWSM (
      • Takahashi H.
      • Ono N.
      • Eguchi Y.
      • Eguchi T.
      • Kitajima Y.
      • Kawaguchi Y.
      • Nakashita S.
      • Ozaki I.
      • Mizuta T.
      • Toda S.
      • Kudo S.
      • Miyoshi A.
      • Miyazaki K.
      • Fujimoto K.
      Evaluation of acoustic radiation force impulse elastography for fibrosis staging of chronic liver disease: a pilot study.
      ,
      • Yoon K.T.
      • Lim S.M.
      • Park J.Y.
      • Kim do Y.
      • Ahn S.H.
      • Han K.H.
      • Chon C.Y.
      • Cho M.
      • Lee J.W.
      • Kim S.U.
      Liver stiffness measurement using acoustic radiation force impulse (ARFI) elastography and effect of necroinflammation.
      ,
      • Chen S.H.
      • Li Y.F.
      • Lai H.C.
      • Kao J.T.
      • Peng C.Y.
      • Chuang P.H.
      • Su W.P.
      • Chiang I.P.
      Effects of patient factors on noninvasive liver stiffness measurement using acoustic radiation force impulse elastography in patients with chronic hepatitis C.
      ), but not in others (
      • Friedrich-Rust M.
      • Wunder K.
      • Kriener S.
      • Kriener S.
      • Sotoudeh F.
      • Richter S.
      • Bojunga J.
      • Herrmann E.
      • Poynard T.
      • Dietrich C.F.
      • Vermehren J.
      • Zeuzem S.
      • Sarrazin C.
      Liver fibrosis in viral hepatitis: noninvasive assessment with acoustic radiation force impulse imaging versus transient elastography.
      ;
      • Palmeri M.L.
      • Wang M.H.
      • Rouze N.C.
      • Abdelmalek M.F.
      • Guy C.D.
      • Moser B.
      • Diehl A.M.
      • Nightingale K.R.
      Noninvasive evaluation of hepatic fibrosis using acoustic radiation force-based shear stiffness in patients with nonalcoholic fatty liver disease.
      ,
      • Rizzo L.
      • Calvaruso V.
      • Cacopardo B.
      • Alessi N.
      • Attanasio M.
      • Petta S.
      • Fatuzzo F.
      • Montineri A.
      • Mazzola A.
      • L'abbate L.
      • Nunnari G.
      • Bronte F.
      • Di Marco V.
      • Craxì A.
      • Cammà C.
      Comparison of transient elastography and acoustic radiation force impulse for non-invasive staging of liver fibrosis in patients with chronic hepatitis.
      ,
      • Nishikawa T.
      • Hashimoto S.
      • Kawabe N.
      • Harata M.
      • Nitta Y.
      • Murao M.
      • Nakano T.
      • Mizuno Y.
      • Shimazaki H.
      • Kan T.
      • Nakaoka K.
      • Takagawa Y.
      • Ohki M.
      • Ichino N.
      • Osakabe K.
      • Yoshioka K.
      Factors correlating with acoustic radiation force impulse elastography in chronic hepatitis C.
      ).
      The grade of liver steatosis appears not to influence PSWSM (
      • Friedrich-Rust M.
      • Wunder K.
      • Kriener S.
      • Kriener S.
      • Sotoudeh F.
      • Richter S.
      • Bojunga J.
      • Herrmann E.
      • Poynard T.
      • Dietrich C.F.
      • Vermehren J.
      • Zeuzem S.
      • Sarrazin C.
      Liver fibrosis in viral hepatitis: noninvasive assessment with acoustic radiation force impulse imaging versus transient elastography.
      ;
      • Rizzo L.
      • Calvaruso V.
      • Cacopardo B.
      • Alessi N.
      • Attanasio M.
      • Petta S.
      • Fatuzzo F.
      • Montineri A.
      • Mazzola A.
      • L'abbate L.
      • Nunnari G.
      • Bronte F.
      • Di Marco V.
      • Craxì A.
      • Cammà C.
      Comparison of transient elastography and acoustic radiation force impulse for non-invasive staging of liver fibrosis in patients with chronic hepatitis.
      ,
      • Rifai K.
      • Cornberg J.
      • Mederacke I.
      • Bahr M.J.
      • Wedemeyer H.
      • Malinski P.
      • Bantel H.
      • Boozari B.
      • Potthoff A.
      • Manns M.P.
      • Gebel M.
      Clinical feasibility of liver elastography by acoustic radiation force impulse imaging (ARFI).
      ).
      Measurement failure with PSWSM is reported in less than 3% of patients (
      • Friedrich-Rust M.
      • Nierhoff J.
      • Lupsor M.
      • Sporea I.
      • Fierbinteanu-Braticevici C.
      • Strobel D.
      • Takahashi H.
      • Yoneda M.
      • Suda T.
      • Zeuzem S.
      • Herrmann E.
      Performance of Acoustic Radiation Force Impulse imaging for the staging of liver fibrosis: a pooled meta-analysis.
      ). No invalid measurement occurred in the series of
      • Rizzo L.
      • Calvaruso V.
      • Cacopardo B.
      • Alessi N.
      • Attanasio M.
      • Petta S.
      • Fatuzzo F.
      • Montineri A.
      • Mazzola A.
      • L'abbate L.
      • Nunnari G.
      • Bronte F.
      • Di Marco V.
      • Craxì A.
      • Cammà C.
      Comparison of transient elastography and acoustic radiation force impulse for non-invasive staging of liver fibrosis in patients with chronic hepatitis.
      and in the study of
      • Crespo G.
      • Fernández-Varo G.
      • Mariño Z.
      • Casals G.
      • Miquel R.
      • Martínez S.M.
      • Gilabert R.
      • Forns X.
      • Jiménez W.
      • Navasa M.
      ARFI, FibroScan®, ELF, and their combinations in the assessment of liver fibrosis: A prospective study.
      . PSWSM provided valid results in all patients whereas TE failed in 11% of cases. In the series of
      • Bota S.
      • Sporea I.
      • Sirli R.
      • Popescu A.
      • Danila M.
      • Jurchis A.
      • Gradinaru-Tascau O.
      Factors associated with the impossibility to obtain reliable liver stiffness measurements by means of Acoustic Radiation Force Impulse (ARFI) elastography–analysis of a cohort of 1,031 subjects.
      , reliable measurements were obtained in 93.3% of cases. Older age, higher BMI and male gender were associated with the risk of failed and unreliable measurements.
      A recent meta-analysis, which included either full papers or abstracts for a total of 36 studies, has shown that BMI has a significant influence for the diagnosis of significant fibrosis (F ≥ 2) (
      • Nierhoff J.
      • Chavez Ortiz A.A.
      • Herrmann E.
      • Zeuzem S.
      • Friedrich-Rust M.
      The efficiency of acoustic radiation force impulse imaging for the staging of liver fibrosis: a meta-analysis.
      ). In this meta-analysis, the diagnostic accuracy expressed as the area under the ROC curve was 0.84, 0.89 and 0.91 for the diagnosis of significant fibrosis, advanced fibrosis, and cirrhosis, respectively. Measurements are not limited by ascites because the US push beam, which generates the shear waves, propagates through fluids and appears not to be influenced by clinical and biochemical variables (
      • Rizzo L.
      • Calvaruso V.
      • Cacopardo B.
      • Alessi N.
      • Attanasio M.
      • Petta S.
      • Fatuzzo F.
      • Montineri A.
      • Mazzola A.
      • L'abbate L.
      • Nunnari G.
      • Bronte F.
      • Di Marco V.
      • Craxì A.
      • Cammà C.
      Comparison of transient elastography and acoustic radiation force impulse for non-invasive staging of liver fibrosis in patients with chronic hepatitis.
      ).
      The possibility to evaluate several areas of the liver parenchyma could be another advantage of PSWSM. Indeed, histological studies have shown that liver fibrosis is not homogeneously distributed within the liver, and can be missed when performing liver biopsy at one site only, thus leading to underestimation of liver fibrosis (
      • Bedossa P.
      • Dargère D.
      • Paradis V.
      Sampling variability of liver fibrosis in chronic hepatitis C.
      ,
      • Maharaj B.
      • Maharaji R.J.
      • Leary W.P.
      • Cooppan R.M.
      • Naran A.D.
      • Pirie D.
      • Pudifin D.J.
      Sampling variability and its influence on the diagnostic yield of percutaneous needle biopsy of the liver.
      ). It should be noted that
      • D'Onofrio M.
      • Gallotti A.
      • Mucelli R.P.
      Tissue quantification with acoustic radiation force impulse imaging: Measurement repeatability and normal values in the healthy liver.
      reported significant differences between intercostal and subcostal scans, and
      • Kaminuma C.
      • Tsushima Y.
      • Matsumoto N.
      • Kurabayashi T.
      • Taketomi-Takahashi A.
      • Endo K.
      Reliable measurement procedure of virtual touch tissue quantification with acoustic radiation force impulse imaging.
      found that PSWSM were more reliable when performed in a deep portion of the right lobe. In their series of patients with chronic hepatitis,
      • Toshima T.
      • Shirabe K.
      • Takeishi K.
      • Motomura T.
      • Mano Y.
      • Uchiyama H.
      • Yoshizumi T.
      • Soejima Y.
      • Taketomi A.
      • Maehara Y.
      New method for assessing liver fibrosis based on acoustic radiation force impulse: a special reference to the difference between right and left liver.
      obtained significantly higher values in the left lobe of the liver than the right lobe. It has been suggested that oscillation of the left liver by cardiac activity may interfere with stiffness measurements (
      • Osaki A.
      • Kubota T.
      • Suda T.
      • Igarashi M.
      • Nagasaki K.
      • Tsuchiya A.
      • Yano M.
      • Tamura Y.
      • Takamura M.
      • Kawai H.
      • Yamagiwa S.
      • Kikuchi T.
      • Nomoto M.
      • Aoyagi Y.
      Shear wave velocity is a useful marker for managing nonalcoholic steatohepatitis.
      ).
      Karlas T et al. (2011) found that, in healthy individuals, the shear wave speed was higher in the left liver than in the right, but no difference in speed was observed in patients with advanced fibrosis and cirrhosis. The authors suggest that the absence of differences between the two sides could be a criterion for the diagnosis of advanced liver disease.
      Preliminary results of PSWSM using ElastPQ® in 102 patients with chronic hepatitis C have shown that the accuracy of the method for staging liver fibrosis is similar to that of TE and the best cut-off value for significant fibrosis (F ≥ 2) is 5.7 kPa (
      • Ferraioli G.
      • Tinelli C.
      • Lissandrin R.
      • Zicchetti M.
      • Dal Bello B.
      • Filice G.
      • Filice C.
      Point shear wave elastography method for assessing liver stiffness.
      ). In a series of 291 patients with chronic hepatitis B, the AUROCs for significant fibrosis and cirrhosis were 0.94 and 0.89, respectively (
      • Ma J.J.
      • Ding H.
      • Mao F.
      • Sun H.C.
      • Xu C.
      • Wang W.P.
      Assessment of liver fibrosis with elastography point quantification technique in chronic hepatitis B virus patients: a comparison with liver pathological results.
      ).

      Monitoring disease progression and prognosis

      Very few studies regarding disease progression and prognosis have been published with conflicting results. In the cohort of
      • Vermehren J.
      • Polta A.
      • Zimmermann O.
      • Herrmann E.
      • Poynard T.
      • Hofmann W.P.
      • Bojunga J.
      • Sarrazin C.
      • Zeuzem S.
      • Friedrich-Rust M.
      Comparison of acoustic radiation force impulse imaging with transient elastography for the detection of complications in patients with cirrhosis.
      , the diagnostic accuracy of PSWSM of the liver and the spleen for the prediction of esophageal varices was not significantly different from that of TE and the Fibrotest; however, the AUROCs of all methods were fairly low, ranging from 0.50 to 0.58. In the series of
      • Morishita N.
      • Hiramatsu N.
      • Oze T.
      • Harada N.
      • Yamada R.
      • Miyazaki M.
      • Yakushijin T.
      • Miyagi T.
      • Yoshida Y.
      • Tatsumi T.
      • Kanto T.
      • Takehara T.
      Liver stiffness measurement by acoustic radiation force impulse is useful in predicting the presence of esophageal varices or high-risk esophageal varices among patients with HCV-related cirrhosis.
      , a cutoff value of 2.39 m/s had a sensitivity of 81% and a specificity of 82% for detecting high-risk esophageal varices.
      In a recent study, a spleen stiffness value <3.3 m/s ruled out the presence of high-risk varices in patients with compensated or decompensated liver cirrhosis (negative predictive value, 99.4%). Regardless of the etiologies of liver disease, spleen stiffness was highly accurate for the detection of esophageal varices (
      • Takuma Y.
      • Nouso K.
      • Morimoto Y.
      • Tomokuni J.
      • Sahara A.
      • Toshikuni N.
      • Takabatake H.
      • Shimomura H.
      • Doi A.
      • Sakakibara I.
      • Matsueda K.
      • Yamamoto H.
      Measurement of spleen stiffness by acoustic radiation force impulse imaging identifies cirrhotic patients with esophageal varices.
      ).

      Nonalcoholic fatty liver disease (NAFLD)

      Only few studies in small series of patients are available (
      • Yoneda M.
      • Suzuki K.
      • Kato S.
      • Fujita K.
      • Nozaki Y.
      • Hosono K.
      • Saito S.
      • Nakajima A.
      Nonalcoholic fatty liver disease: US-based acoustic radiation force impulse elastography.
      ,
      • Osaki A.
      • Kubota T.
      • Suda T.
      • Igarashi M.
      • Nagasaki K.
      • Tsuchiya A.
      • Yano M.
      • Tamura Y.
      • Takamura M.
      • Kawai H.
      • Yamagiwa S.
      • Kikuchi T.
      • Nomoto M.
      • Aoyagi Y.
      Shear wave velocity is a useful marker for managing nonalcoholic steatohepatitis.
      ,
      • Palmeri M.L.
      • Wang M.H.
      • Rouze N.C.
      • Abdelmalek M.F.
      • Guy C.D.
      • Moser B.
      • Diehl A.M.
      • Nightingale K.R.
      Noninvasive evaluation of hepatic fibrosis using acoustic radiation force-based shear stiffness in patients with nonalcoholic fatty liver disease.
      ,
      • Friedrich-Rust M.
      • Romen D.
      • Vermehren J.
      • Kriener S.
      • Sadet D.
      • Herrmann E.
      • Zeuzem S.
      • Bojunga J.
      Acoustic radiation force impulse-imaging and transient elastography for non-invasive assessment of liver fibrosis and steatosis in NAFLD.
      ,
      • Fierbinteanu Braticevici C.
      • Sporea I.
      • Panaitescu E.
      • Tribus L.
      Value of acoustic radiation force impulse imaging elastography for non-invasive evaluation of patients with nonalcoholic fatty liver disease.
      ).
      In 172 patients diagnosed with NAFLD, a cutoff of 4.24 kPa distinguished low (fibrosis stage 0–2) from high (fibrosis stage 3–4) fibrosis stages with a sensitivity of 90% and a specificity of 90% (AUROC 0.90) (
      • Palmeri M.L.
      • Wang M.H.
      • Rouze N.C.
      • Abdelmalek M.F.
      • Guy C.D.
      • Moser B.
      • Diehl A.M.
      • Nightingale K.R.
      Noninvasive evaluation of hepatic fibrosis using acoustic radiation force-based shear stiffness in patients with nonalcoholic fatty liver disease.
      ). In a study on 61 patients with NAFLD/NASH, the paired comparison of diagnostic accuracies between TE and PSWSM for the diagnosis of significant fibrosis, severe fibrosis and liver cirrhosis were similar (
      • Friedrich-Rust M.
      • Romen D.
      • Vermehren J.
      • Kriener S.
      • Sadet D.
      • Herrmann E.
      • Zeuzem S.
      • Bojunga J.
      Acoustic radiation force impulse-imaging and transient elastography for non-invasive assessment of liver fibrosis and steatosis in NAFLD.
      ). In 64 patients with histologically proven NAFLD, the diagnostic performance of PSWSM in predicting significant fibrosis and cirrhosis had an AUROC of 0.94 and 0.98, respectively (
      • Fierbinteanu Braticevici C.
      • Sporea I.
      • Panaitescu E.
      • Tribus L.
      Value of acoustic radiation force impulse imaging elastography for non-invasive evaluation of patients with nonalcoholic fatty liver disease.
      ).

      Shear Wave Speed Imaging

      SWSI expresses the results in m/sec or kPa (Figure 5).
      • Ferraioli G.
      • Tinelli C.
      • Zicchetti M.
      • Above E.
      • Poma G.
      • Di Gregorio M.
      • Filice C.
      Reproducibility of real-time shear wave elastography in the evaluation of liver elasticity.
      found ICCs of 0.95 and 0.93 for expert and novice operators when comparing measurements performed on the same day, and 0.84 and 0.65 for measurements performed on different days. The interobserver agreement was 0.88. These results have been confirmed in the recently published study of
      • Hudson J.M.
      • Milot L.
      • Parry C.
      • Williams R.
      • Burns P.N.
      Inter- and intra-operator reliability and repeatability of shear wave elastography in the liver: a study in healthy volunteers.
      . Like conventional US, SWSI technology may be user dependent, so it is recommended that at least 50 supervised scans and measurements should be performed by a novice to obtain consistent measurements (
      • Ferraioli G.
      • Tinelli C.
      • Zicchetti M.
      • Above E.
      • Poma G.
      • Di Gregorio M.
      • Filice C.
      Reproducibility of real-time shear wave elastography in the evaluation of liver elasticity.
      ).
      Figure thumbnail gr5
      Figure 5SWSI technique in a patient with decompensated liver cirrhosis. Measurements of liver stiffness are given in kPa. The mean value along with the minimum and maximum values and the standard deviation are shown.
      Values ranging from 2.6 to 6.2 kPa have been reported for histologically proven normal livers (
      • Suh C.H.
      • Kim S.Y.
      • Kim K.W.
      • Lim Y.S.
      • Lee S.J.
      • Lee M.G.
      • Lee J.
      • Lee S.G.
      • Yu E.
      Determination of normal hepatic elasticity by using real-time shear wave elastography.
      ).
      In patients with chronic hepatitis C, cut-off values for SWSI are reported in two publications based on 4 (
      • 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.
      ) or 5 (
      • Bavu E.
      • Gennisson J.L.
      • Couade M.
      • Bercoff J.
      • Mallet V.
      • Fink M.
      • Badel A.
      • Vallet-Pichard A.
      • Nalpas B.
      • Tanter M.
      • Pol S.
      Noninvasive in vivo liver fibrosis evaluation using supersonic shear imaging: a clinical study on 113 hepatitis C virus patients.
      ) measurements from an intercostal space.
      • Bavu E.
      • Gennisson J.L.
      • Couade M.
      • Bercoff J.
      • Mallet V.
      • Fink M.
      • Badel A.
      • Vallet-Pichard A.
      • Nalpas B.
      • Tanter M.
      • Pol S.
      Noninvasive in vivo liver fibrosis evaluation using supersonic shear imaging: a clinical study on 113 hepatitis C virus patients.
      evaluated 113 patients with chronic hepatitis C, comparing the results to those obtained with TE; liver biopsy was not performed. The results showed a good agreement between fibrosis staging and elasticity assessment. SWSI showed a higher accuracy in assessing mild and intermediate stages of fibrosis. The diagnostic accuracy of SWSI in the assessment of liver fibrosis in patients with chronic hepatitis C was evaluated in a pilot study on 121 patients (
      • 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.
      ). The optimal cut-off values of SWSI were 7.1 kPa for significant fibrosis (F ≥ 2), 8.7 kPa for advanced fibrosis (F ≥ 3), and 10.4 kPa for cirrhosis (F=4). Areas under the ROC curves were 0.92 for F ≥ 2; 0.98 for F ≥ 3 and 0.98 for F=4. A better performance of SWSI compared to TE has also been observed in 226 patients with chronic hepatitis B (
      • Leung V.Y.
      • Shen J.
      • Wong V.W.
      • Abrigo J.
      • Wong G.L.
      • Chim A.M.
      • Chu S.H.
      • Chan A.W.
      • Choi P.C.
      • Ahuja A.T.
      • Chan H.L.
      • Chu W.C.
      Quantitative elastography of liver fibrosis and spleen stiffness in chronic hepatitis B carriers: comparison of shear-wave elastography and transient elastography with liver biopsy correlation.
      ). In a study that evaluated liver fibrosis in a cohort of 422 patients without a gold standard,
      • Poynard T.
      • Munteanu M.
      • Luckina E.
      • Perazzo H.
      • Ngo Y.
      • Royer L.
      • Fedchuk L.
      • Sattonnet F.
      • Pais R.
      • Lebray P.
      • Rudler M.
      • Thabut D.
      • Ratziu V.
      Liver fibrosis evaluation using real-time shear wave elastography: applicability and diagnostic performance using methods without a gold standard.
      report that the applicability of SWSI is lower than that of TE whereas the performance of the two methods is similar. In the same study, the applicability of SWSI was higher than that of TE in patients with ascites.
      It has been reported that stiffness values are not correlated with liver steatosis (
      • 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.
      ;
      • Suh C.H.
      • Kim S.Y.
      • Kim K.W.
      • Lim Y.S.
      • Lee S.J.
      • Lee M.G.
      • Lee J.
      • Lee S.G.
      • Yu E.
      Determination of normal hepatic elasticity by using real-time shear wave elastography.
      ) or with necro-inflammation (
      • 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.
      ).

      Limitations

      • -
        SWSI accuracy has only been assessed in the right lobe through intercostal access. Interlobe variations of liver stiffness have been reported with PSWSM. Body habitus (obesity, narrow intercostal spaces) may hamper the results.
      • -
        Because of the frequency-dependency of the elasticity properties of tissue, great care and consideration must be used when comparing quantitative results among these techniques.
      • -
        Results in kilopascals are not comparable between SWSI, PSWSM and TE.
      • -
        The majority of the studies has been performed in patients with chronic hepatitis C, therefore these cut-offs may not be applicable to other viral etiologies or to NAFLD. Only small series of patients with NAFLD have been studied, therefore the cut-offs in these patients need further assessment.
      • -
        Readings may be higher in patients with ALT levels greater than five times the upper limit of normal; thus, the effect of inflammation should be taken into account, and the results should always be evaluated in the clinical setting. As with TE, it is likely that congestive heart failure, and feeding will be associated with a stiffer liver.

      Recommendations

      PSWSM and SWSI can be used to assess the severity of liver fibrosis in patients with chronic viral hepatitis, best evidenced in patients with hepatitis C. Nonetheless, the evidence that is available is still limited, particularly for SWSI. Like TE, PSWSM and SWSI are more accurate in detecting cirrhosis than significant fibrosis.

      Strain Elastography

      Procedures

      Scanning method

      Successful real-time strain elastography (SE) depends on the clarity of B-mode images - the fundamental US images - and therefore, B-mode images need to be of good quality and free from artifacts.
      • Visualize the right liver through a right intercostal space with the patient supine and the right arm elevated to widen the intercostal spaces;
      • Place the probe lightly on the skin without moving it, since the method relies on intrinsic, mainly cardiac, movement to displace the tissue;
      • Select a region of interest in which B-mode images are free from interfering structures;
      • Obtain images displaying axial, not lateral, movement by pointing the probe towards the heart;
      • With a transient breath hold, make sure that SE images are displayed consistently. (
        • Fujimoto K.
        • Kato M.
        • Kudo M.
        • Yada N.
        • Shiina T.
        • Ueshima K.
        • Yamada Y.
        • Ishida T.
        • Azuma M.
        • Yamasaki M.
        • Yamamoto K.
        • Hayashi N.
        • Takehara T.
        Novel image analysis method using ultrasound elastography for non-invasive evaluation of hepatic fibrosis in patients with chronic hepatitis C.
        ,
        • Morikawa H.
        • Fukuda K.
        • Kobayashi S.
        • Fujii H.
        • Iwai S.
        • Enomoto M.
        • Tamori A.
        • Sakaguchi H.
        • Kawada N.
        Real-time tissue elastography as a tool for the noninvasive assessment of liver stiffness in patients with chronic hepatitis C.
        ,
        • Tatsumi C.
        • Kudo M.
        • Ueshima K.
        • Kitai S.
        • Ishikawa E.
        • Yada N.
        • Hagiwara S.
        • Inoue T.
        • Minami Y.
        • Chung H.
        • Maekawa K.
        • Fujimoto K.
        • Kato M.
        • Tonomura A.
        • Mitake T.
        • Shiina T.
        Non-invasive evaluation of hepatic fibrosis for type C chronic hepatitis.
        ,
        • Tatsumi C.
        • Kudo M.
        • Ueshima K.
        • Kitai S.
        • Takahashi S.
        • Inoue T.
        • Minami Y.
        • Chung H.
        • Maekawa K.
        • Fujimoto K.
        • Akiko T.
        • Takeshi M.
        Noninvasive evaluation of hepatic fibrosis using serum fibrotic markers, transient elastography (FibroScan) and real-time tissue elastography.
        ,
        • Yada N.
        • Kudo M.
        • Morikawa H.
        • Fujimoto K.
        • Kato M.
        • Kawada N.
        Assessment of liver fibrosis with real-time tissue elastography in chronic viral hepatitis.
        )

      Region of Interest (ROI) placement

      The manufacturer recommends that the ROI should be placed deep to the liver capsule (
      • Fujimoto K.
      • Kato M.
      • Kudo M.
      • Yada N.
      • Shiina T.
      • Ueshima K.
      • Yamada Y.
      • Ishida T.
      • Azuma M.
      • Yamasaki M.
      • Yamamoto K.
      • Hayashi N.
      • Takehara T.
      Novel image analysis method using ultrasound elastography for non-invasive evaluation of hepatic fibrosis in patients with chronic hepatitis C.
      ,
      • Morikawa H.
      • Fukuda K.
      • Kobayashi S.
      • Fujii H.
      • Iwai S.
      • Enomoto M.
      • Tamori A.
      • Sakaguchi H.
      • Kawada N.
      Real-time tissue elastography as a tool for the noninvasive assessment of liver stiffness in patients with chronic hepatitis C.
      ,
      • Tatsumi C.
      • Kudo M.
      • Ueshima K.
      • Kitai S.
      • Ishikawa E.
      • Yada N.
      • Hagiwara S.
      • Inoue T.
      • Minami Y.
      • Chung H.
      • Maekawa K.
      • Fujimoto K.
      • Kato M.
      • Tonomura A.
      • Mitake T.
      • Shiina T.
      Non-invasive evaluation of hepatic fibrosis for type C chronic hepatitis.
      ,
      • Tatsumi C.
      • Kudo M.
      • Ueshima K.
      • Kitai S.
      • Takahashi S.
      • Inoue T.
      • Minami Y.
      • Chung H.
      • Maekawa K.
      • Fujimoto K.
      • Akiko T.
      • Takeshi M.
      Noninvasive evaluation of hepatic fibrosis using serum fibrotic markers, transient elastography (FibroScan) and real-time tissue elastography.
      ,
      • Yada N.
      • Kudo M.
      • Morikawa H.
      • Fujimoto K.
      • Kato M.
      • Kawada N.
      Assessment of liver fibrosis with real-time tissue elastography in chronic viral hepatitis.
      ). Some researchers include the surrounding tissues, such as the subcutaneous and muscle layers (
      • Kanamoto M.
      • Shimada M.
      • Ikegami T.
      • Uchiyama H.
      • Imura S.
      • Morine Y.
      • Kanemura H.
      • Arakawa Y.
      • Nii A.
      Real time elastography for noninvasive diagnosis of liver fibrosis.
      ,
      • Saftoiu A.
      • Gheonea D.I.
      • Ciurea T.
      Hue histogram analysis of real-time elastography images for noninvasive assessment of liver fibrosis.
      ); however, placing the ROI entirely inside the liver is the key to generate uniform images (
      • Ferraioli G.
      • Lissandrin R.
      • Filice C.
      Real-time tissue elastography in the assessment of liver stiffness.
      ,
      • Morikawa H.
      • Fukuda K.
      • Kobayashi S.
      • Fujii H.
      • Iwai S.
      • Enomoto M.
      • Tamori A.
      • Sakaguchi H.
      • Kawada N.
      Real-time tissue elastography as a tool for the noninvasive assessment of liver stiffness in patients with chronic hepatitis C.
      ,
      • Tatsumi C.
      • Kudo M.
      • Ueshima K.
      • Kitai S.
      • Ishikawa E.
      • Yada N.
      • Hagiwara S.
      • Inoue T.
      • Minami Y.
      • Chung H.
      • Maekawa K.
      • Fujimoto K.
      • Kato M.
      • Tonomura A.
      • Mitake T.
      • Shiina T.
      Non-invasive evaluation of hepatic fibrosis for type C chronic hepatitis.
      ,
      • Yada N.
      • Kudo M.
      • Morikawa H.
      • Fujimoto K.
      • Kato M.
      • Kawada N.
      Assessment of liver fibrosis with real-time tissue elastography in chronic viral hepatitis.
      ). To avoid large blood vessels, imaging using a 2.5 × 2.5cm ROI is recommended (
      • Fujimoto K.
      • Kato M.
      • Kudo M.
      • Yada N.
      • Shiina T.
      • Ueshima K.
      • Yamada Y.
      • Ishida T.
      • Azuma M.
      • Yamasaki M.
      • Yamamoto K.
      • Hayashi N.
      • Takehara T.
      Novel image analysis method using ultrasound elastography for non-invasive evaluation of hepatic fibrosis in patients with chronic hepatitis C.
      ,
      • Yada N.
      • Kudo M.
      • Morikawa H.
      • Fujimoto K.
      • Kato M.
      • Kawada N.
      Assessment of liver fibrosis with real-time tissue elastography in chronic viral hepatitis.
      ).
      Elimination of artifacts requires attention to technique. The ROI should not include large blood vessels to eliminate anechoic areas. It should not be placed close to ribs or the liver capsule, or too deep in the parenchyma as acoustic shadows, reverberation artifacts, and lack of sufficient penetration will generate incorrect higher readings. Experimentation with placement of the transducer between the ribs will lead to the optimal positioning.
      When an examination is difficult, it is recommended to try another intercostal space, selecting one that is softer and has a thinner subcutaneous layer. Other subcutaneous structures, such as ribs and lungs, should not be included in the image.
      For the analysis, frames with strain generated in the depth direction with no artifacts should be selected. Good images may be obtained at the end of diastole with electrocardiographic gating or at the largest downward wave on a strain graph.

      Results

      Reproducibility of the technique

      The intra-observer variability and intra-observer agreement of SE for the assessment of liver fibrosis have been criticized in several studies (
      • Friedrich-Rust M.
      • Schwarz A.
      • Ong M.
      • Dries V.
      • Schirmacher P.
      • Herrmann E.
      • Samaras P.
      • Bojunga J.
      • Bohle R.M.
      • Zeuzem S.
      • Sarrazin C.
      Real-time tissue elastography versus FibroScan for noninvasive assessment of liver fibrosis in chronic liver disease.
      ;
      • Saftoiu A.
      • Gheonea D.I.
      • Ciurea T.
      Hue histogram analysis of real-time elastography images for noninvasive assessment of liver fibrosis.
      ,
      • Ferraioli G.
      • Gulizia R.
      • Filice C.
      Real-time elastography in the assessment of liver fibrosis.
      ). In a recent study, a Japanese group (
      • Koizumi Y.
      • Hirooka M.
      • Kisaka Y.
      • Konishi I.
      • Abe M.
      • Murakami H.
      • Matsuura B.
      • Hiasa Y.
      • Onji M.
      Liver fibrosis in patients with chronic hepatitis C: noninvasive diagnosis by means of real-time tissue elastography–establishment of the method for measurement.
      ) used a semi-quantitative method (elastic ratio) and found that the measurements obtained from four separate locations had no observed variation between the two operators (ICC 0.97).

      Chronic hepatitis

      In chronic hepatitis, the liver tissue hardens unevenly as fibrosis advances. Accordingly, if the ROI is placed only over the liver, it will highlight the color variation of the SE images, emphasizing areas with relatively low strain (blue areas). This generates images with a mottled appearance (Fig. 6) (
      • Tatsumi C.
      • Kudo M.
      • Ueshima K.
      • Kitai S.
      • Takahashi S.
      • Inoue T.
      • Minami Y.
      • Chung H.
      • Maekawa K.
      • Fujimoto K.
      • Akiko T.
      • Takeshi M.
      Noninvasive evaluation of hepatic fibrosis using serum fibrotic markers, transient elastography (FibroScan) and real-time tissue elastography.
      ,
      • Yada N.
      • Kudo M.
      • Morikawa H.
      • Fujimoto K.
      • Kato M.
      • Kawada N.
      Assessment of liver fibrosis with real-time tissue elastography in chronic viral hepatitis.
      ).
      Figure thumbnail gr6
      Figure 6SE images of different stages of liver fibrosis in patients with chronic hepatitis C. The histogram displays the color dispersion in the region of interest. The x-axis shows the color scale of the elastogram, coded from 0 (dark blue) to 255 (dark red); the y-axis shows the percentage of each color. LF index can be calculated on the ultrasound device. F1 (a), F2 (b), F3 (c) and F4 fibrosis stage (d).

      Evaluation methods

      The examiner’s experience and subjectivity influence the outcome of visual assessments. To overcome this, various quantitative methods have been developed to assess tissue stiffness objectively.
      • Image pattern recognition
      Indices obtained by adjusting grayscale, histogram, and binarization are called feature values, and are used in pattern recognition. In SE imaging, feature values given by the scanner or by separate imaging software can be used to calculate correlations with liver fibrosis. The strain estimate is converted to numerical values using color gradations, with blue being 0 and red being 255.
      Tatsumi et al. and Morikawa et al. have reported that mean strain values inversely correlated with liver stiffness and fibrosis in patients with chronic hepatitis C. On the other hand, the standard deviation of mean values of strain, the percentage of area of low strain and its complexity were positively correlated with liver stiffness and fibrosis (
      • Morikawa H.
      • Fukuda K.
      • Kobayashi S.
      • Fujii H.
      • Iwai S.
      • Enomoto M.
      • Tamori A.
      • Sakaguchi H.
      • Kawada N.
      Real-time tissue elastography as a tool for the noninvasive assessment of liver stiffness in patients with chronic hepatitis C.
      ,
      • Tatsumi C.
      • Kudo M.
      • Ueshima K.
      • Kitai S.
      • Takahashi S.
      • Inoue T.
      • Minami Y.
      • Chung H.
      • Maekawa K.
      • Fujimoto K.
      • Akiko T.
      • Takeshi M.
      Noninvasive evaluation of hepatic fibrosis using serum fibrotic markers, transient elastography (FibroScan) and real-time tissue elastography.
      ).

      Calculation of function values

      • a.
        Liver Fibrosis (LF) Index
      For the calculation of the LF index, nine features - mean and standard deviation of the relative strain value, complexity and ratio of the blue area in the ROI, skewness, kurtosis, entropy, inverse difference moment, angular second moment – are extracted (
      • Fujimoto K.
      • Kato M.
      • Kudo M.
      • Yada N.
      • Shiina T.
      • Ueshima K.
      • Yamada Y.
      • Ishida T.
      • Azuma M.
      • Yamasaki M.
      • Yamamoto K.
      • Hayashi N.
      • Takehara T.
      Novel image analysis method using ultrasound elastography for non-invasive evaluation of hepatic fibrosis in patients with chronic hepatitis C.
      ).
      In a validation study of the LF Index using 245 patients with cirrhosis and chronic hepatitis B and C, Yada et al. observed significant differences between advanced fibrosis and cirrhosis (AUROC 0.80) but not between other consecutive stages of liver fibrosis (
      • Yada N.
      • Kudo M.
      • Morikawa H.
      • Fujimoto K.
      • Kato M.
      • Kawada N.
      Assessment of liver fibrosis with real-time tissue elastography in chronic viral hepatitis.
      ).
      LF index is a company-recommended standard analytic method.
      The positive results obtained in the Japanese series were not confirmed in other series (
      • Ferraioli G.
      • Tinelli C.
      • Malfitano A.
      • Dal Bello B.
      • Filice G.
      • Filice C.
      • Liver Fibrosis Study Group
      • Above E.
      • Barbarini G.
      • Brunetti E.
      • Calderon W.
      • Di Gregorio M.
      • Lissandrin R.
      • Ludovisi S.
      • Maiocchi L.
      • Michelone G.
      • Mondelli M.
      • Patruno S.F.
      • Perretti A.
      • Poma G.
      • Sacchi P.
      • Zaramella M.
      • Zicchetti M.
      Performance of real-time strain elastography, transient elastography, and aspartate-to-platelet ratio index in the assessment of fibrosis in chronic hepatitis C.
      ).
      • b.
        Strain ratios
      There are two types of evaluation methods that use the strain ratio for analysis. The mainstream method places the ROI only in the liver parenchyma for analysis and calculates the ratio between the parenchyma and a blood vessel. In another method, the ROI includes the liver parenchyma and the surrounding tissue, and the strain ratio between the two tissues is used in the analysis.
      • Koizumi Y.
      • Hirooka M.
      • Kisaka Y.
      • Konishi I.
      • Abe M.
      • Murakami H.
      • Matsuura B.
      • Hiasa Y.
      • Onji M.
      Liver fibrosis in patients with chronic hepatitis C: noninvasive diagnosis by means of real-time tissue elastography–establishment of the method for measurement.
      imaged 70 chronic hepatitis C patients with the ROI placed only in the liver parenchyma; they used the strain ratio (elastic ratio) between the liver parenchyma and a peripheral hepatic vein for evaluation. The elastic ratio increased with the progression of liver fibrosis and was not affected by inflammation.
      In patients with NAFLD,
      • Ochi H.
      • Hirooka M.
      • Koizumi Y.
      • Miyake T.
      • Tokumoto Y.
      • Soga Y.
      • Tada F.
      • Abe M.
      • Hiasa Y.
      • Onji M.
      Real-time tissue elastography for evaluation of hepatic fibrosis and portal hypertension in nonalcoholic fatty liver diseases.
      observed a significant correlation between the elasticity ratio and liver fibrosis. In addition, there was a significant difference in elasticity ratios between patients with NAFLD activity score ≤4 and those with scores ≥ 5.
      The elasticity ratio is not the manufacturer-recommended technique for SE.
      • c.
        Other methods
      In patients with hepatitis B and C, Friedrich-Rust et al. calculated the tissue elasticity from every pixel in SE images and performed multivariate analysis to obtain a unique formula (
      • Friedrich-Rust M.
      • Ong M.F.
      • Herrmann E.
      • Dries V.
      • Samaras P.
      • Zeuzem S.
      • Sarrazin C.
      Real-time elastography for noninvasive assessment of liver fibrosis in chronic viral hepatitis.
      ). Elasticity scores calculated using that formula showed a significant correlation with liver fibrosis. These results were not confirmed in a more recent study by the same group (
      • Friedrich-Rust M.
      • Schwarz A.
      • Ong M.
      • Dries V.
      • Schirmacher P.
      • Herrmann E.
      • Samaras P.
      • Bojunga J.
      • Bohle R.M.
      • Zeuzem S.
      • Sarrazin C.
      Real-time tissue elastography versus FibroScan for noninvasive assessment of liver fibrosis in chronic liver disease.
      ).
      • Influences other than liver fibrosis
      SE can evaluate liver fibrosis without being affected by inflammation, jaundice, and blood congestion. SE evaluation is possible in patients with ascites (
      • Hirooka M.
      • Koizumi Y.
      • Hiasa Y.
      • Abe M.
      • Ikeda Y.
      • Matsuura B.
      • Onji M.
      Hepatic elasticity in patients with ascites: evaluation with real-time tissue elastography.
      ).

      Limitations

      Various SE imaging and analysis methods are currently available, and they all show a clear correlation with liver fibrosis. However, a comparative study is needed to reveal the best method. Although the technique that uses cardiac activity as the driving force is most popular today, weak pulsation can adversely affect the quality of SE images. Moreover, even though SE can be applied to most cases because it can assess patients with ascites and narrow intercostal spaces, it is difficult to generate clear SE images in severely obese patients. It is also necessary to learn to avoid artifacts. The experience and skill of examiners can influence the accuracy of ultrasonography; however, variability among examiners with proper training is reportedly low (
      • Koizumi Y.
      • Hirooka M.
      • Kisaka Y.
      • Konishi I.
      • Abe M.
      • Murakami H.
      • Matsuura B.
      • Hiasa Y.
      • Onji M.
      Liver fibrosis in patients with chronic hepatitis C: noninvasive diagnosis by means of real-time tissue elastography–establishment of the method for measurement.
      ). To expand the use of liver SE and further improve accuracy, the imaging and analysis methods need to be standardized and an effective SE training system needs to be established. The current standard analytic method of SE is the LF index (
      • Fujimoto K.
      • Kato M.
      • Kudo M.
      • Yada N.
      • Shiina T.
      • Ueshima K.
      • Yamada Y.
      • Ishida T.
      • Azuma M.
      • Yamasaki M.
      • Yamamoto K.
      • Hayashi N.
      • Takehara T.
      Novel image analysis method using ultrasound elastography for non-invasive evaluation of hepatic fibrosis in patients with chronic hepatitis C.
      ,
      • Yada N.
      • Kudo M.
      • Morikawa H.
      • Fujimoto K.
      • Kato M.
      • Kawada N.
      Assessment of liver fibrosis with real-time tissue elastography in chronic viral hepatitis.
      ).
      Lastly, negative results should not be neglected (
      • Ferraioli G.
      • Tinelli C.
      • Malfitano A.
      • Dal Bello B.
      • Filice G.
      • Filice C.
      • Liver Fibrosis Study Group
      • Above E.
      • Barbarini G.
      • Brunetti E.
      • Calderon W.
      • Di Gregorio M.
      • Lissandrin R.
      • Ludovisi S.
      • Maiocchi L.
      • Michelone G.
      • Mondelli M.
      • Patruno S.F.
      • Perretti A.
      • Poma G.
      • Sacchi P.
      • Zaramella M.
      • Zicchetti M.
      Performance of real-time strain elastography, transient elastography, and aspartate-to-platelet ratio index in the assessment of fibrosis in chronic hepatitis C.
      ;
      • Friedrich-Rust M.
      • Schwarz A.
      • Ong M.
      • Dries V.
      • Schirmacher P.
      • Herrmann E.
      • Samaras P.
      • Bojunga J.
      • Bohle R.M.
      • Zeuzem S.
      • Sarrazin C.
      Real-time tissue elastography versus FibroScan for noninvasive assessment of liver fibrosis in chronic liver disease.
      ).

      Recommendations

      Objective assessment can be made only by the use of the LF index.
      Multicenter studies are currently being performed and the results are anticipated.

      Focal Liver Masses

      Diagnosis of focal liver masses is needed to identify patients with malignant liver disease, to determine the correct management and to differentiate these patients from those with benign and insignificant pathology. Although historically, these diagnoses were obtained with liver biopsy, today we live in an era of noninvasive diagnosis. For many years, contrast enhanced CT and MR scans, and more recently contrast enhanced ultrasound (CEUS), have shown their value and ability to provide correct diagnoses without the requirement for surgery or biopsy.
      Currently, the use of elastography for characterization of focal liver masses remains investigational. It is hoped that elastography may supplement imaging to give more specific diagnoses in selected patients.

      Recommendations

      • -
        Is elastography useful in the evaluation of diffuse liver disease?
      Liver elastography is useful for the evaluation of diffuse liver diseases. The level of evidence is high for TE, moderate for PSWSM, and still low for SWSI and SE. Some methods have been used for more than ten years while others have been introduced more recently, resulting in large variability in the number of published manuscripts on different techniques.
      The majority of studies have evaluated patients with viral chronic hepatitis and results obtained in this setting may not be applicable to other clinical situations as the critical cut-offs are strongly dependent on the etiology.
      Values with shear wave-based elastography and with strain techniques vary between manufacturers.
      Thus, the cutoffs are both system and etiology dependent.
      Elastography is capable of distinguishing significant fibrosis (F2 or greater) from non-significant (F0 - F1) fibrosis. However, more data are needed to confirm its use to distinguish between consecutive stages of early fibrosis.
      It is also important to note that each method may provide different values expressed in different units (meters per second, kilopascals) or indices.
      Several confounding factors have been identified, such as liver inflammation, liver congestion and biliary obstruction.
      Elastography results should be interpreted in the full clinical context of the patient, taking into account the method used to obtain the results.
      Elastography can be used for follow-up of patients with chronic liver diseases.
      • -
        Is the method reproducible?
      Generally, the reproducibility of elastography techniques is good. However, manufacturer recommendations should be followed. Dedicated training is required for all elastography methods.
      • -
        What is its accuracy in a range of pathologies?
      The accuracy of elastography methods improves with the severity of fibrosis. The most studied etiology is chronic viral hepatitis. The body of evidence is highly dependent on the method for other etiologies.
      • -
        What are the limitations?
      Obesity is a common limitation of all ultrasound-based elastography methods. Other limitations are narrow intercostal spaces and, for transient elastography, the presence of ascites. Most methods show higher values when the levels of aminotransferases are elevated.
      Some manufacturers do not recommend the use of liver elastography in pregnancy.
      • -
        To what extent can elastography reduce the use of liver biopsies?
      In some countries, where liver elastography is used in clinical practice, the number of liver biopsies has decreased significantly. When elastography results are consistent with other clinical findings, liver biopsy may be avoided.
      • -
        Can elastography provide additional information for focal liver lesions?
      Currently, the body of evidence concerning the use of elastography in focal liver lesions is not strong enough to recommend its use in clinical practice.
      These recommendations are based on the international literature and on the findings of the WFUMB expert group.

      Acknowledgements

      The authors acknowledge the contributions provided by the following companies: Echosens, Esaote, GE Healthcare, Hitachi-Aloka Medical Systems, Philips Healthcare, Siemens Healthcare, Supersonic Imagine and Toshiba Medical Systems. The authors gratefully acknowledge Glynis Harvey and Stephanie Hynes from the WFUMB office for their efficient management.

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