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New imaging techniques for liver diseases

  • Bernard E. Van Beers
    Correspondence
    Corresponding author. Address: Laboratory of Imaging Biomarkers and Department of Radiology, Beaujon University Hospital, 100 Boulevard du General Leclerc, 92110 Clichy, France. Tel.: +33 1 40 87 56 54; fax: +33 1 40 87 44 77.
    Affiliations
    Laboratory of Imaging Biomarkers, UMR1149 INSERM-University Paris Diderot, Sorbonne Paris Cité, Department of Radiology, Beaujon University Hospital Paris Nord, Clichy, France
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  • Jean-Luc Daire
    Affiliations
    Laboratory of Imaging Biomarkers, UMR1149 INSERM-University Paris Diderot, Sorbonne Paris Cité, Department of Radiology, Beaujon University Hospital Paris Nord, Clichy, France
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  • Philippe Garteiser
    Affiliations
    Laboratory of Imaging Biomarkers, UMR1149 INSERM-University Paris Diderot, Sorbonne Paris Cité, Department of Radiology, Beaujon University Hospital Paris Nord, Clichy, France
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Open AccessPublished:October 16, 2014DOI:https://doi.org/10.1016/j.jhep.2014.10.014

      Summary

      Newly developed or advanced methods of ultrasonography and MR imaging provide combined anatomical and quantitative functional information about diffuse and focal liver diseases. Ultrasound elastography has a central role for staging liver fibrosis and an increasing role in grading portal hypertension; dynamic contrast-enhanced ultrasonography may improve tumor characterization. In clinical practice, MR imaging examinations currently include diffusion-weighted and dynamic MR imaging, enhanced with extracellular or hepatobiliary contrast agents. Moreover, quantitative parameters obtained with diffusion-weighted MR imaging, dynamic contrast-enhanced MR imaging and MR elastography have the potential to characterize further diffuse and focal liver diseases, by adding information about tissue cellularity, perfusion, hepatocyte transport function and visco-elasticity. The multiparametric capability of ultrasonography and more markedly of MR imaging gives the opportunity for high diagnostic performance by combining imaging biomarkers. However, image acquisition and post-processing methods should be further standardized and validated in multicenter trials.

      Abbreviations:

      AASLD (American Association for the Study of Liver Diseases), ADC (apparent diffusion coefficient), APRI (aspartate aminotransferase to platelets ratio index), ARFI (acoustic radiation force imaging), AUROC (area under the receiver operating curve), CT (computed tomography), D (pure diffusion coefficient), D∗ (perfusion-related diffusion coefficient), DCE (dynamic contrast-enhanced), DW (diffusion-weighted), EASL (European Association for the Study of the Liver), EFSUMB (European Federation of Societies for Ultrasound in Medicine and Biology), f (fraction of diffusion related to microcirculation), F (plasma flow), G∗ (shear wave modulus), Gd (storage modulus), Gl (loss modulus), HCC (hepatocellular carcinoma), HCV (hepatitis C virus), IVIM (intravoxel incoherent motion), Ktrans (transfer constant), K1a (arterial transfer constant), K1p (portal venous transfer constant), K1t (total liver plasma transfer constant), MR (magnetic resonance), MRP (multidrug resistance protein), MTT (mean transit time), NASH (non-alcoholic steatohepatitis), OATP (organic anion transporting polypeptide), mRECIST (modified response evaluation criteria in solid tumors), RECIST (response evaluation criteria in solid tumors), STARD (standards for reporting diagnostic accuracy), vd (distribution volume), ve (volume of extravascular extracellular space), vp (plasma volume), WFUMB (World Federation for Ultrasound in Medicine and Biology)

      Keywords

      Linked Article

      • Erratum to “New imaging techniques for liver diseases” [J Hepatol 2015;62:690–700]
        Journal of HepatologyVol. 63Issue 3
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          The publisher regrets that an error was introduced in Fig. 2 of the original manuscript. The below Fig. is correct in relation to the position of the regions of interests highlighted in red. The publisher apologises for any inconvenience caused.
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      • Reply to: “Strain ultrasound elastography for liver diseases”
        Journal of HepatologyVol. 63Issue 2
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          We thank Dr. Cui for his comment about the use of ultrasound strain elastography to assess liver disease. The aim of our review was not to perform a detailed analysis of all variants of ultrasound and MR imaging methods in assessing liver disease, but to discuss the value of new quantitative imaging methods, including ultrasound and MR elastography [1].
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      • Strain ultrasound elastography for liver diseases
        Journal of HepatologyVol. 63Issue 2
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          In a review published in a recent issue [1], Van Beers et al. described the new ultrasonography and magnetic resonance imaging (MRI) techniques for the evaluation of diffuse and focal liver diseases. Regarding the section of ultrasound elastography, however, the authors failed to include strain elastography (SE), which is also one of the important elastography techniques for liver disease [2–4].
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      Introduction

      Liver ultrasonography and magnetic resonance (MR) imaging is increasingly used for detecting, characterizing and assessing the response to treatment of focal and diffuse liver diseases [
      • Galea N.
      • Cantisani V.
      • Taouli B.
      Liver lesion detection and characterization: role of diffusion-weighted imaging.
      ,
      • Low R.N.
      Abdominal MRI advances in the detection of liver tumours and characterisation.
      ,
      • Van Beers B.E.
      • Doblas S.
      • Sinkus R.
      New acquisition techniques: fields of application.
      ]. Ultrasonography remains a first-line examination, but it has recently gained increasing capabilities due to the implementation of dynamic contrast-enhanced (DCE) studies and elastography.
      Figure thumbnail fx1

      Ultrasonography

      Dynamic contrast-enhanced ultrasonography

      Method

      Dynamic contrast-enhanced ultrasonography is performed after intravenous injection of ultrasound contrast agents. Ultrasound contrast agents are blood agents that are composed of gas-filled microbubbles stabilized by a shell made of lipids, proteins or polymers. Because of the non-linear oscillation of the microbubbles at low to mid-high mechanical index, harmonic or non-linear imaging is used to increase the contrast-to-tissue-ratio relative to fundamental B-mode imaging [
      • Kiessling F.
      • Fokong S.
      • Bzyl J.
      • Lederle W.
      • Palmowski M.
      • Lammers T.
      Recent advances in molecular, multimodal and theranostic ultrasound imaging.
      ].

      Liver tumors

      Dynamic contrast-enhanced ultrasonography improves the detection and characterization of focal liver lesions [
      • Kiessling F.
      • Fokong S.
      • Bzyl J.
      • Lederle W.
      • Palmowski M.
      • Lammers T.
      Recent advances in molecular, multimodal and theranostic ultrasound imaging.
      ]. Technical and diagnostic guidelines for the detection, characterization, and treatment monitoring of liver lesions at contrast-enhanced ultrasonography have been published under the auspice of the World Federation for Ultrasound in Medicine and Biology (WFUMB) and the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) [
      • Claudon M.
      • Dietrich C.F.
      • Choi B.I.
      • Cosgrove D.O.
      • Kudo M.
      • Nolsoe C.P.
      • et al.
      Guidelines and good clinical practice recommendations for contrast enhanced utrasound (CEUS) in the liver – update 2012: A WFUMB-EFSUMB initiative in cooperation with representatives of AFSUMB, AIUM, ASUM, FLAUS and ICUS.
      ].
      However, the diagnostic role of DCE ultrasonography relative to DCE-CT and MR imaging remains debated [
      • Bolondi L.
      The appropriate allocation of CEUS in the diagnostic algorithm of liver lesions: a debated issue.
      ]. Besides DCE-CT and MR imaging, DCE ultrasonography was included in the diagnostic algorithm for suspected hepatocellular carcinoma (HCC) in liver cirrhosis in the 2005 recommendations of the American Association for the Study of Liver Diseases (AASLD) [
      • Bruix J.
      • Sherman M.
      Management of hepatocellular carcinoma.
      ] and in the recommendations of the Japan society of hepatology [
      • Kudo M.
      • Izumi N.
      • Kokudo N.
      • Matsui O.
      • Sakamoto M.
      • Nakashima O.
      • et al.
      Management of hepatocellular carcinoma in Japan: Consensus-based clinical practice guidelines proposed by the Japan Society of Hepatology (JSH) 2010 updated version.
      ]; however, it was not included in the recent updated versions of either AASLD or European Association for the Study of the Liver (EASL) guidelines [
      • Bruix J.
      • Sherman M.
      Management of hepatocellular carcinoma: an update.
      ,
      • EASL
      • EORTC
      EASL–EORTC clinical practice guidelines: management of hepatocellular carcinoma.
      ]. Reasons for this change have been based on the fact that the typical hypervascularity and washout pattern of HCC may be observed in some intrahepatic cholangiocellular carcinomas at DCE ultrasonography without being observed at DCE MR imaging [
      • Vilana R.
      • Forner A.
      • Bianchi L.
      • Garcia-Criado A.
      • Rimola J.
      • de Lope C.R.
      • et al.
      Intrahepatic peripheral cholangiocarcinoma in cirrhosis patients may display a vascular pattern similar to hepatocellular carcinoma on contrast-enhanced ultrasound.
      ]. The different pattern observed at ultrasonography and MR imaging or CT may be explained by differences in the distribution volumes between the ultrasound microbubbles, which remain intravascular, and the small-molecular-weight CT and MR contrast materials, which instead distribute into the vascular and extravascular-extracellular spaces.
      Other reasons for the variable use of DCE ultrasonography are defect in standardization, dependence on the operator, variability of results related to the physical characteristics of any individual patient, and the lack in three-dimensional dynamic imaging [
      • Bolondi L.
      The appropriate allocation of CEUS in the diagnostic algorithm of liver lesions: a debated issue.
      ]. In contrast, the real-time capability of DCE ultrasonography may be a benefit relative to CT and MR imaging for observing the transient signal intensity enhancement of hypervascular liver tumors such as HCCs [
      • Trillaud H.
      • Bruel J.M.
      • Valette P.J.
      • Vilgrain V.
      • Schmutz G.
      • Oyen R.
      • et al.
      Characterization of focal liver lesions with SonoVue-enhanced sonography: international multicenter study in comparison to CT and MRI.
      ].
      A meta-analysis of sulphur hexafluoride microbubble enhanced ultrasonography reported that it could provide improved cost-effectiveness and similar diagnostic performance to DCE-CT and MR imaging for the assessment of focal liver lesions [
      • Westwood M.
      • Joore M.
      • Grutters J.
      • Redekop K.
      • Armstrong N.
      • Lee K.
      • et al.
      Contrast-enhanced ultrasound using SonoVue(R) (sulphur hexafluoride microbubbles) compared with contrast-enhanced computed tomography and contrast-enhanced magnetic resonance imaging for the characterisation of focal liver lesions and detection of liver metastases: a systematic review and cost-effectiveness analysis.
      ]. However, the authors highlighted limitations in the reporting of many studies of the review, and stressed the need for further high-quality studies, based on the standards for reporting diagnostic accuracy (STARD) criteria, which compare the performance of all three imaging modalities (DCE ultrasonography, CT, and MR imaging) in the same patients and provide standardized definitions of a positive imaging test for each target condition. Moreover, the effectiveness of DCE ultrasonography in the assessment of multiple lesions of the liver should also be considered [
      • Westwood M.
      • Joore M.
      • Grutters J.
      • Redekop K.
      • Armstrong N.
      • Lee K.
      • et al.
      Contrast-enhanced ultrasound using SonoVue(R) (sulphur hexafluoride microbubbles) compared with contrast-enhanced computed tomography and contrast-enhanced magnetic resonance imaging for the characterisation of focal liver lesions and detection of liver metastases: a systematic review and cost-effectiveness analysis.
      ].
      Future perspectives in DCE ultrasonography include quantitative perfusion imaging and molecular imaging [
      • Kiessling F.
      • Fokong S.
      • Bzyl J.
      • Lederle W.
      • Palmowski M.
      • Lammers T.
      Recent advances in molecular, multimodal and theranostic ultrasound imaging.
      ,
      • Lassau N.
      • Koscielny S.
      • Chami L.
      • Chebil M.
      • Benatsou B.
      • Roche A.
      • et al.
      Advanced hepatocellular carcinoma: early evaluation of response to bevacizumab therapy at dynamic contrast-enhanced US with quantification–preliminary results.
      ]. The in vivo feasibility of determining absolute tumor perfusion parameters at DCE ultrasonography with deconvolution of the tumor enhancement curve by the arterial input function has been shown [
      • Gauthier M.
      • Tabarout F.
      • Leguerney I.
      • Polrot M.
      • Pitre S.
      • Peronneau P.
      • et al.
      Assessment of quantitative perfusion parameters by dynamic contrast-enhanced sonography using a deconvolution method: an in vitro and in vivo study.
      ].
      In animal models, molecular imaging of angiogenesis and inflammation has been performed with targeted ultrasound contrast agents directed to surface receptor molecules expressed on the luminal side of activated endothelium, in response to either inflammatory or angiogenic stimuli [
      • Kiessling F.
      • Fokong S.
      • Bzyl J.
      • Lederle W.
      • Palmowski M.
      • Lammers T.
      Recent advances in molecular, multimodal and theranostic ultrasound imaging.
      ]. However, the unspecific accumulation of microbubbles within Kupffer cells limits targeted imaging approaches in liver diseases [
      • Palmowski M.
      • Morgenstern B.
      • Hauff P.
      • Reinhardt M.
      • Huppert J.
      • Maurer M.
      • et al.
      Pharmacodynamics of streptavidin-coated cyanoacrylate microbubbles designed for molecular ultrasound imaging.
      ].

      Dynamic ultrasound elastography

      Method

      Dynamic elastography is based on the assessment of the propagation of shear waves within tissues to calculate the visco-elastic properties [
      • Dewall R.J.
      Ultrasound elastography: principles, techniques, and clinical applications.
      ]. Displacements can be measured with ultrasonography or MR imaging and stress can be applied either externally or internally. In the former case, an external actuator is generally directly in contact with the skin. The latter case includes methods that apply a force internally, for example by using focused ultrasound pulses generating acoustic radiation force (ARF). Acoustic pulses are used to “push” tissue, as well as capture the resulting tissue motion [
      • Dewall R.J.
      Ultrasound elastography: principles, techniques, and clinical applications.
      ].
      External mechanical excitation may be either continuous or transient. With ultrasonography, transient pulses are usually used to avoid the problem of reflections caused by continuous vibration.
      Transient elastography (Fibroscan©, Echosens, Paris, France) is a first-generation dynamic ultrasound elastography method. It relies on the application of a short external shear wave pulse that is tracked by using one-dimensional ultrasound imaging [
      • Sandrin L.
      • Fourquet B.
      • Hasquenoph J.M.
      • Yon S.
      • Fournier C.
      • Mal F.
      • et al.
      Transient elastography: a new noninvasive method for assessment of hepatic fibrosis.
      ]. Second generation ultrasound elastography methods are based on ARF. ARF methods include acoustic radiation force imaging (ARFI) (Siemens Healthcare, Erlangen, Germany), supersonic shear imaging also called shear wave elastography (Supersonic Imagine, Aix en Provence, France) and shear wave dispersion ultrasound vibrometry (Philips Healthcare, Best, The Netherlands) [
      • Nightingale K.
      • Soo M.S.
      • Nightingale R.
      • Trahey G.
      Acoustic radiation force impulse imaging: in vivo demonstration of clinical feasibility.
      ,
      • Bercoff J.
      • Tanter M.
      • Fink M.
      Supersonic shear imaging: A new technique for soft tissue elasticity mapping.
      ,
      • Chen S.
      • Sanchez W.
      • Callstrom M.R.
      • Gorman B.
      • Lewis J.T.
      • Sanderson S.O.
      • et al.
      Assessment of liver viscoelasticity by using shear waves induced by ultrasound radiation force.
      ]. Quantitative ARFI estimates shear wave speed by tracking the shear wave generated by the push at lateral offsets from the push location, whereas supersonic shear imaging uses ultrafast imaging at a frame rate up to 4000 frames per second to assess the displacements resulting from the shear wave propagation [
      • Dewall R.J.
      Ultrasound elastography: principles, techniques, and clinical applications.
      ,
      • Vappou J.
      Magnetic resonance- and ultrasound imaging-based elasticity imaging methods: a review.
      ].
      Because transient waves are usually used at ultrasound elastography, only the wave speed can be calculated. This speed is proportional to tissue stiffness or elasticity, if one assumes that tissues are purely elastic. In fact, biological tissues are visco-elastic because they are both liquid and solid. The visco-elasticity can be assessed with ultrasound elastography by using Voigt model fitting of the frequency-dependent wave speed dispersion [
      • Chen S.
      • Sanchez W.
      • Callstrom M.R.
      • Gorman B.
      • Lewis J.T.
      • Sanderson S.O.
      • et al.
      Assessment of liver viscoelasticity by using shear waves induced by ultrasound radiation force.
      ]. However, the relevance of the Voigt model in human tissues remains controversial [
      • Sinkus R.
      • Siegmann K.
      • Xydeas T.
      • Tanter M.
      • Claussen C.
      • Fink M.
      MR elastography of breast lesions: understanding the solid/liquid duality can improve the specificity of contrast-enhanced MR mammography.
      ].
      With the first generation transient elastography method, shear wave speed is measured in a cylindrical volume 10-mm wide, 40-mm long, located 25–65 mm below the skin surface. The Fibroscan is an ultrasound apparatus that is dedicated for assessing liver fibrosis. No conventional B-mode ultrasound image is available. The proper positioning of the elastography box within the liver can thus not be assessed, nor can transient elastography be performed in focal liver lesions.
      Second generation ARF-based elastography methods have advantages relative to transient elastography. First, the regions of interest for elasticity measurements are overlaid on conventional B mode images. Second, elastograms can be obtained in patients with ascites when using ARF based methods, but not with transient elastography. This is explained by the fact that focused ultrasound beams in contrast to shear waves do penetrate trough liquids. Third, as the shear waves are generated internally with ARF methods, deeper regions of the liver can be assessed. However, the deepest regions of the liver can be difficult to evaluate, as the depth limit for ARFI and shear wave elastography has been reported to be 8 cm [
      • Frulio N.
      • Laumonier H.
      • Carteret T.
      • Laurent C.
      • Maire F.
      • Balabaud C.
      • et al.
      Evaluation of liver tumors using acoustic radiation force impulse elastography and correlation with histologic data.
      ,
      • Guibal A.
      • Boularan C.
      • Bruce M.
      • Vallin M.
      • Pilleul F.
      • Walter T.
      • et al.
      Evaluation of shearwave elastography for the characterisation of focal liver lesions on ultrasound.
      ]. ARFI provides a single estimate of tissue stiffness in a small region of tissue (10 × 5 mm), whereas a whole elasticity map can be obtained within a region of interest with shear wave elastography [
      • Guibal A.
      • Boularan C.
      • Bruce M.
      • Vallin M.
      • Pilleul F.
      • Walter T.
      • et al.
      Evaluation of shearwave elastography for the characterisation of focal liver lesions on ultrasound.
      ].

      Diffuse liver diseases

      Validation of dynamic elastography in liver diseases is ongoing. For liver fibrosis, transient elastography is currently the most validated method for the assessment of liver fibrosis, mainly in viral hepatitis [
      • Castera L.
      Noninvasive methods to assess liver disease in patients with hepatitis B or C.
      ]. Its diagnostic accuracy is better for cirrhosis than for significant fibrosis, with mean areas under the receiver operating characteristic curves (AUROCs) of 0.94 and 0.84 in patients with interpretable results [
      • Friedrich-Rust M.
      • Ong M.F.
      • Martens S.
      • Sarrazin C.
      • Bojunga J.
      • Zeuzem S.
      • et al.
      Performance of transient elastography for the staging of liver fibrosis: a meta-analysis.
      ]. The diagnostic accuracy of transient elastography for significant fibrosis is not high enough to recommend transient elastography as the sole examination in clinical practice [
      • Friedrich-Rust M.
      • Ong M.F.
      • Martens S.
      • Sarrazin C.
      • Bojunga J.
      • Zeuzem S.
      • et al.
      Performance of transient elastography for the staging of liver fibrosis: a meta-analysis.
      ,
      • Degos F.
      • Perez P.
      • Roche B.
      • Mahmoudi A.
      • Asselineau J.
      • Voitot H.
      • et al.
      Diagnostic accuracy of FibroScan and comparison to liver fibrosis biomarkers in chronic viral hepatitis: a multicenter prospective study (the FIBROSTIC study).
      ,
      • 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.
      ]. Moreover, the main limitation of transient elastography is its limited applicability: in about 20% of the patients, examination fails or results are non-interpretable, mostly because of obesity, ascites or limited operator experience [
      • Castera L.
      • Foucher J.
      • Bernard P.H.
      • Carvalho F.
      • Allaix D.
      • Merrouche W.
      • et al.
      Pitfalls of liver stiffness measurement: a 5-year prospective study of 13,369 examinations.
      ].
      The accuracy of ARFI in liver fibrosis is reported to be similar to that of transient elastography, whereas a single center study suggests that shear wave elastography is more accurate than transient elastography for diagnosing significant fibrosis in HCV patients [
      • Friedrich-Rust M.
      • Nierhoff J.
      • Lupsor M.
      • Sporea I.
      • Fierbinteanu-Braticevici C.
      • Strobel D.
      • et al.
      Performance of Acoustic Radiation Force Impulse imaging for the staging of liver fibrosis: a pooled meta-analysis.
      ,
      • Ferraioli G.
      • Tinelli C.
      • Dal Bello B.
      • Zicchetti M.
      • Filice G.
      • Filice C.
      Accuracy of real-time shear wave elastography for assessing liver fibrosis in chronic hepatitis C: a pilot study.
      ]. Besides the staging of liver fibrosis, ultrasound elastography is emerging as an accurate method for staging portal hypertension and detecting esophageal varices [
      • Berzigotti A.
      • Seijo S.
      • Arena U.
      • Abraldes J.G.
      • Vizzutti F.
      • Garcia-Pagan J.C.
      • et al.
      Elastography, spleen size, and platelet count identify portal hypertension in patients with compensated cirrhosis.
      ,
      • Takuma Y.
      • Nouso K.
      • Morimoto Y.
      • Tomokuni J.
      • Sahara A.
      • Toshikuni N.
      • et al.
      Measurement of spleen stiffness by acoustic radiation force impulse imaging identifies cirrhotic patients with esophageal varices.
      ].

      Liver tumors

      Some studies have assessed the potential role of second generation ultrasound elastography in characterizing liver tumors [
      • Frulio N.
      • Laumonier H.
      • Carteret T.
      • Laurent C.
      • Maire F.
      • Balabaud C.
      • et al.
      Evaluation of liver tumors using acoustic radiation force impulse elastography and correlation with histologic data.
      ,
      • Guibal A.
      • Boularan C.
      • Bruce M.
      • Vallin M.
      • Pilleul F.
      • Walter T.
      • et al.
      Evaluation of shearwave elastography for the characterisation of focal liver lesions on ultrasound.
      ]. Despite the fact that significant overlap of lesion stiffness has been observed between benign and malignant lesions, ultrasound elastography might be useful for more specific clinical questions, such as the differentiation between adenoma and focal nodular hyperplasia as well as between hepatocellular and cholangiocellular carcinomas. Indeed, lesions of focal nodular hyperplasia are stiffer than adenomas (Fig. 1), and cholangiocellular carcinomas are stiffer than hepatocellular carcinomas [
      • Frulio N.
      • Laumonier H.
      • Carteret T.
      • Laurent C.
      • Maire F.
      • Balabaud C.
      • et al.
      Evaluation of liver tumors using acoustic radiation force impulse elastography and correlation with histologic data.
      ,
      • Guibal A.
      • Boularan C.
      • Bruce M.
      • Vallin M.
      • Pilleul F.
      • Walter T.
      • et al.
      Evaluation of shearwave elastography for the characterisation of focal liver lesions on ultrasound.
      ]. Moreover, higher stiffness is observed in inflammatory than in steatotic adenomas [
      • Ronot M.
      • Di Renzo S.
      • Gregoli B.
      • Duran R.
      • Castera L.
      • Van Beers B.E.
      • et al.
      Characterization of fortuitously discovered focal liver lesions: additional information provided by shearwave elastography.
      ].
      Figure thumbnail gr1
      Fig. 1Hepatic shearwave elastograms. (A) Patient with focal nodular hyperplasia and (B) patient with steatotic adenoma Higher stiffness (30.9 ± 1.7 kPa) is observed in (A) focal nodular hyperplasia than (B) in adenoma (14.4 ± 1.7 kPa).
      Preliminary results suggest that combined DCE ultrasonography and ultrasound elastography might be superior to each method alone for characterizing liver tumors [
      • Zhang P.
      • Zhou P.
      • Tian S.M.
      • Qian Y.
      • Li J.L.
      • Li R.Z.
      Diagnostic performance of contrast-enhanced sonography and acoustic radiation force impulse imaging in solid liver lesions.
      ]. Tissue biomechanical parameters may thus become additional useful biomarkers to those obtained with Doppler and DCE ultrasonography [
      • Tanter M.
      • Fink M.
      Ultrafast imaging in biomedical ultrasound.
      ]. Further efforts on validation and standardization of ultrasound elastography should be performed before the full clinical impact of the method can be observed. Finally, one should remind that multiple factors including hepatic fibrosis, inflammation, cholestasis, congestion, steatosis and portal hypertension can lead to overestimation of liver stiffness [
      • Fraquelli M.
      • Rigamonti C.
      • Casazza G.
      • Donato M.F.
      • Ronchi G.
      • Conte D.
      • et al.
      Etiology-related determinants of liver stiffness values in chronic viral hepatitis B or C.
      ,
      • Berzigotti A.
      • Castera L.
      Update on ultrasound imaging of liver fibrosis.
      ].

      MR imaging

      The role of MR imaging in assessing focal and diffuse liver diseases has been reinforced these last years by the introduction of quantitative imaging methods that add functional information and can provide new imaging biomarkers. These methods include diffusion-weighted (DW) MR imaging, DCE MR imaging and MR elastography.

      Diffusion-weighted MR imaging

      Method

      Diffusion-weighted MR imaging probes intracellular and extracellular diffusion of water molecules by adding, in an echo-planar MR imaging sequence, two diffusion gradients that decrease the signal intensity according to tissue diffusibility and gradient strength (b value). On high b-value MR images, the signal intensity of lesions with high diffusibility such as cysts or hemangiomas will be nearly zero, whereas lesions with restricted diffusion such as highly cellular malignant tumors will have preserved high signal.
      The decrease of signal intensity of tissues according to increasing b-values is exponential, and the slope of this decrease on a semi-logarithmic plot corresponds to the apparent diffusion coefficient (ADC). Additional diffusion parameters can be assessed by probing signal intensity with multiple b-values. Indeed, according to the intravoxel incoherent motion (IVIM) model, signal intensity decrease on DW MR images at low b values (<100 s/mm2) is mainly caused by perfusion, whose speed is much faster than that of extravascular diffusion [
      • Le Bihan D.
      • Breton E.
      • Lallemand D.
      • Aubin M.L.
      • Vignaud J.
      • Laval-Jeantet M.
      Separation of diffusion and perfusion in intravoxel incoherent motion MR imaging.
      ,
      • Padhani A.R.
      • Liu G.
      • Koh D.M.
      • Chenevert T.L.
      • Thoeny H.C.
      • Takahara T.
      • et al.
      Diffusion-weighted magnetic resonance imaging as a cancer biomarker: consensus and recommendations.
      ]. Therefore, at low b-values, the perfusion-related diffusion coefficient (D) and the fraction of diffusion related to microcirculation (f) can be calculated, whereas at high b-values the pure molecular diffusion coefficient (D) can be obtained.
      The reproducibility and precision of the diffusion parameter measurements in the liver are limited by macroscopic motion, including respiratory and cardiac motion. Multiple methods have been proposed for motion compensation, including signal averaging, respiratory triggering or tracking, breath-holding, and cardiac triggering. However, the value of these methods remains debated because they have drawbacks, including increase in scan duration or decrease in signal-to-noise ratio [
      • Dyvorne H.A.
      • Galea N.
      • Nevers T.
      • Fiel M.I.
      • Carpenter D.
      • Wong E.
      • et al.
      Diffusion-weighted imaging of the liver with multiple b values: effect of diffusion gradient polarity and breathing acquisition on image quality and intravoxel incoherent motion parameters–a pilot study.
      ].
      The reproducibility of the diffusion parameters varies. High reproducibility has been observed for ADC and D, the apparent and true diffusion coefficients, but lower reproducibility for f, the fraction of diffusion related to microcirculation, and mainly for D, the perfusion-related diffusion coefficient. The reported repeatability coefficients of ADC and D are 10–15% in the liver and 25–30% in malignant liver tumors [
      • Kim S.Y.
      • Lee S.S.
      • Byun J.H.
      • Park S.H.
      • Kim J.K.
      • Park B.
      • et al.
      Malignant hepatic tumors: short-term reproducibility of apparent diffusion coefficients with breath-hold and respiratory-triggered diffusion-weighted MR imaging.
      ,
      • Heijmen L.
      • Ter Voert E.E.
      • Nagtegaal I.D.
      • Span P.
      • Bussink J.
      • Punt C.J.
      • et al.
      Diffusion-weighted MR imaging in liver metastases of colorectal cancer: reproducibility and biological validation.
      ,
      • Andreou A.
      • Koh D.M.
      • Collins D.J.
      • Blackledge M.
      • Wallace T.
      • Leach M.O.
      • et al.
      Measurement reproducibility of perfusion fraction and pseudodiffusion coefficient derived by intravoxel incoherent motion diffusion-weighted MR imaging in normal liver and metastases.
      ]. The reproducibility and robustness of the diffusion parameter measurements can be improved by acquiring MR images during breath-holdings (Fig. 2), increasing the number of b-values, and using Bayesian analysis [
      • Kim S.Y.
      • Lee S.S.
      • Park B.
      • Kim N.
      • Kim J.K.
      • Park S.H.
      • et al.
      Reproducibility of measurement of apparent diffusion coefficients of malignant hepatic tumors: effect of DWI techniques and calculation methods.
      ,
      • Orton M.R.
      • Collins D.J.
      • Koh D.M.
      • Leach M.O.
      Improved intravoxel incoherent motion analysis of diffusion weighted imaging by data driven Bayesian modeling.
      ].
      Figure thumbnail gr2
      Fig. 2Higher robustness of breathhold acquisition of DW-MR imaging data in calculating diffusion parameters. (A and C) Hepatic diffusion-weighted MR images and (B and D) maps of perfusion fractions (%) in patients with metastases (red contours) from colorectal cancer. Panels A and B are acquired during free breathing, whereas C and D are acquired with breathholding in the same patient. Black dots on B and D maps represent voxels with undetermined perfusion fraction because of failure of least-square algorithm to calculate perfusion fraction. More failures are observed on (B) free-breathing than (D) on corresponding breathhold image, especially in metastasis of liver segment VI (short arrow) and in upper pole of right kidney (long arrow). This figure illustrates the higher robustness of breathhold acquisition of DW- MR imaging data in calculating diffusion parameters.

      Liver tumors

      Diffusion-weighted MR imaging is nowadays routinely performed in patients with focal liver diseases. It can be used to improve detection, characterization, and assessment of response to treatment of liver tumors. DW MR imaging markedly improves the detection of solid liver tumors relative to T2-weighted fast spin-echo imaging, with lower to comparable accuracy compared with DCE MR imaging [
      • Coenegrachts K.
      • Delanote J.
      • Ter Beek L.
      • Haspeslagh M.
      • Bipat S.
      • Stoker J.
      • et al.
      Improved focal liver lesion detection: comparison of single-shot diffusion-weighted echoplanar and single-shot T2 weighted turbo spin echo techniques.
      ,
      • Parikh T.
      • Drew S.J.
      • Lee V.S.
      • Wong S.
      • Hecht E.M.
      • Babb J.S.
      • et al.
      Focal liver lesion detection and characterization with diffusion-weighted MR imaging: comparison with standard breath-hold T2-weighted imaging.
      ,
      • Hardie A.D.
      • Naik M.
      • Hecht E.M.
      • Chandarana H.
      • Mannelli L.
      • Babb J.S.
      • et al.
      Diagnosis of liver metastases: value of diffusion-weighted MRI compared with gadolinium-enhanced MRI.
      ,
      • Lowenthal D.
      • Zeile M.
      • Lim W.Y.
      • Wybranski C.
      • Fischbach F.
      • Wieners G.
      • et al.
      Detection and characterisation of focal liver lesions in colorectal carcinoma patients: comparison of diffusion-weighted and Gd-EOB-DTPA enhanced MR imaging.
      ,
      • Wagner M.
      • Maggiori L.
      • Ronot M.
      • Paradis V.
      • Vilgrain V.
      • Panis Y.
      • et al.
      Diffusion-weighted and T2-weighted MR imaging for colorectal liver metastases detection in a rat model at 7 T: a comparative study using histological examination as reference.
      ,
      • Donati O.F.
      • Fischer M.A.
      • Chuck N.
      • Hunziker R.
      • Weishaupt D.
      • Reiner C.S.
      Accuracy and confidence of Gd-EOB-DTPA enhanced MRI and diffusion-weighted imaging alone and in combination for the diagnosis of liver metastases.
      ]. Analyzing DW MR images with DCE MR images improves the diagnostic performance relative to the individual analysis of each imaging sequence.
      Diffusion-weighted MR imaging is also useful for tumor characterization. Malignant liver tumors have lower ADC than benign lesions [
      • Bruegel M.
      • Holzapfel K.
      • Gaa J.
      • Woertler K.
      • Waldt S.
      • Kiefer B.
      • et al.
      Characterization of focal liver lesions by ADC measurements using a respiratory triggered diffusion-weighted single-shot echo-planar MR imaging technique.
      ]. This is generally explained by the higher cellularity in malignant tumors. In clinical practice, DW MR imaging criteria have been defined for characterizing benign and malignant lesions based on the tumor-to-liver contrast. According to these criteria, a lesion is considered benign if it appears hyperintense on DW images with a b-value of 0 s/mm2, with a strong decrease in signal intensity with a b-value of 500 s/mm2 or higher, and if the lesion is hyperintense relative to the liver on the ADC map. A lesion is considered malignant if the lesion is mildly to moderately hyperintense on DW images with a b-value of 0 s/mm2 and remains hyperintense compared with liver parenchyma with a b-value of 500 s/mm2 or higher, and if the lesion appears hypointense on the ADC map [
      • Parikh T.
      • Drew S.J.
      • Lee V.S.
      • Wong S.
      • Hecht E.M.
      • Babb J.S.
      • et al.
      Focal liver lesion detection and characterization with diffusion-weighted MR imaging: comparison with standard breath-hold T2-weighted imaging.
      ].
      However, the characterization of liver tumors with ADC measurements shows variable overlap between benign and malignant lesions. Benign lesions with high fluid content such as liver cysts and hemangiomas clearly have higher ADC than non-cystic malignant lesions, but the ADC of solid benign hepatocellular lesions such as focal nodular hyperplasia and adenoma does not significantly differ from that of solid malignant tumors [
      • Agnello F.
      • Ronot M.
      • Valla D.C.
      • Sinkus R.
      • Van Beers B.E.
      • Vilgrain V.
      High-b-value diffusion-weighted MR imaging of benign hepatocellular lesions: quantitative and qualitative analysis.
      ]. Therefore, the DW MR criteria for tumor characterization are not useful for differentiating between benign hepatocellular and malignant liver lesions in the normal liver.
      One area where tumor characterization with DW MR imaging appears useful is the characterization of nodules in cirrhosis. Indeed, most HCC are hyperintense on DW MR images, whereas dysplastic nodules rarely are [
      • Xu P.J.
      • Yan F.H.
      • Wang J.H.
      • Shan Y.
      • Ji Y.
      • Chen C.Z.
      Contribution of diffusion-weighted magnetic resonance imaging in the characterization of hepatocellular carcinomas and dysplastic nodules in cirrhotic liver.
      ]. It has been reported that lesion hyperintensity on DW MR images is a more accurate sign of HCC than delayed hypointensity on DCE MR images enhanced with non-specific or hepatobiliary contrast agents [
      • Xu P.J.
      • Yan F.H.
      • Wang J.H.
      • Shan Y.
      • Ji Y.
      • Chen C.Z.
      Contribution of diffusion-weighted magnetic resonance imaging in the characterization of hepatocellular carcinomas and dysplastic nodules in cirrhotic liver.
      ,
      • Piana G.
      • Trinquart L.
      • Meskine N.
      • Barrau V.
      • Van Beers B.
      • Vilgrain V.
      New MR imaging criteria with a diffusion-weighted sequence for the diagnosis of hepatocellular carcinoma in chronic liver diseases.
      ,
      • Park M.J.
      • Kim Y.K.
      • Lee M.H.
      • Lee J.H.
      Validation of diagnostic criteria using gadoxetic acid-enhanced and diffusion-weighted MR imaging for small hepatocellular carcinoma (<=2.0 cm) in patients with hepatitis-induced liver cirrhosis.
      ]. The value of the IVIM-derived parameters to characterize liver lesions has been assessed in some studies. In a study of patients with 86 solid liver tumors, Doblas et al. observed that the diffusion parameters derived from the IVIM model did not improve the determination of malignancy and characterization of hepatic tumor type, when compared with the ADC [
      • Doblas S.
      • Wagner M.
      • Leitao H.S.
      • Daire J.L.
      • Sinkus R.
      • Vilgrain V.
      • et al.
      Determination of malignancy and characterization of hepatic tumor type with diffusion-weighted magnetic resonance imaging: comparison of apparent diffusion coefficient and intravoxel incoherent motion-derived measurements.
      ]. In a series of 42 surgically confirmed HCC, Woo et al. observed a stronger degree of negative correlation between the pure diffusion coefficient D and tumor grade than between ADC and grade. However, the accuracy of D for differentiating between high- and low-grade HCC remained modest because of substantial overlap in the results (AUROC: 0.84) [
      • Woo S.
      • Lee J.M.
      • Yoon J.H.
      • Joo I.
      • Han J.K.
      • Choi B.I.
      Intravoxel incoherent motion diffusion-weighted MR imaging of hepatocellular carcinoma: correlation with enhancement degree and histologic grade.
      ].
      Diffusion measurements may be useful to assess the tumor response to treatment, by showing early diffusion parameter changes related to necrosis [
      • Braren R.
      • Altomonte J.
      • Settles M.
      • Neff F.
      • Esposito I.
      • Ebert O.
      • et al.
      Validation of preclinical multiparametric imaging for prediction of necrosis in hepatocellular carcinoma after embolization.
      ]. It has been recently shown that the volumetric ADC changes one month after intra-arterial treatment of HCC showed stronger association with tumor response than the size changes as assessed with the response evaluation criteria in solid tumors (RECIST), the modified response evaluation criteria in solid tumors (mRECIST) and the EASL criteria [
      • Vandecaveye V.
      • Michielsen K.
      • De Keyzer F.
      • Laleman W.
      • Komuta M.
      • Op de Beeck K.
      • et al.
      Chemoembolization for hepatocellular carcinoma: 1-month response determined with apparent diffusion coefficient is an independent predictor of outcome.
      ,
      • Bonekamp S.
      • Halappa V.G.
      • Geschwind J.F.
      • Li Z.
      • Corona-Villalobos C.P.
      • Reyes D.
      • et al.
      Unresectable hepatocellular carcinoma: MR imaging after intraarterial therapy. Part II. Response stratification using volumetric functional criteria after intraarterial therapy.
      ]. These results are explained not only by the use of a functional imaging biomarker (ADC) rather than structural criteria (RECIST), but also by the use of three-dimensional tumor volume analysis for the diffusivity measurements. Indeed, because of tumor heterogeneity, semi-automatic three-dimensional assessment of tumor volume ADC after trans-catheter arterial embolization has shown better interobserver agreement compared with manual two-dimensional region of interest measurements [
      • Bonekamp D.
      • Bonekamp S.
      • Halappa V.G.
      • Geschwind J.F.
      • Eng J.
      • Corona-Villalobos C.P.
      • et al.
      Interobserver agreement of semi-automated and manual measurements of functional MRI metrics of treatment response in hepatocellular carcinoma.
      ].
      Besides their usefulness in the assessment of the response to trans-catheter embolization, ADC measurements are also potentially useful for predicting the response to radioembolization. One month after treatment of HCC with yttrium-90-labeled microspheres, increase in tumor ADC was observed, without a statistically significant change in tumor size [
      • Kamel I.R.
      • Reyes D.K.
      • Liapi E.
      • Bluemke D.A.
      • Geschwind J.F.
      Functional MR imaging assessment of tumor response after 90Y microsphere treatment in patients with unresectable hepatocellular carcinoma.
      ].
      Some results about the use of quantitative DW imaging after antivascular treatments have been reported. After sunitinib treatment of HCC, perfusion parameters assessed with perfusion MR imaging might be more sensitive biomarkers in predicting early response than ADC [
      • Sahani D.V.
      • Jiang T.
      • Hayano K.
      • Duda D.G.
      • Catalano O.A.
      • Ancukiewicz M.
      • et al.
      Magnetic resonance imaging biomarkers in hepatocellular carcinoma: association with response and circulating biomarkers after sunitinib therapy.
      ]. After sorafenib treatment of HCC in another group of patients, it has been reported that changes of the perfusion fraction f may help differentiating between responders and non-responders [
      • Lewin M.
      • Fartoux L.
      • Vignaud A.
      • Arrive L.
      • Menu Y.
      • Rosmorduc O.
      The diffusion-weighted imaging perfusion fraction f is a potential marker of sorafenib treatment in advanced hepatocellular carcinoma: a pilot study.
      ].
      Few studies report on the potential value of DW MR imaging for assessing the response of colorectal cancer metastases to chemotherapy [
      • Cui Y.
      • Zhang X.P.
      • Sun Y.S.
      • Tang L.
      • Shen L.
      Apparent diffusion coefficient: potential imaging biomarker for prediction and early detection of response to chemotherapy in hepatic metastases.
      ,
      • Chiaradia M.
      • Baranes L.
      • Van Nhieu J.T.
      • Vignaud A.
      • Laurent A.
      • Decaens T.
      • et al.
      Intravoxel incoherent motion (IVIM) MR imaging of colorectal liver metastases: are we only looking at tumor necrosis?.
      ]. Increase in ADC has been reported after treatment. It is expected that the changes of the diffusion parameters after treatment would be less pronounced in colorectal metastases than in HCC, because colorectal metastases are less vascularised and are characterized by fibrosis overgrowth rather than increase of necrosis after successful chemotherapy [
      • Poultsides G.A.
      • Bao F.
      • Servais E.L.
      • Hernandez-Boussard T.
      • DeMatteo R.P.
      • Allen P.J.
      • et al.
      Pathologic response to preoperative chemotherapy in colorectal liver metastases: fibrosis, not necrosis, predicts outcome.
      ]. Fibrotic zones within tumors can be differentiated from viable tumor zones with DW MR imaging by measuring D, the pure diffusion coefficient, but differences in diffusion parameters between fibrotic and viable zones are less pronounced than between necrotic and viable zones [
      • Wagner M.
      • Doblas S.
      • Daire J.L.
      • Paradis V.
      • Haddad N.
      • Leitao H.
      • et al.
      Diffusion-weighted MR imaging for the regional characterization of liver tumors.
      ].

      Diffuse liver diseases

      Progressive decrease of ADC is seen in liver fibrosis, but large overlaps in ADC measurements between fibrosis stages are observed [
      • Lewin M.
      • Poujol-Robert A.
      • Boelle P.Y.
      • Wendum D.
      • Lasnier E.
      • Viallon M.
      • et al.
      Diffusion-weighted magnetic resonance imaging for the assessment of fibrosis in chronic hepatitis C.
      ]. Currently, DW MR imaging alone is not recommended for staging liver fibrosis because its accuracy is not higher than that of plasma biomarkers measurements and transient ultrasound elastography, which are more easily-available methods [
      • Lewin M.
      • Poujol-Robert A.
      • Boelle P.Y.
      • Wendum D.
      • Lasnier E.
      • Viallon M.
      • et al.
      Diffusion-weighted magnetic resonance imaging for the assessment of fibrosis in chronic hepatitis C.
      ]. Moreover, both animal and human studies have shown that the decrease of ADC in liver fibrosis may be influenced by other factors than fibrosis. These factors, including inflammation, steatosis and decreased perfusion, may have a predominant role in ADC decrease [
      • Luciani A.
      • Vignaud A.
      • Cavet M.
      • Nhieu J.T.
      • Mallat A.
      • Ruel L.
      • et al.
      Liver cirrhosis: intravoxel incoherent motion MR imaging–pilot study.
      ,
      • Annet L.
      • Peeters F.
      • Abarca-Quinones J.
      • Leclercq I.
      • Moulin P.
      • Van Beers B.E.
      Assessment of diffusion-weighted MR imaging in liver fibrosis.
      ,
      • Leitao H.S.
      • Doblas S.
      • d’Assignies G.
      • Garteiser P.
      • Daire J.L.
      • Paradis V.
      • et al.
      Fat deposition decreases diffusion parameters at MRI: a study in phantoms and patients with liver steatosis.
      ]. Finally, it has been shown that MR elastography is more accurate than DW MR imaging to stage liver fibrosis [
      • Wang Y.
      • Ganger D.R.
      • Levitsky J.
      • Sternick L.A.
      • McCarthy R.J.
      • Chen Z.E.
      • et al.
      Assessment of chronic hepatitis and fibrosis: comparison of MR elastography and diffusion-weighted imaging.
      ].

      Dynamic contrast-enhanced MR imaging

      Method

      Dynamic contrast-enhanced MR imaging is an integral part of liver MR imaging for the detection and characterization of liver tumors. At least one image acquisition of the whole liver is performed during the arterial, portal venous, and delayed phases (3–5 min after the start of the injection) after bolus injection of an extracellular gadolinium chelate.
      When a hepatocyte-specific contrast agent is used, such as gadoxetate (Primovist©, Bayer, Berlin, Germany), a hepatobiliary phase (20 min) is added to the dynamic phase for the assessment of intracellular retention of the contrast agent. In humans, gadoxetate is taken up within hepatocytes by the organic anion transporting polypeptides OATP1 B1/B3. It is excreted into bile through the multidrug resistance protein MRP2 transporters. Backflow to the sinusoids occurs through MRP3 and the bidirectional OATP1B1/B3 transporters [
      • Van Beers B.E.
      • Pastor C.M.
      • Hussain H.K.
      Primovist, Eovist: what to expect?.
      ,
      • Nassif A.
      • Jia J.
      • Keiser M.
      • Oswald S.
      • Modess C.
      • Nagel S.
      • et al.
      Visualization of hepatic uptake transporter function in healthy subjects by using gadoxetic acid-enhanced MR imaging.
      ,
      • Jia J.
      • Puls D.
      • Oswald S.
      • Jedlitschky G.
      • Kuhn J.P.
      • Weitschies W.
      • et al.
      Characterization of the intestinal and hepatic uptake/efflux transport of the magnetic resonance imaging contrast agent gadolinium-ethoxylbenzyl-diethylenetriamine-pentaacetic acid.
      ]. In chronic liver diseases and HCC, expression and function of the hepatocyte transporters change, leading to changes of gadoxetate enhancement during the hepatobiliary phase. The transporter changes consist mainly in decreased OATP1 B1/B3 and MRP2, as well as increased MRP3 expression [
      • Gu X.
      • Manautou J.E.
      Regulation of hepatic ABCC transporters by xenobiotics and in disease states.
      ,
      • Kitao A.
      • Matsui O.
      • Yoneda N.
      • Kozaka K.
      • Shinmura R.
      • Koda W.
      • et al.
      The uptake transporter OATP8 expression decreases during multistep hepatocarcinogenesis: correlation with gadoxetic acid enhanced MR imaging.
      ,
      • Lagadec M.
      • Doblas S.
      • Giraudeau C.
      • Ronot M.
      • Fasseu M.
      • Paradis V.
      • et al.
      Advanced fibrosis: correlation between pharmacokinetic parameters at dynamic gadoxetate-enhanced MR imaging and hepatocyte organic anion transporter expression in rat liver.
      ], which causes decreased lesion signal intensity on gadoxetate-enhanced MR images. In contrast, some HCC appear hyperintense on gadoxetate-enhanced MR images during the hepatobiliary phase. Increase rather than decrease in OATP1 B3 expression has been found in these tumors [
      • Narita M.
      • Hatano E.
      • Arizono S.
      • Miyagawa-Hayashino A.
      • Isoda H.
      • Kitamura K.
      • et al.
      Expression of OATP1B3 determines uptake of Gd-EOB-DTPA in hepatocellular carcinoma.
      ].
      To perform quantitative perfusion MR imaging, high temporal resolution at DCE MR imaging is needed, and three-dimensional MR images of the whole liver should be obtained with a time resolution <3 s. Simple parameters of lesion enhancement vs. time curve, such as peak enhancement, time to peak, steepest slope or area under the enhancement curve are only semi-quantitative because the shape of the enhancement curve depends on the shape of the arterial input function. Therefore, the arterial input function has to be measured in addition to the tissue enhancement curve, and pharmacokinetic modeling should be performed to obtain physiological parameters such as perfusion or extravascular space volume [
      • Walker-Samuel S.
      • Leach M.O.
      • Collins D.J.
      Evaluation of response to treatment using DCE-MRI: the relationship between initial area under the gadolinium curve (IAUGC) and quantitative pharmacokinetic analysis.
      ].
      For liver perfusion assessment, the dynamic curves should be analyzed with a dual-input model, because the liver has two vascular inputs through the hepatic artery and the portal vein. The dual-input compartmental model as validated by Materne et al. is often used [
      • Materne R.
      • Smith A.M.
      • Peeters F.
      • Dehoux J.P.
      • Keyeux A.
      • Horsmans Y.
      • et al.
      Assessment of hepatic perfusion parameters with dynamic MRI.
      ]. With this model the arterial, portal venous, and total liver plasma transfer constants K1a, K1p, and K1t, respectively, (ml min−1 100 ml−1) can be assessed, as well as the distribution volume vd (%) and the mean transit time MTT (s). K1 is a lumped representation of perfusion and permeability (K1 = F × E with F the plasma perfusion and E the extravascular extraction fraction). When the permeability is high as in the normal liver, which has sinusoids containing fenestrae with 100 nm diameter, the extraction fraction equals one and K1 represents perfusion. If the permeability is low, K1 approximates the permeability-surface area product [
      • Hagiwara M.
      • Rusinek H.
      • Lee V.S.
      • Losada M.
      • Bannan M.A.
      • Krinsky G.A.
      • et al.
      Advanced liver fibrosis: diagnosis with 3D whole-liver perfusion MR imaging–initial experience.
      ]. Because of the large portal venous input into the liver, hepatic perfusion imaging should be performed in fasting patients to obtain reproducible results.
      In contrast to the liver parenchyma, primary and secondary tumors of the liver, except at their early stage, have only an arterial and no portal venous input [
      • Liu Y.
      • Matsui O.
      Changes of intratumoral microvessels and blood perfusion during establishment of hepatic metastases in mice.
      ,
      • International Consensus Group for Hepatocellular Neoplasia
      Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia.
      ]. Therefore, the perfusion of hepatic tumors, except for early HCC, can be analyzed with single input rather than dual-input models. The most used single input models are the Kety and the extended Kety models. The Kety model, also called the Tofts model, is a simple dual-compartmental model, in which Ktrans (=K1) and the extravascular extracellular volume (ve = vd) are calculated. In the extended Kety model, Ktrans, ve, and the plasma volume (vp) are assessed. The use of more complex distributed-parameter models has been proposed, but these models are less precise than the compartmental models because of the interdependency of the multiple free parameters and their sensitivity to initial values [
      • Buckley D.L.
      Uncertainty in the analysis of tracer kinetics using dynamic contrast-enhanced T1-weighted MRI.
      ,
      • Michoux N.
      • Huwart L.
      • Abarca-Quinones J.
      • Dorvillius M.
      • Annet L.
      • Peeters F.
      • et al.
      Transvascular and interstitial transport in rat hepatocellular carcinomas: dynamic contrast-enhanced MRI assessment with low- and high-molecular weight agents.
      ].
      In perfusion measurements, both the transfer constant Ktrans and the extravascular extracellular volume ve should be measured [
      • Leach M.O.
      • Morgan B.
      • Tofts P.S.
      • Buckley D.L.
      • Huang W.
      • Horsfield M.A.
      • et al.
      Imaging vascular function for early stage clinical trials using dynamic contrast-enhanced magnetic resonance imaging.
      ]. The reported coefficients of repeatability of Ktrans in liver tumors are in the range of 20–40% [
      • Ng C.S.
      • Raunig D.L.
      • Jackson E.F.
      • Ashton E.A.
      • Kelcz F.
      • Kim K.B.
      • et al.
      Reproducibility of perfusion parameters in dynamic contrast-enhanced MRI of lung and liver tumors: effect on estimates of patient sample size in clinical trials and on individual patient responses.
      ]. It has been reported that ve has a better reproducibility than Ktrans, and ve measurements allow the assessment of the vascular permeability by looking at the volume accessible to contrast agents of different molecular weights [
      • Michoux N.
      • Huwart L.
      • Abarca-Quinones J.
      • Dorvillius M.
      • Annet L.
      • Peeters F.
      • et al.
      Transvascular and interstitial transport in rat hepatocellular carcinomas: dynamic contrast-enhanced MRI assessment with low- and high-molecular weight agents.
      ,
      • Galbraith S.M.
      • Lodge M.A.
      • Taylor N.J.
      • Rustin G.J.
      • Bentzen S.
      • Stirling J.J.
      • et al.
      Reproducibility of dynamic contrast-enhanced MRI in human muscle and tumours: comparison of quantitative and semi-quantitative analysis.
      ]. Because the reproducibility of the perfusion measurements depends on the organ, the image acquisition and data analysis methods, it has been recommended to assess the reproducibility before starting clinical trials that aim at assessing treatment response with DCE MR imaging [
      • Leach M.O.
      • Morgan B.
      • Tofts P.S.
      • Buckley D.L.
      • Huang W.
      • Horsfield M.A.
      • et al.
      Imaging vascular function for early stage clinical trials using dynamic contrast-enhanced magnetic resonance imaging.
      ].
      It should be noted that there is currently no post-processing standard among the commercially available perfusion analysis solutions, and this causes large variations in the measured perfusion parameters (reported coefficients of repeatability >130%) [
      • Heye T.
      • Davenport M.S.
      • Horvath J.J.
      • Feuerlein S.
      • Breault S.R.
      • Bashir M.R.
      • et al.
      Reproducibility of dynamic contrast-enhanced MR imaging. Part I. Perfusion characteristics in the female pelvis by using multiple computer-aided diagnosis perfusion analysis solutions.
      ]. This variability is mainly explained by the use of different population-based arterial input functions. It underscores the need for standardizing the perfusion measurements and using patient-based rather than population-based arterial input functions. Moreover, the interobserver reproducibility of the perfusion measurements can be improved with semi-automatic registration and histogram analysis [
      • Heye T.
      • Merkle E.M.
      • Reiner C.S.
      • Davenport M.S.
      • Horvath J.J.
      • Feuerlein S.
      • et al.
      Reproducibility of dynamic contrast-enhanced MR imaging. Part II. Comparison of intra- and interobserver variability with manual region of interest placement versus semiautomatic lesion segmentation and histogram analysis.
      ].
      With pharmacokinetic analysis of dynamic gadoxetate-enhanced MR images, liver perfusion and hepatocyte transport function can be assessed separately using deconvolution or compartmental analysis (Fig. 3) [
      • Nilsson H.
      • Nordell A.
      • Vargas R.
      • Douglas L.
      • Jonas E.
      • Blomqvist L.
      Assessment of hepatic extraction fraction and input relative blood flow using dynamic hepatocyte-specific contrast-enhanced MRI.
      ,
      • Sourbron S.
      • Sommer W.H.
      • Reiser M.F.
      • Zech C.J.
      Combined quantification of liver perfusion and function with dynamic gadoxetic acid-enhanced MR imaging.
      ].
      Figure thumbnail gr3
      Fig. 3Parametric perfusion and hepatocyte uptake extraction fraction maps. (A and B) Patient with normal liver, and (C and D) patient with liver cirrhosis, obtained with dynamic gadoxetate-enhanced MR imaging. Liver perfusion (ml min−1 g−1) is more heterogeneous in liver cirrhosis than in normal liver (C vs. A), and uptake extraction fraction (%) is decreased (D vs. B).

      Diffuse liver diseases

      Dynamic contrast-enhanced MR imaging can be used to assess the microcirculatory changes in liver fibrosis and cirrhosis. Decrease of portal and total hepatic perfusion is observed, as well as increases of arterial perfusion and mean transit time, with preserved or increased distribution volume. These perfusion changes occur already at intermediate stages of liver fibrosis, but are more marked in cirrhosis, where they correlate with the degree of liver dysfunction and portal hypertension [
      • Hagiwara M.
      • Rusinek H.
      • Lee V.S.
      • Losada M.
      • Bannan M.A.
      • Krinsky G.A.
      • et al.
      Advanced liver fibrosis: diagnosis with 3D whole-liver perfusion MR imaging–initial experience.
      ,
      • Annet L.
      • Materne R.
      • Danse E.
      • Jamart J.
      • Horsmans Y.
      • Van Beers B.E.
      Hepatic flow parameters measured with MR imaging and Doppler US: correlations with degree of cirrhosis and portal hypertension.
      ]. Decrease of the hepatobiliary excretion of organic anions through the OATP/MRP route in liver fibrosis, cirrhosis and non-alcoholic steatohepatitis (NASH) can be assessed with gadoxetate-enhanced MR imaging [
      • Lagadec M.
      • Doblas S.
      • Giraudeau C.
      • Ronot M.
      • Fasseu M.
      • Paradis V.
      • et al.
      Advanced fibrosis: correlation between pharmacokinetic parameters at dynamic gadoxetate-enhanced MR imaging and hepatocyte organic anion transporter expression in rat liver.
      ,
      • Bastati N.
      • Feier D.
      • Wibmer A.
      • Traussnigg S.
      • Balassy C.
      • Tamandl D.
      • et al.
      Noninvasive differentiation of simple steatosis and steatohepatitis by using gadoxetic acid-enhanced MR imaging in patients with nonalcoholic fatty liver disease: a proof-of-concept study.
      ,
      • Nilsson H.
      • Blomqvist L.
      • Douglas L.
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      • et al.
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      ,
      • Feier D.
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      • Bastati N.
      • Stift J.
      • Badea R.
      • Ba-Ssalamah A.
      Liver fibrosis: histopathologic and biochemical influences on diagnostic efficacy of hepatobiliary contrast-enhanced MR imaging in staging.
      ]. Moreover, gadoxetate-enhanced MR imaging appears promising for the assessment of the risk for liver failure after major liver resection [
      • Wibmer A.
      • Prusa A.M.
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      • Gruenberger T.
      • Schindl M.
      • Ba-Ssalamah A.
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      ].

      Liver tumors

      Dynamic contrast-enhanced MR imaging during the arterial, portal venous and delayed phases is routinely performed for tumor detection, characterization, and assessment of tumor response to treatment. For these purposes, gadoxetate is increasingly used rather than extracellular contrast agents. Indeed, numerous studies have shown that the detection and characterization of focal liver lesions, including HCC, adenomas, focal nodular hyperplasias and liver metastases, is improved during the hepatobiliary phase of gadoxetate-enhanced MR imaging [
      • Golfieri R.
      • Renzulli M.
      • Lucidi V.
      • Corcioni B.
      • Trevisani F.
      • Bolondi L.
      Contribution of the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI to dynamic MRI in the detection of hypovascular small (</=2 cm) HCC in cirrhosis.
      ,
      • Granito A.
      • Galassi M.
      • Piscaglia F.
      • Romanini L.
      • Lucidi V.
      • Renzulli M.
      • et al.
      Impact of gadoxetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance on the non-invasive diagnosis of small hepatocellular carcinoma: a prospective study.
      ,
      • Grazioli L.
      • Bondioni M.P.
      • Haradome H.
      • Motosugi U.
      • Tinti R.
      • Frittoli B.
      • et al.
      Hepatocellular adenoma and focal nodular hyperplasia: value of gadoxetic acid-enhanced MR imaging in differential diagnosis.
      ]. Particularly, some early hypovascular HCC are only observed as hypointense nodules during the hepatobiliary phase at gadoxetate-enhanced MR imaging, without being readily seen during dynamic imaging. The subgroup of lesions showing both absence of enhancement during the arterial phase and hypointensity during the hepatobiliary phase is challenging because not all of these lesions correspond to HCC or will evolve into HCC [
      • Akai H.
      • Matsuda I.
      • Kiryu S.
      • Tajima T.
      • Takao H.
      • Watanabe Y.
      • et al.
      Fate of hypointense lesions on Gd-EOB-DTPA-enhanced magnetic resonance imaging.
      ,
      • Ronot M.
      • Vilgrain V.
      Hepatocellular carcinoma: Diagnostic criteria by imaging techniques.
      ]. In this setting, hyperintensity on DW MR images increases the likelihood of early HCC or progression to hypervascular HCC [
      • Ronot M.
      • Vilgrain V.
      Hepatocellular carcinoma: Diagnostic criteria by imaging techniques.
      ,
      • Kim Y.K.
      • Lee W.J.
      • Park M.J.
      • Kim S.H.
      • Rhim H.
      • Choi D.
      Hypovascular hypointense nodules on hepatobiliary phase gadoxetic acid-enhanced MR images in patients with cirrhosis: potential of DW imaging in predicting progression to hypervascular HCC.
      ].
      In contrast to the qualitative assessment of liver tumors with DCE MR imaging, quantitative perfusion MR imaging of liver tumors is not often obtained in clinical practice. The main indication of perfusion MR imaging is the assessment of tumor response to antiangiogenic or local treatments [
      • O’Connor J.P.
      • Jackson A.
      • Parker G.J.
      • Roberts C.
      • Jayson G.C.
      Dynamic contrast-enhanced MRI in clinical trials of antivascular therapies.
      ].
      In patients with HCC who received sorafenib plus metronomic tegafur/uracil therapy, Ktrans measured with DCE-MR imaging correlated well with tumor response and survival [
      • Hsu C.Y.
      • Shen Y.C.
      • Yu C.W.
      • Hsu C.
      • Hu F.C.
      • Hsu C.H.
      • et al.
      Dynamic contrast-enhanced magnetic resonance imaging biomarkers predict survival and response in hepatocellular carcinoma patients treated with sorafenib and metronomic tegafur/uracil.
      ]. In patients with HCC treated with sunitinib, it was found that the perfusion parameters were more sensitive biomarkers in predicting early response and progression free survival than RECIST and mRECIST [
      • Sahani D.V.
      • Jiang T.
      • Hayano K.
      • Duda D.G.
      • Catalano O.A.
      • Ancukiewicz M.
      • et al.
      Magnetic resonance imaging biomarkers in hepatocellular carcinoma: association with response and circulating biomarkers after sunitinib therapy.
      ]. In another study of HCC treated with sunitinib, it was observed that the extent of decrease in Ktrans in patients who experienced partial response or stable disease according to RECIST was significantly greater (twofold on average) compared with patients with progressive disease or who died during the first two cycles of therapy [
      • Zhu A.X.
      • Sahani D.V.
      • Duda D.G.
      • di Tomaso E.
      • Ancukiewicz M.
      • Catalano O.A.
      • et al.
      Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: A phase II study.
      ]. Similar results were reported in patients with potentially resectable metastatic colorectal cancer treated with chemotherapy and bevacizumab. In these patients, progression-free survival benefit was shown for patients with >40% reduction in Ktrans [
      • De Bruyne S.
      • Van Damme N.
      • Smeets P.
      • Ferdinande L.
      • Ceelen W.
      • Mertens J.
      • et al.
      Value of DCE-MRI and FDG-PET/CT in the prediction of response to preoperative chemotherapy with bevacizumab for colorectal liver metastases.
      ].
      Dynamic contrast-enhanced MR imaging and DW MR imaging may bring complementary predictive information. In patients with HCC, Bonekamp et al. performed volumetric DCE MR imaging and DW MR imaging one month after intraarterial therapy and observed that there were significant differences in overall survival between patients who were dual-parameter responders (namely patients having decrease in venous enhancement of more than 65% and increase in ADC of more than 25%) and single-parameter responders, as well as between single-parameter responders and those with stable disease [
      • Bonekamp S.
      • Halappa V.G.
      • Geschwind J.F.
      • Li Z.
      • Corona-Villalobos C.P.
      • Reyes D.
      • et al.
      Unresectable hepatocellular carcinoma: MR imaging after intraarterial therapy. Part II. Response stratification using volumetric functional criteria after intraarterial therapy.
      ]. These results show the usefulness of multiparametric functional MR imaging in the assessment of treatment response.

      MR elastography

      Method

      For MR elastography, external vibrators are used to generate shear or compression waves. When using compression waves, the shear waves needed for calculating the visco-elastic parameters are obtained by mode conversion at interfaces within the tissue. The advantage of using compression waves is that they penetrate within tissues better than shear waves [
      • Sinkus R.
      • Tanter M.
      • Xydeas T.
      • Catheline S.
      • Bercoff J.
      • Fink M.
      Viscoelastic shear properties of in vivo breast lesions measured by MR elastography.
      ]. With three-dimensional MR elastography, the full visco-elastic properties of the tissue can be evaluated by measuring shear wave propagation and attenuation. These visco-elastic properties include the shear modulus G, the storage modulus Gd reflecting elasticity, and the loss modulus Gl reflecting viscosity. Moreover, with multifrequency MR elastography, the wave scattering coefficient corresponding to the slope of the visco-elasticity vs. frequency curve can be obtained [
      • Sinkus R.
      • Siegmann K.
      • Xydeas T.
      • Tanter M.
      • Claussen C.
      • Fink M.
      MR elastography of breast lesions: understanding the solid/liquid duality can improve the specificity of contrast-enhanced MR mammography.
      ,
      • Garteiser P.
      • Sahebjavaher R.S.
      • Ter Beek L.C.
      • Salcudean S.
      • Vilgrain V.
      • Van Beers B.E.
      • et al.
      Rapid acquisition of multifrequency, multislice and multidirectional MR elastography data with a fractionally encoded gradient echo sequence.
      ].
      Breathhold MR elastography has a reported repeatability coefficient of 22% for elasticity and 26% for viscosity in the liver [
      • Bohte A.E.
      • Garteiser P.
      • De Niet A.
      • Groot P.F.
      • Sinkus R.
      • Stoker J.
      • et al.
      MR elastography of the liver: defining thresholds for detecting viscoelastic changes.
      ]. The reproducibility of MR elastography for liver fibrosis has been reported to be better than that of Fibroscan© [
      • Huwart L.
      • Sempoux C.
      • Salameh N.
      • Jamart J.
      • Annet L.
      • Sinkus R.
      • et al.
      Liver fibrosis: noninvasive assessment with MR elastography versus aspartate aminotransferase-to-platelet ratio index.
      ].

      Diffuse liver diseases

      Single center studies have shown that MR elastography is a robust, reproducible, and accurate method to detect and stage liver fibrosis [
      • Huwart L.
      • Sempoux C.
      • Salameh N.
      • Jamart J.
      • Annet L.
      • Sinkus R.
      • et al.
      Liver fibrosis: noninvasive assessment with MR elastography versus aspartate aminotransferase-to-platelet ratio index.
      ,
      • Huwart L.
      • Sempoux C.
      • Vicaut E.
      • Salameh N.
      • Annet L.
      • Danse E.
      • et al.
      Magnetic resonance elastography for the noninvasive staging of liver fibrosis.
      ,
      • Yin M.
      • Talwalkar J.A.
      • Glaser K.J.
      • Manduca A.
      • Grimm R.C.
      • Rossman P.J.
      • et al.
      Assessment of hepatic fibrosis with magnetic resonance elastography.
      ,
      • Asbach P.
      • Klatt D.
      • Schlosser B.
      • Biermer M.
      • Muche M.
      • Rieger A.
      • et al.
      Viscoelasticity-based staging of hepatic fibrosis with multifrequency MR elastography.
      ]. MR elastography outperforms transient ultrasound elastography and aspartate aminotransferase to platelets ratio index (APRI) for hepatic fibrosis staging [
      • Huwart L.
      • Sempoux C.
      • Salameh N.
      • Jamart J.
      • Annet L.
      • Sinkus R.
      • et al.
      Liver fibrosis: noninvasive assessment with MR elastography versus aspartate aminotransferase-to-platelet ratio index.
      ]. In animal studies, it has been shown that the visco-elastic properties of the liver correlate with the percentage of hepatic fibrosis determined at morphometry [
      • Salameh N.
      • Peeters F.
      • Sinkus R.
      • Abarca-Quinones J.
      • Annet L.
      • Ter Beek L.C.
      • et al.
      Hepatic viscoelastic parameters measured with MR elastography: correlations with quantitative analysis of liver fibrosis in the rat.
      ].
      As already mentioned, several conditions in addition to fibrosis may increase the mechanical properties of the liver, including inflammation, cholestasis, congestion and portal hypertension [
      • Coco B.
      • Oliveri F.
      • Maina A.M.
      • Ciccorossi P.
      • Sacco R.
      • Colombatto P.
      • et al.
      Transient elastography: a new surrogate marker of liver fibrosis influenced by major changes of transaminases.
      ]. The various visco-elastic parameters determined at multifrequency MR elastography may help in disease characterization. Indeed, studies suggest that liver fibrosis stage mainly correlates with tissue elasticity, whereas inflammation grade mainly correlates with wave scattering coefficient (Fig. 4) and portal hypertension degree with liver and spleen viscosity [
      • Ronot M.
      • Lambert S.
      • Elkrief L.
      • Doblas S.
      • Rautou P.E.
      • Castera L.
      • et al.
      Assessment of portal hypertension and high-risk oesophageal varices with liver and spleen three-dimensional multifrequency MR elastography in liver cirrhosis.
      ,
      • Ronot M.
      • Lambert S.
      • Wagner M.
      • Garteiser P.
      • Doblas S.
      • Albuquerque M.
      • et al.
      Viscoelastic parameters for quantifying liver fibrosis: three-dimensional multifrequency MR elastography study on thin liver rat slices.
      ,

      Garteiser P, D’Assignies G, Leitao H, Mouri F, Vilgrain V, Sinkus R, et al. Abstract 373: The influence of inflammation and fibrosis on multifrequency and monofrequency MR elastography parameters: a study in 47 patients with chronic viral hepatitis. Proceedings of the 2014 annual meeting of the International Society of Magnetic Resonance in Medicine.

      ].
      Figure thumbnail gr4
      Fig. 4Multifrequency MR elastography parametric maps of elasticity and wave dispersion coefficient. Patients with chronic hepatitis C infection classified as (A and B) F2 fibrosis, A1 inflammation and (C and D) F2 fibrosis, A3 inflammation according to METAVIR. Storage modulus values (elasticity in kPa) are similar in patient with F2, A1 (A) and patient with F2, A3 (C), whereas wave dispersion coefficients (arbitrary units) are lower in patients with higher inflammation grade (D vs. B). This figure illustrates the superiority of wave dispersion coefficient measurements at multifrequency MR elastography relative to elasticity measurements in discriminating between patients with different grades of hepatic inflammation.
      Studies in animals and humans have shown that MR elastography may be useful for the early diagnosis of NASH, by showing early increase in elasticity explained by inflammation and activation of stellate cells [
      • Salameh N.
      • Larrat B.
      • Abarca-Quinones J.
      • Pallu S.
      • Dorvillius M.
      • Leclercq I.
      • et al.
      Early detection of steatohepatitis in fatty rat liver by using MR elastography.
      ,
      • Chen J.
      • Talwalkar J.A.
      • Yin M.
      • Glaser K.J.
      • Sanderson S.O.
      • Ehman R.L.
      Early detection of nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease by using MR elastography.
      ].
      If the high diagnostic performance of MR elastography is further shown in multicenter trials, it may be particularly relevant to use this method to complement ultrasound elastography and avoid liver biopsy in intermediate stages of fibrosis, to stage portal hypertension and to assess the response to antifibrotic treatments [
      • Castera L.
      Noninvasive methods to assess liver disease in patients with hepatitis B or C.
      ].

      Liver tumors

      MR elastography may help in the characterization of liver tumors and the assessment of response to treatment. In a preliminary study, it has been shown that malignant tumors have a higher stiffness than benign ones [
      • Venkatesh S.K.
      • Yin M.
      • Glockner J.F.
      • Takahashi N.
      • Araoz P.A.
      • Talwalkar J.A.
      • et al.
      MR elastography of liver tumors: preliminary results.
      ]. In a more recent study, it has been observed that malignant liver tumors are mainly characterized by increased viscosity [
      • Garteiser P.
      • Doblas S.
      • Daire J.L.
      • Wagner M.
      • Leitao H.
      • Vilgrain V.
      • et al.
      MR elastography of liver tumours: value of viscoelastic properties for tumour characterisation.
      ].
      Small animal studies have shown that MR elastography is useful for assessing the early tumor response to vascular disrupting agents and to chemotherapy [
      • Juge L.
      • Doan B.T.
      • Seguin J.
      • Albuquerque M.
      • Larrat B.
      • Mignet N.
      • et al.
      Colon tumor growth and antivascular treatment in mice: complementary assessment with MR elastography and diffusion-weighted MR imaging.
      ,
      • Pepin K.M.
      • Chen J.
      • Glaser K.J.
      • Mariappan Y.K.
      • Reuland B.
      • Ziesmer S.
      • et al.
      MR elastography derived shear stiffness-a new imaging biomarker for the assessment of early tumor response to chemotherapy.
      ,
      • Li J.
      • Jamin Y.
      • Boult J.K.
      • Cummings C.
      • Waterton J.C.
      • Ulloa J.
      • et al.
      Tumour biomechanical response to the vascular disrupting agent ZD6126 in vivo assessed by magnetic resonance elastography.
      ]. Further human trials are needed to clarify the role of multi-frequency MR elastography in characterizing liver tumors and assessing their response to treatment.

      Conclusions

      Ultrasonography and MR imaging of liver diseases evolve from qualitative anatomical imaging methods to combined quantitative anatomical and functional imaging methods. Imaging biomarkers obtained with diffusion and perfusion – hepatocyte transport imaging, as well as with elastography, have an increasing role in the detection and characterization of diffuse liver diseases and liver tumors, and in the assessment of response to treatment. The multiparametric capability of ultrasonography and more markedly of MR imaging gives the opportunity of improved diagnostic performance by combining imaging biomarkers. For widespread clinical use in liver disease, imaging biomarkers should be further validated in large multicenter trials. The image acquisition and post-processing methods should be further improved and standardized to increase diagnostic accuracy and reproducibility.

      Conflict of interest

      The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

      Acknowledgements

      The authors thank Dr. Maxime Ronot and Benjamin Leporq from Laboratory of Imaging Biomarkers, UMR1149 INSERM-University Paris Diderot for providing Figs. 1 and 3, respectively.

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