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Contrast-enhanced ultrasound imaging of the liver: a review of the clinical evidence for SonoVue and Sonazoid

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Abstract

Contrast-enhanced ultrasound (CEUS) has become an established modality in various clinical indications for liver diseases. SonoVue®, a pure blood pure agent, and Sonazoid®, which exhibits an additional Kupffer phase, are contrast agents approved for liver imaging. This review discusses and compares the current clinical evidence for these two ultrasound contrast agents in the characterization and detection of focal liver lesions in the non-cirrhotic and cirrhotic liver, as well as for the use in interventional procedures such as liver biopsy guidance, and local ablation treatment monitoring. Reference is made to clinical studies which evaluated the accuracy of CEUS using a standard of reference, its safety, or to comparative studies of these two agents.

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References

  1. Claudon M, Dietrich CF, Choi BL, et al. Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) in the liver – update 2012. Ultraschall Med 2013;34(1):11-29.

  2. Ferraioli G, Meloni MF. Contrast-enhanced ultrasonography of the liver using SonoVue. Ultrasonography. 2018; 37(1):25-35.

  3. Tarantino L, Ambrosino P, Di Minno MND. Contrast-enhanced ultrasound in differentiating malignant from benign portal vein thrombosis in hepatocellular carcinoma. World J Gastroenterol. 2015; 21(32):9457-9460.

  4. Bracco Sine Pharmaceutical Corp Safety Update Report for SonoVue (China) 01 January 2009 to 31 December 2015.

  5. Bracco Imaging S.p.A. Periodic Safety Update Report 01 October 2017 to 30 September 2018

  6. Bracco Diagnostics Inc. Internal sales data.

  7. Information Medical Statistics Health data accessed 17 May 2019.

  8. Zhai H-Y, Liang P, Yu J, et al. Comparison of Sonazoid and Sonovue in the diagnosis of focal liver lesions. J Ultrasound Med 2019 Jan 25 EPub.

  9. Jiang Y, Lv K, Liang P, et al. A Phase 3 Multicentre, Randomised, Comparative study of the efficacy and safety of Sonazoid and SonoVue in subjects with focal liver lesions undergoing pre- and post-contrast ultrasound imaging. Ultrasound Med Biol. 2017;43 Suppl 1 S34-S35.

  10. Lumason [SonoVue] (sulfur hexafluoride lipid-type A microspheres) for injectable suspension, for intravenous use. Full Prescribing Information. December 2016.

  11. GE Healthcare brochure: Sonazoid, Innovatively long-lasting microbubbles enabling confident diagnosis with Kupffer image. 2013

  12. Morel DR, Schwieger I, Hohn L, et al. Human pharmacokinetics and safety evaluation of SonoVue, a new contrast agent for ultrasound imaging. Invest Radiol. 2000;35(1) 80-85.

  13. Li P, Hoppmann S, Du P, et al. Pharmacokinetics of perfluorobutane after intra-venous bolus injection of Sonazoid in healthy Chinese volunteers. Ultrasound Med Biol. 2017;43(5) 1031-1039.

  14. Yanagisawa K, Moriyasu F, Miyahara T, et al. Phagocytosis of ultrasound contrast agent microbubbles by Kupffer cells. Ultrasound Med Biol. 2007;33(2):318-325.

  15. Dixon LJ, Barnes M, Tang H, et al. Kupffer cells in the liver. Compr Physiol. 2013;3(2):785-797.

  16. Shunichi S, Hiroko I, Fuminori M, et al. Definition of contrast enhancement phases of the liver using a perfluoro-based microbubble agent, perflubutane microbubbles. Ultrasound Med Biol. 2009;35(11) 1819-1827.

  17. Nihonmatsu H, Numata K, Fukuda H, et al. Low mechanical index contrast mode versus high mechanical index contrast mode: which is a more sensitive method for detecting Sonazoid microbubbles in the liver of normal subjects? J Med Ultrasonics. 2016;43(2):211-217

  18. Duisyenbi Z, Numata K, Nihonmatsu H, et al. Comparison between low mechanical index and high mechanical index contrast modes of contrast-enhanced ultrasonography: evaluation of perfusion defects of hypervascular hepatocellular carcinomas during the post–vascular phase. J Ultrasound Med. 2019 Jan 17 EPub.

  19. American College of Radiology https://www.acr.org/Clinical-Resources/Reporting-and-Data-Systems/LI-RADS/CEUS-LI-RADS-v2017 accessed 03 July 2019.

  20. Lyshchik A, Kono Y, Dietrich CF, et al. Contrast-enhanced ultrasound of the liver: technical and lexicon recommendations from the ACR CEUS LI-RADS working group. Abdom Radiol. 2018; 43(4):861-879.

  21. Xie D-Y, Ren Z-G, Zhou J, et al. Critical appraisal of Chinese 2017 guideline on the management of hepatocellular carcinoma. HepatoBiliary Surg Nutr. 2017;6(6):387-396.

  22. Nolsøe CP, Nolsøe AB, Klubien J, et al. Use of ultrasound contrast agents in relation to percutaneous interventional procedures a systematic review and pictorial essay. J Ultrasound Med. 2018;37(6):1305-1324.

  23. Friedrich-Rust M, Klopffleisch T, Nierhoff J, et al. Contrast-Enhanced Ultrasound for the differentiation of benign and malignant focal liver lesions: a meta-analysis. Liver Int. 2013;33(5):739-755.

  24. Niu Y, Huang T, Lian F, et al. Contrast-enhanced ultrasonography for the diagnosis of small hepatocellular carcinoma: a meta-analysis and meta-regression analysis. Tumor Biol. 2013;34(6):3667-3674.

  25. Guang Y, Xie L, Ding H et al. Diagnosis value of focal liver lesions with SonoVue-enhanced ultrasound compared with contrast-enhanced computed tomography and contrast-enhanced MRI: a meta-analysis. J Cancer Res Clin Oncol.2011;137(11):1595-1605.

  26. NICE Diagnostics guidance: SonoVue (sulphur hexafluoride microbubbles) – contrast agent for contrast-enhanced ultrasound imaging of the liver29 August 2012. https://www.nice.org.uk/guidance/dg5. Accessed 03 July 2019.

  27. Westwood M, Joore M, Grutters J, et al. Contrast-enhanced ultrasound using SonoVue® (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. Health Technol Assessment. 2013;17(16):1-243.

  28. D’Onofrio M, Crosara S, De Robertis R, et al. Contrast-enhanced ultrasound of focal liver lesions. Am J Roentgenol. 2015;205(1):W56-W66.

  29. Shiozawa K, Watanabe M, Kikuchi Y, et al. Evaluation of sorafenib for hepatocellular carcinoma by contrast-enhanced ultrasonography: A pilot study. World J Gastroenterol. 2012;18(40):5753-5758.

  30. Sidhu PS, Cantisani V, Dietrich CF, et al. The EFSUMB guidelines and recommendations for the clinical practice of contrast-enhanced ultrasound (CEUS) in non-hepatic applications: update 2017 (long version). Ultraschall in Med. 2018;39(2):e2-e44.

  31. Oldenburg A, Hohmann J, Foert E, et al. Detection of hepatic metastases with low MI real time contrast enhanced sonography and SonoVue. Ultraschall Med. 2005;26(4):277-284.

  32. Bartolotta TV, Taibbi A, Picone D, et al. Detection of liver metastases in cancer patients with geographic fatty infiltration of the liver: the added value of contrast-enhanced sonography. Ultrasonography. 2017;36(2):160-169.

  33. Hoeffel C, Job L, Ladam-Marcus V, et al. Detection of hepatic metastases from carcinoid tumor: prospective evaluation of contrast-enhanced ultrasonography. Dig Dis Sci. 2009;54(9):2040-2046.

  34. Huf S, Platz Batista da Silva N, Wiesinger I, et al. Analysis of Liver Tumors Using Preoperative and Intraoperative Contrast-Enhanced Ultrasound (CEUS/IOCEUS) by Radiologists in Comparison to Magnetic Resonance Imaging and Histopathology. Rofo. 2017;189(5):431-440.

  35. Janica JR, Lebkowska U, Ustymowicz A, et al. Contrast-enhanced ultrasonography in diagnosing liver metastases. Med Sci Monit. 2007;13 Suppl 1:111-115.

  36. Konopke R, Kersting S, Bergert H, et al. Contrast-enhanced ultrasonography to detect liver metastases: a prospective trial to compare transcutaneous unenhanced and contrast-enhanced ultrasonography in patients undergoing laparotomy. Int J Colorectal Dis. 2007;22(2):201-207.

  37. Konopke R1, Bunk A, Kersting S. Contrast-enhanced ultrasonography in patients with colorectal liver metastases after chemotherapy. Ultraschall Med. 2008;29 Suppl 4:S203-209.

  38. Piscaglia F, Corradi F, Mancini M, et al. Real time contrast enhanced ultrasonography in detection of liver metastases from gastrointestinal cancer. BMC Cancer. 2007;7:171.

  39. Quaia E, D’Onofrio M, Palumbo A et al. Comparison of contrast-enhanced ultrasonography versus baseline ultrasound and contrast-enhanced computed tomography in metastatic disease of the liver: diagnostic performance and confidence. Eur Radiol. 2006;16(7):1599-1609.

  40. Cantisani V, Ricci P, Erturk M, et al. Detection of hepatic metastases from colorectal cancer: prospective evaluation of gray scale US versus SonoVue® low mechanical index real time-enhanced US as compared with multidetector-CT or Gd-BOPTA-MRI. Ultraschall in Med 2010;31(5):500-505.

  41. Rafaelsen SR, Jakobsen A. Detection of hepatic metastases from colorectal cancer: prospective evaluation of gray scale US versus SonoVue® low mechanical index real time-enhanced US as compared with multidetector-CT or Gd-BOPTA-MRI. Colorectal Dis. 2011;13(4):420-425.

  42. Dietrich CF, Kratzer W, Strobel D, et al. Assessment of metastatic liver disease in patients with primary extrahepatic tumors by contrast-enhanced sonography versus CT and MRI. World J Gastroenterol. 2006;12(11):1699-1705.

  43. Correas J-M, Low G, Needleman L, et al. Contrast enhanced ultrasound in the detection of liver metastases: a prospective multi-centre dose testing study using a perfluorobutane microbubble contrast agent (NC100100). Eur Radiol. 2011;21(8):1739-1746.

  44. Alaboudy A, Inoue T, Hatanaka K, et al. Usefulness of combination of imaging modalities in the diagnosis of hepatocellular carcinoma using Sonazoid -enhanced ultrasound, gadolinium diethylene-triamine-pentaacetic acid-enhanced magnetic resonance imaging, and contrast-enhanced computed tomography. Oncology. 2011;81 (Suppl 1):66-72.

  45. Kunishi Y, Numata K, Morimoto M, et al. Efficacy of fusion imaging combining sonography and hepatobiliary phase MRI with Gd-EOB-DTPA to detect small hepatocellular carcinoma. Am J Roentgenol. 2012;198(1):106-114.

  46. Goto E, Masuzaki R, Tateishi R, et al. Value of post-vascular phase (Kupffer imaging) by contrast-enhanced ultrasonography using Sonazoid in the detection of hepatocellular carcinoma. J Gastroenterol. 2012;47(4):477-485.

  47. Mandai M, Koda M, Matono T, et al. Assessment of hepatocellular carcinoma by contrast-enhanced ultrasound with perfluorobutane microbubbles: comparison with dynamic CT. Br J Radiol. 2011;84(1002):499-507.

  48. Arita J, Hasegawa K, Takahashi M, et al. Correlation between contrast- enhanced intraoperative ultrasound using Sonazoid and histologic grade of resected hepatocellular carcinoma. Am J Roentgenol. 2011;196(6):1314-1321.

  49. Park JH, Park M-S, Lee SJ, et al. Contrast-enhanced US with perfluorobutane for hepatocellular carcinoma surveillance: a multicenter diagnostic trial (SCAN). Radiology. 2019;292(3): 638-646.

  50. Spârchez Z, Radu P, Zaharia T, et al. Contrast enhanced ultrasound guidance: a new tool to improve accuracy in percutaneous biopsies. Med Ultrason. 2010;12(2):133-138.

  51. Spârchez Z, Radu P, Kacso G, et al. Prospective comparison between real time contrast enhanced and conventional ultrasound guidance in percutaneous biopsies of liver tumors. Med Ultrason. 2015;17(4):456-463.

  52. Eso Y, Takai A, Takeda H, et al. Sonazoid-enhanced ultrasonography guidance improves the quality of pathological diagnosis in the biopsy of focal hepatic lesions. Eur J Gastroenterol Hepatol. 2016;28(12):1462–1467.

  53. Park HS, Kim YJ, Yu MH, et al. Real-time Contrast-enhanced sonographically guided biopsy or radiofrequency ablation of focal liver lesions using perflurobutane microbubbles (Sonazoid). J Ultrasound Med. 2015;34(3) 411-421.

  54. Kang TW, Lee MW, Song KD, et al. Added value of contrast-enhanced ultrasound on biopsies of focal hepatic lesions invisible on fusion imaging guidance. Korean J Radiol. 2017;18(1):152-161.

  55. McDermott S, Gervais DA. Radiofrequency ablation of liver tumors. Semin Intervent Radiol. 2013;30(1):49–55.

  56. Brace CL. Radiofrequency and microwave ablation of the liver, lung, kidney and bone: What are the differences: “Organ-specific thermal ablation”. Curr Probl Diagn Radiol. 2009;38(3):135-143.

  57. Wiggerman P, Zuber-Jerger I, Zausig Y, et al. Contrast-enhanced ultrasound improves real-time imaging of ablation region during radiofrequency ablation: preliminary results. Clin Hemorheol Microcirc. 2011;49(1-4):43-54.

  58. Liu F, Yu X, Liang P, et al. Contrast-enhanced ultrasound-guided microwave ablation for hepatocellular carcinoma inconspicuous on conventional ultrasound. Int J Hyperthermia. 2011;27(6):555-562.

  59. Yan S-Y, Zhang Y, Sun C, et al. Comparison of real-time contrast-enhanced ultrasonography and standard ultrasonography in liver cancer microwave ablation. Exper Therapeutic Med. 2016;12(3):1345-1348.

  60. Miyamoto N, Hiramatsu K, Tsuchiya K, et al. Sonazoid-enhanced sonography for guiding radiofrequency ablation for hepatocellular carcinoma: better tumor visualization by Kupffer-phase imaging and vascular-phase imaging after reinjection. Japan J Radiol.2009:27(4):185-193.

  61. Mauri G, Porazzi E, Cova L, et al. Intraprocedural contrast-enhanced ultrasound (CEUS) in liver percutaneous radiofrequency ablation: clinical impact and health technology assessment. Insights Imaging. 2014;5(2):209-216.

  62. Du J, Li H-L, Zhai B, et al. Radiofrequency ablation for hepatocellular carcinoma: utility of conventional ultrasound and contrast-enhanced ultrasound in guiding and assessing early therapeutic response and short-term follow-up results. Ultrasound Med Biol. 2015;41(9):2400-2411.

  63. Luo W, Numata K, Morimoto M, et al. Role of Sonazoid-enhanced three-dimensional ultrasonography in the evaluation of percutaneous radiofrequency ablation of hepatocellular carcinoma. Eur J Radiol. 2010;75(1):91-97.

  64. Zheng S-G, Xu H-X, Lu M-D, et al. Role of contrast-enhanced ultrasound in follow-up assessment after ablation for hepatocellular carcinoma. World J Gastroenterol. 2013;19(6):855-865.

  65. Bo X-W, Xu H-X, Sun L-P, et al. Bipolar radiofrequency ablation for liver tumors: comparison of contrast-enhanced ultrasound with contrast-enhanced MRI/CT in the posttreatment imaging evaluation. Int J Clin Exp Pathol 2014;7(9):6108-6116.

  66. Frieser M, Kiesel J, Lindner A, et al. Efficacy of contrast-enhanced US versus CT or MRI for the therapeutic control of percutaneous radiofrequency ablation in the case of hepatic malignancies. Ultraschall in Med. 2011;32(2):148-153.

  67. Bo X-W, Xu H-X, Guo L-H, et al. Ablative safety margin depicted by fusion imaging with post-treatment contrast-enhanced ultrasound and pretreatment CECT/CEMRI after radiofrequency ablation for liver cancers. Br J Radiol. 2017;90:20170063.

  68. Xu E-J, Lv S-M, Li K, et al. Immediate evaluation and guidance of liver cancer thermal ablation by three-dimensional ultrasound/contrast-enhanced ultrasound fusion imaging. Int J Hypertherm. 2017;34(6)870-876.

  69. Piscaglia F, Bolondi L, et al. The Safety of SonoVue in abdominal applications: retrospective analysis of 23188 investigations. Ultrasound Med Biol. 2006;32(9):1369-1375.

  70. Tang C, Fang K, Guo Y, et al. Safety of sulfur hexafluoride microbubbles in sonography of abdominal and superficial organs: Retrospective analysis of 30,222 cases. J Ultrasound Med. 2017;36(3):531-538.

  71. Chou YH, Liang JD, Wang SY, Hsu SJ, Hu JT, Yang SS, et al. Safety of perfluorobutane (Sonazoid) in characterizing focal liver lesions. J Med Ultrasound 2019;27:81-5.

  72. Sonazoid (Perfluorobutane) Microspheres for Injection. Prescribing Information. GE Healthcare Co., Ltd. Shanghai, China. July 31, 2018.

  73. Ishibashi H, Maruyama H, Takahashi M, et al. Demonstration of intrahepatic accumulated microbubble on ultrasound represents the grade of hepatic fibrosis. Eur Radiol. 2012;22(5):1093-1090.

  74. Lizardi-Cervera J, Cuéllar-Gamboa L, Motola-Kuba D. Focal nodular hyperplasia and hepatic adenoma: a review. Annals Hepatol. 2006;5(3):206-211.

  75. Deitrich CF, N.C., Barr RG et. al., Guidelines and Good Clinical Practice Recommendations for Contrast Enhanced Ultrasound (CEUS) in the Liver – Update 2020. WFUMB in Cooperation with EFSUMB, AFSUMB, AIUM, and FLAUS. Ultrasound in Medicine and Biology, 2020 (in Press)

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Authors and Affiliations

  1. Department of Radiology, Northeastern Ohio Medical University, Rootstown, OH, USA

    Richard G. Barr

  2. Southwoods Imaging, 7623 Market Street, Youngstown, OH, 44512, USA

    Richard G. Barr

  3. Department of Ultrasound, Second Affiliated Hospital of Zhejiang University, Hangzhou, China

    Pintong Huang

  4. Department of Ultrasound, West China Hospital of Sichuan University, Chengdu, China

    Yan Luo

  5. Department of Ultrasound, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China

    Xiaoyan Xie

  6. Department of Ultrasound, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China

    Rongqin Zheng

  7. Department of Ultrasound, Peking University Cancer Hospital, Beijing, China

    Kun Yan

  8. Department of Ultrasound, Tianjin Third Central Hospital, Tianjin, China

    Xiang Jing

  9. Department of Ultrasound, Chinese People’s Liberation Army General Hospital, Beijing, China

    Yukun Luo & Xiang Fei

  10. Department of Ultrasound, Shanghai Tenth People’s Hospital, Shanghai, China

    Huixiong Xu

  11. Department of Radiology, Seoul National University College of Medicine, Seoul, Korea

    Jeong Min Lee

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Correspondence to Richard G. Barr.

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Conflict of interest

RGB has the following COI: research grants from Philips Ultrasound, Siemens Ultrasound, Mindray, GE Ultrasound, SuperSonic Imagine, B and K Ultrasound. He is on the speaker’s bureau of Philips Ultrasound, Mindray, Siemens Ultrasound, and Bracco Diagnostics. He is on the advisory board of Bracco Diagnostics and Lantheus Medical. He receives royalties from Thieme Publishers. RZ—research grants from Philips Ultrasound and Mindray. She is on the speaker’s bureau of Mindray, Esaote, Sonoscape, Philips Ultrasound and Bracco Diagnostics. PH, YanL, XX, KY, XJ, YukunL, HX, JML declare that they have no conflict of interest.

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Barr, R.G., Huang, P., Luo, Y. et al. Contrast-enhanced ultrasound imaging of the liver: a review of the clinical evidence for SonoVue and Sonazoid. Abdom Radiol 45, 3779–3788 (2020). https://doi.org/10.1007/s00261-020-02573-9

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