The Role of Sonazoid-contrast-enhanced Ultrasound In Precision Diagnosis and Guidance for Radiofrequency Ablation Therapy of Hepatocellular Carcinoma: a Literature Review

doi:10.26599/AUDT.2026.250084

Abstract

Abstract:

Hepatocellular carcinoma (HCC), constituting 75-85% of primary liver cancer cases, ranks as the third leading cause of global cancer-related mortality. The early diagnosis of HCC is critical for determining optimal clinical therapeutic strategies. Radiofrequency ablation (RFA) has emerged as a preferred for managing early-stage HCC cases, primarily due to its less invasive nature, simplicity and safety. Advanced imaging for pre-operative evaluation of HCC has been increasingly used. Contrast-enhanced ultrasound (CEUS) has improved the clinical application of ultrasound (US) in HCC. It also provide more accurate informations for guiding RFA procedures. In the future, CEUS, through its convergence with emerging artificial intelligence (AI)-driven technologies, will play an even greater role in HCC management. This systematic review evaluates the utility of Sonazoid-enhanced contrast ultrasound (Sonazoid-CEUS), particularly its unique Kupffer phase imaging, in improving HCC diagnostic and optimizing RFA precision via real-time monitoring capabilities and prolonged imaging windows (up to 60 minutes).

Key words: Hepatocellular carcinoma; Kupffer cell; Sonazoid-enhanced contrast ultrasound; Radiofrequency ablation

Liu Taixia, Wang Hanxiang, Wang Dan, Zhang Yuke, Guo Yunyun, Liu Shuo, Zhang Minfeng, Nie Hongming, Shen Rui. The Role of Sonazoid-contrast-enhanced Ultrasound In Precision Diagnosis and Guidance for Radiofrequency Ablation Therapy of Hepatocellular Carcinoma: a Literature Review. Advanced Ultrasound in Diagnosis and Therapy, 2026, 10(1): 20-28.

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References 66

[1]	Rumgay H, Arnold M, Ferlay J, Lesi O, Cabasag CJ, Vignat J, et al. Global burden of primary liver cancer in 2020 and predictions to 2040. J Hepatol 2022; 77: 1598-1606.
[2]	Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71: 209-249.
[3]	Dodd GD, Soulen MC, Kane RA, Livraghi T, Lees WR, Yamashita Y, et al. Minimally invasive treatment of malignant hepatic tumors: at the threshold of a major breakthrough. Radiographics 2000; 20: 9-27.
[4]	Taibbi A, Furlan A, Sandonato L, Bova V, Galia M, Marin D, et al. Imaging findings of liver resection using a bipolar radiofrequency electrosurgical device—initial observations. Eur J Radiol 2012; 81: 663-670.
[5]	European Association for the Study of the Liver; European Organisation for Research, Treatment of Cancer. EASL–EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012; 56: 908-943. doi: 10.1016/j.jhep.2011.12.001
[6]	Department of Medical Administration, National Health Commission of the People's Republic of China, Clinical practice guideline for primary liver cancer (2024 edition). Med J PUMCH 2024;15:532-559.
[7]	Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology 2011; 53: 1020-1022.
[8]	Livraghi T, Meloni F, Di Stasi M, Rolle E, Solbiati L, Tinelli C, et al. Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: is resection still the treatment of choice?. Hepatology 2007; 47: 82-89.
[9]	Tiong L, Maddern GJ. Systematic review and meta-analysis of survival and disease recurrence after radiofrequency ablation for hepatocellular carcinoma. Br J Surg 2011; 98: 1210-1224.
[10]	Tanaka T, Ikeda K, Sorin Y, Fukushima T, Kawamura Y, Kobayashi M, et al. Three-dimensional imaging using contrast-enhanced and three-dimensional ultrasound techniques in the ablative zone treated with a multipolar radiofrequency ablation system for hepatocellular carcinoma. Oncology 2016; 90: 255-260.
[11]	Leen E, Kumar S, Khan SA, Low G, Ong KO, Tait P, et al. Contrast-enhanced 3D ultrasound in the radiofrequency ablation of liver tumors. World J Gastroenterol 2009; 15: 289-299.
[12]	Rajesh S, Mukund A, Arora A, Jain D, Sarin SK. Contrast-enhanced US-guided radiofrequency ablation of hepatocellular carcinoma. J Vasc Interv Radiol 2013; 24: 1235-1240.
[13]	Pan T, Xie QK, Lv N, Li XS, Mu LW, Wu PH, et al. Percutaneous CT-guided radiofrequency ablation for lymph node oligometastases from hepatocellular carcinoma: a propensity score-matching analysis. Radiology 2017; 282: 259-270.
[14]	Inoue T, Kudo M, Hatanaka K, Arizumi T, Takita M, Kitai S, et al. Usefulness of contrast-enhanced ultrasonography to evaluate the post-treatment responses of radiofrequency ablation for hepatocellular carcinoma: comparison with dynamic CT. Oncology 2013; 84: 51-57.
[15]	Marrero JA, Kulik LM, Sirlin CB, Zhu AX, Finn RS, Abecassis MM, et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatology 2018; 68: 723-750.
[16]	Dietrich CF, Nolsøe CP, Barr RG, Berzigotti A, Burns PN, Cantisani V, 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 Med Biol 2020; 46: 2579-2604.
[17]	Claudon M, Dietrich CF, Choi BI, Cosgrove DO, Kudo M, Nolsøe CP, et al. Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) in the liver--update 2012: a WFUMB-EFSUMB initiative in cooperation with representatives of AFSUMB, AIUM, ASUM, FLAUS and ICUS. Ultraschall Med 2013; 34: 11-29.
[18]	Bansa S, Gui J, Merrill C, Wong JK, Burak KW, Wilson SR. Contrast-enhanced US in local ablative therapy and secondary surveillance for hepatocellular carcinoma. RadioGraphics 2019; 39: 1302-1322.
[19]	Numata K, Luo W, Morimoto M, Kondo M, Kunishi Y, Sasaki T, et al. Contrast enhanced ultrasound of hepatocellular carcinoma. World J Radiol 2010; 2: 68-82.
[20]	Yanagisawa K, Moriyasu F, Miyahara T, Yuki M, Iijima H. Phagocytosis of ultrasound contrast agent microbubbles by Kupffer cells. Ultrasound Med Biol 2007; 33: 318-325.
[21]	Lee J, Minami Y, Choi B, Lee W, Chou YH, Jeong W, et al. The AFSUMB consensus statements and recommendations for the clinical practice of contrast-enhanced ultrasound using Sonazoid. J Med Ultrasound 2020; 28: 59-82.
[22]	Kudo M, Hatanaka K, Kumada T, Toyoda H, Tada T. Double-contrast ultrasound: a novel surveillance tool for hepatocellular carcinoma. Am J Gastroenterol 2011; 106: 368-370.
[23]	Kudo M, Ueshima K, Osaki Y, Hirooka M, Imai Y, Aso K, et al. B-mode ultrasonography versus contrast-enhanced ultrasonography for surveillance of hepatocellular carcinoma: a prospective multicenter randomized controlled trial. Liver Cancer 2019; 8: 271-280.
[24]	Goto E, Masuzaki R, Tateishi R, Kondo Y, Imamura J, Goto T, 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: 477-485.
[25]	Park JH, Park MS, Lee SJ, Jeong WK, Lee JY, Park MJ, et al. Contrast-enhanced US with perfluorobutane (Sonazoid) used as a surveillance test for hepatocellular carcinoma (HCC) in Cirrhosis (SCAN): an exploratory cross-sectional study for a diagnostic trial. BMC Cancer 2017; 17: 279.
[26]	Ohama H, Imai Y, Nakashima O, Kogita S, Takamura M, Hori M, et al. Images of Sonazoid-enhanced ultrasonography in multistep hepatocarcinogenesis: comparison with Gd-EOB-DTPA-enhanced MRI. J Gastroenterol 2014; 49: 1081-1093.
[27]	Ding J, Zhou Y, Wang Y, Zhou H, Jing X. Clinical value of contrast-enhanced ultrasound in differential diagnosis of early hepatocellular carcinoma and dysplastic nodules. AUDT 2017; 01: 010-014.
[28]	Hwang JA, Jeong WK, Kang HJ, Lee ES, Park HJ, Lee JM. Perfluorobutane-enhanced ultrasonography with a Kupffer phase: improved diagnostic sensitivity for hepatocellular carcinoma. Eur Radiol 2022; 32: 8507-8517.
[29]	Bokor D, Chambers JB, Rees PJ, Mant TG, Luzzani F, Spinazzi A. Clinical safety of SonoVue, a new constrast agent for ultrasound imaging, in healthy volunteers and in patients with chronic obstructive pulmonary disease. Invest Radiol 2001; 36: 104-109.
[30]	Landmark KE, Johansen PW, Johnson JA, Johansen B, Uran S, Skotland T. Pharmacokinetics of perfluorobutane following instravenous bolus injection and continuous infusion of sonazoid in healthy volunteers and in patients with reduced pulmonary diffusing capacity. Ultrasoubd Med Biol 2008; 34: 494-501.
[31]	Hvattum E, Uran S, Sandbaek AG, Karlsson AA, Skotland T. Quantification of phosphatidy lserine, phosphatidic acid and free fatty acids in an ultrasound contrast agent by normal-phase high-performance liquid chromatography with evaporative light scattering detection. J Pharm Biomed Anal 2006; 42: 506-512.
[32]	Kang HJ, Lee JM, Yoon JH, Yoo J, Choi Y, Joo I, et al. Sonazoid^TM versus SonoVue^® for diagnosing hepatocellular carcinoma using contrast-enhanced ultrasound in at-risk individuals: a prospective, single-center, intraindividual, noninferiority study. Korean J Radiol 2022; 23: 1067-1077.
[33]	Kang HJ, Lee JM, Yoon JH, Lee K, Kim H, Han JK. Contrast-enhanced US with sulfur hexafluoride and perfluorobutane for the diagnosis of hepatocellular carcinoma in individuals with high risk. Radiology 2020; 297: 108-116.
[34]	Huang J, Gao L, Li J, Yang R, Jiang Z, Liao M, et al. Head-to-head comparison of Sonazoid and SonoVue in the diagnosis of hepatocellular carcinoma for patients at high risk. Front Oncol 2023; 13: 1140277.
[35]	Zhai H, Liang P, Yu J, Cao F, Kuang M, Liu F, et al. Comparison of Sonazoid and SonoVue in the diagnosis of focal liver lesions: a preliminary study. J Ultrasound Med 2019; 38: 2417-2425.
[36]	Hatanaka K, Kudo M, Minami Y, Maekawa K. Sonazoid-enhanced ultrasonography for diagnosis of hepatic malignancies: comparison with contrast-enhanced CT. Oncology 2008; 75: 42-47.
[37]	Yang WY, Park HS, Kim YJ, Yu MH, Jung SI, Jeon HJ. Visibility of focal liver lesions: comparison between Kupffer phase of CEUS with Sonazoid and hepatobiliary phase of gadoxetic acid-enhanced MRI. J Clin Ultrasound 2017; 45: 542-550.
[38]	Imai Y, Murakami T, Yoshida S, Nishikawa M, Ohsawa M, Tokunaga K, et al. Superparamagnetic iron oxide-enhanced magnetic resonance images of hepatocellular carcinoma: correlation with histological grading. Hepatology 2000; 32: 205-212.
[39]	Inoue T, Kudo M, Hatanaka K, Takahashi S, Kitai S, Ueda T, et al. Imaging of hepatocellular carcinoma: qualitative and quantitative analysis of postvascular phase contrast-enhanced ultrasonography with Sonazoid. Oncology 2008; 75: 48-54.
[40]	Korenaga K, Korenaga M, Furukawa M, Yamasaki T, Sakaida I. Usefulness of Sonazoid contrast-enhanced ultrasonography for hepatocellular carcinoma: comparison with pathological diagnosis and superparamagnetic iron oxide magnetic resonance images. J Gastroenterol 2009; 44: 733-741.
[41]	Numata K, Morimoto M, Ogura T, Sugimori K, Takebayashi S, Okada M, et al. Ablation therapy guided by contrast-enhanced sonography with Sonazoid for hepatocellular carcinoma lesions not detected by conventional sonography. J Ultrasound Med 2008; 27: 395-406.
[42]	Bouwens L, Baekeland M, De Zanger R, Wisse E. Quantitation, tissue distribution and proliferation kinetics of Kupffer cells in normal rat liver. Hepatology 1986; 6: 718-722.
[43]	Tanaka M, Nakashima O, Wada Y, Kage M, Kojiro M. Pathomorphological study of Kupffer cells in hepatocellular carcinoma and hyperplastic nodular lesions in the liver. Hepatology 1996; 24: 807-812.
[44]	Kang HJ, Kim JH, Yoo J, Han JK. Diagnostic criteria of perfluorobutane-enhanced ultrasonography for diagnosing hepatocellular carcinoma in high-risk individuals: how is late washout determined?. Ultrasonography 2022; 41: 530-542.
[45]	Sugimoto K, Moriyasu F, Saito K, Taira J, Saguchi T, Yoshimura N, et al. Comparison of kupffer-phase Sonazoid-enhanced sonography and hepatobiliary-phase gadoxetic acid-enhanced magnetic resonance imaging of hepatocellular carcinoma and correlation with histologic grading. J Ultrasound Med 2012; 31: 529-538.
[46]	Zou RH, Lin QG, Huang W, Li XL, Cao Y, Zhang J, et al. Quantitative contrast-enhanced ultrasonic imaging reflects microvascularization in hepatocellular carcinoma and prognosis after resection. Ultrasound Med Biol 2015; 41: 2621-2630.
[47]	Gatos I, Tsantis S, Spiliopoulos S, Skouroliakou A, Theotokas I, Zoumpoulis P, et al. A New Automated Quantification Algorithm for the Detection and Evaluation of Focal Liver Lesions with Contrast‐enhanced Ultrasound. Medical Physics 2015; 42: 3948-3959.
[48]	Kondo S, Takagi K, Nishida M, Iwai T, Kudo Y, Ogawa K, et al. Computer-aided diagnosis of focal liver lesions using contrast-enhanced ultrasonography with perflubutane microbubbles. IEEE Trans Med Imaging 2017; 36: 1427-1437.
[49]	Guo LH, Wang D, Qian YY, Zheng X, Zhao CK, Li XL, et al. A two-stage multi-view learning framework based computer-aided diagnosis of liver tumors with contrast enhanced ultrasound images. Clin Hemorheol Microcirc 2018; 69: 343-354.
[50]	Wang Z, Yao J, Jing X, Li K, Lu S, Yang H, et al. A combined model based on radiomics features of sonazoid contrast-enhanced ultrasound in the kupffer phase for the diagnosis of well-differentiated hepatocellular carcinoma and atypical focal liver lesions: a prospective, multicenter study. Abdom Radiol 2024; 49: 3427-3437.
[51]	Zuo D, Cao JY, Qiu YY, Wang HZ, Tian XF, Wang WP, et al. Radiomics study on predictive model of microvascular invasion in hepatocellular carcinoma based on kupffer phase image of Sonazoid contrast-enhanced ultrasound. J Clin Ultrasound 2022; 24: 485-489.
[52]	Zhang Y, Wei Q, Huang Y, Yao Z, Yan C, Zou X, et al. Deep learning of liver contrast-enhanced ultrasound to predict microvascular invasion and prognosis in hepatocellular carcinoma. Front Oncol 2022; 12: 878061.
[53]	Qin Q, Wen R, Bai XM, Gao RZ, Yang YP, Gan XY, et al. Deep learning based on kupffer phase of Sonazoid contrast-enhanced ultrasound to predict microvascular invasion in hepatocellular carcinoma. Oncoradiology 2024; 33: 432-441.
[54]	Sugimoto K, Kakegawa T, Takahashi H, Tomita Y, Abe M, Yoshimasu Y, et al. Usefulness of modified CEUS LI-RADS for the diagnosis of hepatocellular carcinoma using Sonazoid. Diagnostics 2020; 10: 828.
[55]	Sugimoto K, Saito K, Shirota N, Kamiyama N, Sakamaki K, Takahashi H, et al. Comparison of modified CEUS LI-RADS with Sonazoid and CT/MRI LI-RADS for diagnosis of hepatocellular carcinoma. Hepatol Res 2022; 52: 730-738.
[56]	Hwang JA, Jeong WK, Min JH, Kim YY, Heo NH, Lim HK. Sonazoid-enhanced ultrasonography: comparison with CT/MRI Liver Imaging Reporting and Data System in patients with suspected hepatocellular carcinoma. Ultrasonography 2021; 40: 486-498.
[57]	Liao W, Que Q, Wen R, Lin P, Chen Y, Pang J, et al. Comparison of the feasibility and diagnostic performance of ACR CEUS LI‐RADS and a modified CEUS LI‐RADS for HCC in examinations using Sonazoid. J Ultrasound Med 2023; 42: 2501-2511.
[58]	Pox C, Aretz S, Bischoff S, Graeven U, Hass M, Heußner P, et al. S3-Leitlinie Kolorektales KarzinomVersion 1.0-Juni 2013 AWMF-Registernummer: 021/007OL. Z Gastroenterol 2013; 51: 753-854.
[59]	Minami Y, Kudo M. Imaging modalities for assessment of treatment response to nonsurgical hepatocellular carcinoma therapy: contrast-enhanced US, CT, and MRI. Liver Cancer 2015; 4: 106-114.
[60]	Gao Y, Zheng DY, Cui Z, Ma Y, Liu YZ, Zhang W. Predictive value of quantitative contrast-enhanced ultrasound in hepatocellular carcinoma recurrence after ablation. World J Gastroenterol 2015; 21: 10418-10426.
[61]	Park HS, Kim YJ, Yu MH, Jung SI, Jeon HJ. Real‐time contrast‐enhanced sonographically guided biopsy or radiofrequency ablation of focal liver lesions using perflurobutane microbubbles (Sonazoid): value of kupffer‐phase imaging. J Ultrasound Med 2015; 34: 411-421.
[62]	Moriyasu F, Itoh K. Efficacy of perflubutane microbubble-enhanced ultrasound in the characterization and detection of focal liver lesions: phase 3 multicenter clinical trial. AJR Am J Roentgenol 2009; 193: 86-95.
[63]	Kudo M. Defect reperfusion imaging with Sonazoid®: a breakthrough in hepatocellular carcinoma. Liver Cancer 2016; 5: 1-7.
[64]	Kim TK, Jang HJ. Contrast-enhanced ultrasound in the diagnosis of nodules in liver cirrhosis. World J Gastroenterol 2014; 20: 3590-3596.
[65]	Martin RC 2nd, Reuter NP, Woodall C. Intra-operative contrast-enhanced ultrasound improves image enhancement in the evaluation of liver tumors. J Surg Oncol 2010; 101: 370-375.
[66]	Nishigaki Y, Hayashi H, Tomita E, Suzuki Y, Watanabe N, Watanabe S, et al. Usefulness of Contrast‐enhanced ultrasonography using Sonazoid for the assessment of therapeutic response to percutaneous radiofrequency ablation for hepatocellular carcinoma. Hepatol Res 2015; 45: 432-440.

Characteristics	Sonazoid	SonoVue
Gas	Perfluorobutane	Sulfur hexafluoride
Diameter	2 um	2.5 um
Shell	Sodium hydrolecithinylserine	Distearoyl hosphatidylcholine
Characteristic	Transpulmonary circulation blood vessel + organ specific imaging	Transpulmonary circulation angiography