Journal of Gastroenterology

, Volume 44, Issue 7, pp 733–741 | Cite as

Usefulness of Sonazoid contrast-enhanced ultrasonography for hepatocellular carcinoma: comparison with pathological diagnosis and superparamagnetic iron oxide magnetic resonance images

  • Keiko Korenaga
  • Masaaki Korenaga
  • Matakazu Furukawa
  • Takahiro Yamasaki
  • Isao Sakaida
Original Article—Liver, Pancreas, and Biliary Tract



We investigated the usefulness of Sonazoid contrast-enhanced ultrasonography (Sonazoid-CEUS) in the diagnosis of hepatocellular carcinoma (HCC). The examination was performed by comparing the images during the Kupffer phase of Sonazoid-CEUS with superparamagnetic iron oxide magnetic resonance (SPIO-MRI).


The subjects were 48 HCC nodules which were histologically diagnosed (well-differentiated HCC, n = 13; moderately differentiated HCC, n = 30; poorly differentiated HCC, n = 5). We performed Sonazoid-CEUS and SPIO-MRI on all subjects. In the Kupffer phase of Sonazoid-CEUS, the differences in the contrast agent uptake between the tumorous and non-tumorous areas were quantified as the Kupffer phase ratio and compared. In the SPIO-MRI, it was quantified as the SPIO-intensity index. We then compared these results with the histological differentiation of HCCs.


The Kupffer phase ratio decreased as the HCCs became less differentiated (P < 0.0001; Kruskal–Wallis test). The SPIO-intensity index also decreased as HCCs became less differentiated (P < 0.0001). A positive correlation was found between the Kupffer phase ratio and the SPIO-MRI index (r = 0.839). In the Kupffer phase of Sonazoid-CEUS, all of the moderately and poorly differentiated HCCs appeared hypoechoic and were detected as a perfusion defect, whereas the majority (9 of 13 cases, 69.2%) of the well-differentiated HCCs had an isoechoic pattern. The Kupffer phase images of Sonazoid-CEUS and SPIO-MRI matched perfectly (100%) in all of the moderately and poorly differentiated HCCs.


Sonazoid-CEUS is useful for estimating histological grading of HCCs. It is a modality that could potentially replace SPIO-MRI.


Sonazoid Contrast-enhanced ultrasonography Kupffer phase SPIO-MRI Hepatocellular carcinoma 



We thank Masahiro Saitoh and Ritsuko Fukushima, from Mochida Siemence systems Co., Ltd., for their helpful advice and expert technical assistance.


  1. 1.
    Kudo M. Contrast harmonic imaging in the diagnosis and treatment of hepatic tumors. Tokyo: Springer; 2003.Google Scholar
  2. 2.
    Wen YL, Kudo M, Zheng RQ, Ding H, Zhou P, Minami Y, et al. Characterization of hepatic tumors: value of contrast-enhanced coded phase-inversion harmonic angio. AJR Am J Roentgenol. 2004;182:1019–26.PubMedGoogle Scholar
  3. 3.
    von Herbay A, Vogt C, Häussinger D. Late-phase pulse-inversion sonography using the contrast agent Levovist: differentiation between benign and malignant focal lesions of the liver. AJR Am J Roentgenol. 2002;179:1273–9.Google Scholar
  4. 4.
    Inoue T, Kudo M, Watai R, Pei Z, Kawasaki T, Minami Y, et al. Differential diagnosis of nodular lesions in cirrhotic liver by post-vascular phase contrast-enhanced US with Levovist: comparison with superparamagnetic iron oxide magnetic resonance images. J Gastroenterol. 2005;40:1139–47.PubMedCrossRefGoogle Scholar
  5. 5.
    Minami Y, Kudo M, Kawasaki T, Kitano M, Chung H, Maekawa K, et al. Transcatheter arterial chemoembolization of hepatocellular carcinoma: usefulness of coded phase-inversion harmonic sonography. AJR Am J Roentgenol. 2003;180:703–8.PubMedGoogle Scholar
  6. 6.
    Numata K, Isozaki T, Ozawa Y, Sakaguchi T, Kiba T, Kubota T, et al. Percutaneous ablation therapy guided by contrast-enhanced sonography for patients with hepatocellular carcinoma. AJR Am J Roentgenol. 2003;180:143–9.PubMedGoogle Scholar
  7. 7.
    Minami Y, Kudo M, Chung H, Kawasaki T, Yagyu Y, Shimono T, et al. Contrast harmonic sonography-guided radiofrequency ablation therapy versus B-mode sonography in hepatocellular carcinoma: prospective randomized controlled trial. AJR Am J Roentgenol. 2007;188:489–94.PubMedCrossRefGoogle Scholar
  8. 8.
    Watanabe R, Matsumura M, Chen CJ, Kaneda Y, Ishihara M, Fujimaki M. Gray-scale liver enhancement with Sonazoid (NC100100), a novel ultrasound contrast agent; detection of hepatic tumors in a rabbit model. Biol Pharm Bull. 2003;26:1272–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Hagen EK, Forsberg F, Aksnes AK, Merton DA, Liu JB, Tornes A, et al. Enhanced detection of blood flow in the normal canine prostate using an ultrasound contrast agent. Invest Radiol. 2000;35:118–24.PubMedCrossRefGoogle Scholar
  10. 10.
    Yao J, Teupe C, Takeuchi M, Avelar E, Sheahan M, Connolly R, et al. Quantitative 3-dimensional contrast echocardiographic determination of myocardial mass at risk and residual infarct mass after reperfusion: experimental canine studies with intravenous contrast NC100100. J Am Soc Echocardiogr. 2000;13:570–81.PubMedCrossRefGoogle Scholar
  11. 11.
    Yanagisawa K, Moriyasu F, Miyahara T, Yuki M, Iijima H. Phagocytosis of ultrasound contrast agent microbubbles by Kupffer cells. Ultrasound Med Biol. 2007;33:318–25.PubMedCrossRefGoogle Scholar
  12. 12.
    Watanabe R, Matsumura M, Chen CJ, Kaneda Y, Fujimaki M. Characterization of tumor imaging with microbubble-based ultrasound contrast agent, Sonazoid, in rabbit liver. Biol Pharm Bull. 2005;28:972–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Kindberg GM, Tolleshaug H, Roos N, Skotland T. Hepatic clearance of Sonazoid perfluorobutane microbubbles by Kupffer cells does not reduce the ability of liver to phagocytose or degrade albumin microspheres. Cell Tissue Res. 2003;312:49–54.PubMedGoogle Scholar
  14. 14.
    Watanabe R, Matsumura M, Munemasa T, Fujimaki M, Suematsu M. Mechanism of hepatic parenchyma-specific contrast of microbubble-based contrast agent for ultrasonography: microscopic studies in rat liver. Invest Radiol. 2007;42:643–51.PubMedCrossRefGoogle Scholar
  15. 15.
    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;24:807–12.PubMedCrossRefGoogle Scholar
  16. 16.
    Forsberg F, Piccoli CW, Liu JB, Rawool NM, Merton DA, Mitchell DG, et al. Hepatic tumor detection: MR imaging and conventional US versus pulse-inversion harmonic US of NC100100 during its reticuloendothelial system-specific phase. Radiology. 2002;222:824–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Nakano H, Ishida Y, Hatakeyama T, Sakuraba K, Hayashi M, Sakurai O, et al. Contrast-enhanced intraoperative ultrasonography equipped with late Kupffer-phase image obtained by sonazoid in patients with colorectal liver metastases. World J Gastroenterol. 2008;14:3207–11.PubMedCrossRefGoogle Scholar
  18. 18.
    Hatanaka K, Kudo M, Minami Y, Ueda T, Tatsumi C, Kitai S, et al. Differential diagnosis of hepatic tumors: value of contrast-enhanced harmonic sonography using the newly developed contrast agent, Sonazoid. Intervirology. 2008;51(Suppl 1):61–9.PubMedCrossRefGoogle Scholar
  19. 19.
    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.PubMedGoogle Scholar
  20. 20.
    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;32:205–12.PubMedCrossRefGoogle Scholar
  21. 21.
    International Working Party. Terminology of nodular hepatocellular lesions. Hepatology. 1995;22:983–93.Google Scholar
  22. 22.
    Kudo M, Hatanaka K, Chung H, Minami Y, Maekawa K. A proposal of novel treatment-assist technique for hepatocellular carcinoma in the Sonazoid-enhanced ultrasonography: value of defect re-perfusion imaging. Acta Hepatol Jpn. 2007;48:299–301.Google Scholar
  23. 23.
    Moriyasu F. Phase III multicenter clinical trial of Sonazoid in Japan for the characterization and the detection of focal liver lesions. Hepatology. 2004;40(Suppl 1):707A.Google Scholar
  24. 24.
    Asahina Y, Izumi N, Uchihara M, Noguchi O, Ueda K, Inoue K, et al. Assessment of Kupffer cells by ferumoxides-enhanced MR imaging is beneficial for diagnosis of hepatocellular carcinoma: comparison of pathological diagnosis and perfusion patterns assessed by CT hepatic arteriography and CT angioportography. Hepatol Res. 2003;27:196–204.PubMedCrossRefGoogle Scholar
  25. 25.
    Imai Y, Murakami T, Hori M, Fukuda K, Kim T, Marukawa T, et al. Hypervascular hepatocellular carcinoma: combined dynamic MDCT and SPIO-enhanced MRI versus combined CTHA and CTAP. Hepatol Res. 2008;38:147–58.PubMedGoogle Scholar
  26. 26.
    Kono Y, Steinbach GC, Peterson T, Schmid-Schönbein GW, Mattrey RF. Mechanism of parenchymal enhancement of the liver with a microbubble-based US contrast medium: an intravital microscopy study in rats. Radiology. 2002;224:253–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Huppertz A, Balzer T, Blakeborough A, Breuer J, Giovagnoni A, Heinz-Peer G, et al. Improved detection of focal liver lesions at MR imaging: multicenter comparison of gadoxetic acid-enhanced MR images with intraoperative findings. Radiology. 2004;230:266–75.PubMedCrossRefGoogle Scholar
  28. 28.
    Kim SK, Kim SH, Lee WJ, Kim H, Seo JW, Choi D, et al. Preoperative detection of hepatocellular carcinoma: ferumoxides-enhanced versus mangafodipir trisodium-enhanced MR imaging. AJR Am J Roentgenol. 2002;179:741–50.PubMedGoogle Scholar
  29. 29.
    Giorgio A, Ferraioli G, Tarantino L, de Stefano G, Scala V, Scarano F, et al. Contrast-enhanced sonographic appearance of hepatocellular carcinoma in patients with cirrhosis: comparison with contrast-enhanced helical CT appearance. AJR Am J Roentgnol. 2004;183:1319–26.Google Scholar

Copyright information

© Springer 2009

Authors and Affiliations

  • Keiko Korenaga
    • 1
    • 3
  • Masaaki Korenaga
    • 1
  • Matakazu Furukawa
    • 2
  • Takahiro Yamasaki
    • 1
  • Isao Sakaida
    • 1
  1. 1.Department of Gastroenterology and Hepatology, Graduate School of MedicineYamaguchi UniversityUbeJapan
  2. 2.Department of Radiology, Graduate School of MedicineYamaguchi UniversityUbeJapan
  3. 3.Division of Hepatology and Pancreatology, Department of Internal MedicineKawasaki Medical CollegeKurashikiJapan

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