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Page 2 of 11 Minami et al. Hepatoma Res 2020;6:46 I http://dx.doi.org/10.20517/2394-5079.2020.32

highly sensitive and specific diagnosis of HCC, clinical HCC guidelines now recommend imaging tests. The
specificity of single contrast-enhanced imaging is adequate for diagnosing HCC when typical features are
observed on dynamic images. Recently, a critical milestone was achieved with integration of Liver Imaging
Reporting and Data System (LI-RADS) into the AASLD HCC clinical practice guideline. LI-RADS is a
comprehensive algorithm for standardizing the terminology, technique, interpretation and reporting for
[5]
patients at high risk for HCC .
Contrast-enhanced ultrasonography (CEUS) is now widely used in clinical practice and has markedly
expanded the scope of the diagnosis of focal liver lesions(FLLs) by US. In CEUS, second-generation contrast
agents, including SonoVue (sulfur hexafluoride), Definity (perflutren lipid), and Sonazoid (perflubutane),
[6]
are microbubbles composed of a low-solubility gas enveloped by a phospholipid shell . Kupffer cells in
the reticuloendothelial system of the liver take up Sonazoid, which remains in these cells for several hours,
resulting in two contrast enhancement phases: a vascular phase and Kupffer phase. Sonazoid is advantageous
for the diagnosis of HCC because of the higher diagnostic sensitivity of images obtained in the Kupffer
phase for hepatic malignancies; the majority of hepatic neoplasms, particularly malignant tumors, do not
[7]
contain Kupffer cells . CEUS LI-RADS is a standardized system for CEUS exams and can allow for accurate
[8]
categorization of observations in patients with chronic hepatitis B or cirrhosis . The utility of SonoVue and
Definity is supported by CEUS LI-RADS, whereas Sonazoid alone has not been included yet. It is expected
that Sonazoid utilization will be incorporated in the next version of CEUS LI-RADS.

[9]
Sonazoid was approved for use as an ultrasound contrast agent in Japan in 2007 , followed by Norway,
Korea, and Singapore. It was subsequently approved in Taiwan in 2018 and China in 2019. CEUS with
Sonazoid is now regarded as a valuable diagnostic tool in the management of HCC patients. The principles,
clinical applications and techniques of CEUS with Sonazoid in the management of HCC will be reviewed
herein.

STRUCTURE AND PHARMACOKINETICS OF SONAZOID
Sonazoid (GE Healthcare, Waukesha, WI, USA) consists of lipid-coated microbubbles containing
perfluorocarbon within a well-defined size range (median diameter of approximately 3 µm). These
microbubbles are stabilized by a monomolecular membrane of hydrogenated egg phosphatidyl serine that
[6]
is embedded in an amorphous sucrose structure . Sonazoid powder is reconstituted with 2 mL of sterile
water for administration by injection. The clinical dose of Sonazoid that is generally employed to image liver
lesions is 0.015 mL/kg body weight; however, the recommended dose is decreased to 0.0075-0.0010 mL/kg
body weight when an US machine with high sensitivity for the detection of contrast agents is used.

Regarding the two contrast enhancement phases in real-time CEUS, the vascular phase (between 10 s and
5-7 min after the injection of Sonazoid) shows tumor vascularity, while the Kupffer phase (from 10 min
after the injection) shows hepatic parenchymal findings because Kupffer cells or liver sinusoids take up
this contrast agent. The artery- and portal-dominant time zones in the vascular phase are referred to as the
arterial and portal phases, respectively [Figure 1] [10,11] . Contrast enhancement in the Kupffer phase provides
important information on FLLs because hypoenhancement indicates HCC, while benign lesions mostly
show iso- or hyperenhancement. Imaging patterns, namely, arterial enhancement with Kupffer defects, are
an important distinguishing feature of hepatic malignancies.

Dynamic CEUS displays similar, but distinct, vascular patterns to contrast-enhanced computed tomography
(CECT); the contrast agents used in US are retained within blood vessels (blood pool contrast agents),
whereas those for CT and magnetic resonance imaging (MRI) move into the extracellular space until their
[12]
concentrations balance between the intravascular and extracellular spaces .