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Page 2 of 11 Wilson et al. Hepatoma Res 2020;6:57 I http://dx.doi.org/10.20517/2394-5079.2020.48

performed for an unrelated reason, is common, especially for benign tumors. Alternately, tumors may be
found as a result of a directed search in those with symptoms, with primary malignancy elsewhere, or in
those identified to be at risk for hepatocellular carcinoma (HCC).

Regardless of the nature or method of discovery of a focal liver mass, contrast-enhanced imaging is now
a mainstay for its noninvasive characterization. Originally, computed tomography (CT) and magnetic
resonance (MR) scans comprised the recommended modalities for this purpose. However, since the
introduction of microbubble contrast agents for ultrasound (US) two decades ago, CEUS has become an
[1]
additional lower cost and safer option with unique benefits .

The late approval of a contrast agent for CEUS in the United States in 2016 makes this an expanding but
still introductory modality in North America today. However in other parts of the world, such as Europe,
[2-4]
the role of CEUS has been well established by international and national guidelines . Here, we describe
the CEUS technique, emphasizing its unique benefits for characterization of focal liver disease.

Ultrasound contrast agents: what are they and how do they work?
Ultrasound contrast agents are comprised of tiny encapsulated bubbles of a perfluoropropane gas within
a variable, usually lipid, shell. They are on the same order of size as a red blood cell, and their distribution
in the circulation is sparse. They are purely intravascular as their size does not allow them to pass into the
interstitial tissues. After their venous injection, they are quickly exhaled by the lungs. They are very safe
in clinical practise for adults and for children, they have no nephrotoxicity, and their imaging requires no
[5-7]
ionizing radiation .
Specialized imaging techniques
The successful imaging of microbubble contrast agents is facilitated by their oscillation when they
are viewed in a low-power US field. To detect the signal from the oscillating microbubbles in the
[8]
circulation, CEUS is performed with contrast specific software . This generally includes pulse inversion
[9]
imaging, whereby two pulses are sent down each scan line with subtraction of the returning echoes .
The background tissue, a linear reflector, sends back a wave which is a reflection of the insonating
wave. Their subtraction, therefore, equals zero, totally removing the background signal. The result is a
relatively black image at the beginning of an imaging sequence for CEUS. The returning echoes from
the oscillating microbubble contrast agents, by comparison, will produce additive signals so that there is
great augmentation of the Doppler signal from blood. The result of these sequences is the creation of an
incredibly sensitive microbubble only image, with removal of the signals from the background tissues.
The intensity of the signal on the image occurs in direct proportion to the volume of microbubbles within
the region of view. Today, all high-end US systems offer a contrast specific software package with low
mechanical index (MI) imaging and also a bubble tracking technique. This bubble tracking may involve
a transient brief high MI insonation which destroys bubbles within the field of view, following which the
refilling of the vessels may be tracked, improving their visualization.

Contrast-enhanced imaging diagnosis of all liver masses on all modalities focuses on their enhancement
following contrast injection. Although CEUS follows the very same principles as CT and MR scan for
diagnoses, with similar result, CEUS shows, in addition, unique capabilities that give it a special place for
[10]
this application .
Unique capabilities of CEUS
Dynamic real-time imaging
Microbubble contrast agents allow US imaging of organ and lesion perfusion in real time. In comparison
to CT or MR which creates single snapshots in time, CEUS shows all images as dynamic real-time studies.