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de Santis et al. Hepatoma Res 2019;5:1 I http://dx.doi.org/10.20517/2394-5079.2018.65 Page 3 of 16

multidetector computed tomography (MDCT) or multi-phase nuclear magnetic resonance imaging (MRI)
with contrast agents.

Contrast-enhanced ultrasound (CEUS) may be a useful imaging modality for the noninvasive diagnosis of
[12]
small, newly detected liver nodules during surveillance of cirrhotic patients . Ultrasound contrast agents
(“microbubbles”) comprise an albumen or phospholipid shell containing a stable perfluorocarbon or sulphur
hexafluoride gas. They are predominantly blood-pool agents, as the encapsulated microbubbles are small
enough to pass through both pulmonary and systemic circulation after intravenous injection and durable
[13]
enough to re-circulate for several minutes . CEUS can also be utilized in the presence of renal impairment
and can be performed at the time in which the lesion is discovered but it does not eliminate the need for CT
[14]
and/or MRI in order to characterize the lesion and to stage the disease . CEUS was inserted as a method
[15]
for characterizing nodules arising in cirrhotic livers, in the 2005 AASLD guidelines but was subsequently
eliminated in 2011, partly due to lack of availability of ultrasound contrast in the USA and partly due to false
[3]
positive diagnoses in patients with intra-hepatic cholangiocarcinoma .

CT AND MRI
As already mentioned, the identification of a liver focal lesion greater than 1 cm in the course of surveillance
with ultrasonography of patients at risk imposes the study with higher level image techniques such
as MDCT or MRI with an extracellular contrast medium (iodized compound or gadolinium-based
compounds: gadoteric acid, gadopentetic acid, gadodiamide, gadoteridol, gadobutrol) that remain in the
extracellular space and allows the characterization of blood flow. Multi-phase MRI may be performed also
with an hepatospecific contrast agents such as gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid
or Gd-EOB-DTPA, gadobenate dimeglumine or Gd-BOPTA, which is captured by “healthy” hepatocytes
and excreted in the biliary tract, or by iron oxide particles (SPIO) with superparamagnetic activity, which
are captured by Kupffer cells located in the non-neoplastic hepatic parenchyma and in benign lesions but not
in malignant ones.

The goals of the evaluation by MRI or MDCT of a hepatic nodule in a patient with liver cirrhosis are not
only the determination of the nature of the lesion but also, in the case of an HCC, the estimate of the hepatic
extension of the neoplasia and the possible localization in extrahepatic sites in order to propose a treatment
based on the exact staging of the disease.

There is universal consensus that the diagnosis of HCC can be achieved without biopsy in a situation where
the pre-test probability is very high, as happens in liver cirrhosis, but there is no consensus as to which
technique is the best. The angiographic features of HCC are identical in MDCT and MRI, but the latter offers
a series of additional imaging sequences such as T2-weighted sequences, diffusion-weighted imaging and
in combination with the use of a hepatospecific contrast agent it can improve diagnostic performance [16-19] .
However, MRI presents greater technical complexity, longer scan times, greater susceptibility to artifacts, a
[20]
less consistent image quality, higher cost, lower availability, longer scheduling backlogs and its diagnostic
yield becomes void if the patient is unable to hold his breath, to remain still or presents a high-volume
ascites. For these reasons the superiority of one method over the other, especially in real-life contexts
remains uncertain.

In a recent meta-analysis in which MDCT was compared with MRI with an extracellular agent, or MRI
[20]
with gadoxetate disodium, Roberts et al. concluded that the latter showed significantly higher sensitivity
(0.82; 95% CI, 0.75-0.87 vs. 0.66; 95 % CI, 0.60-0.72) and lower negative likelihood ratio (0.20; 95% CI, 0.15-0.28;
vs. 0.37; 95% CI, 0.30-0.44) in diagnosis of HCC lesions. Pooled analysis demonstrated that both gadoxetate
enhanced MRI and extracellular contrast - enhanced MRI provided significantly higher sensitivity and