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Kobayashi et al. Hepatoma Res 2020;6:36 I http://dx.doi.org/10.20517/2394-5079.2020.24 Page 11 of 14

weighted MR images. In cases where the normal structure of sinusoids is lost (metastatic liver cancer etc.),
signal intensity changes do not occur because there are no Kupffer cells. Similarly, the function of Kupffer
cells are decreased despite their presence due to irradiation etc., the degree of SPIO uptake is lowered, and
such areas show relatively high signal intensities on T2-weighted images compared to the surrounding
[17]
normal liver where normal Kupffer cells are present and take up SPIO .

[18]
On histopathological analysis, Imai et al. found that in multi-step hepatocarcinogenesis, as the nodular
degree of differentiation is lowered, the number of Kupffer cells within the nodule is decreased, and there
was a significant difference between the number of Kupffer cells in DN, well differentiated HCC, moderately
differentiated HCC, and poorly differentiated HCC. In most DN and 46% of well differentiated HCC, the
number of Kupffer cells was increased compared with the surrounding liver; the number of Kupffer cells
decreased to 30% compared with the surrounding liver in moderately differentiated HCC; and the number of
Kupffer cells decreased to 13% on average in poorly differentiated HCC [Figure 14].

On SPIO-enhanced MRI, DN and well-differentiated HCC present with iso- to slightly low-intensity on
T2 weighted MR images compared to the surrounding liver. In well-differentiated HCC especially, 46%
of the nodules presented with a low-intensity compared to the surrounding liver. Moderately and poorly
differentiated HCC though presented with a high-intensity compared with the surrounding liver. There was
a significant difference in signal intensity between DN with well-differentiated HCC, and moderately and
[18]
poorly differentiated HCC [Figure 14] . These results show that SPIO-enhanced MRI is a good tool to
estimate the degree of differentiation in HCC, but it has a limit in differentiating DN from well-differentiated
HCC.

Approach from the function of hepatocyte membrane transporter
Approximately 50% of Gd-EOB-DTPA (EOB), as well as other extracellular contrast agents, is excreted from
the kidneys and the remaining 50% is taken up by hepatocytes and then excreted into the biliary tract, hence,
it is called hepatocyte-specific contrast agent. The advantage of this MRI contrast agent is it can evaluate both
blood flow information and hepatocyte function simultaneously. However, in EOB-enhanced MRI, there
are some drawbacks of low accumulation in hepatocytes depending on liver function and the low degree of
arterial enhancement, and there are also limitations in viewing true washout or enhancement of capsules,
which are major features characterizing overt HCC.

After rapid intravenous injection of EOB, blood flow evaluation by dynamic study is performed similarly
to other extracellular contrast agents. In the hepatobiliary phase after 15-20 min of injection, the liver
parenchyma presents high signal intensity on T1-weighted images because of EOB uptake by normal
hepatocytes. Areas that do not have normal hepatocytes (metastatic liver cancer etc.) or areas where
hepatocytes have poor EOB uptake ability (irradiated area etc.) present with low intensities compared to the
surrounding normal liver.

EOB is taken up into the intracellular space of hepatocytes by organic anion transporting polypeptide
(OATP) 1B3, which is expressed on the sinusoidal side of hepatocyte membranes and excreted in the biliary
tract through multidrug resistance associated protein 2 (MRP2), which is expressed on the bile canalicular
[19]
side of hepatocyte membrane . Under the conditions of bile duct obstruction, MRP3, which is expressed
[19]
on the sinusoidal side of hepatocyte membranes, increase and EOB is excreted into the sinusoids .
[20]
Kitao et al. compared the degree of OATP1B3 expression in hepatocellular nodules undergoing multi-
step hepatocarcinogenesis with the surrounding normal liver, and found that it was preserved in LGDN but
decreased in approximately 30% of HGDN and approximately 70% of early HCC [Figure 15].

In most moderately differentiated HCC, there was decreased expression of OATP1B3. As well, in the
hepatobiliary phase of EOB-enhanced MRI, the signal enhancement ratio was significantly lowered in well to