Yonago Acta medica 1996;39:135–142

Reticuloendothelial Negative Contrast Media for Hepatocellular
Carcinoma: Initial Comparison of Chondroitin Sulfate Iron Colloid andFerrixan in Fast T2-Weighted MR Imaging
Shuji Sugihara, Yuji Suto, Masayuki Kamba and Kotaro Yoshida
Department of Radiology, Faculty of Medicine, Tottori University, Yonago 683, Japan
Chondroitin sulfate iron colloid (CSIC), a paramagnetic substance, and Ferrixan(SHU555A), a superparamagnetic substance, were administered to 20 patients with 26
nodules of hepatocellular carcinoma, and the visualization of the lesions by fast T2weighted magnetic resonance imaging (MRI) was quantitatively evaluated. Conventional
spin-echo (CSE), turbo spin-echo (TSE), and turbo gradient spin-echo (TGSE) sequenceswere performed in all patients before and after the administration of the iron colloid
preparations. The signal-to-noise ratio (SNR) in the liver decreased significantly afteradministration of iron colloid preparations by all sequences and at all doses. A reductionin SNR in the liver similar to that obtained with SHU555A could be obtained byincreasing the dose of CSIC, which has a weaker T2-shortening effect. In the TSE
sequence with a weaker susceptibility effect, the decrease in SNR in the liver tended tobe equalized to those in the CSE or TGSE sequences by high dose administration of theiron colloid preparation. We think perhaps that the imaging ability for hepatocellular
carcinoma, similar to that of superparamagnetic contrast media, can be obtained withparamagnetic CSIC by administering it at a higher dose.
Key words: fast MR imaging; iron colloid; liver neoplasm

of normal liver parenchyma by their T2shortening effects, and increase the liver-tumor
contrast, serving as negative contrast media(Stark et al., 1988; Ferruci and Stark, 1990;
Yuasa et al., 1992; Reimer et al., 1995; Taylor
et al., 1995). We previously evaluated hepatocellular carcinoma by fast T2-weighted imaging using chondroitin sulfate iron colloid(CSIC; Blutal, Dainippon Pharmaceuticals,
Osaka, Japan), which is a paramagnetic substance, and reported the usefulness of this contrast media (Sugihara et al., 1996). Generally,iron colloid preparations that have been foundto be useful for detection of liver tumors aresuperparamagnetic substances, but their abili-

The diagnostic usefulness of magnetic resonance imaging (MRI), which takes time forscanning, has been reduced due to deteriorationof the image resolution by artifacts associatedwith respiration in the abdominal region. Recently, however, fast imaging has become possible due to improvements in the instrument,
and the usefulness of techniques such as turbo
spin-echo (TSE) sequence has been reported bya number of investigators (Nghiem et al., 1992;
Catasca and Mirowitz, 1993; Outwater et al.,
1994; Siewert et al.,1994). Iron colloid preparations, which are used in MRI for detection oftumoral lesions of the liver, are incorporated innormal reticuloendothelial cells, reduce signals

Abbreviations: BKG, background; CNR, contrast-to-noise ratio; CSE, conventional spin-echo; CSIC,
chondroitin sulfate iron colloid; DR, decrease ratio; DRCSE, DR of CSE; DRTGSE, DR of TGSE; DRTSE, DR of
TSE; Ferrixan, SHU555A; FOV, field of view; MR, magnetic resonance; MRI, MR imaging; RDR, relative
DR; RDR TGSE, RDR of TGSE; RDRTSE, RDR of TSE; ROI, region of interest; SDBKG, SD of the backgroud;SI, signal intensity; SIL, SI of the liver; SIT, SI of the tumor; SNR, signal-to-noise ratio; TE, echo time;
TGSE, turbo gradient spin-echo; TR, repetition time; TSE, turbo spin-echo.

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Table 1. Signal-to-noise ratio (SNR) in the liver before and after intravenous injection of iron
colloid preparations
SNR
CSIC(µmol Fe/kg)
23.6[n = 10]4[n = 4]

SHU555A(µmol Fe/kg)
8[n = 2]16[n = 4]

Unenhanced
CSE
10.4 ± 5.2
10.7 ± 3.5
14.5 ± 2.2
7.0 ± 3.1
TSE
13.4 ± 5.3
10.7 ± 1.6
7.8 ± 0.7
13.0 ± 4.5
TGSE
13.7 ± 3.7
12.9 ± 2.5
14.6 ± 1.3
13.5 ± 4.7
Iron colloid-enhanced
CSE
5.4 ± 1.7*
6.9 ± 3.2*
7.1 ± 2.0*
2.9 ± 0.5*TSE
8.7 ± 4.0*
8.0 ± 2.1**
5.0 ± 0.5**
7.1 ± 1.3*TGSE
7.5 ± 2.7*
8.3 ± 3.0*
7.0 ± 0.3*
4.7 ± 0.2*
CSE, conventional spin-echo; CSIC, chondroitin sulfate iron colloid; TGSE, turbo gradient spin-echo; TSE,
turbo spin-echo.
SNR of the liver decreases significantly after administration of iron colloid preparations at all doses and in all
image sequences: *P < 0.01, **P < 0.05.

ties to contrast lesions have not been evaluatedcomparatively with those of paramagnetic substances. We obtained an opportunity to use
Ferrixan (SHU555A; Schering, Berlin, Germany)in a phase II clinical trial. In this study, the abilities to contrast lesions of superparamagnetic
SHU555A and paramagnetic CSIC for hepatocellular carcinoma were compared quantitatively in fast T2-weighted imaging.

Subjects and Methods
The subjects were 20 patients (13 males and 7
females; 26 nodules) diagnosed as having hepatocellular carcinoma on the basis of the clinicalcourse and imaging findings. They ranged inage from 42 to 74 years (mean 63.8 years). The
tumor size was 1.2 cm to 5.3 cm (mean 2.6 cm).
CSIC was administered at 23.6 µmol Fe/kg to
10 patients (13 nodules), and SHU555A wasadministered at 4 µmol Fe/kg to 4 patients (6 nodules), at 8 µmol Fe/kg to 2 patients (2 nodules),and at 16 µmol Fe/kg to 4 patients (5 nodules).
All patients consented to participate in the study
after explanation of the intention of the study.
MRI was performed using a 1.5 T superconducting MRI system (Magnetom Vision:
Siemens, Erlangen, Germany). Conventional

spin-echo (CSE) images were obtained with arepetition time (TR) of 1800 ms and an echo
time (TE) of 80 ms, with 2 signal excitations.
Turbo spin-echo (TSE) images were obtainedwith a TR of 3500 ms, an effective TE of 99 ms
and 11 echo trains, with 5 signal excitations.
Turbo gradient spin-echo (TGSE) images wereobtained with a TR of 4500 ms, an effective TEof 108 ms and 33 echo trains, with 4 signal excitations. All imaging was performed in thetransaxial plane with a slice thickness of 10mm, gap of 1 mm, and field of view (FOV) of
35–42 cm using a rectangular FOV with a phase
encode reduction of 6/8 or 7/8. Also, presaturation pulses were superimposed at the upper andlower imaging limits. Imaging was performed
before and after administration of iron colloid
preparations, and imaging after administration
was started 2 h after intravenous administrationof CSIC and 30 min after intravenous administration of SHU555A.
For quantitative evaluation, the region ofinterest (ROI) containing the liver (L) and thesolid portion of the tumor (T) was determinedas widely as possible and at the same site byavoiding blood vessels in all imaging sequences. The ROI was determined as widely as
possible over the background (BKG) on theabdominal side, which was the phase encode136

Iron colloid-enhanced MR imaging

Table 2. Decrease ratio (DR) and relative DR (RDR) of signal-to-noise ratio (SNR) of the livercaused by administration of iron colloid preparations
CSIC(µmol Fe/kg)
23.6

SHU555A(µmol Fe/kg)
8

4

16

CSE
0.41 ± 0.19
0.36 ± 0.21
0.51 ± 0.12
0.54 ± 0.12
TSE
0.33 ± 0.21
0.24 ± 0.25
0.36 ± 0.00
0.42 ± 0.09
RDR TSE
0.80
0.67
0.71
0.78
TGSE
0.45 ± 0.14
0.37 ± 0.13
0.54 ± 0.02
0.62 ± 0.10
RDR TGSE
1.10
1.03
1.06
1.15
CSE, conventional spin-echo; CSIC, chondroitin sulfate iron colloid; RDR TGSE , RDR of TGSE; RDRTSE,
RDR of TSE; TGSE, turbo gradient spin-echo; TSE, turbo spin-echo.
Among imaging sequences, DR of SNR of the liver is the highest in TGSE. RDRTSE tend to be higher in the
CSIC group and 16 µmol Fe/kg SHU555A group.

direction. The minimum area of the ROI was
35 pixels, and the mean signal intensity (SI) andSD per pixel were calculated. From thesevalues the signal-to-noise ratio (SNR) in theliver and tumor-to-liver contrast-to-noise ratio(CNR) were calculated as follows. SNR = SIL/SD BKG ; CNR = (SIT – SIL)/SD BKG . The
decrease rate of SNR in the liver after theadministration of the iron colloid preparations,as compared with before, [decrease ratio (DR) =(preSNR – postSNR)/preSNR] was calculated.
To compare the DR of the SNR of the liver
among imaging sequences at the same dose, theratios of DRs by TSE and TGSE to DRs by CSE(relative DR, RDR) were calculated (RDR TSE =DR TSE/DRCSE, RDRTGSE = DRTGSE/DRCSE). A
paired t-test was used for the comparison of the
SNR and CNR between the pre- and postadministration of the contrast media in each
imaging sequence. The SNR of the liver and its
DR were compared among imaging sequencesby Student’s t-test when the variance was equal
but by Welch’s t-test when the variance was unequal. P values less than 0.05 were considered
to be significant.

of the SNR of the liver was highest in the 16µmol Fe/kg SHU555A group, followed by the 8µmol Fe/kg SHU555A group, CSIC group, and4 µmol Fe/kg SHU555A group in all sequences.
Among imaging sequences, the DR of the SNRof the liver was highest in TGSE, followed by
CSE and TSE at all doses. RDRTSE tended to behigher in the CSIC group and 16 µmol Fe/kg
group than in the 4 µmol Fe/kg group or 8 µmol
Fe/kg group (Table 2). The tumor-to-liver CNR
increased significantly (P < 0.01, 0.05) after theadministration of the iron colloid preparations
in all dose groups except the 8 µmol Fe/kg
SHU555A group in all imaging sequences. It
showed no significant difference among thedose groups (Table 3). Compared with theimages of each sequence in the CSIC group andthe 16 µmol Fe/kg group, the tumor-to-liver
CNR increases after the administration of CSIC
with each sequence and with each dose.
Artifacts show markedly in TGSE. Lesion
conspicuity is best viewed by TSE both before
and after the administration of CSIC (Figs. 1
and 2).

Discussion
Results
Various superparamagnetic substances arebeing tested clinically as liver-specific MRI
contrast media, and many reports have suggested their usefulness (Stark et al., 1988;
Ferruci and Stark, 1990; Yuasa et al., 1992;

The SNR of the liver decreased significantly
after the administration of iron colloid preparations at all doses and in all imaging
sequences (P < 0.01, 0.05) (Table 1). The DR
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S. Sugihara et al.

Table 3. Tumor-to-liver contrast-to-noise ratio (CNR) before and after intravenous injectionof iron colloid preparations
Tumor-to-liver CNR
SHU555A(µmol Fe/kg)
4
8

CSIC
(µmol Fe/kg)
23.6

16

Unenhanced
CSE
9.2 ± 3.5
5.1 ± 3.0
5.8 ± 5.3
5.4 ± 7.7TSE
9.0 ± 3.8
5.6 ± 2.7
2.5 ± 2.8
5.8 ± 4.1
TGSE
10.5 ± 3.5
7.9 ± 4.4
4.6 ± 2.1
8.0 ± 8.5
Iron colloid-enhanced
CSE
12.0 ± 3.4**
10.0 ± 5.3**
8.0 ± 8.0
6.2 ± 7.1**
TSE
13.6 ± 5.1*
9.6 ± 5.1**
5.2 ± 4.3
9.6 ± 2.8**
TGSE
15.4 ± 6.6**
11.1 ± 3.7**
9.8 ± 4.8
11.2 ± 8.6**
CSE, conventional spin-echo; CSIC, chondroitin sulfate iron colloid; TGSE, turbo gradient spin-echo; TSE,
turbo spin-echo.
Tumor-to-liver CNR increases significantly after administration of iron colloid preparations in all dosegroups expect the 8 µmol Fe/kg SHU555A group in all sequences: *P < 0.01, **P < 0.05.

Reimer et al., 1995; Taylor et al., 1995). CSIC,
which we have used, is a paramagnetic iron
colloid preparation in wide and safe clinical use
as a treatment for iron-deficiency anemia. Its
primary physical properties are: a mean
molecular weight of 75,000, a particle size inwater solution of 100 nm or above, and T1 andT2 relaxations of 0.44, 2.3 s-1 • mM -1 (1.5 T
spectrometer, 22˚C), respectively (Okuhata,1992). SHU555A, which was used in thisstudy, is a stable colloid of a complex of superparamagnetic iron oxide particles (bivalent ironcontent: 5% or less of total iron content) andcarboxy dextran (numerical mean molecularweight: 2600 g/mol). Its primary physicalproperties are: a colloid particle size of 57.4 ±2.1 nm and T1 and T2 relaxations of 9.48 and229.5 s -1 •mM -1 (1.5 T spectrometer, 22˚C),respectively. Its T2 relaxation is about 100
times that of CSIC (Hamm et al., 1994).
In this study, a fast T2-weighted MRI was
performed by the administration of SHU555A
at 3 doses to patients with hepatocellular
carcinoma, and its ability to contrast lesions
was quantitatively evaluated in comparison
with CSIC.
Among the 3 groups which were administered SHU555A, the DR of the SNR in theliver was greatest in the 16 µmol Fe/kg group,
followed by 8 µmol Fe/kg and 4 µmol Fe/kg

groups in this order, showing dose-dependence.
The DR of the SNR in the liver in the CSIC
group was between the values of the 4 µmol Fe/
kg and 8 µmol Fe/kg SHU555A groups. We
administered CSIC at 23.6 µmol Fe/kg, which
was higher than the doses of SHU555A. Therefore, it is expected to be distributed more densely in the reticuloendothelial cells of the normalliver parenchyma than the superparamagnetic
contrast media. The T2-shortening effect of aniron colloid preparation is affected by its
concentration and distribution density. Its
effect is reported to be weaker as its concentration is lower and its distribution is moresparse (Tanimoto et al., 1994). Probably forthis reason, a satisfactory DR of the SNR in theliver was obtained with a large dose of CSIC
despite its weaker T2-shortening effect.
The fast T2-weighted imaging sequencesused in this study were TSE and TGSE. In TSE,
fast imaging is made possible by using several
180-degree refocusing pulses per excitation
pulse and performing phase encoding for eachecho obtained, but the T2-shortening effect isreported to be markedly attenuated by therepeated use of 180-degree refocusing pulses(Hennig et al., 1986; Majumdar et al., 1989;
Muller et al., 1991; Tanimoto et al., 1995). In
TGSE, gradient echoes are generated on bothsides of the spin echoes obtained by TSE with138

Iron colloid-enhanced MR imaging

Fig. 1. T2-weighted images for a 66-year-old patientwith hepatocellular carcinoma (HCC). Conventional spin-echo images (A), turbo spin-echo images(B), turbo gradient spin-echo images (C) show HCC(arrows). Upper images: preadministration of 16µmol Fe/kg SHU555A. Lower images: postadministration of 16 µmol Fe/kg SHU555A. With eachsequence, tumor-to-liver contrast-to-noise ratio isalmost equal after SHU555A administration. The
images in TGSE are noisy.

several 180-degree refocusing pulses per
excitation pulse by repeatedly inverting thegradient of the magnetic field. As a result,
TGSE is reported to allow faster imaging thanTSE and to become more sensitive to changes
in magnetic susceptibility (Feinberg andOshio,1991). This may explain the finding thatthe DR of the SNR in the liver was highest in
TGSE and lowest in TSE at all doses. When the
DR of the SNR in the liver was comparedaccording to the dose and imaging sequence,
RDRTSE tended to be higher in the CSIC and 16µmol Fe/kg SHU555A groups than in the 4µmol Fe/kg or 8 µmol Fe/kg SHU555A group.
These results reflect the fact that the attenuationof the T2-shortening effect at low iron colloid
concentration and density is more striking in
TSE (Majumdar et al., 1989; Muller et al.,
1991; Tanimoto et al., 1995). Generally, insuperparamagnetic substances, temporary
hypotension and bradycardia were noted as side
effects after administration at 15 µmol Fe/kg(Gandon et al., 1991), and their safety in large

139

S. Sugihara et al.

Fig. 2. T2-weighted images for a 58-year-old patientwith hepatocellular carcinomas (HCCs). Conventional spin-echo images (A), turbo spin-echo (TSE)
images (B), turbo gradient spin-echo images (C)show HCCs (arrows). Upper images: preadministration of chondroitin sulfate iron colloid (CSIC).
Lower images: postadministration of CSIC. With
each sequence, tumor-to-liver contrast-to-noise ratio(CNR) increases after CSIC administration. Tumorto-liver CNR is best on TSE image after CSIC administraton.

doses has not been established. Their optimaldose is often suggested to be 8–10 µmol Fe/kg(Reimer et al.,1995; Yuasa et al., 1992). The

safety of CSIC for our routine clinical doses has
been established, and it could be administeredin large doses. For this reason, liver signals are
considered to be suppressed to a similar degree
in TSE as well as in CSE and TGSE by administering high doses of CSIC, and we believe theimaging ability of TSE for hepatocellular carcinoma has been improved. The tumor-to-liver
CNR showed no significant increase after theadministration of SHU555A at 8 µmol Fe/kg.
The contrast enhancement appears to have beenslight, because SHU555A was administered at
8 µmol Fe/kg to only 2 patients (2 nodules), theSI of the tumor was reduced after the admin-140

Iron colloid-enhanced MR imaging

istration of the iron colloid preparation, and thetumor is considered to have been well differentiated hepatocellular carcinoma (Hirohashi etal., 1993), although no histological evidence
was available.
In TGSE, the image quality was worse withtruncation artifacts, which is characteristic in
TGSE. Therefore, TGSE was considered to beunsuitable for diagnosis of hepatocellular
carcinoma, although TGSE obtained a higher
SNR in the liver and higher tumor-to-liver
CNR.
From these findings, the SI of the liver isconsidered to be reduced by a high dose of paramagnetic CSIC similarly to a superparamagnetic preparation, although the T2-shortening
effect of CSIC is weaker than those of thesuperparamagnetic preparation. In TSE, inwhich the susceptibility effect is unremarkable
among fast T2-weighted sequences, the signalsof the liver parenchyma appear to be reduced toa similar degree to CSE and TGSE by administering an iron colloid preparation in a highdose and increasing the density of its distribution in the normal liver parenchyma.

Conclusion
The imaging abilities of fast T2-weighted MRI
using paramagnetic and superparamagnetic iron
colloid preparations (CSIC and SHU555A,
respectively) for hepatocellular carcinoma werecompared quantitatively. In the 8 µmol Fe/kg
SHU555A group at their optimal dose, a decrease in the SI of the liver was worse in TSE
compared with CSE. Therefore it is considered
to be unsuitable for the diagnosis of hepatocellular carcinoma in TSE. In TSE, CSIC
caused a similar decrease in the SI of the liver to
CSE by increasing the dose. Therefore, CSIC isconsidered to be a more effective MR contrast
agent for the diagnosis of hepatocellular carcinoma in TSE.
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(Received August 19, Accepted September 18, 1995)

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