Acta Radiologica

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Lung Deposits of Lipiodol in Normal and Cirrhotic

Rats

J.-H. Chiang, Hui-Cheng Cheng, M. C. M. Yang, J.-G. Lo, C.-W. Chi, W.-Y. Lui, R.-
S. Liu & T. Chang

To cite this article: J.-H. Chiang, Hui-Cheng Cheng, M. C. M. Yang, J.-G. Lo, C.-W. Chi, W.-
Y. Lui, R.-S. Liu & T. Chang (1991) Lung Deposits of Lipiodol in Normal and Cirrhotic Rats, Acta
Radiologica, 32:6, 474-478

To link to this article: https://doi.org/10.3109/02841859109177609

Published online: 07 Jan 2010.

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FROM THE DEPARTMENTS OF RADIOLOGY, MEDICAL RESEARCH, SURGERY, AND NUCLEAR MEDICINE,
VETERANS GENERAL HOSPITAL-TAIPEI, AND THE INSTITUTE OF NUCLEAR SCIENCE, NATIONAL TSING-HUA
UNIVERSITY, TAIWAN, REPUBLIC OF CHINA.
LUNG DEPOSITS OF LIPIODOL IN NORMAL AND CIRRHOTIC RATS
H.-C. CHENG,M. C. M. YANG,J.-G. Lo, C.-W. CHI, W.-Y. LUI, R.-S. LIU and T. CHANG
J.-H. CHIANG,
Abstract
The distribution of Lipiodol in the liver and lungs following
arterial or portal injection was studied in normal (n = 55) and cir-
rhotic rats (n =20). Using magnified xeroradiography and radioiso-
tope labeled tracers, it was found that Lipiodol was deposited
mainly in the liver and lung after either arterial or portal administra-
tion. In control rats after arterial injection, deposits in the lung
peaked after 2 hours and gradually declined over 48 hours; whereas
after portal injection, the deposit steadily increased for 48 hours.
Twenty-five percent of cirrhotic rats demonstrated a Lipiodol-in-
duced miliary pattern in the lung. An increased number of portosys-
temic shunts in cirrhotic rats was also noted. These results suggest
that cirrhosis of the liver may be a potential risk factor for develop-
ing pulmonary complications after Lipiodol administration.
Key words: Liver, cirrhosis; -, interventional procedures; hepatic
arteries. chemotherapeutic infusions; portal vein, chemotherapeutic
infusions; lung, effects of drugs on; Lipiodol; experimental investi-
gations.
Lipiodol, an oily contrast medium, is generally used for
Iymphangiography, fistulography, and sialography (13). Re-
cently it has been reported that when injected into the
hepatic artery, Lipiodol preferentially accumulates in the
tumor rather than in the normal tissue (10). Consequently,
many investigators have used it as a carrier of chemothera-
peutic agents in the treatment of hepatocellular carcinoma
(3, 6). However, previous studies have mainly concentrated
on the distribution of Lipiodol inside the liver (4, 9, 11).
NAKAMURA et al. (11) have demonstrated that Lipiodol
appeared in the portal vein after hepatic arterial injection
in healthy dogs. Their finding was confirmed by an in vivo
microscopy study (4) in which Lipiodol reached portal ven-
ules rapidly and passed through sinusoids into hepatic ven-
ules following hepatic arterial injection. These results indi-
cate the importance of arterioportal communications in the
liver. However, the behavior of Lipiodol after it passed the
liver has not been discussed. Despite the increasing demand,
474
Acta Radiologica 32 (1991) Fasr. 6
information about the potential risk and complication of
intraarterial or portal administration of Lipiodol has not
been available. In our previous study of 1-13 1 labeled Lipio-
do1 in the treatment of hepatocellular carcinoma (7), the
peak lung deposit was 40.0f3.6%, which is higher than
what is reported in the literature (8). In the follow-up period
after 2 treatments of 3 370 MBq in all, one case developed
ventilation impairment and thyroid insufficiency. Thus,
there is potential risk using radioisotope labeled Lipiodol
after intraarterial treatment of hepatocellular carcinoma. It
is therefore important to investigate the risk of subsequent
embolization of other vital organs after hepatic artery or
portal vein injection before a wide application in human
beings. In the present study we investigated the total lung
and liver deposits after arterial and portal injection.
Material and Methods
The iodine content of Lipiodol was substituted with
Na'251by a simple exchange method. The labeling efficiency
was more than 99% as analyzed by thin layer chromatogra-
phy. Free iodide released within 28 days after labeling was
less than 1%. Radiolabeled microspheres, "Co and '%n
(1 5 & 3 pm) (New England Nuclear, MA), were diluted with
0.05% Tween 80 in normal saline and mixed thoroughly by
to-and-fro flush between 2 syringes immediately before use.
About 5 000 to 10 000 microspheres were injected for each
administration.
Male Sprague-Dawley rats were used. Cirrhosis was in-
duced according to the method of PROCTOR & CHATAMRA
(12). In brief, the rats weighing about 200 g first drank
water containing phenobarbital 0.33 mg/ml. Ten days later,
gastric feeding of CC14 was applied weekly for 14 weeks
Accepted for publication 22 May 1991.
 LUNG DEPOSITS OF LIPIODOL
while the drinking of phenobarbital water continued. Both
treatments were discontinued one week before the experi-
ment. At the time of experiment the average weight of
control rats was 413f7 g (n=55) and of cirrhotic rats
438+18 g (n=20).
In the first study, time course of total lung deposits was
investigated with control rats. Lipiodol (Ultra-Fluide, 0.2
mg/kg) was administered either via the hepatic artery ( 5
groups: 15 min, 2, 24, 48, 72 hours; n = 5 in each group) or
the portal vein (3 groups: 15 min, 24, 48 hours; n = 5 in
each group). In the treatment of hepatocellular carcinoma,
it has been questioned whether therapeutic agents have
better anticancer effect when mixed with Lipiodol in emul-
sion preparation or when mixed with Lipiodol directly ( 5 ) .
In addition, a beneficial effect was documented when hepat-
ic arterial blood flow was blocked after Lipiodol-therapeu-
tic agent injection (14, 15). For these reasons, in the second
study, we compared the extent of lung deposits in 3 groups
(n = 5 in each group): hepatic arterial injection of a higher
dose (Ultra-Fluide, 0.5 mg/ kg), Lipiodol emulsion (Guer-
bet, Lipiodol:Telebrix= 1.4, 0.2 mg/kg) and ligation of he-
patic artery immediately after injection. Finally with CC14-
induced cirrhotic rats, the total lung deposits after either
intraarterial or intraportal administration were examined
15 min and 2 hours later (n=5 in each group). Magnified
xeroradiographs were performed in 30 of the control rats
and in 16 of the cirrhotic rats.
Surgical preparation. Animals were anesthetized by sodi-
um pentobarbital 50 mg/kg intraperitoneally. The gastrodu-
odenal artery was dissected free through an abdominal mid-
line incision. A polyethylene tubing with tapered tip (Clay
Adams, PEIO) was cannulated and tied with its tip toward
the proper hepatic artery, which was verified by the free
reflux of blood with arterial pulsation. The catheter was
then fixed to the mesentery by cyanoacrylate glue. The
ileocolic vein was cannulated by a PESO tubing (Clay Ad-
ams) to measure portal pressure. The macroscopic criteria
of cirrhosis of the liver were a nodular surface with caudate
lobe hypertrophy and elevated portal pressure ( > 10 mm
Hg). The range of portal pressure in normal rats is about 6
to 9 mm Hg. Ascites and splenomegaly occur occasionally.
The portal-systemic (P-S) and arteriovenous (AV) shuntings
were estimated through injection of 57C0 and Il3Sn mi-
crospheres via the portal vein and the hepatic artery, respec-
tively. The interval between 57C0and II3Sn injections was 2
min. The Lipiodol administration was applied slowly 3 rnin
after the above 2 tracer injections. When necessary, the
proper hepatic artery was ligated 30 s after injection. At
desired time intervals, the animals were sacrificed with a
bolus of saturated KC1. The solid organs (such as thyroid,
lung, heart, esophagus, stomach, liver, spleen, pancreas,
kidneys, testis, muscle, and bone) were dissected, blotted,
and weighed.
Magnified xeroradiographs with 30 kVp and 50 mAs
exposure were obtained to demonstrate the gross morpho-
logic distribution of Lipiodol. The resolution was about 0.1
475
a b
C d
Fig. 1. Magnified xeroradiographs showing distribution of Lipiodol
in the liver. a) 2 hours after arterial injection in normal rat; b) 2
hours after arterial injection in cirrhotic rat; c) 24 hours after arterial
injection in normal rat; d) 24 hours after portal injection in normal
rat.
to 0.2 mm. The tissues were then cut into small pieces and
placed into plastic counting tubes. The radioactivity of each
organ was measured by a gamma scintillation counter
(Packard, Minaxi 5000) with the energy window set at 35
to 70 keV for '251,70 to 160 keV for 57C0,and 300 to 450 keV
for 'I3C0. Spillover between radioisotopes was corrected by
Compusphere program (Packard).
Calculation. In a preliminary experiment, '251-Lipiodol
was found to be distributed mainly to the liver and the
lungs and negligibly to the other organs. The total uptake
percentage of 1251-Lipiodolin the lungs was calculated as
1251radioactivity in l ~ n g / ( ' radioactivity
~~I in lung+ "'I ra-
dioactivity in liver) x 100%. Percentages of P-S and AV
shunts were estimated by the radioactivities of 57C0 and
II3Sn by a similar formula: (radioactivity in lung/radioactiv-
ity in lung + radioactivity in liver) x 100%. Data presented
were mean fS.E. Statistical significance was determined by
2-tailed Student's t-test.
Results
Magnified xeroradiography. A homogeneous branching
tree pattern (vascular phase) was observed 15 min after
arterial injection and persisted for 2 hours (Fig. 1 a). After
24 hours, it became fine-granular in appearance (paren:
chymal phase, Fig. 1 c). However, when administered via
the portal vein, a faint vascular structure was still present
in the peripheral region after 24 hours (Fig. 1 d), suggesting
that clearance of Lipiodol was more rapid by the arterial
than by the portal injection. Also, hpiodol in the central
vascular l h e n was pushed out more to the periphery and
became heterogeneous in pattern. Gross observation re-
416 J.-H. CHIANG ET AL.

5-
W
.m2 4 -
0

-0
3 -
M
d
d
? 2-
9-4
O 1-
8
n-
v

higher
control emulsion ligation dose
Fig. 4. Comparison of the lung deposits at 15 rnin after arterial
injection of various preparations. Data for control (0.2 mg/kg) were
taken from Fig. 3. Percent of lung deposits was calculated as the
Fig. 2. Magnified xeroradiograph showing the classical "Lipiodol- radioactivity ratio of lung and lung plus liver.
induced miliary pattern" of the lung in the cirrhotic rats after
arterial injection.

::3
.H
m
0
a
a2
=M 2 '
FI
5
4
/,' 1 normal cirrhosis
"0 1c Fig. 5. Lung deposits of Lipiodol in the normal and cirrhotic rats
at 15 min after arterial (HA) and portal (PV) administration. Data
for normal rats were taken from Fig. 3 (control). Percent of lung
deposits was calculated as the radioactivity ratio of lung and lung
plus liver. * Significantly different from arterial injection.
I
1 f ' '2 24 48 72
min hour hour hour hour
control rats. It should be noted that the significantly higher
Time (25% vs. 0%; p < 0.05) probability of pulmonary embolism
Fig. 3 . Time course of Lipiodol deposits in the lung via arterial (miliary pattern) in cirrhotic rats suggests a higher degree
(HA) and portal (PV) injections. * Significantly different from the
of shunting.
portal injection at the corresponding time point at p<O.O5. t Signi-
ficantly different from the earlier time point at p < 0.05. Percent of Lung deposit and shunts. The deposit patterns of Lipiodol
lung deposits was calculated as the radioactivity ratio of lung and in the lungs by arterial and portal injections were different.
lung plus liver. In control rats deposits in the lung were significantly greater
by hepatic arterial (2.26 f0.64%) than by portal injection
(0.03f0.01%) after 15 rnin (p<O.Ol) and after 24 hours
vealed irregular focal congestion on the liver surface 3 to (2.43f0.25 vs. 0.35f0.11%, p<O.Ol; Fig. 3). A peak up-
5 min after either hepatic artery or portal vein administra- take appeared 2 hours after arterial administration and
tion of Lipiodol. The congestive area gradually extended to gradually declined afterward. A graded increase (p < 0.05)
the whole liver about 30 min later. It took 48 to 72 hours was observed after portal injection and reached the same
for recovery of normal liver appearance. extent as that of arterial injection at 48 hours later. Statis-
In cirrhosis of the liver, a sparse tortuous branching was tically, both increasing the dose of Lipiodol to 0.5 mg/kg
manifested in the nodular transformation area (Fig. 1 b). and the emulsified preparation failed to alter the total lung
Moreover, the classical pattern of Lipiodol-induced miliary deposits (Fig. 4). Surprisingly, there was also no significant
distribution in the lung (Fig. 2) could be demonstrated in 4 decrease in lung deposits when the hepatic artery was oc-
of the 16 cirrhotic rats (25%) studied but in none of the 30 cluded immediately after injection (Fig. 4). In the cirrhotic
 LUNG DEPOSITS OF LIPIODOL
rats, the level of lung deposits varied too widely to find
statistical difference among groups (Fig. 5).
In the experiment with microspheres we found a small
degree of AV-shunting (0.10 f0.05Y0),which was yet signi-
ficantly greater than that of P-S shunting (0.001 f0.001%;
p < 0.05) in the normal liver.
In cirrhotic rats, data on AV and P-S shuntings were
pooled since there was no significant difference between
them. However, a significantly greater extent of shunting
was observed in the rats with miliary distribution in the
lungs (16.26+ 10.8 YO)as compared with those without
(0.13+0.05%, p<0.05).
Discussion
The present study is the first to demonstrate the different
patterns of Lipiodol deposit in the lungs after arterial or
portal administration. An initial peak at 2 hours followed
by a gradual decline over 48 hours was observed after
arterial injection whereas a gradual increase over 48 hours
was observed after portal injection. Both magnified xerora-
diography and microsphere experiments suggest a higher
degree of lung deposits in cirrhotic rats. These results indi-
cate that cirrhosis of the liver can be a risk factor inducing
pulmonary complications.
The results of this study lead to the hypothesis that there
are 2 phases of Lipiodol clearance after hepatic arterial
injection. Initially the high pressure provides a driving force
to push this highly viscous oil into the portal venules
through arterioportal communications (4). The later phase
of decrease implies a rather slow elimination by the low
pressure in the portal system as compared with the initial
phase. When injected into the portal vein without the aid of
arterial washout, portal washout of Lipiodol only resulted in
the rather constant increase in lung deposit.
There was no significant increase in Lipiodol deposit in
the lungs at the higher dose. However, at a higher dose the
miliary pattern in the lungs was induced in one normal rat,
suggesting a detrimental consequence. When comparing the
results of lung deposits with the emulsion form of Lipiodol,
the emulsion preparation of Lipiodol did not significantly
increase the lung deposits. A slight increase was probably
due to reduction of viscosity. The suspension form of Lipio-
do1 is therefore recommended since it does not contain
water-soluble additives. This is in accordance with the re-
sults of KATAGIRI et al. (5), who argue that the Adriamycin-
Lipiodol suspension may be a useful preparation for target-
ing chemotherapy to hepatocellular carcinoma. Further-
more, it did not seem to be of any advantage to ligate the
artery immediately after administration because the lung
deposits of Lipiodol were the same. Despite the lung de-
posits, in the treatment of hepatocellular carcinoma, TAKAY-
ASU et al. (15) have demonstrated a beneficial effect by
combination of central (artery blockade) and peripheral
(Lipiodol injection) embolization.
477
Lung deposits appeared to be more prominent in the
cirrhotic rats as indicated by xeroradiography, even though
the results from radiolabeled Lipiodol and microsphere ex-
periments did not reach statistical difference between con-
trol and cirrhotic rats. Once the shunting exceeds a certain
level, the risk of pulmonary embolism may possibly increase.
Therefore, it would be helpful to estimate the magnitude of
shunting before the application of Lipiodol.
It is known that cirrhotic patients have a relatively high
prevalence of chronic pulmonary disease which may be
aggravated by the complication of ascites or pleural effu-
sion. More than 113 of patients with cirrhosis suffer from
arterial hypoxemia even in the absence of apparent cardio-
pulmonary impairment (1, 2), the so-called hepato-pulmon-
ary syndrome. For these reasons, even a minor pulmonary
embolism may initiate severe respiratory problems. Since
hepatocellular carcinoma is frequently associated with liver
cirrhosis, the potential risk of pulmonary insufficiency
should not be neglected.
Metabolism of Lipoidol may occur in the liver since it
can be detected in the bile (3). The deiodination process of
iodinated fatty acid has been demonstrated in the cultured
hepatocytes of rats (16). In our preliminary experiment, the
radioactivity in the urine was found to account for 10 to
20% of the injected dose within 3 days and only 0.1% of
radioactivity was accumulated in the thyroid. The radioac-
tivities in the other organs were negligible (unpublished
observation). Thus, it is conceivable that Lipiodol releases
its iodine content in the liver which then excretes via the
kidneys. Lipiodol deposit in the lungs is most likely in the
intact form which plugs the pulmonary capillary but re-
mains in the lung for a certain period of time. Lymphatic
drainage and Kupffer cells may also play roles in the clear-
ance of Lipiodol.
ACKNOWLEDGMENT
This work was supported by a research grant from the National
Science Council (NSC79-4012-B075-43).
Request for reprints: Dr. Hui-Cheng Cheng, Department of Radi-
ology, Veterans General Hospital-Taipei, Taipei, Taiwan 11217, Re-
public of China.
REFERENCES
1. AGUSTIA. N., ROCAJ., BOSCHJ. & RODRIGUEZ-ROISIN R.: The
lung in the patients with cirrhosis. J. Hepatol. 10 (1990), 251..
2. CAMPILLO B., FOUETP.,BONNET J. & ATLANG.: Submaximal
oxygen consumption in the liver cirrhosis. Evidence of severe
functional aerobic impairment. J. Hepatol. 10 (1990), 163.
3. IWAIK., MAEDAH. & KONNOT.: Use of oily contrast medium
for selective drug targeting to tumor. Enhanced therapeutic
effect and X-ray image. Cancer Res. 44 (1984), 21 15.
4. KANZ.,'~VANCEV K., HAGERSTRAND I., CHUANG V. P. & LUND-
ERQUIST A,: In vivo microscopy of the liver after injection of
478 J.-H. CHIANG ET AL.

Lipiodol into hepatic artery or portal vein in the rat. Acta cancer treatment with an oily anticancer drug injected into the
Radiol. 30 (1989), 419. ligated feeding hepatic artery for liver cancer. Cancer 52 (1983),
5. KATACIRI Y.,MABUCHI K., ITAKURA T. et al.: Adriamycin- 2193.
Lipiodol suspension for i.a. chemotherapy of hepatocellular 1I. NAKAMURA H., HASHIMOTO T., 01H. & SAWADA S.: Iodized oil
carcinoma. Cancer Chemother. Pharmacol. 23 (1989), 238. in the portal vein after arterial embolization. Radiology 167
6. KOBAYASHI H., HIDAKAY.,KAJIYAY. et al.: Treatment of (1987), 415.
hepatocellular carcinoma by transarterial injection of antican- 12. PROCTOR E. & CHATAMRA K.: High yield micronodular cirrhosis
cer agents in iodized oil suspension or of radioactive iodized in the rats. Gastroenterology 83 (1982), 1183.
oil solution. Acta Radiol. Diagnosis 27 (1986), 139. 13. SCHAFFER B., KOEHLER P. R., DANIELC. R. et al.: A critical
evaluation of lymphangiography. Radiology 80 (1963), 917.
7. LUIW. Y., Lnr R. S., CHIANG J. H. et al.: Report of a pilot study
of intra-arterial injection of 1-131 Lipiodol for the treatment of
14. SHIMAMURA Y.,GUNVENP., TAKENAKA Y. et al.: Combined
peripheral and central chemoembolization of liver tumors. Ex-
hepatoma. Chin. Med. J. 46 (1990), 125. perience with Lipiodol-doxorubicin and gelatin sponge. Cancer
8. MADSENM. T., PARKC. H. & THAKURM. L.: Iodine-131 61 (1988), 238.
ethiodol in the treatment of hepatoma. J. Nucl. Med. 29 (1988), 15. TAKAYASU K., SHIMAY.,MURAMATSU Y.et al.: Hepatocellular
1038. carcinoma. Treatment with intraarterial iodized oil with and
9. MILLERD. L., O’LEARYT. J. & GIRTONM.: Distribution of without chemotherapeutic agents. Radiology I62 (1987). 345.
iodized oil within the liver after hepatic arterial injection. Radi- 16. THOMAS G., PEPIND., LORIETTE C. et al.: Metabolism of methyl-
ology 162 (1987), 849. branched iodo-palmitic acids in cultured hepatocytes. Eur. J.
10. NAKAKUMA K., TASHIRO S., HIRAOKA T. et al.: Studies on anti- Nucl. Med. 15 (1989), 367.