Keywords Future liver remnant - N-butyl cyanoacrylate glue - Portal vein embolization
Introduction
Complete resection of hepatic tumors remains the first choice for curative treatment
of primary and secondary liver malignancies, giving the patient the only chance of
long-term survival.[[1 ]],[[2 ]] The variable deciding the extent of resection include tumor size, tumor location,
and tumor burden. Often extensive liver parenchymal resection may be needed for curative
treatment making the tumor unresectable. The reason for unresectability may be insufficient
remnant liver volume to support postoperative liver function, which itself is the
principal cause of postoperative death after major hepatectomy. It has been demonstrated
that liver failure is directly related to the size of a remnant functional liver volume.[[3 ]]
Portal vein embolization (PVE) to induce hypertrophy of an insufficient future liver
remnant (FLR) prior to hepatic tumor resection is currently recognized as a standard
practice to minimize the risk of postoperative failure as well as increase the number
of resectable patients.[[4 ]],[[5 ]],[[6 ]],[[7 ]],[[8 ]],[[9 ]],[[10 ]],[[11 ]],[[12 ]],[[13 ]]
Currently, various embolic agents, including gel-foam, coils, polyvinyl alcohol (PVA)
particles, absolute alcohol, and N-butyl-cyanoacrylate (NBCA) glue, have been used
for PVE.[[14 ]],[[15 ]],[[16 ]] However, there is no consensus in the most effective and safe embolic agents for
PVE.[[17 ]] The ideal embolic agent is one that causes permanent embolization without recanalization.
In previous studies, NBCA has been used for PVE because it causes permanent embolization
without recanalization.[[18 ]],[[19 ]],[[20 ]],[[21 ]] However, NBCA is difficult to control because of its liquidity and rapid polymerization.
In this study, we analyzed the outcome of PVE using NBCA. The primary objective was
to evaluate the post PVE change in future liver remnant (FLR) volume, biochemical
parameters, and procedure-related complications. The factors affecting the FLR hypertrophy
with emphasis on patients with liver parenchymal disease. The rate of resection was
also evaluated.
Materials and Methods
A retrospective review of our hospital electronic database was performed to search
all patients who underwent PVE between January 2012 and December 2017 for primary
hepatobiliary malignancies requiring right hepatectomy. The study protocol was approved
by our institutional review board and conducted according to the standards of the
declaration of Helsinki. The indications of right hepatectomy or extended hepatectomy
and pre-resection PVE were elaborated through a case-by-case discussion at a multidisciplinary
team meeting (including hepatologists, hepatobiliary surgeons, and interventional
radiologists). Pre-embolization computed tomography (CT) was performed to evaluate
the extent of hepatobiliary disease, the portal vein anatomy, and biliary obstruction
[[Figure 1 ]]A. The PVE was suggested according to the hepatic volumetry and underlying disease.
For healthy liver, the FLR should be at least 25% of the total liver volume (TLV);
whereas in case of liver cirrhosis, the FLR must be at least 40% of the TLV. For the
patients undergoing preoperative chemotherapy, the FLR should be at least 30% of TLV.
The exclusion criteria were as follows: unresectable tumor, patients who had any type
of liver resection before PVE, PVE done with embolic agents other than NBCA, portal
vein thrombosis, and renal failure.
Figure 1 (A-F): (A) Contrast-enhanced CT, axial image showing hilar mass (white arrows) with minimal
biliary dilatation (black arrow) and small left lobe of the liver. (B) Fluoroscopic
image showing NBCA-lipiodol cast (white arrows) in the right portal vein branches.
(C) Post PVE portal venogram showing non-opacification of right portal vein branches
(black arrows) suggestive of complete embolization of all right portal vein branches.
(D) Follow-up axial CECT image showing lipiodol deposition in right portal vein branches
(black arrows) with right lobe atrophy and hypertrophy of left lobe of the liver.
Comparative liver volumetry images, pre PVE (E), and post PVE (F) showing hypertrophy
of the left lateral segments of the liver. Post right hepatectomy follow-up axial
CECT image (G) showing remnant left lobe of liver
Percutaneous biliary drainage was performed in patients with biliary obstruction before
PVE either previously or same day of PVE procedure.
Portal vein embolization technique
PVE was usually performed 4–5 weeks before the planned surgery. Percutaneous PVE was
performed under conscious sedation (induced with intravenous administered midazolam
and fentanyl citrate) and a local anesthetic (1% lidocaine hydrochloride) at the skin
puncture site for local pain control.
The portal venous system was accessed percutaneously under ultrasound and fluoroscopic
guidance using either contralateral approach (puncture of the left portal vein branch
and embolization of the right portal vein branches) or ipsilateral approach (puncture
of the right portal vein branch to embolize the right portal vein branches). A 22
gauge Chiba needle (Neff Percutaneous Access Set, Cook, Bloomington, Indiana, USA)
was used to puncture the distal selected portal vein, and the Neff set assembly was
advanced in the main portal vein thereafter replaced by a 0.035” hydrophilic guidewire
(Terumo, Tokyo, Japan). After that, a 6F vascular sheath was placed into the portal
vein over the wire to facilitate subsequent catheter exchange. Flush portography was
performed with a 5F KMP catheter in the main portal vein to identify variations of
the intra-hepatic portal tree. KMP catheter was used to cannulate segmental portal
vein branches in the contralateral approach, and a combination of SIM 1, C1/2, and
KMP catheter was needed to achieve complete embolization in the ipsilateral approach.
Before embolization, contrast venogram of selected right portal vein branches was
performed using a 5F angiographic catheter. Further, NBCA (glue) mixed with lipiodol
(1:4 ratio) was injected under fluoroscopic guidance into each selected portal vein
branch in small aliquots (0.5 to 1.0 ml) [[Figure 1 ]]B. The catheter was flushed with 5% dextrose solution (5% DW) both prior to glue
injection and after the glue injection to prevent polymerization of NBCA within the
catheter. If a right extended hepatectomy (including segment IV) was planned, then
additional embolization of segment IV portal vein branches was also done. In contralateral
approach, a final flush portography was done with 5F KMP catheter placed in the main
portal vein to assess the completeness of the embolization [[Figure 1 ]]C. At the end of the procedure, while removing the access sheath, the punctured
portal vein radicle was embolized with NBCA and coils in ipsilateral approach; whereas
in contralateral approach, the catheter and sheath were removed under manual compression
for 10 min, without tract embolization owing to the anterior and superficial location
of the left lobe of liver.
Follow-up
Patients were kept under observation with monitoring of vitals for 3–6 h after the
procedure. Clinical and laboratory findings were evaluated for post-embolization syndrome,
liver dysfunction, or catheter-related complications. Patients were discharged when
they were clinically stable and without any complaints. Liver function tests and complete
blood counts were assessed prior to the procedure, on day 2 and at 3–4 weeks of PVE.
The complications were recorded and classified according to the Society of Interventional
Radiology complication guidelines. Technical success rate was defined as the successful
occlusion of the targeted branches of portal veins after PVE.
Assessment of hypertrophy
A follow-up CT scan of the abdomen was performed 3–4 weeks after PVE to determine
the degree of liver hypertrophy [[Figure 1 ]]D. A triple-phase CT scan protocol (non-contrast scan, acquisitions at arterial
phase, obtained 35 s after injection, and venous phase obtained 75–90 s after injection)
was used to define the liver segments precisely. All measurements were obtained on
the venous phase to delineate both portal vein and the hepatic veins.
Volumetric measurements were performed using liver volumetry software (Myrian XP,
Intrasense, France) on serial transverse scans at 2.5 mm interval from the dome of
the liver to the most inferior part of liver. These measurements included total liver
volume (TLV), future liver remnant (FLR) volume, and ratio of FLR/TLV, the ratio before
and after PVE and increase of FLR hypertrophy [[Figure 1 ]]E and F].
Statistical analysis
All data were expressed as mean ± standard deviation (SD). The paired student t test
or the Mann-Whitney test was used to compare continuous variables depending on the
distribution of data, and the Fisher exact test was used for categorical variables.
Statistical significance was set at a P value < 0.05. All analyses were performed using the SPSS software version 16.
Results
From January 2012 to December 2017, total 29 patients underwent PVE prior to right
hepatectomy for hepatobiliary malignancies. One patient was excluded from the study
as PVA and coil were used as embolic agents. Hence, the data of 28 patients (20 male
and 8 female) was included and analyzed in this study. Twenty-two patients underwent
PVE through contralateral approach, whereas in the remaining six, PVE was done using
ipsilateral approach. Out of 28 patients, embolization of segment IV was done in six
patients. The demographic details are presented in [[Table 1 ]].
Table 1
Patient demographics
Parameters
Patient numbers (n =28)
Sex (M/F)
22/6
Age (mean, range)
55.6 years (35-72)
Tumor type (n %)
Cholangiocarcinoma
14
Hepatocellular carcinoma
5
Gall bladder carcinoma
9
Underlying liver damage/Systemic disease
Cirrhosis
19
Neoadjuvant chemotherapy
5
Diabetes mellitus
6
PVE approach
Ipsilateral PVE
6
Contralateral PVE
22
Technical success of PVE
The technical success was achieved in all patients with complete occlusion of all
targeted portal vein branches throughout both contralateral and ipsilateral approach.
Assessment of hypertrophy [[Table 2 ]]
Table 2
Change in liver volume (CT volumetry values) before and after PVE
Parameters
Before PVE (mean±SD) (range)
After PVE (mean±SD) (range)
P
TLV (cm3 )
1602±328 (2250-1050)
1537±323 (2128-1090)
0.71
FLR (cm3 )
371.18±87 (228-650)
567.3±142 (303-922)
<0.0001
FLR/TLV (%)
23.33±4.7 (15.5-32.3)
37.4±8.1 (26.9-51.2)
<0.0001
Hypertrophy of FLR (%)
52±32
Increase of the FLR/TLV ratio (%)
14.1±2.8
All post-embolization volumetric CT scans were performed from 20 days to 30 days (mean
24 days ± 6 days) after PVE. The mean TLVs were 1602 ± 328 cm2 before and 1537 ± 323 cm2 after PVE and showed no significant changes (P < 0.71). The mean absolute FLR volumes were 371 ± 87 cm3 before and 567 ± 142 cm3 after PVE. The mean absolute FLR volume was increased by 52%±32%. The pre-embolization
FLR/TLV ratio was 23.33%± 4.7% and the post-embolization was 37.4%±8.1%, and this
difference was statistically significant (P < 0.0001). The mean increase in the FLR/TLV ratio after PVE was 14.1%± 2.8%.
Biochemical changes after PVE
Mild transient transaminitis was noted in the majority of patients after PVE, which
required no treatment. There was no significant change seen in bilirubin, hemoglobin,
and WBC value after PVE. Similarly, the mean platelet count and the international
normalized ratio (INR), (indicating hepatic failure), measured prior to the procedure,
on day 2 and at 3–4 weeks did not show any significant change (P > 0.05). The laboratory values before and after PVE are summarized in [[Table 3 ]].
Table 3
Change of laboratory parameters before and after PVE
Parameters
Mean (range)
Before PVE
After PVE (2 days)
After PVE (3-4 weeks)
AST (U/L)
48.2 (18.2-404)
68.51 (22.5-512)
50.2 (16.7-466)
ALT (U/L)
46.3 (12.7-388)
69.33 (14.2-566)
54.6 (12-390)
ALP (U/L)
319.04 (81-951)
289.1 1 (66-699)
238.44 (54-530)
Bilirubin
2.9 (0.4-12.7)
2.69 (0.3-10.4)
2.8 (0.6-14.1)
HB
11.68 (7.9-15.7)
11.82 (8.9-15)
11.92 (8.5-15.3)
WBC
9.2 (18.2-5.4)
10.3 (5.7-22.1)
9.8 (5.7-16.5)
Platelet count × 103 /ml
293.44 (607-96)
265.92 (552-81)
272.18 (100-520.22)
INR
1.25 (0.8-2.4)
1.44 (0.7-2.8)
1.34 (0.7-2.8)
Complications of PVE
No patient in this cohort developed post-embolization syndrome or liver failure after
PVE. The median length of hospital stay was 2 days (range 1 day to 16 days). Four
patients experienced mild abdominal pain after PVE, which was managed by administering
intravenous analgesics. Three patients developed mild fever on the next day of the
procedure but was self-limiting and required no treatment. In four patients, minor
non-targeted migration of NBCA into left lobe was noted. This partial non-target embolization
was not symptomatic and did not prevent from sufficient hypertrophy in these patients.
Major complications were noted in two patients out of 28 patients. One patient developed
bile leak after PVE with the formation of biloma along left epigastrium, however,
it subsided after aspiration and percutaneous biliary drainage of the affected segment,
and the patient was discharged after 16 days. One patient developed partial thrombus
in the main portal vein, however, no signs of portal hypertension was seen on clinical
examination and imaging findings. All patients with above-cited complications did
undergo surgery except one owing to extra-hepatic peritoneal metastasis on staging
laparotomy.
Resection rate and outcome
Of the 28 patients who underwent PVE, 18 patients (64.28%) underwent successful hepatectomy
[right hepatectomy (n = 9), modified right hepatectomy (n = 5), and extended right hepatectomy (n = 4)] after 4 to 8 weeks of PVE. However, 10 patients did not undergo resection because
of extrahepatic metastasis detected either on follow-up imaging or staging laparotomy,
and most of these patients (n = 5) had gall bladder cancer as the primary disease. Among the patients who were
operated, one patient developed transient postoperative liver failure on day 5 of
surgery but recovered by day 10. One patient died after 7 days of surgery owing to
severe cholangitis leading to sepsis. One patient having diabetes mellitus and coronary
artery disease developed perihepatic and abdominal collections and ultimately died
after 30 days secondary to sepsis and cardiac failure. Remaining 15 patients did not
show any postoperative complication or any other complication up to 3 months follow-up.
Factors affecting FLR volume [[Table 4 ]]
Clinical parameters including age, sex, underlying liver damage such as chronic liver
disease and previous chemotherapy, and underlying diabetes mellitus were studied in
relation to the mean FLR volume. The patients were grouped below 60 years and above
60 years to study the variation in hypertrophy according to the age. However, both
groups showed a similar rate of FLR hypertrophy. Hypertrophy rate was similar in male
and female. Surprisingly, in our study, even the underlying liver parenchymal damage
(cirrhosis or preoperative chemotherapy) did not significantly affect the enlargement
of FLR. However, patients with diabetes mellitus showed a lower rate of FLR hypertrophy
than non-diabetic patients [statistically significant (P < 0.005)].
Table 4
Factors affecting change in FLR
Clinical Parameters
Future Liver Remnant (FLR) (mean- cm3 )
P *
Pre PVE
Post PVE
FLR hypertrophy (%)
*Statistical difference of increased FLR after PVE was compared between different
groups
Age
<0.72
≤60 years (n = 15)
393±101
585±153
53±29
<60 years (n = 13)
349±62
543±121
51±37
Gender
<0.029
Male (n =22)
380±90
587±139
56±37
Female (n =6)
343±67.4
483±120
46±28
Chronic Liver Disease
<0.04
Cirrhotic (n = 19)
363±73
508±138
46±34
Non cirrhotic (n =9)
374±92
590±191
57±30
Chemotherapy
<0.27
No-chemotherapy (n =23)
382±87
572±111
55±31
Adjuvant Chemotherapy (n =5)
324±68
546±228
49±34
Diabetes Mellitus
<0.005
Non-diabetic (n =22)
350±68
572±137
59±36
Diabetic (n =6)
450±102
549±155
44±31
Discussion
PVE has been proposed to increase the size of the FLR after major hepatectomy, thus
reducing the risks of postoperative liver insufficiency.[[4 ]],[[5 ]],[[6 ]],[[7 ]],[[8 ]],[[9 ]],[[10 ]],[[11 ]],[[12 ]],[[13 ]] Permanent embolization of portal branches is frequently preferred because the liver
after embolization is resected in most cases. Some authors consider NBCA to be the
most effective for PV embolization because it induces proximal and distal PV occlusion
and incites a periportal inflammatory reaction that may also play a role in liver
regeneration stimulation.[[6 ]]
Previous literature showed that NBCA is effective for PVE to induce FLR.[[18 ]],[[19 ]],[[20 ]],[[21 ]] Few previous studies reported that hardening of vein and difficulty in tissue resection
occurred after PVE with NBCA because of its strong inflammatory reaction and subsequent
fibrosis.[[5 ]],[[6 ]],[[22 ]]
Limited literatures have been published for PVE using appropriate dilution of NBCA
for effective FLR hypertrophy and causing no difficulty in resection. Our study shows
that percutaneous transhepatic PVE using NBCA mixed with lipiodol (1:4) is feasible
and safe, along with low morbidity and no mortality. The technical success rate of
PVE in this study was 100%, which is similar to previous studies.[[18 ]],[[21 ]],[[22 ]]
The dilution of the NBCA with lipiodol reported in the literature varies, is often
not clearly quantified, and ranges from 1 ml of NBCA mixed with 1–9 ml of lipiodol.[[11 ]],[[18 ]],[[20 ]],[[21 ]] Optimal NBCA penetration is governed by several factors; however, the three main
variables include a choice of NBCA dilution, portal venous flow, and rate of injection.
In the current study, we used 1: 4 ratio of NBCA with lipiodol resulting delayed polymerization
of NBCA mixture leading to more peripheral embolization. In the present study, minor
non-target NBCA embolization was seen in left lobe in four patients but did not hinder
for effective FLR hypertrophy.
In this study, marked FLR hypertrophy was found after PVE using NBCA with lipiodol
(ratio 1:4). We found a mean increase of FLR 194 ± 64 cm3 in absolute volume and 52% in percentage (statistically significant, P < 0.0001). The increase of FLR/TLV ratio was 14.1 ± 2.8 (statistically significant,
P < 0.0001). Our results showed equivalent efficacy compared to previous large cohort
studies.[[20 ]],[[21 ]],[[22 ]],[[23 ]]
The main principle of PVE is occlusion of ispilateral portal vein to induce hypertrophy
of contralateral lobe of the liver. Several techniques of portal vein occlusion have
been proposed and broadly divided into two main category – surgical (including operative
ligation, trans-ileocolic PVE) and percutaneous (ipsilateral and contralateral PVE).
In comparison to the surgical approach, percutaneous PVE is a minimally invasive method
and preferable. One previous study compared the PVE and surgical portal vein ligation
for FLR hypertrophy and observed a more effective increase in FLR volume and shorter
hospital stay after percutaneous PVE. PVE seems to be more effective than surgical
ligation of portal vein branch by preventing the development of other collateral circulation
to the right lobe of liver because of distal occlusion of the portal vessels.[[24 ]] Moreover, PVE keeps the hilum free of adhesion caused by the hilar dissection required
for ligation and reduced the complication during liver resection.[[10 ]]
In our study, most of the PVE was done through the contralateral approach. The contralateral
approach has several advantages such as easy cannulation of anterior and posterior
right portal branches, absence of sharp angulation, and no risk of tumor seeding.
In current study, a mild transient increase of hepatobiliary enzyme was found after
2 days of PVE. It is reported that aspartate aminotransferase and alanine aminotransferase
reach a peak level at 1–3 days after PVE, usually rising to less than three times
the baseline values. There was no statistically significant change seen in hemoglobin,
platelet counts, INR, and albumin level after PVE in our study. Major complications
were noted in only 2 (7.1%) patients of 28 patients. This result is comparable to
the other previous study.[[18 ]],[[21 ]],[[22 ]],[[23 ]],[[25 ]],[[26 ]] Most of our patients had no fever except three patients following PVE. Partial
main portal vein thrombosis in one patient, bile leak causing biloma in one patient,
and minor non-target embolization in three patients were found in our study. However,
all patients who had complications showed clinical improvement after conservative
treatments and survived, and these did not hinder in surgery. From our study, we experienced
that non-target embolization can be reduced through a slower rate of injection of
NBCA. To reduce the risk of embolic agent migration in the left branches, NBCA was
injected selectively in the segmental branches. With this technique, refluxed embolic
material is less likely to migrate to the left portal branches. Moreover, the contralateral
approach allows better control of glue release starting distally in the right portal
vessels with flow directed embolization leading to less chance of non-target embolization.
Further, from contralateral approach, we can perform a final portography and can be
used as a good tool to measure intra-portal pressure before and after portal vein
embolization if needed. The contralateral approach could, however, induce injury to
the future remnant segments, but in our study, we did not find any such complication.
The primary parameter used to evaluate the efficacy of PVE is the resectability rate
after PVE and post-resection liver insufficiency. The limiting factors in performing
a curative hepatic resection after PVE are the final volume of FLR and the absence
of disease progression. In the current series, the resectability rate was 64.28% (18/28).
This low resectability may be attributable to high rejection of patients with gall
bladder cancer having aggressive behavior with rapid progression (only 4 of 9 making
to surgery). Although the resectability rate appears low, it is similar to previous
literature.[[20 ]],[[21 ]],[[22 ]],[[23 ]] In this study, adequate FLR hypertrophy after PVE was achieved in all patients
before surgery. Only one patient with cirrhosis developed transient liver insufficiency
after extended right hepatectomy for hilar cholangiocarcinoma. Remaining ten patients
(35.72%) did not undergo resection because of extrahepatic metastasis found on follow-up
imaging or peritoneal metastatic deposit seen on preoperative laparotomy. Different
authors have shown that similar observation.[[20 ]],[[23 ]] The previous few literatures demonstrated that differences in age, gender, underlying
liver disease, and diabetes may cause differences in increased FLR hypertrophy.[[6 ]],[[7 ]],[[10 ]],[[27 ]] In the present study, patients of age group <60 years, male gender, patients without
cirrhosis, and those who have not received chemotherapy had better mean FLR hypertrophy
than age group >60 years, female patients, and those with underlying cirrhosis or
receiving chemotherapy. However, these results were not statistically significant
(P > 0.05). Moreover, noteworthy hypertrophy was noted in patients with underlying liver
parenchymal disease as well. However, we found that non-diabetic patient achieved
higher FLR hypertrophy than patients with diabetes mellitus, and it was statistically
significant (P < 0.001). Our study had several limitations. First, it is a retrospective single-center
study. Second, total number of patients in this study is relatively small, which may
limit statistical power. Third, it is not randomized and lacks comparison with other
embolic material. Fourth, as this study is retrospective comparing the different groups,
this could result in selection bias.
Conclusion
In our experience, PVE using NBCA (Glue) mixed with lipiodol (ratio1:4) is safe and
highly effective in inducing future liver remnant hypertrophy in all age group and
even in patients with underlying liver parenchymal disease before right hepatectomy
in the patients with hepatobiliary malignancies. Lesser hypertrophy was noted in patients
with diabetes. A reasonable resectability was achieved despite having a high rejection
in gall bladder cancer subgroup owing to rapid disease progression.
