Formosan Journal of Surgery (2015) 48, 198e202

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ORIGINAL ARTICLE

Gallstone formation after gastrectomy for

adenocarcinoma of the stomach
Chia-Yuan Chang a, Tsung-Yen Cheng a,*, Chen-Fang Hung b,
Ben-Long Yu a, Tzu-Jung Tsai a, Chung-Wei Lin a

a
Department of Surgery, Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan
b
Office of Clinical Research, Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan

Received 28 April 2015; received in revised form 7 July 2015; accepted 17 August 2015
Available online 11 December 2015

KEYWORDS Abstract Background/Introduction: An increased incidence of gallstones after gastrectomy

gallstone; has been reported, but with varying risk factors.
gastrectomy; Purposes/Aims: To delineate the incidence of and risk factors for gallstone formation after
gastric cancer gastrectomy.
Methods: We retrospectively analyzed patients with Stages 0, I, and II adenocarcinoma of the
stomach who had undergone curative gastrectomy with routine lymph node dissection be-
tween August 1996 and November 2010. We reviewed the clinical factors, radiographic presen-
tation of the gallstones, and follow-up records.
Results: We included 215 patients (124 men and 91 women), with a median age of 53 years (range,
16e89 years). Gallstones were observed in 46 patients (21.4%) during follow-up periods of 6 months
e14.5 years. Gallstones were diagnosed at a median of 2.3 years after gastrectomy. The cumula-
tive incidence of gallstones at 5 years and 10 years was 18% and 20%, respectively. Total gastrec-
tomy, Billroth II reconstruction (vs. Billroth I), age  60 years, and diabetes mellitus (multivariate
odds ratios of 3.8, 3.3, 2.7, and 2.6, respectively) were the risk factors for gallstone formation.
Complicated cholelithiasis was identified in seven patients (15.2% of patients with gallstones
and 3.3% of all patients) and was more prevalent in patients who had undergone total gastrectomy
(5 of 14; 35.7%) than in those who had undergone subtotal gastrectomy (2 of 32; 6.2%; p Z 0.02).
Conclusion: The incidence of gallstone formation was 21.4%. Total gastrectomy, Billroth II recon-
struction, age  60 years, and diabetes mellitus were risk factors for gallstone formation. Total
gastrectomy is also a risk factor for complicated gallstone.
Copyright ª 2015, Taiwan Surgical Association. Published by Elsevier Taiwan LLC. All rights
reserved.

Conflicts of interest: The authors declare no conflicts of interest.

* Corresponding author. Department of Surgery, Koo Foundation Sun Yat-Sen Cancer Center, 125 Lih-Der Road, Pei-Tou District, Taipei
11259, Taiwan.
E-mail address: cheng@kfsyscc.org (T.Y. Cheng).

http://dx.doi.org/10.1016/j.fjs.2015.08.005
1682-606X/Copyright ª 2015, Taiwan Surgical Association. Published by Elsevier Taiwan LLC. All rights reserved.
Gallstone formation after gastrectomy
1. Introduction
A cross-sectional study conducted in a rural Taiwanese
village reported a 5.0% prevalence of gallstones, with a
slight propensity for the female sex. Risk factors for gall-
stone disease in both sexes included age and fatty liver. In
females, diabetes mellitus, a history of gallstone disease in
first-degree relatives, and the use of oral contraceptives
were additional risk factors.1 Liu et al2 reported a 5.3%
prevalence of gallstones in a Taiwanese population that had
undergone a paid health examination. In their study, older
age, higher body mass index, and type 2 diabetes mellitus
were associated with an increased prevalence of gallstone
disease.2
A higher incidence of gallstones has been reported in
gastrectomy patients than in the general population.3e8 Wu
et al8 reported cholelithiasis in 30% of patients receiving
radical gastrectomy. The pathophysiology remains unclear,
but the current theories posit that the surgical dissection of
the vagal trunk affects gallbladder contractility and that a
nonphysiological reconstruction of the gastrointestinal
tract, such as duodenal exclusion, results in increased
gallstone formation. The present study evaluated the inci-
dence of gallstone formation after gastrectomy for stomach
cancer and identified risk factors for gallstones.
2. Methods
The medical records of patients who had undergone radical
gastrectomy for gastric adenocarcinoma were reviewed,
and clinical information was retrospectively collected. This
study was approved by the Institutional Review Committee
of Koo Foundation Sun Yat-Sen Cancer Center, Taipei,
Taiwan.
In total, 657 patients had undergone gastrectomy with
lymph node dissection between August 1996 and November
2010 at our cancer institute. Curative resection (R0)
without microscopic or macroscopic residual diseases was
achieved in 503 patients with Stage 0, I, or II cancer
[pathologically staged according to the American Joint
Committee on Cancer (AJCC) Staging Manual, 7th Edition].
Patients with Stage III and IV cancer were excluded owing
to poor survival and early recurrence. Moreover, patients
with previous cholecystectomy or cholecystectomy com-
bined with gastrectomy (n Z 159); gallstones diagnosed
preoperatively or within 6 months of gastrectomy (n Z 29);
previous partial gastrectomy (n Z 7); a history of chole-
cystitis and obstructive jaundice (n Z 3); and insufficient
clinical data, imaging, and follow-up (n Z 57) and those
who underwent reconstruction methods other than Billroth
I, Billroth II, Roux-en-Y, and uncut Roux-en-Y (n Z 33),
were excluded.
In total, 215 patients (124 men and 91 women), with a
median age at operation of 53 years (range, 16e89 years)
were included. Pathological staging according to the sev-
enth edition of the AJCC Manual showed Stages 0, I, and II
for three patients, 142 patients, and 70 patients, respec-
tively. Overall, 180 distal subtotal gastrectomies and 35
total gastrectomies were performed. All patients had un-
dergone lymph node dissections [D1 or more (over D1), 197
patients; D0, 18 patients]. The extent of lymph node
199
dissection was classified according to the Japanese gastric
cancer treatment guidelines 2010 (version 3).9 Lymph node
dissection around the liver hilum was not routinely per-
formed in our patients. Moreover, splenectomy was also not
a routine procedure accompanying total gastrectomy.
Thirty-seven patients received postoperative concurrent
chemoradiation therapy; 24 patients had type 2 diabetes
mellitus.
Gallstones were identified through abdominal ultraso-
nography or abdominal computed tomography. According to
the in-house guidelines, radiographic imaging after radical
gastrectomy for gastric cancer was performed every 6
months for the first 2 years and annually thereafter.
Gallstone-related symptoms and complications include
typical biliary colic, acute cholecystitis, common bile duct
stones with obstructive jaundice, and gallstone pancreatitis.
Clinical factorsdage at gastrectomy, sex, cancer stage,
diabetes mellitus, method of gastrectomy, extent of lymph
node dissection, method of reconstruction, and post-
operative concurrent chemoradiation therapydwere
recorded for analysis.
The cumulative incidence of gallstones after gastrec-
tomy was evaluated using the KaplaneMeier method. Uni-
variate analysis of risk factors for gallstone formation was
performed using the Chi-square and Fisher’s exact tests for
categorical variables and Student t test for numerical var-
iables. Multivariate analysis was performed using a logistic
regression model. A p value < 0.05 was considered statis-
tically significant. Statistical analyses were performed
using SAS software, version 9.3 (SAS Institute, Cary, NC,
USA).
3. Results
Gallstones were detected in 46 of the 215 patients (21.4%)
during a median follow-up period of 3.5 years (range,
0.5e14.5 years). Gallstones were diagnosed at a median of
2.3 years (range, 0.5e11.5 years) after gastrectomy. Half of
the patients with gallstones were diagnosed within 2 years
after surgery, mostly during routine abdominal ultrasonog-
raphy. The incidence of new cases peaked 1e2 years after
gastrectomy and then gradually decreased (Figure 1). The
cumulative incidence of gallstones at 5 years and 10 years
after gastrectomy was 18% and 20%, respectively (Figure 2).
Furthermore, univariate and multivariate analyses revealed
that an age at operation of  60 years, type 2 diabetes
mellitus, total gastrectomy, and Billroth II reconstruction
(vs. Billroth I) were independent risk factors for gallstone
formation (Tables 1 and 2).
Seven patients with complicated gallstones, account-
ing for 3.3% of all gastrectomy patients and 15.2% of pa-
tients with newly diagnosed gallstones, were clinically
diagnosed with acute cholecystitis. Three patients had
undergone cholecystectomy soon after visiting the emer-
gency department of other hospitals, three patients had
undergone urgent operations in our hospital, and one
patient refused surgery. Moreover, three patients had
common bile duct stones with associated bile duct
obstruction and infection. An episode of acute cholecys-
titis occurred at a median of 4.3 years (range, 1.7e6
years) after the initial surgery. This event was more
200 C.Y. Chang et al.

Table 1 Univariate analysis of risk factors for gallstones

after radical gastrectomy.
Variable No. of No. of pts with Ratio p
patients gallstones (%)
Age at
operation (y)
 60 99 31 31.3
< 60 116 15 12.9 0.001
Sex
Male 124 32 25.8
Female 91 14 15.4 0.092
Stage
I&0 145 28 19.3
II 70 18 25.7 0.292
Figure 1 Annual incidence of gallstone after radical gas- Type 2 diabetes
trectomy. The imaging modality (abdominal ultrasound or mellitus
computed tomography) used to detect gallstones was Yes 24 10 33.3
recorded. No 191 36 16.9 0.016
Gastrectomy
Subtotal 180 32 17.8
Total 35 14 40.0 0.006
Lymph node
dissectiona
D0 18 4 22.2
 D1 197 42 21.3 > 0.99
Reconstruction
Billroth I 56 6 10.7
Billroth II 51 16 31.4 0.008
Roux-en-Y 64 16 25.0 0.058
Uncut 44 8 18.2 0.039
Roux-en-Y
Postoperative
CCRT
Yes 37 6 16.2
Figure 2 Cumulative incidence of gallstone formation after
No 178 40 22.5 0.292
radical gastrectomy by using the KaplaneMeier method. The
curve shows a steep increase in the initial years. The cumula- CCRT Z concurrent chemoradiation therapy; pts Z patients.
tive incidence of gallstone formation at 5 years and 10 years
a
D0 Z less than D1; D1 Z perigastric plus left gastric artery
was 18% and 20%, respectively. lymph node dissection.

significant in patients who had undergone total gastrec-

tomy (5 of 14; 35.7%) than in those who had undergone Table 2 Multivariate analysis of risk factors for gallstones
distal subtotal gastrectomy (2 of 32; 6.2%; p Z 0.02). after gastrectomy.
Diabetes mellitus and age at operation were unassociated Variable OR (95% CI) p
with complicated gallstone.
Age at operation  60 y 2.7 (1.3e5.7) 0.005
Diabetes mellitus 2.6 (1.0e6.8) 0.045
4. Discussion Total gastrectomy 3.8 (1.3e10.9) 0.010
Billroth II vs. Billroth I 3.3 (1.1e9.7) 0.026
Our study showed a cumulative incidence of gallstones in CI Z confidence interval; OR Z odds ratio.
21.4% (46 of 215 patients), which is consistent with previous
reports.3e7 A pooled analysis of 16 studies on gallstone
formation after upper gastrointestinal surgery reported an
incidence of 17.5%.3 Moreover, a Peruvian observational Factors associated with gallstone formation after gas-
case series analyzed the frequency and development of trectomy include lymph node dissection, extent of gas-
gallbladder stones after subtotal and total gastrectomy and trectomy, and method of reconstruction. Increased
reported a 19.6% incidence, with a mean development gallstone formation has been observed after radical gas-
period of 3.1 years.4 In this study, the cumulative incidence trectomy compared with that after simple gastrectomy.8,10
of gallstones at 5 years and 10 years after gastrectomy was More extensive lymph node dissection results in higher in-
18% and 20%, respectively, which is consistent with the cidences of gallstone formation.6,7 In our study, almost all
report of Kobayashi et al5 (13.6% and 22.1%, respectively). patients had undergone an over-D1 dissection; therefore,
Gallstone formation after gastrectomy
this difference was not observed. Kobayashi et al5 reported
that the dissection of lymph nodes in the hepatoduodenal
ligament was the most significant risk factor for gallstones.
However, a thorough dissection of the nodes of the hep-
atoduodenal ligament was not routinely performed in our
patients.
Furthermore, Kobayashi et al5 reported that the inci-
dence of gallstones was significantly higher after total
gastrectomy than after partial gastrectomy; our study
presented similar findings (40% vs. 17.8%; odds ratio, 3.8).
Furthermore, an increased incidence of acute cholecystitis
was observed in patients who had undergone total gas-
trectomy compared with those who had undergone distal
subtotal gastrectomy [35.7% (5 of 14 patients) vs. 6.2% (2 of
32 patients); p Z 0.02]. However, the difference between
total gastrectomy and distal gastrectomy was nonsignificant
in the study of Fukagawa et al.7 Gastrectomy as a risk
factor might be affected by the extent of lymph node
dissection.
The reconstruction method applied affects the risk of
gallstone formation. Segawa et al10 and Ikeda et al11 re-
ported no difference between Billroth II and Billroth I
reconstruction in terms of the risk of gallstones. Similarly,
Inokuchi et al12 found no difference between Roux-en-Y and
Billroth I reconstruction after laparoscopic distal gastrec-
tomy. However, Kobayashi et al5 identified duodenal
exclusion as a crucial risk factor for gallstone formation.
Our results showed that Billroth II was associated with an
increased incidence of gallstones compared with Billroth I
(31.4% vs. 10.7%). The differences in the effects of Roux-
en-Y, uncut Roux-en-Y, and Billroth I reconstruction were
nonsignificant.
We observed gallstone formation in half of the analyzed
patients within 2 years of gastrectomy; this incidence
gradually decreased in the following years (Figure 2).
Fukagawa et al7 reported that 64.7% of the detected gall-
stones appeared within 1 year of radical gastrectomy.
A prospective observational study conducted by Inoue
et al13 showed that 42% of 46 patients had gallbladder
sludge formation and significantly decreased gallbladder
contractility 1 month after radical gastrectomy. However,
most sludge disappeared within 12 months, in tandem with
the gradual recovery of gallbladder contractility. Never-
theless, further follow-up revealed that 18.8% of the pa-
tients developed gallstones, mostly at > 6 months after
gastrectomy. Gallbladder stones evolved in only two pa-
tients who had received intravenous hyperalimentation.13
Gallbladder enlargement and suddenly decreased contrac-
tile dysfunction in the early postgastrectomy period is
closely associated with the formation of debris echoge-
nicity in the gallbladder, but it is not presumed to be the
essential factor in the pathogenesis of gallstone forma-
tion.14 In our study, a subgroup analysis of 35 patients
diagnosed with gallstones at > 6 months after gastrectomy
showed that almost all radiographic findings demonstrated
small stones with or without sludge. These stones typically
persisted throughout the follow-up period, and gallstones
could not be visualized later in only one patient.
Gallbladder stones development is considered a multi-
factorial process. The motility of the gallbladder is
controlled by both neural and hormonal interactions, such
as vagal signaling and cholecystokinin (CCK)15; both factors
201
induce gallbladder contraction, and the disruption of either
pathway can potentially cause gallbladder dysfunction. Yi
et al16 conducted an anatomical study of the human gall-
bladder and showed three pathways of nerve innervation of
the gallbladder: through the anterior hepatic plexus, pos-
terior hepatic plexus, and phrenic nerve. In particular, the
preservation of the neural pathway from the anterior he-
patic plexus through the cystic artery and duct is crucial for
maintaining gallbladder innervation.16 Because patients
with total gastrectomy typically undergo the division of
both vagal trunks, vagal signaling would be blocked at the
proximal site.
CCK, a peptide secreted in the duodenum, stimulates the
release of digestive enzymes from the pancreas and bile
from the gallbladder. Masclee et al17 reported significantly
delayed gallbladder emptying after the ingestion of a fatty
meal in patients who had undergone partial gastrectomy
compared with normal patients. Both groups exhibited the
same basal CCK levels, but gastrectomy patients had a lower
CCK peak after oral intake. However, an analysis of CCK
levels an hour after meal ingestion showed that both groups
had comparable CCK levels and gallbladder emptying.17 The
correlation between CCK levels and gallstone formation has
not yet been reported, possibly because of its minor role or
other compensatory mechanisms.
Whether prophylactic cholecystectomy is indicated for
patients with adenocarcinoma of the stomach undergoing
radical gastrectomy remains unclear. Fukagawa et al7
examined 672 patients and reported that 173 (25.7%) pa-
tients developed gallstones after surgery, and only 12 (6.9%
of 173) were symptomatic and required cholecystectomy.
They found that prophylactic cholecystectomy is not
beneficial for most patients, and that only patients with
extensive lymph node dissection should be considered for
prophylactic cholecystectomy. Kobayashi et al5 demon-
strated that most patients with gallstones were asymp-
tomatic after radical gastrectomy, and < 0.5% of the
patients required cholecystectomy. Gillen et al3 reviewed
concurrent cholecystectomy during gastric and esophageal
resection and reported higher calculated additional
morbidity compared with late cholecystectomy. However,
the preliminary report of the CHOLEGAS (Gastrectomy Plus
Prophylactic Cholecystectomy in Gastric Cancer Surgery)
study, a multicenter randomized study examining the
safety of prophylactic cholecystectomy during gastrectomy
for cancer, found no increase in perioperative morbidity,
mortality, and costs.18,19 Cholecystectomy is an uncompli-
cated procedure; the theoretical advantage of prophylactic
cholecystectomy is that it avoids reintervention for chole-
lithiasis.18 In our study, total gastrectomy was a crucial
factor for postoperative gallstone formation and subse-
quent complications. However, most patients do not
benefit from combined cholecystectomy. Prophylactic
cholecystectomy is definitely not indicated in patients with
distal subtotal gastrectomy. Furthermore, the widespread
application of minimally invasive gastrectomy may reduce
the necessity of prophylactic gallbladder removal for pre-
venting future open cholecystectomy. For early gastric
cancer management, procedures for preserving the vagus
nerve may be an alternative.
In summary, the incidence of gallstone formation after
gastrectomy for adenocarcinoma of the stomach was 21.4%.
202
Half of the gallstones were detected within 2 years of
gastrectomy. The cumulative incidence of gallstone for-
mation at 5 years and 10 years after gastrectomy was 18%
and 20%, respectively. Total gastrectomy, Billroth II
reconstruction (vs. Billroth I), age at operation  60 years,
and type 2 diabetes mellitus were the independent risk
factors for gallstone formation. Furthermore, gallstones
observed 6 months after gastrectomy were typically small
and persistent. Only seven patients had acute cholecystitis,
and three had common bile duct stones. Total gastrectomy
may be the most crucial risk factor for complicated
cholelithiasis.
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