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Pediatrics and Neonatology xxx (xxxx) xxx

Available online at www.sciencedirect.com

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Original Article

Choledochal cyst as an important risk factor

for pediatric gallstones in low-incidence
populations: A single-center review
Shu-Chao Weng a,b, Hung-Chang Lee a, Chun-Yan Yeung a,c,
Wai-Tao Chan a,d, Hsi-Che Liu c,e, Chuen-Bin Jiang a,c,*

a
Department of Pediatric Gastroenterology, Hepatology and Nutrition, MacKay Children’s Hospital,
Taipei, Taiwan
b
Department of Pediatrics, Taitung Mackay Memorial Hospital, Taitung County, Taiwan
c
Department of Medicine, Mackay Medical College, Taipei, Taiwan
d
MacKay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan
e
Department of Hematology-Oncology, MacKay Children’s Hospital, Taipei, Taiwan

Received Mar 26, 2020; received in revised form May 15, 2020; accepted Jul 10, 2020
Available online - - -

Key Words Background: Gallstones are uncommon in infants and children and Asian children are thought
cholestasis; to have very low risk. Diagnoses have increased in recent years with the widespread use of ul-
choledochal cyst; trasonography (USG). This study aimed to review our experience with risk factors, complica-
gallstones; tions, and treatment of pediatric gallstones in low-incidence populations.
pediatrics Methods: We retrospectively reviewed patients younger than 18 years old diagnosed with gall-
stones using USG between November 2006 and December 2012 in a tertiary referral hospital in
Taiwan. Demographic information including age and sex, follow-up period, USG findings, pre-
disposing factors, complications, treatment approaches and outcomes were recorded.
Results: Ninety-eight children with gallstones diagnosed with USG were enrolled and reviewed
in our study. Females comprised 55% of patients, with no specific gender tendency. No risk fac-
tor could be identified in 30.8% of patients. The most common risk factors were cephalosporin
(CS) use, presence of a choledochal cyst (CC), and spherocytosis. CS use was not associated
with a higher dissolution rate. The presence of type IVa CC implied a high rate of gallstone
recurrence after Roux-en-Y hepaticojejunostomy. Complications were seen in 22.4% of pa-
tients, but only two needed emergency stone removal. Expectant management was performed
in 61% of patients and 62.5% of them achieved spontaneous resolution; the stone dissolution

Abbreviations: BA, biliary atresia; CC, choledochal cyst; CS, cephalosporin; ERCP, endoscopic retrograde cholangiopancreatography; LC,
laparoscopic cholecystectomy; PN, parenteral nutrition; RYHJ, Roux-en-Y hepaticojejunostomy; UDCA, ursodeoxycholic acid; USG,
ultrasonography.
* Corresponding author. No. 92, Sec. 2, Zhongshan N. Rd., Taipei City 10449, Taiwan. Fax: þ886 2 2543 3642.
E-mail addresses: shuchao@gmail.com (S.-C. Weng), 8231boss@gmail.com (H.-C. Lee), cyyeung1029@gmail.com (C.-Y. Yeung), taody@
mmh.org.tw (W.-T. Chan), hsiche@mmh.org.tw (H.-C. Liu), ped.dr@yahoo.com.tw (C.-B. Jiang).

https://doi.org/10.1016/j.pedneo.2020.07.013
1875-9572/Copyright ª 2020, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-
NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article as: Weng S-C et al., Choledochal cyst as an important risk factor for pediatric gallstones in low-incidence pop-
ulations: A single-center review, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2020.07.013
 + MODEL
2 S.-C. Weng et al

rate was not lower than in the group treated with ursodeoxycholic acid (UDCA). Stone size was
significantly decreased after UDCA use if resolution did not occur.
Conclusions: Pediatric gallstones showed high resolution rate, and the clinical course was
largely benign. CS use was the most common risk factor and did not predict a higher dissolution
rate. Type IVa CC was also an important risk factor associated with a high recurrence rate. Con-
servative treatment and oral UDCA may be reasonable strategies in most patients, unless com-
plications are present.
Copyright ª 2020, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/
by-nc-nd/4.0/).

1. Introduction excluded. Gallstones were defined as highly-reflective

Gallstones are uncommon in infants and children, with a
prevalence of 0.13e0.3%, compared to more prevalent
populations such as older subjects, women, and Native
Americans.1e4 Asian children are thought to have very low
risk. One epidemiologic study conducted in East Asia re-
ported a 0% prevalence of gallstone disease in those aged
less than 19 years.5 Diagnoses have increased in recent
years with the widespread use of ultrasonography (USG).6
Risk factors for gallstones in children including hemolytic
disease, parenteral nutrition (PN), cephalosporin (CS) use,
choledochal malformation, prematurity, sepsis, short
bowel syndrome, cardiac surgery, and genetic factors.7
The reported incidence of complications caused by gall-
stones, such as cholecystitis and obstruction, has a wide
range.8,9
Although the treatment guidelines for adult gallstone
disease are well established,10,11 there are no guidelines for
pediatric gallstone management, and treatment strategies
were largely based on adult experience including use of
oral ursodeoxycholic acid (UDCA), cholecystotomy, and
cholecystectomy.7 In adults, cholecystectomy is preferred
for symptomatic gallbladder stones. Routine treatment was
not recommended for asymptomatic gallbladder stones,
and litholysis using bile acids alone was not recommended,
either.10 For bile duct stones, endoscopic sphincterotomy
and stone extraction is recommended.
Several series on pediatric gallstones from West
Asia,3,9,12e14 North America,1,8 and Europe2,15 have been
published, but few have been reported from East Asia. This
study reviews our single-center experience with clinical
features, risk factors, complications, and treatment of
pediatric gallstones in this population.
2. Methods
2.1. Patients
Institutional Review Board approval for a Clinical Trial was
obtained. We retrospectively reviewed patients younger
than 18 years old diagnosed with gallstones using USG be-
tween November 2006 and December 2012 at MacKay Me-
morial Hospital, a tertiary referral hospital in Taiwan.
Patients with incomplete USG report and image were
echogenic foci within the biliary system and with promi-
nent posterior acoustic shadowing. Records were reviewed
through October 2016.
2.2. Data collection
Demographic information including age, sex, follow-up
period, USG indications and findings, predisposing factors,
complications, treatment approaches and outcomes was
recorded. While puberty is expected to begin after the age
of eight years in girls and nine in boys,16 we set the cut-
point of puberty at nine years old.
USG findings included stone size at diagnosis, largest
stone size, presence of single or multiple stones, and stone
location (gallbladder, extrahepatic or intrahepatic bile
duct). Use and duration of PN were recorded. Short bowel
syndrome was evaluated according to remaining bowel
length and ileocecal valve preservation. Hematologic dis-
eases included spherocytosis and other hemolytic anemias,
thalassemia, leukemia, and sickle cell disease. Use of CS,
furosemide, octreotide, or antiepileptic drugs for any
duration was recorded. History of biliary atresia (BA),
choledochal cyst (CC) (including CC type according to the
classification by Todani et al.),17 Wilson’s disease, Down
syndrome, cardiac surgery, and cystic fibrosis were recor-
ded. Hypertriglyceridemia and hypercholesterolemia were
defined as serum triglyceride and cholesterol over 130 and
190 mg/dL, respectively. Obesity was defined using rec-
ommended body mass index values for children and teen-
agers in Taiwan.18
Treatment strategies included expectant management
(in other words, watchful waiting), use of oral UDCA, open
cholecystectomy, laparoscopic cholecystectomy (LC),
laparoscopic cholecystotomy or choledochoscopy, Roux-en-
Y hepaticojejunostomy (RYHJ), and endoscopic retrograde
cholangiopancreatography (ERCP). Complications included
cholecystitis, cholangitis, and biliary tract obstruction.
Cholecystitis was defined as a positive sonographic Mur-
phy’s sign with either gallbladder wall thickening (>3 mm)
or pericholecystic fluid. Cholangitis was defined as thick-
ening of the walls of the bile ducts on USG when at least
one symptom of the Charcot triad was present. Subgroup
analysis was performed for infants and for risk factors of CS
use and presence of CC.

Please cite this article as: Weng S-C et al., Choledochal cyst as an important risk factor for pediatric gallstones in low-incidence pop-
ulations: A single-center review, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2020.07.013
 + MODEL
Pediatric gallstones 3

2.3. Statistical analysis 3.2. Risk factors (Table 2)

Data analysis was performed using Statistical Package for
Social Sciences (SPSS). Descriptive statistics were used for
the sample. The chi-squared (c2) test was used to compare
categorical variables. Continuous variables were compared
using two-tailed Wilcoxon signed-rank test for paired sam-
ples, and ManneWhitney U test and KruskaleWallis test for
independent samples. P < 0.05 was considered statistically
significant.
3. Results
3.1. Demographic data, USG indications and
findings (Table 1)
During the review period, a total of 29,934 abdominal USGs
were done. In total, 105 patients were identified and seven
were excluded due to missing USG images. The discovery
rate was 0.33% (98/29,934). Of 98 patients, 55 were female
(Fig. 1A). At least one follow-up USG was performed in 83
(84.7%) patients, and the median duration of follow-up was
33 months (range 1e185 months). Thirteen (13.3%) patients
were diagnosed in infancy. There was no specific tendency
for females after puberty compared to pre-pubertal ages
(54.1% vs. 57.3%, P Z 0.11).
Forty-five patients underwent abdominal USG for one or
more of the following symptoms and signs: abdominal pain,
emesis, jaundice, fever, irritability, acholic stool, and
weight loss. Among asymptomatic patients, nine each
received USG for CC follow-up or acute enterocolitis; seven
for BA follow-up; six for fever work-up; five for a hemo-
globinopathy follow-up program; four after intestinal sur-
gery; three each for liver tumor, non-liver tumor, or chronic
liver disease; and two for bile duct dilatation follow-up,
one for an obesity survey, and one for acalculous chole-
cystitis after cholecystectomy.
Stones were most commonly found in the gallbladder
(n Z 64), followed by extrahepatic and intrahepatic ducts
(n Z 27 and 13, respectively). The largest stone size at
diagnosis ranged from 0.1 to 3.1 cm (median 0.7 cm).
Of the 98 patients enrolled, thirty patients had no identi-
fiable risk factors. Six patients had three or more risk fac-
tors and all six patients had history of CSs usage; of the six
patients, four also had dyslipidemia, two used PN for more
than four months, two had CC, one had BA, and one had
leukemia. Those with three or more risk factors had a
younger median age (0.8 years) than those with two or
fewer risk factors (P Z 0.007; P Z 0.001, 0.016, and 0.02
when comparing patients with zero, one, or two risk factors
to patients with three or more risk factors, respectively).
The most prevalent risk factors were CS use, CC, and
spherocytosis. Fig. 1B shows the association of risk factors
with the number of stones. Patients with CC or obesity had
higher prevalence of multiple stones. Analysis of the five
most prevalent risk factors showed that patients with
spherocytosis were older (median, 10.1 years) and those
using CS were younger (median, 2.5 years) (P Z 0.019).
There was no history of sickle cell disease, octreotide or
antiepileptic use, Wilson’s disease, Down syndrome, car-
diac surgery, or cystic fibrosis in our series.
3.3. Complications
Complications were observed in 22 (22.4%) patients,
including 15 at diagnosis, four at follow-up, and three at
both diagnosis and follow-up. Cholecystitis was the most
common complication (n Z 16; one also had cholangitis and
one had concurrent cholangitis and obstruction). Isolated
cholangitis was seen in three patients, while obstruction
alone was seen in two patients. The development of com-
plications was not related to the presence of risk factors or
stone size at diagnosis (P Z 0.98 and 0.35, respectively).
Only two patients needed emergency stone removal due to
biliary obstruction.
3.4. Treatment
Of the 98 patients, 38 (38.8%) were treated and others were
managed expectantly. Open cholecystectomy was per-
formed in one patient who underwent splenectomy for Hb
Perth hemoglobinopathy. LC was performed in six patients,
including three who underwent splenectomy for

Table 1 Demographic data, complication and spontaneous resolution rates.

Group Total (N Z 98) Female (N Z 55) Male (N Z 43) Infant (N Z 13)
% of total 100 56.1 43.9 13.3
Median agea (range) 6.2 (0e17.4) 6.4 (0e17.4) 5.9 (0e17.2) 0.4 (0e0.8)
Follow-up patients, n (% of group) 83 (87.4) 47 (85.5) 36 (83.7) 10 (76.9)
Median follow-up durationb (range) 33 (1e185) 33 (1e185) 32.5 (1e151) 40.5 (1e103)
Patients developed complication N (% of group) 22 (22.4) 10 (18.2) 12 (27.9) 0
Agea, median (range) 8.7 (1.0e17.2) 8.7 (1.6e17.2) 9.0 (1.0e15.8) N/A
Patients achieved spontaneous N (% of group) 30 (30.6) 18 (38.3) 12 (27.9) 4 (40)
resolution Agea, median (range) 6.0 (0.1e17.4) 6.2 (0.8e17.4) 5.5 (0.1e14.3) 0.5 (0.1e0.8)
N/A, not applicable.
a
Years.
b
Months.

Please cite this article as: Weng S-C et al., Choledochal cyst as an important risk factor for pediatric gallstones in low-incidence pop-
ulations: A single-center review, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2020.07.013
 + MODEL
4 S.-C. Weng et al

A 9

Number of pa ents
6

0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Age (years)

male female

BA 18
16
Number of pa ents

14
12
10
8
6
4
2
0

Risk factor

Single stone Mul ple stones

Figure 1 (A) Age and sex distribution of children with gallstones. (B) The association of risk factors with the number of stones.
The total patient number was greater than 98 because some patients had more than 1 risk factor. BA, biliary atresia; CC, chol-
edochal cyst; CS, cephalosporin; TPN, total parenteral nutrition; SBS, short bowel syndrome.

hemoglobinopathies. Three patients underwent laparo-
scopic cholecystotomy and choledochoscopy. RYHJ was
performed in 13 patents with CC. Three ERCPs were
performed.
Eighteen patients treated with UDCA and 48 patients
managed expectantly were followed (Table 3). The stone
dissolution rate in the UDCA group was not higher than in
the group managed expectantly. Within the UDCA group,
patients with stone dissolution had smaller stone size. In
those whose stones did not resolve, the median stone size
decreased by 1.1 cm (P Z 0.043).
3.5. Subgroup analysis
3.5.1. Infants (Tables 1 and 2)
Thirteen (13.3%) infants were found in our series. The
presence of risk factors was not statistically different be-
tween infants and those aged one year or older (P Z 0.48).
Ten of 13 were followed for a median duration of
40.5 months. Stone dissolution was seen in 90% and no
complications developed.
Use of CS (38.5%) and PN (30.8%) were the most frequent
risk factors in infants. Among infants with an uncommon
history, one had Ehlers-Danlos syndrome, one had an
omphalocele, and one was born at 26 weeks of gestation
weight 800 g.
3.5.2. Cephalosporin use
CS use was identified in 24 patients and was the most
common risk factor. More than half (n Z 13) of them had no
other risk factors. The median duration of CS use was five
days. Ceftriaxone, cefuroxime, and cefotaxime were the
most commonly used CSs (n Z 23, 12, and 9).
In comparison to the 13 patients having CS use as the
only risk factor, the 38 patients with a single risk factor
other than CS use showed no difference in stone size

Please cite this article as: Weng S-C et al., Choledochal cyst as an important risk factor for pediatric gallstones in low-incidence pop-
ulations: A single-center review, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2020.07.013
 + MODEL
Pediatric gallstones 5

Table 2 Number of risk factor and specific risk factors in relation to age and gender.
Group Total (N Z 98) Female (N Z 55) Male (N Z 43) Infant (N Z 13)
Number of risk factors Patient number (% of group)
Median age in years (range)
No risk factor 30 (30.8) 16 (29.1) 15 (34.9) 3 (23.1)
8.9 (0.3e17.4) 8.7 (0.3e17.4) 9.1 (0.3e16.8) 0.3 (0.3e0.8)
1 risk factor 51 (52.0) 32 (58.2) 19 (44.2) 5 (38.5)
5.2 (0e17.2) 5.4 (0e17.2) 4.9 (0.2e17.2) 0.2 (0e0.8)
2 risk factors 11 (11.2) 6 (10.9) 5 (11.6) 2 (15.4)
6.3 (0.4e16.8) 4.1 (0.4e16.8) 10.3 (4.7e12.4) 0.6 (0.4e0.8)
3 risk factors 4 (4.1) 2 (3.6) 2 (4.7) 2 (15.4)
0.8 (0.1e2.6) 1.5 (0.5e2.6) 0.5 (0.1e1.0) 0.3 (0.1e0.5)
4 risk factors 2 (2.0) 0 2 (4.7) 1 (7.7)
2.8 (0.4e5.2) N/A 2.8 (0.4e5.2) 0.4
At least 1 risk factor 68 (69.4) 39 (70.9) 28 (65.1) 10 (76.9)
4.9 (0e17.2) 4.9 (0e17.2) 4.8 (0.1e17.2) 0.4 (0e0.8)
Specific risk factor
Cephalosporin 24 (24.5) 12 (21.8) 12 (27.9) 5 (38.5)
2.5 (0.1e11.1) 2.1 (0.5e8.3) 3.5 (0.1e11.1) 0.5 (0.1e0.8)
Choledochal cyst 20 (20.4) 18 (32.7) 2 (4.7) 2 (15.4)
2.9 (0e16.5) 2.8 (0e16.5) 8.4 (5.2e11.6) 0 (0e0.1)
Spherocytosis 8 (8.2) 3 (5.5) 5 (11.6) 0
10.1 (4.7e15.8) 10.0 (8.6e15.6) 10.3 (4.7e15.8) N/A
Biliary atresia 7 (7.1) 3 (5.5) 4 (9.3) 1 (7.7)
5.2 (0.5e11.1) 6.3 (0.5e10.2) 4.0 (1.3e11.1) 0.5
Hypertriglyceridemia (>130 mg/dL) 7 (7.1) 3 (5.5) 4 (9.3) 2 (15.4)
2.6 (0.4e12.8) 2.6 (0.4e12.8) 3.1 (0.4e12.4) 0.4 (0.4e0.4)
Hypercholesterolemia (>190 mg/dL) 6 (6.1) 4 (7.3) 2 (4.7) 1 (7.7)
11.8 (0.4e16.8) 14.3 (10.8e16.8) 2.8 (0.4e5.2) 0.4
Total parenteral nutrition 5 (5.1) 1 (1.8) 4 (9.3) 4 (30.8)
0.4 (0.1e4.7) 0.4 0.3 (0.1e4.7) 0.3 (0.1e0.4)
Leukemia 4 (4.1) 1 (1.8) 3 (7.0) 1 (7.7)
1.3 (0.8e15.8) 0.8 1.6 (1.0e15.8) 0.8
Obesity 4 (4.1) 1 (1.8) 3 (7.0) 0
10.0 (4.7e16.8) 16.8 9.8 (4.7e10.3) N/A
Thalassemia 3 (3.1) 1 (1.8) 2 (4.7) 0
17.1 (15.2e17.2) 15.2 17.1 (17.1e17.2) N/A
Other hemolytic anemia 2 (2.0) 2 (3.6) 0 0
(Hb-Perth hemoglobinopathy and suspected 11.0 (4.9e17.2) 11.0 (4.9e17.2) N/A N/A
congenital dyserythropoietic anemia)
Furosemide 2 (2.0) 1 (1.8) 1 (2.3) 2 (15.4)
0.5 (0.5e0.6) 0.5 0.6 0.5 (0.5e0.6)
Short bowel syndrome 1 (1.0) 0 1 (2.3) 1 (7.7)
0.1 N/A 0.1 0.1
N/A, not applicable.

(median 1.0 vs. 0.9 cm, P Z 0.86) or stone dissolution rate
(90.0% vs. 74.3%, P Z 0.29).
3.5.3. Choledochal cyst
CC was the second most common risk factor in our cohort. Of
20 patients with CC, 19 were followed for a median duration
of 55 months (range 1e151 months). Thirteen patients (one
was lost to follow-up) had gallstones before RYHJ, with no
postoperative recurrence. Six patients had postoperative
gallstones, and one did not undergo surgery. Further analysis
of the 12 patients with stone resolution after RYHJ showed
that 10 had type I CC with stones in the lesion only, one had
type I CC and stones in both the lesion and gallbladder, and
one had type IVa CC and stone in an extrahepatic cyst.
Among the six patients with gallstone formation after RYHJ,
three had type IVa CC, one had type I CC, and two had no
type recorded. All postoperative recurrent gallstones were
in the intrahepatic duct. The CC type, postoperative
recurrence rates, and stone sites are shown in Fig. 2.
4. Discussion
Most series on pediatric gallstones focused on specific risk
factors. Some cohorts underwent extensive review for

Please cite this article as: Weng S-C et al., Choledochal cyst as an important risk factor for pediatric gallstones in low-incidence pop-
ulations: A single-center review, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2020.07.013
 + MODEL
6 S.-C. Weng et al

statistically older than boys at diagnosis, in contrast to the

Table 3 Comparison between (A) patients who received
results from three other studies.3,9,13 Female patients were
ursodeoxycholic acid (UDCA) or were treated expectantly,
slightly more common than males in our cohort, with a sex
and (B) those with or without stone dissolution after UDCA
ratio consistent with that in previous studies.2,3,12,13 Mur-
use. (A) The dissolution rate with UDCA was not higher than
phy et al. reported a significant increase in the incidence of
the rate with expectant treatment. The patient age, largest
pediatric cholecystectomy in the past 20 years, with 15.6%
stone size, and follow-up duration showed no statistical
performed for cholelithiasis.19 A significant female pre-
difference between these 2 groups. Two out of 20 patients
dominant trend was demonstrated in those aged 12 years or
in the UDCA group and 12 out of 60 patients in the expec-
older. The evolving obesity epidemic and prescription of
tant group lost follow-up, and only patients with follow-up
oral contraceptives leading to high estrogen levels were
are included in this table. (B) Within the UDCA group, pa-
thought to play a role. Khoo et al. reported that 74.2% of
tients with stone dissolution had smaller stone size.
2808 cholecystectomies were performed in girls, with me-
(A) UDCA Expectant P dian age at surgery of 15 years.20 The incidence of chole-
follow-up cystectomy in both males and females was comparable
Patient number 18 48 until the age of 10, and it was dramatically higher in girls
Age (median, years) 5.8 6.2 0.65a thereafter. Hormonal changes of puberty affecting gall-
Largest stone size 1.0 0.8 0.40a bladder motility were postulated as contributory. However,
(median, cm) we failed to replicate these results, possibly due to the
Follow-up duration 52 24.5 0.15a small number of patients aged not less than nine years in
(median, months) our cohort (20 girls and 17 boys).
Dissolution rate (%) 61.1 62.5 0.92b In previous studies, 23.2e56.6% of patients with gall-
stones had no identifiable risk factors, comparable to the
(B) UDCA, UDCA, not P
results in our study.1e3,8,9,12e15 Only six patients had three
dissolved dissolved
or more risk factors. These patients were significantly
Patient number 11 7 younger and had complicated clinical conditions.
Age (median, years) 4.9 10.1 0.22a Use of CS, especially ceftriaxone, is a well-documented
Largest stone size 0.5 2.1 0.005a,c cause of gallstones or pseudolithiasis. Ceftriaxone, an anion,
(median, cm) is rapidly excreted into bile and the concentration is 20e150
Follow-up duration 33 81 0.59a times higher in bile than in serum. A calcium-ceftriaxone salt
(median, months) precipitates when the solubility product is exceeded.21
a
KruskaleWallis test. Although ceftriaxone causes biliary pseudolithiasis due to
b
Chi-square. its natural tendency for spontaneous dissolution and cannot
c
Statistically different. be considered a classic type of gallstone disease, many
studies have included its use as an important risk fac-
tor.1,3,12,13 A prospective study of 73 pediatric patients
concluded that pseudolithiasis associated with ceftriaxone
predisposing factors, clinical presentations, complications, occurred in 40% of recipients, with a trend toward self-
and outcomes, but few were conducted in East resolution, although about 20% had symptoms.22 In two co-
Asia.1e3,8,9,12e15 Thus, we performed this single-center re- horts, 20e27.3% of patients with gallstones or pseudolithiasis
view to provide a clinical picture of pediatric gallstones in had used ceftriaxone, the most commonly associated risk
this population. factor.3,14 We found that many patients with CS use devel-
The median age at gallstone diagnosis of our patient was oped pseudolithiasis within the gallbladder but they were
slightly lower than the average age in other articles, which not enrolled in this study. We found that about a quarter of
ranged from 6.6 to 10.5 years.1e3,9,12e15 Girls were not our study population who met the USG criteria of gallstones
had used CS. The dissolution rate was not significantly higher
in patients who have CS use as the only risk factor than in
those with other single risk factors. Our result may have
contradicted the impression that ceftriaxone-induced stones
tend to resolve easily because we excluded pseudolithiasis.
CC affected 20 patients in our study and it was the
second most common risk factor. Lee et al. reviewed 100
patients with CC diagnosed at age one year or older and
reported that five developed intrahepatic stones after
surgery.23 Bile flow stasis is a determining factor in gall-
stone formation. Poor gallbladder contractility and biliary
stasis observed during PN, rapid weight loss, and diabetes
have been linked to increased cholesterol gallstone for-
mation.7 Abnormal dilatation of the biliary tree seen in CC
can also cause biliary stasis. Of 12 type I CC cases, 10
Figure 2 Stone type, postoperative recurrence, and stone formed gallstones within the dilated extrahepatic bile duct
sites in 20 patients with choledochal cysts. EHD, extrahepatic and 11 were free from gallstones after RYHJ, indicating
duct; GB, gallbladder; RYHJ, Roux-en-Y hepaticojejunostomy. that unobstructed bile flow is crucial for gallstone

Please cite this article as: Weng S-C et al., Choledochal cyst as an important risk factor for pediatric gallstones in low-incidence pop-
ulations: A single-center review, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2020.07.013
 + MODEL
Pediatric gallstones
prevention. In contrast, three out of four type IVa CC cases
had gallstone recurrence after RYHJ. RYHJ is the standard
surgery for extrahepatic cysts, but it does not treat intra-
hepatic cysts. Liver transplantation may be the only way to
overcome gallstone recurrence in type IVa CC.
Hemolytic anemia was found in 13.3% of our cohort,
which was comparable to that in other studies.3,13,14 The
absence of patients with sickle cell disease reflected the
extremely low prevalence in our study population. The
average age at which patients with spherocytosis devel-
oped gallstones was 10.1 years, a median age older than
that associated with other common risk factors. The
average age at which thalassemia patients developed gall-
stones was even older (17.1 years). This finding may be
useful in the timing of USG screening in these patients.
The complication rate in our patients was 22.4%, with
68.2% of complications found at diagnosis. One study re-
ported idiopathic gallstones in 48 of 105 patients aged two
years or older, among whom up to 50% developed compli-
cations.8 Other authors reported a complication rate of
7.1e27.7%, indicating that the clinical course of pediatric
gallstones is rather benign.1,3,9,13,24
Based on the physicians’ clinical judgement and pref-
erence, less than 40% of the patients in our cohort were
actively treated. There was no obvious benefit when
comparing UDCA and expectant treatment, although UDCA
may have a role in gallstone size reduction. UDCA reduces
biliary cholesterol saturation by 40%e60% and decreases
bile acid toxicity to cell membranes.25 None of our patients
with hemoglobinopathies were successfully treated with
UDCA, reflecting the resistance of black pigment stones to
UDCA.12 Our findings did not help to clarify whether UDCA
was useful for gallstone dissolution, but UDCA may still be
worth prescribing, especially when the gallstone is not
hemolysis-induced.3,9,13e15 ERCP with sphincterotomy has
also been considered safe in the management of pediatric
bile duct stones, even in infants as young as 1 month
old.26,27 Due to a small number of surgical and ERCP cases,
we are unable to make any comments.
The incidence of pediatric gallstones first peaks in in-
fancy, and even prenatal gallstones have been reported.1,28
Some differences were found in the clinical presentation of
infantile gallstones. Risk factors were not more prevalent in
infants, but use of PN was prominent in this age group. No
complications were found and 90% of infants showed reso-
lution without surgical or endoscopic treatment. Infantile
gallstones appear to be self-limited, and aggressive ap-
proaches are not warranted in asymptomatic infants.1,29
The greatest strength of our work was that it provided a
broad review of an uncommon disease in low-incidence
populations, but there were limitations. First, as a retro-
spective, cross-sectional study, missing clinical data can
affect the results, and the heterogeneous population made
statistical inference difficult. Second, this study was done
in a tertiary referral center specializing in pediatric hep-
atology, hematology, neonatology, and surgery, and selec-
tion bias associated with a non-normally distributed base
population is expected. For example, although CC is more
prevalent among Asian population,30 it is still uncommon,
and evaluation of a large unselected sample would be
useful. Third, no data on gallstone composition was avail-
able in our study, even in patients who underwent surgery.
Please cite this article as: Weng S-C et al., Choledochal cyst as an important risk factor for pediatric gallstones in low-incidence pop-
ulations: A single-center review, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2020.07.013
7
Last, the small sample size in this low-prevalence popula-
tion may not be large enough to represent the actual
situation.
5. Conclusion
Pediatric gallstones showed high resolution rate and the
clinical course was largely benign, especially in infants. CS
use was the most common risk factor and did not predict a
higher dissolution rate. The presence of CC was also an
important risk factor, especially with regard to the high
recurrence rate in type IVa CC. Conservative treatment and
oral UDCA may be reasonable strategies in most patients,
except in those who develop complications.
Declaration of competing interest
The authors declare that they have no conflict of interest.
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