Seema Mehta, Monica E. Lopez, Bruno P. Chumpitazi, Mark V.... Brandt and Douglas S. Fishman Disease

Seema Mehta, Monica E. Lopez, Bruno P. Chumpitazi, Mark V.... Brandt and Douglas S. Fishman Disease

Clinical Characteristics and Risk Factors for Symptomatic Pediatric Gallbladder
Disease
Seema Mehta, Monica E. Lopez, Bruno P. Chumpitazi, Mark V. Mazziotti, Mary L.
Brandt and Douglas S. Fishman
Pediatrics 2012;129;e82; originally published online December 12, 2011;
DOI: 10.1542/peds.2011-0579
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/129/1/e82.full.html
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
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Clinical Characteristics and Risk Factors for
Symptomatic Pediatric Gallbladder Disease
WHAT’S KNOWN ON THIS SUBJECT: Gallbladder disease in
children is an evolving entity and studies suggest an increasing
frequency of symptomatic pediatric gallbladder disease and
resultant cholecystectomies.
WHAT THIS STUDY ADDS: Hispanic ethnicity and obesity are
epidemiologically significant risk factors for symptomatic
gallbladder disease in the pediatric population.
AUTHORS: Seema Mehta, MD,a Monica E. Lopez, MD,b
Bruno P. Chumpitazi, MD,a Mark V. Mazziotti, MD,b
Mary L. Brandt, MD,b and Douglas S. Fishman, MDa
aDepartment of Pediatrics, Baylor College of Medicine, Section of
Gastroenterology, Hepatology, and Nutrition, Texas Children’s
Hospital, Houston, Texas; bMichael E. DeBakey Department of
Surgery, Baylor College of Medicine; Division of Pediatric Surgery,
Texas Children’s Hospital, Houston, Texas
KEY WORDS
children, cholecystectomy, gallbladder, Hispanic, obesity
ABBREVIATIONS
ERCP—endoscopic retrograde cholangiopancreatography
HIDA—hepatobiliary iminodiacetic acid
IOC—intraoperative cholangiogram
TCH—Texas Children’s Hospital
abstract
OBJECTIVE: Our center previously reported its experience with pediatric gallbladder disease and cholecystectomies from 1980 to 1996. We
aimed to determine the current clinical characteristics and risk factors for symptomatic pediatric gallbladder disease and cholecystectomies and compare these findings with our historical series.
STUDY DESIGN: Retrospective, cross-sectional study of children, 0 to 18
years of age, who underwent a cholecystectomy from January 2005 to
October 2008.
RESULTS: We evaluated 404 patients: 73% girls; 39% Hispanic and 35%
white. The mean age was 13.10 6 0.91 years. The primary indications
for surgery in patients 3 years or older were symptomatic cholelithiasis (53%), obstructive disease (28%), and biliary dyskinesia (16%).
The median BMI percentile was 89%; 39% were classified as obese. Of
the patients with nonhemolytic gallstone disease, 35% were obese and
18% were severely obese; BMI percentile was 99% or higher. Gallstone
disease was associated with hemolytic disease in 23% (73/324) of patients
and with obesity in 39% (126/324). Logistic regression demonstrated older
age (P = .019) and Hispanic ethnicity (P , .0001) as independent risk
factors for nonhemolytic gallstone disease. Compared with our historical
series, children undergoing cholecystectomy are more likely to be
Hispanic (P = .003) and severely obese (P , .0279).
All authors contributed extensively to this study. Drs Mehta,
Lopez, Brandt, and Fishman conceived and designed the study.
Drs Mehta, Lopez, and Fishman acquired the data. Drs Mehta,
Chumpitazi, and Fishman analyzed and interpreted the data. Drs
Mehta, Brandt, and Fishman drafted the manuscript. All authors
contributed to critical revisions of the manuscript and gave final
approval of the version to be published.
www.pediatrics.org/cgi/doi/10.1542/peds.2011-0579
doi:10.1542/peds.2011-0579
Accepted for publication Sep 9, 2011
Address correspondence to Seema Mehta, MD, 6621 Fannin
Street, CC1010.02, Houston, TX 77030. E-mail: [email protected]
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2012 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have
no financial relationships relevant to this article to disclose.
CONCLUSION: Obesity and Hispanic ethnicity are strongly correlated
with symptomatic pediatric gallbladder disease. In comparison with
our historical series, hemolytic disease is no longer the predominant
risk factor for symptomatic gallstone disease in children. Pediatrics
2012;129:e82–e88
e82
MEHTA et al
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ARTICLE
Gallbladder disease in children is
evolving and studies suggest an everincreasing frequency of gallbladder
disease and resultant cholecystectomies in children.1–8 In 1959, the prevalence of cholelithiasis in children
younger than 16 years was noted to be
0.15%.9 Since that time, the prevalence
has increased with estimates ranging
from 1.9% to 4.0%.3–6 The number of
cholecystectomies has increased accordingly. At our own institution, 36 cholecystectomies were performed from
1960 to 1980, and 128 were performed
over the next 17 years (1980–1997).1,10
We hypothesize that the epidemiologic
risk factors for pediatric gallbladder
disease now resemble those seen in
adults (eg, female gender, race, and
obesity).19,25–28 In this retrospective
series of consecutive children undergoing cholecystectomy, we aimed to
identify the clinical characteristics and
risk factors for pediatric gallbladder
disease resulting in cholecystectomy
and to compare current demographics
and indications for surgery with our
historical series.1
Cholelithiasis in infancy is typically related to prematurity, total parenteral
nutrition use, abdominal surgery, or
sepsis.2,11–13 During adolescence, previous reports identified hemolytic disease as the most common associated
comorbidity. More recent data suggest that gallbladder disease related
to nonhemolytic risk factors, including
pregnancy, oral contraceptive use, and
obesity, is on the rise.1,2,14–16
The Texas Children’s Hospital (TCH) pathology database was used to identify
all patients, 0 to 18 years of age, who
underwent a cholecystectomy from
January 2005 through October 2008. All
patients who underwent an incidental
cholecystectomy secondary to liver
transplantation or hepatobiliary surgery (eg, Kasai portoenterostomy) were
excluded.
The change in etiology of gallbladder
disease is temporally related to the
well-documented rise in childhood
obesity. The NHANES data from 2003 to
2004 revealed the prevalence of childhood obesity in the United States to be
17.1%, compared with 13.9% from 1999
to 2000.17 In addition, the prevalence of
severe obesity, BMI percentile of 99%
or higher, increased by more than
300%: 0.8% from 1976 to 2000 to 3.8%
from 1999 to 2004.18 Severe obesity was
noted to be the highest among African
American and Hispanic individuals.18
The relationship between obesity and
gallbladder disease is well recognized in
the adult population.19,20 Obesity has
previously been described as a rare risk
factor for gallbladder disease in children; however, as a result of the obesity
epidemic, obesity-related comorbidities,
including gallbladder disease, are increasingly affecting the pediatric population.1,2,13,14,21–24
METHODS
The medical records of study patients
were examined for demographics (age,
gender, race/ethnicity), anthropomorphic measurements (weight, height),
comorbidities, primary and secondary
indications for cholecystectomy, findings on imaging studies (hepatobiliary
iminodiacetic acid [HIDA] scan, abdominal ultrasound, magnetic resonance
cholangiopancreatography) and/or
endoscopic retrograde cholangiopancreatography (ERCP), and histopathology. Patients were identified as
having a primary indication of complicated obstructive disease if they were
diagnosed with gallstone pancreatitis,
jaundice, choledocholithiasis, or found
to have dilation of the common bile duct
on an imaging study. This study was
conducted after approval from the
Baylor College of Medicine Institutional
Review Board.
BMI (kg/m2), Z-scores, and BMI percentiles were calculated using the
Baylor College of Medicine Children’s
Nutrition and Research Center computerized calculator, which is based
on the Centers for Disease Control
and Prevention’s standardized charts
(http://www.bcm.edu/cnrc/bodycomp/
bmiz2.html). BMI percentiles were categorized as follows: lower than 85%,
normal weight; 85% to 94.9%, overweight; 95% to 98.9%, obese; and 99%
or higher, severely obese.
SPSS 17.0 (Chicago, IL) was used for all
statistical analyses. Comparison of
categorical values between groups was
done via x 2 analyses. Comparison of
continuous variables between groups
was completed with Mann-Whitney
U analysis. Binary multivariate logistic
regression analysis with presence or
absence of gallstone disease as the
dependent variable was completed. A
P value # .05 was used to indicate
statistical significance. Z-scores were
used for all statistical analyses of BMI.
BMI was not calculated for patients
younger than 3 years because only a
length was available for these patients,
not a height; therefore, these patients
were excluded from BMI analyses.29
Hemolytic disease is a well-described,
strong independent risk factor for
cholelithiasis; therefore, patients with
hemolytic disease (sickle cell anemia,
hereditary spherocytosis, hemoglobin
H disease, autoimmune hemolytic anemia, congenital dyserythropoietic anemia) were excluded when assessing the
impact of other potential risk factors,
age, gender, BMI, and race, on gallstone
formation.30–33
RESULTS
Patient Population
A total of 455 cholecystectomies were
completed at TCH from January 2005 to
October 2008. Of these, 404 patients met
inclusion criteria (Fig 1). Demographic
data for these patients are shown in
Table 1. The BMI distribution of all
patients $3 years of age was as follows:
45% (n = 174) were considered to be
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e83
TABLE 2 Primary Comorbidities
Hemolytic disease
Obesity
Post partum
Malignancy
Polycystic ovary syndrome
Thyroid disease
Cardiac disease
Diabetes
Prematurity
Hyperlipidemia
Cystic fibrosis
Gilbert disease
Others
None
FIGURE 1
Excluded patients.
TABLE 1 Demographics
Age, y
Range
Mean
Median
Age categories, n (%)
13–18 y
8–12 y
3–7 y
Younger than 3 y
Gender
Males, n (%)
Females, n (%)
Male:Female
Race/Ethnicity, n (%)
Hispanic
White
African American
Other
Unknown
0.6–18.0
13
14
271 (67)
88 (22)
38 (9)
7 (2)
111 (27)
293 (73)
1.0:2.6
144 (39)
126 (35)
90 (25)
5 (1)
39 (10)
a normal weight, 16% (n = 63) were
overweight, 24% (n = 94) were obese,
and 15% (n = 57) were severely obese.
The median BMI percentile was 89%.
Of the patients with a BMI percentile
$95%, 52% (n = 79) were Hispanic. A
height or weight was unavailable for
9 patients; therefore, these patients
were excluded from all BMI analyses.
(n = 2). A primary indication was not
identified for one patient. For those
patients younger than 3 years, symptomatic cholelithiasis (n = 5, 71%) and
complicated obstructive disease (n = 2,
29%) were the primary indications for
surgery. Gallstones were identified on
gross pathology or imaging in 80%
(324/404) of patients. None of the patients with biliary dyskinesia (n = 64)
or gallbladder polyps (n = 3) had evidence of gallstones.
Patients with complicated obstructive
disease (n = 112) presented with one or
a combination of the following: choledocholithiasis (n = 43), gallstone pancreatitis (n = 42), jaundice (n = 16), and
dilation of the common bile duct (n = 64).
More than one-third of patients with
complicated obstructive disease (n = 42;
38%) presented with a combination of
obstructive findings.
Associated comorbidities were identified for 189 (47%) of 404 patients. These
are listed in Table 2. A positive family
history of cholelithiasis was reported
for only 9 patients.
Indications
The primary indications for cholecystectomy in patients $3 years of age
were symptomatic cholelithiasis (n =
211; 53%), complicated obstructive
disease (n = 112; 28%), and biliary
dyskinesia (n = 64; 16%). Other indications included acalculous cholecystitis (n = 4), gallbladder polyps (n = 3),
and persistent right upper quadrant
abdominal pain of unknown etiology
e84
Gallstone Disease: Risk Factors
Of the 76 children with hemolytic disease, 73 (96%) were diagnosed with
gallstone disease. Nonhemolytic gallstone disease occurred in 77% (251/
324) of patients. The age distribution
of patients with nonhemolytic gallstone
disease was as follows: 76% (n = 192)
were 13 to 18 years old, 16% (n = 39)
were 8 to 12 years old, 5% (n = 13) were
76 (19%)
18 (4%)
14 (3%)
9 (2%)
6 (2%)
5 (2%)
7 (1.5%)
5 (1%)
4 (1%)
4 (1%)
2 (0.5%)
1 (0.2%)
38 (9%)
216
3 to 7 years old, and 3% (n = 7) were
younger than 3 years. Most of the
patients (76%, n = 190) were girls.
For patients $3 years old with nonhemolytic gallstone disease (n = 244),
the BMI percentile distribution was as
follows: 31% (n = 74) were considered
to be a normal weight, 16% (n = 37)
were overweight, 35% (n = 82) were
obese, and 18% (n = 44) were severely
obese. As such, ∼69% (n = 163/237) of
patients with gallstone disease were
overweight or obese. The median BMI
percentile for these patients was 95%
and the mean BMI percentile was 81%. A
height or weight was absent for 7 patients with gallstone disease; therefore,
these patients were excluded from all
BMI analyses.
Logistic regression was used to predict
the impact of gender, age, BMI, and
Hispanic ethnicity on the incidence of
nonhemolytic gallstone disease. Older
age (P = .019) and Hispanic ethnicity
(P , .0001) were independent risk
factors for nonhemolytic gallstone disease. Gender and BMI percentile were
not independent risk factors.
Complicated Obstructive Disease
Complicated obstructive disease was
the primary indication for a cholecystectomy in 112 patients $3 years of age.
Of these, 61 had a BMI percentile $85%
(P = .496). Univariate analysis identified
a significant association between the
risk for gallstone pancreatitis and a BMI
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ARTICLE
percentile $85% (P = .003); however,
this association was not found for
jaundice (P = not significant). Hispanic
patients (n = 55, 65%) were more likely
than non-Hispanic patients (n = 29,
35%) to have obstructive disease (P =
.005). Of the 112 patients with complicated obstructive disease, 56% (n = 63)
underwent the following additional
procedures: ERCP (n = 21), intraoperative cholangiogram (IOC) (n = 28),
or ERCP and IOC (n = 14).
Biliary Dyskinesia
Biliary dyskinesia, by definition, is a
gallbladder ejection fraction of ,35%
with a cholecystokinin analog infusion
on HIDA scan.34–37 Biliary dyskinesia was
the third leading indication for a cholecystectomy in our patient cohort.
Females comprised 78% of these
patients, and 18% were of Hispanic ethnicity. Fifty-one percent of patients were
overweight and, of these, 30% were
severely obese. HIDA scans completed
on all 64 patients revealed an ejection
fraction of less than 35% (median of
10%; range 0%–34%). Histologic features of chronic cholecystitis were
identified in 80% (n = 51) of patients
with a preoperative diagnosis of biliary
dyskinesia.
Comparison With Historical Control
Miltenburg et al published data on pediatric cholecystectomies at TCH from
1980 to 1996.1 We compared our data
with this historical cohort (Table 3).
There has been a notable increase in
the percentage of Hispanic (22% vs
36%, P = .003) and severely obese (6%
vs 18%, P , .027) patients undergoing
cholecystectomy. Patients in the historical cohort were subjectively categorized as being morbidly obese. BMI
data for this historical cohort of
patients was not available for direct
comparison.
In our historical series, 52 (41%) of 128
cholecystectomies were performed on
children with hemolytic disease. The
overall percentage of patients with
hemolytic disease as an indication for
cholecystectomy has decreased significantly (41% vs 18%, P , .0001).
Additionally, no cholecystectomies were
previously performed for biliary dyskinesia, whereas now it is the third leading indication (0% vs 16%, P , .0001).
Another significant change has been in
the approach to surgery. In our current
series, 97% of cholecystectomies were
performed laparoscopically versus 15%
in our previous series. The major complication rate remains similar (9% vs
9%) (Table 3). The most common major
complications were postoperative fever
and pancreatitis/pseudocyst formation
(Table 4). Of the obese patients, 15% (n =
23) had a minor or major postoperative
complication (P = .4). No deaths occurred as a result of a cholecystectomy
in our current series. In our previous
series, 3 children with congenital heart
disease who required emergent cholecystectomy died after surgery.1
DISCUSSION
We have found that cholecystectomies
for gallbladder disease are performed
more often in children and the risk
factors for cholecystectomies have
TABLE 3 Texas Children’s Hospital Historical Comparison1
Total no. of patients
Age, y
Mean
Gender
Males
Females
Male:Female
Race/Ethnicity
Hispanic
White
African American
Other
BMI
Severely obese
Comorbidities
Hemolytic disease
Biliary dyskinesia
Surgery
Laparoscopic
Open
Major complication
1980–1996
2005–2008
128
404
10
P Value
13.00 6 0.19
59 (46%)
69 (54%)
0.8:1
111 (27%)
293 (73%)
1:2.6
.0001
.0001
28 (22%)
57 (45%)
39 (30%)
4 (3%)
144 (36%)
126 (31%)
90 (22%)
5 (1%)
.003
NS
NS
NS
8 (6%)
57 (15%)
.013
52 (41%)
0
76 (19%)
64 (16%)
,.0001
,.0001
19 (15%)
109 (85%)
11 (9%)
379 (96%)
17 (4%)
38 (9%)
,.0001
,.0001
NS
NS, not significant.
TABLE 4 Postoperative Complications From the 2005–2008 Texas Children’s Hospital Cohort
Major (n)
Minor (n)
Postoperative fever (8)
Pancreatitis/pseudocyst formation (7)
Infection (eg, fungemia, urinary tract infection,
wound infection) (5)
Papillary stenosis/stricture (4)
Retained stone (4)
Jaundice (4)
Bile leak (2)
Vascular injury (1)
Hemobilia (1)
Small bowel obstruction (1)
Prolonged intubation (1)
Abdominal pain (13)
Nausea/Vomiting (nonbilious) (6)
Ileus (2)
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e85
changed. In the initial series from TCH,
36 cholecystectomies were performed
in 20 years (1.8 per year), followed by
128 in next 17 years (7.5 per year), and
now 404 in almost 4 years (101 per
year).1,10 Previously described risk
factors such as prematurity (n = 4, 1%)
and hemolytic disease (n = 76, 19%) did
not account for this dramatic increase.
Rather, risk factors responsible for the
development of gallbladder disease in
adults (female gender, age, obesity,
and ethnicity) were identified as key
contributors to this increase in pediatric gallbladder disease resulting in
cholecystectomy.
Our study mirrors previous observations that female children are at higher
risk of gallbladder disease than male
children.1,2,7 A greater proportion of
patients in our series were female
(73%, n = 293), reflecting the trend toward gender bias. In adults, the high
prevalence of cholelithiasis in women
has been attributed to pregnancy and
oral contraceptive use.38–43 We identified 14 women with a documented
pregnancy; however, our study design
precluded the evaluation of patients
taking oral contraceptives.
We found an increase in the mean age of
diagnosis for gallstone disease. The
previous mean age for children with
gallstone disease has ranged from 8.4
to 10.0 years; however, our mean age
was notably higher at 13.0 years1,2
(67% were 13 to 18 years of age). This
phenomenon has previously been
suggested and attributed to biliary
cholesterol saturation occurring secondary to hormonal changes during
puberty.43,44 An increase in the mean
age at diagnosis may also be attributable to the rising incidence of obesity in
adolescents.
The hormonal changes associated with
puberty may also play a role in the
etiology of biliary dyskinesia. Of the
patients who underwent a cholecystectomy for the primary indication of biliary
e86
dyskinesia, 78% were female and 70%
were $13 years of age. These findings
may support the suggestion that the
hormonal changes occurring during
puberty may contribute to the impairment of gallbladder motility in biliary
dyskinesia by altering the lipid composition of bile, increasing cholesterol
saturation, and promoting gallbladder
hypomotility.43,45,46
We also demonstrate a strong independent correlation between BMI percentile and the presence of gallstone
disease. Based on their BMI, a remarkable 69% of our patients with nonhemolytic gallstone disease were
overweight or obese; however, only 6%
of our patients had “obesity” documented with an International Classification of Diseases, Ninth Revision
code as a comorbidity in their medical
record, demonstrating a significant
underreporting of this condition. Obesity is a major health care issue and its
contribution to the prevalence of cholelithiasis has been well elucidated
in the adult population.19,20,27,28 The
pathogenesis of gallstone formation in
obese individuals has been described
as multifactorial with key factors, including hepatic hypersecretion of
cholesterol with resultant supersaturation of bile and altered gallbladder
motility.20,27,47 Our study strongly suggests the obesity epidemic in children
has contributed significantly to the
striking increase in pediatric gallstone
disease.
Our data suggest that Hispanic ethnicity is also a significant risk factor for
pediatric gallbladder disease resulting
in cholecystectomy. It has previously
been shown that Hispanic adults are at
increased risk for cholelithiasis.48–51
Genetic and environmental influences
have been explored as potential explanations for this epidemiologic association.48,49,52,53 The impact of racial
and ethnic variations on gallbladder
disease in the pediatric population has
not previously been investigated. Despite 25% of the Hispanic children
being overweight or obese, we demonstrate that independent of their BMI
percentiles, Hispanic children are at
a greater risk for cholecystectomy because of gallstone disease. This finding
supports the possible genetic risk
predisposition for stone formation in
Hispanic children similar to that seen
in Hispanic adults.52 Interestingly, we
identified only 9 patients, of whom only
5 were Hispanic, with a positive family
history of cholelithiasis. We anticipate
that a positive family history may have
been underreported or family members may have asymptomatic cholelithiasis. As such, race/ethnicity may be
a greater risk factor for gallstone disease than obesity alone. Further studies examining the independent risk of
race/ethnicity on the development of
gallstone disease are needed.
To our knowledge, this is the largest
single-center study examining gallbladder disease in children who underwent a cholecystectomy. Bogue et al8
recently studied 382 patients diagnosed with cholelithiasis based on
ultrasonography. In this series, only
122 patients underwent a cholecystectomy. The racial and ethnic distribution
of their study population and its impact
on the development of cholelithiasis
was not described. Obesity was identified in a significantly lower percentage of patients than our study population,
,1% vs 53%. In addition, we report a
higher rate of complicated disease in
patients requiring surgery, 10% vs 28%;
however, the definitions for complicated disease varied between studies.
Our definition did not include acute
cholecystitis, whereas Bogue et al8 did
not include jaundice or dilation of the
common bile duct.
Our study’s major strengths are a large
sample size and diverse patient population. The study is limited by its retrospective design. At the time of our
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ARTICLE
final analysis, some data, including
a height or weight for 9 of 404 patients,
a race or ethnicity for 39 of 404, and an
indication for cholecystectomy for 1
patient, were missing. We believe that
given our large sample size, the missing data would not have significantly
altered our results. Additionally, BMI
data for our historical cohort was not
available for direct comparison. With
our stringent search criteria, all patients
who underwent a cholecystectomy
during our study period should be
represented; however, patients with
gallbladder disease who did not have
a cholecystectomy were not included in
our epidemiologic data.30
We recognize that some of the notable
differences identified between our
historical cohort and current patient
population may have been influenced
by the changing demographics of
Houston and advances in medical care.
The Hispanic population of Houston,
Texas, has been steadily increasing
since 1980.54 This demographic change
likely contributed to the increase in
the proportion of Hispanic children
undergoing cholecystectomies. We also
surmise that biliary dyskinesia was
identified as the third leading indication
for cholecystectomy in our cohort secondary to the rising awareness of the
disease in the pediatric population.55,56
In addition, the significant difference in
surgical practice is likely a reflection of
the shift in standard of care from open
cholecystectomies to laparoscopic
cholecystectomies.
CONCLUSION
Hispanic ethnicity and obesity are
epidemiologically significant risk factors for gallbladder disease in the
pediatric population. Ethnicity is an
unalterable risk factor, but increased
awareness and early screening by
pediatric health care providers could
potentially limit the occurrence of
complicated obstructive disease. Obesity is a modifiable risk factor. With
the prevalence of childhood obesity on
the rise, pediatric health care providers need to be more aware of
obesity-related comorbidities, including gallbladder disease.
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MEHTA et al
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Clinical Characteristics and Risk Factors for Symptomatic Pediatric Gallbladder
Disease
Seema Mehta, Monica E. Lopez, Bruno P. Chumpitazi, Mark V. Mazziotti, Mary L.
Brandt and Douglas S. Fishman
Pediatrics 2012;129;e82; originally published online December 12, 2011;
DOI: 10.1542/peds.2011-0579
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