J Pediatr Rev. In Press(In Press):e9114.
Published online 2016 December 6.
Cholelithiasis in Children: A Diagnostic and Therapeutic Approach
Hasan Karami,1,* Hamid Reza Kianifar,2and Shahryar Karami3
1Department of Pediatric Gastroenterology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, IR Iran
2Department of Pediatric Gastroenterology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, IR Iran
3Departement of Dentistry, Faculty of Dentistry, Mazandaran University of Medical Sciences, Sari, IR Iran
*Corresponding author: Hasan Karami, Department of Pediatric Gastroenterology, Bouali Sina Hospital, Pasdaran bulevard, Sari, Mazandaran Province, IR Iran. Tel:
+98-1133344506, E-mail: firstname.lastname@example.org
Received 2016 September 24; Revised 2016 November 19; Accepted 2016 November 29.
Context: Although cholelithiasis is not a common condition in children, recent studies have documented an increasing incidence rate, owing to
the development of diagnostic tools. The prevalence of cholelithiasis in children has been reported to be 0.13% - 0.3%, whereas in obese children and
adolescents, the prevalence rate has been estimated at 2% - 6.1%. In this study, we aimed to review cholelithiasis in children. The gathered results
could be useful in ﬁnding a suitable method and proper clinical practice for this complication.
Evidence Acquisition: For literature review, international databases, including PubMed and Google Scholar, were searched, using keyword combi-
nations, e.g., “cholelithiasis in children”, “gallstone in children”, and “childhood cholelithiasis”, to review diagnostic and therapeutic approaches for
cholelithiasis in children from 2006 to 2016. Also, some articles were retrieved through hand searching and reviewing the reference lists of papers,
regardless of the date of publication. Abstracts, duplicates, and articles irrelevant to childhood cholelithiasis were excluded.
Results: A total of 39 out of 93 articles were reviewed. The results showed that the prevalence of childhood cholelithiasis varies in diﬀerent commu-
nities, with a global rate of 1.9%. Most cases of cholelithiasis in children were associated with underlying diseases. Hemolytic diseases, hereditary
blood disorders, and cirrhosis were among the main causes of cholelithiasis in children. Cholelithiasis was detected incidentally or via diagnostic
evaluations due to the presentation of symptoms.
Conclusions: Although evaluation of the underlying causes of gallstone formation and appropriate diagnostic/therapeutic implications is still a
challenging issue in the management of childhood cholelithiasis, in asymptomatic cases or those with gallstones of certain sizes, it is only recom-
mended to monitor the disease or rule out the underlying causes. It should be noted that long periods of diagnostic and therapeutic approaches
can impose stress and tension on families.
Keywords: Cholelithiasis, Childhood, Diagnosis, Therapy
With the development of diagnostic methods such as
ultrasonography, cholelithiasis in children is being fre-
quently reported. This disease may be either symptomatic
or asymptomatic, even though the asymptomatic presen-
tation is less likely in children (17% - 50%) (1-5). Although
both genders are equally aﬀected in early childhood, most
previous studies have demonstrated a female predomi-
nance in pediatric gallbladder disease, starting from pu-
berty. In fact, most cases of cholelithiasis at young age are
diagnosed in the second decade of life (1,6-8).
Cholelithiasis is sometimes diagnosed in patients in-
cidentally or as silent stones. In some other cases, they
are reported in association with clinical symptoms such
as cholecystitis and cholangitis (9-11). Although hemolytic
diseases are the most common causes of cholelithiasis in
children, some other factors such as obesity, metabolic syn-
drome, prematurity, necrotizing enterocolitis (NEC), con-
genital heart diseases, cystic ﬁbrosis, parenteral nutrition,
use of certain medicines, and anatomic stenosis of bile
ducts should be also considered.
Information about cholelithiasis and bile duct stones
causes stress and anxiety in parents and sometimes leads
to the use of improper diagnostic and therapeutic ap-
proaches by physicians (9,10,12). Evaluation of the
causes of cholelithiasis and utilization of a proper ther-
apeutic method are among the challenges of cholelithia-
sis management in children. Considering the use of gall-
bladder lithotripsy procedures in certain cases and sta-
tus of pharmacological treatments in gallbladder stone
management, we aimed to review diﬀerent types of
cholelithiasis, clinical symptoms, underlying causes, and
pharmacological/non-pharmacological therapies in chil-
2. Evidence Acquisition
For the purpose of literature review, international
databases, including PubMed and Google Scholar, were
searched, using keyword combinations, e.g., “cholelithi-
asis in children”, “gallstone in children”, and “childhood
cholelithiasis”, to review diagnostic and therapeutic ap-
proaches for cholelithiasis in children from 2006 to 2016.
Also, some articles were retrieved by hand searching and
reviewing the articles’ references, regardless of the date of
publication. After removing duplicates, abstracts, and ar-
ticles irrelevant to cholelithiasis in children, 39 eligible ar-
Copyright © 2016, Mazandaran University of Medical Sciences. This is an open-access article distributed under the terms of the Creative Commons
Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in
noncommercial usages, provided the original work is properly cited.
Karami H et al.
ticles were obtained and reviewed. The qualitative results
are presented in this article.
3.1. Epidemiological Review
Generally, the incidence and prevalence of cholelithia-
sis are inﬂuenced by age, gender, genetics, race, and geo-
graphical factors (9-12). Epidemiological studies have indi-
cated the involvement of genetic factors in the formation
of cholelithiasis. The eﬀect of a gene on incontinentia pig-
menti chromosome has been conﬁrmed in the formation
of cholelithiasis. In fact, patients with ABCB11 mutations
are at a higher risk of cholelithiasis.
The ﬁrst report of cholelithiasis in children was pre-
sented by Gibson in 1737. The prevalence of cholelithia-
sis in children is variable, with a global rate of 1.9% in dif-
ferent communities. Children under 26 months of age
constitute 10% of cholelithiasis cases. Sometimes, cases
of fetal cholelithiasis are reported, most of which are
asymptomatic and gradually resolve following the postna-
tal monitoring of newborns (9,10,13,14).
Most cases of cholelithiasis in children are associ-
ated with underlying factors, such as hemolytic diseases,
history of treatment with total prenatal nutrition (TPN),
Wilson’s disease, and cystic ﬁbrosis; also, use of some
medicines should be always considered. Hemolytic causes
appear mostly in one- to ﬁve-year-old children. On the
other hand, cholelithiasis in adolescents is usually associ-
ated with obesity, pregnancy, and medication use (10,11,15).
The ﬁve main constituents of bile include water, biliru-
bin, cholesterol, bile pigments, and phospholipids; also,
lecithin is the precursor of bile phospholipids. The early
stage of gallstone formation initiates from the sedimen-
tation of insoluble primary components of bile, which
mainly include cholesterol, bile pigments, and calcium
salts (10). Gallstones are mainly categorized in three
groups of cholesterol, pigment, and mixture, among
which the mixture is more common. Imbalance in bile
constituents, such as cholesterol, lecithin, and bile salts, is
the main cause of gallstone formation. As the concentra-
tion of cholesterol increases, the rate of crystallization also
elevates, which gives rise to underlying conditions for gall-
stone formation (15,16).
3.3. Cholesterol Stones
When the bile includes higher levels of cholesterol and
bilirubin, along with lower levels of bile salts, cholesterol
stones are formed. Generally, three factors are involved in
the formation of cholesterol stones: 1) Bile saturates with
cholesterol which creates solid cholesterol; 2) bile kinetics
majorly contribute to cholesterol crystal formation; and
3) cholesterol crystals bind to the central core. It should
be noted that most cholesterol stones are yellow-white in
3.4. Pigment Stones
These stones are mostly reported in cases with
hemolytic disease, cirrhosis, bile tract infection, and
hereditary blood disorders, such as spherocytosis and
sickle cell anemia. These stones are black-brown in color
and are more common in adolescents (10,12,16).
3.5. Cholelithiasis in Infants
Bile is more diluted in infants than older children.
Lower concentrations of bile salts, short period of core
formation, and higher levels of cholesterol saturation
may predispose infants to bile deposition and gallbladder
sludge. According to diﬀerent studies, more than half of
gallstone cases in infancy are resolved spontaneously fol-
lowing the postnatal monitoring of newborns; therefore,
surgical interventions or symptomatic treatments are nec-
essary only in some certain cases (13,16-18). The features of
cholesterol and pigment stones are presented in Table1 (16,
3.6. Clinical Symptoms of Cholelithiasis
In most cases, cholelithiasis is asymptomatic in chil-
dren and is incidentally diagnosed in abdominal sonog-
raphy assessments. Cholelithiasis can be symptomatic if
leading to cholestasis, cholecystitis, and cholangitis. The
main clinical symptoms include icterus, abdominal pain,
nausea, vomiting, and Murphy’s sign. In case of any under-
lying factors, the clinical symptoms of the causes of stone
formation should be also included (12,13,16).
3.7. Diagnosis of Cholelithiasis
Diagnostic interventions for cholelithiasis should be
performed to identify the stones and to determine the un-
derlying causes. Liver, gallbladder, and biliary tract ultra-
sonography is the optimal diagnostic method with high
sensitivity and speciﬁcity. Deposition of biles due to dif-
ferent pharmacological therapies, fasting of the patients,
and reduced physical activity lead to no posterior opacity
in ultrasonography; however, opacity can appear in cases
Abdominal plain sonography can be helpful in cases
of pigmented stones, considering the sedimentation of
calcium bilirubinate, whereas it is not eﬀective in cases
with cholesterol or radiolucent stones (12,13,16,23). Along
2J Pediatr Rev. In Press(In Press):e9114.
Karami H et al.
Table1. The Features of Cholesterol and Pigment Stones
Characteristics Cholesterol Stones Pigment Stones
Color Yellow-white (often with a dark core) Black to brown Brown to orange
Consistency Hard, crystalline, and layered Hard, shiny,and crystalline Soft, greasy,50% amorphous, and
crystalline at rest with inorganic salts
Number and morphology Multiple: 2 - 25 mm, faceted, and smooth,
Solitary: 2 - 4 cm (~ 10%), round, and
Multiple: < 5 mm, irregular, or smooth Multiple: 10 - 30 mm, round, and smooth
Composition Cholesterol monohydrate > 50%
,glycoprotein, Calcium salts
Bile pigment polymer ~ 40%, Calcium
carbonate or phosphate, salts~ 15%,
Cholesterol ~ 5%, Mucin glycoprotein
Calcium bilrubinate ~ 60%, Calcium
palmitate and ,stearate soaps ~ 15%,
Cholesterol ~ 15%, Mucin glycoprotein
Radiopaque No Yes, ~ 50% No
Location Gallbladder ±common bile duct Gallbladder ±common bile duct Common bile duct, Intrahepatic bile duct
Clinical associations Hyperlipidemia, Obesity,Cloﬁbrate use,
Pregnancy,Cystic ﬁbrosis, Octreotide use
Hemolytic anemia, Cirrhosis, Total
parenteral nutrition (TPN) ,Ileal disease
(after puberty), Ceftriaxone use
Bacterial infection, (Escherichia coli),
Parasitic infection, Bile duct anomaly,Use
of birth control pills
Recurrence Yes No Yes
Sex Female > Male No diﬀerence No diﬀerence
Age Puberty (increasing with age) Anyage (increasing with age) Any age (increasing with age)
Bacteria No No Yes (consistently found at the core)
Soluble Yes No No (minimally)
with the diagnosis of cholelithiasis, the underlying etiol-
ogy should be also evaluated through medical history tak-
ing and patient examination, as gallstone is a sign indicat-
ing an underlying pathophysiological cause.
The evaluations should include positive history of
hemolytic diseases in the child or his/her family mem-
bers, metabolic syndrome in the child, history of recur-
rent icterus in the child or his/her family members, history
of splenectomy in relatives, anemia, clinical symptoms of
liver dysfunction, symptoms of chronic liver disease in the
child, family history of mortality possibly due to liver dis-
orders (e.g., Wilson’s disease), chronic diarrhea, steator-
rhea, weight loss, severe skin itching in the child (Bayler
disease), obesity, and the underlying causes of gallstone
Use of ceftriaxone, as a routine prescribed medicine,
as well as cloﬁbrate, is the main pharmacological cause
of stone formation. The results of laboratory tests such
as complete blood count, diﬀerential tests, Coombs test,
reticulocyte count, hemoglobin electrophoresis, glucose-
6-phosphate dehydrogenase (G6PD) test, liver functional
tests, evaluation of amylase, lipase, and copper serum lev-
els, Wilson’s disease diagnostic tests, as well as sweat and
stool exams can be helpful in the diagnosis of cholelithia-
sis. Evaluation of patients’ medical history, contributing
factors for gallstone formation, and clinical symptoms of
systemic diseases, along with laboratory ﬁndings, can help
determine the etiology of stone formation (12,13,16).
The most common causes of cholelithiasis in children
include idiopathic diseases, TPN, hemolytic disease, malab-
sorption, NEC, hepatobiliary diseases, obesity, abdominal
surgery, epilepsy medications, and acute leukemia (1,5,24-
26). A review of 382 Canadian children with cholelithiasis
reported complications attributable to gallstone disease in
less than 5% of asymptomatic children. Also, about 20% of
the asymptomatic children revealed eventual resolution of
the gallstones. There was a similarly low rate of complica-
tion (8.6%) among infants in this study, and a high rate of
spontaneous resolution of gallstones (34.1%) was reported
among infants who were followed-up via ultrasound.
With this background in mind, expectant manage-
ment seems appropriate, particularly for otherwise
healthy infants and children with stones less than 2 cm in
size. For patients with smaller stones, serial ultrasound
examinations appear warranted to monitor spontaneous
disappearance of stones. Larger stones are more prob-
lematic. Gallstones may play a role in the development of
gallbladder carcinoma, with larger stones (> 2 cm) carry-
ing a greater risk than smaller ones. As larger stones are
unlikely to disappear spontaneously, there is a reasonable
argument for removing the gallbladder in an otherwise
asymptomatic child, given the inherent enhanced risk of
J Pediatr Rev. In Press(In Press):e9114. 3
Karami H et al.
gallbladder carcinoma, caused by the presence of a stone
in the gallbladder over several decades (5) (Table 2) Friesen
and Roberts, 1989 (12).
Table2. Diagnosis of Cholelithiasis
Age Percentage of TotalCases
0 - 12 months
Total parenteral nutrition (TPN) 29.1
Abdominal surgery 29.1
Bronchopulmonary dysplasia 12.7
Hemolytic disease 5.5
Necrotizing enterocolitis (NEC) 5.5
Hepatobiliary disease 3.6
1 - 5 years
Hepatobiliary disease 28.6
Abdominal surgery 21.4
Artiﬁcial heart valve implantation 14.3
6 - 11 years
Hemolytic disease 22.5
Abdominal surgery 5.1
Hepatobiliary disease 2.7
Total parenteral nutrition (TPN) 2.7
3.8. Treatment of Cholelithiasis
Treatment of cholelithiasis is aﬀected by several con-
tributing factors, such as the anatomical status of gall-
stone, rate of symptoms in the child, underlying anatomic
disorders, other underlying causes of stone formation, in-
ﬂammatory changes of the biliary system, and age of the
child. While the gallstone is located in the common bile
duct or around the pupillary sphincter, it can cause cholan-
gitis, obstruction of bile ﬂow, and icterus in the child,
which deﬁnitely require stone removal.
Gallstones with diameters less than 10 mm, which
ﬂoat in the gallbladder and are diagnosed incidentally
in asymptomatic children, should be investigated for
hemolytic diseases and underlying disorders and need to
be treated after diagnosis. On the other hand, one or
more gallstones, a few millimeters in size, ﬂoating in the
gallbladder, are mostly asymptomatic and should be only
monitored once every few months (11,17). In case of the oc-
currence of cholecystitis and cholangitis after the adminis-
tration of antibiotics, serum therapy, and vital sign moni-
toring, it is recommended to remove the gallstone (prefer-
ably by laparoscopy) as soon as possible.
In cases receiving TPN, the child should be monitored
due to time limitations on the use of TPN regimens; also,
asymptomatic patients should be assessed (13,27). By dis-
continuation of TPN regimen, onset of an oral nutritional
regimen, and establishment of bile ﬂow, bile sedimenta-
tion and cholelithiasis development would gradually re-
solve. In cases with more severe underlying diseases such
as intestinal pseudo-obstruction or short bowel syndrome,
TPN regimen should be continued and repeated, as there is
no chance for enteral feeding; in these patients, cholecys-
tectomy is a preferable therapeutic approach.
Patients should be monitored to receive ceftriaxone
and cloﬁbrate after completing the therapeutic period. In
most cases, cholelithiasis resolves after several months of
monitoring. However, cholelithiasis is not usually resolved
spontaneously in older children and should be removed
in symptomatic cases. Cholecystectomy is applicable in
cases requiring acute drainage of gallbladder and also se-
vere cases of the disease. Removal of cholelithiasis through
performing cholecystectomy (via laparoscopy) in children
is an alternative, as adopted in adult cases. Non-surgical,
therapeutic approaches for cholelithiasis in children are
increasing, although there are still some controversies in
this context (9,11,15).
3.9. Oral Medications
Ursodeoxycholic acid (Ursobil®) and chenodeoxy-
cholic acid (chenodiol) can be only eﬀective in cholesterol
stones and therapy–resistant cases. However, their admin-
istration is restricted due to the long course of treatment,
diﬀerent eﬃcacies, and side-eﬀects such as diarrhea
and liver consequences. Administration of hydroxyurea
has been shown to be useful in reducing the frequency
of cholelithiasis in some hemolytic diseases, such as
thalassemia intermedia or major (10,28,29).
Extracorporeal shock–wave lithotripsy is another ther-
apeutic method, which can be applied whenever the
patient is asymptomatic or the gallstone is radiolucent
(1,30); consequently, the best result is obtained in sin-
gle cholelithiasis. The most common complications of
cholelithiasis include cholecystitis and pancreatitis. In
cases with cholesterol stones, methyl tert-butyl ether
4J Pediatr Rev. In Press(In Press):e9114.
Karami H et al.
Less than 20mm Greater than 20mm
Need to treatment
Follow up Cholecystectomy
Cholecystom ERCP + basket
Figure 1. Recommended Therapeutic Methods for Childhood Cholelithiasis
should be injected into the gallbladder by a catheter. Al-
though the results in adults seem to be satisfactory, imple-
mentation of this method in children is faced with some
limitations due to its numerous side-eﬀects, such as intra-
venous hemolysis, duodenitis, nausea, and vomiting.
Partial internal biliary diversion can be helpful in
cases with progressive familial cholestasis (Bayler disease).
Weight control in children with obesity, use of hypolipi-
demic drugs in high-risk populations, exercise, early re-
turn to oral nutrition in hospitalized children, and pre-
vention of drug-induced calculi by prescription of proper
medications are suggested. The recommended therapeu-
tic methods are presented in Figure 1 (9,13,31) and Table 3
Children with gallbladder disease may be either symp-
tomatic or asymptomatic, although the asymptomatic pre-
sentation is less likely in children. The risk factors in chil-
dren vary according to age, geographical localization, eth-
nicity, referral status, and medical facilities. Hemolytic
anemia, family history, oncologic diseases, and ceftriax-
one use were the most frequent risk factors in the asymp-
tomatic group. Non-speciﬁc abdominal symptoms, es-
pecially in younger children, may mimic the gallstones;
therefore, more children might have been factitiously clas-
siﬁed in the symptomatic group. Although both genders
are equally aﬀected in early childhood, most previous stud-
ies have demonstrated a female predominance in pediatric
gallbladder disease, starting from puberty. The results
have shown that most gallstones at young age are diag-
nosed in the second decade of life. It seems that evaluation
of the underlying causes of gallstone formation and appro-
priate diagnostic and therapeutic implications is still chal-
Table3. Therapeutic Approaches for Childhood Cholelithiasis
Cholecystectomy Method of choice in most cases
Cholecystostomy Eﬀective for acute gallbladder
drainage (i.e., acalculous
Laparoscopic cholecystectomy Eﬀective for severely ill patients (e.g.,
cystic ﬁbrosis), shortening the
length of hospital stay
Basket removal Bile duct stone removal
Mechanical basket lithotripsy Stone crushing within the bile ducts
Electrohydraulic lithotripsy Stone destruction within the bile
Laser lithotripsy Stone destruction within the bile
Limited experience (unpublished)
only for cholesterol stones currently
Ursodeoxycholic acid and
Blockage of HMG-CoA reductase and
reduction of cholesterol synthesis
Methyl tert-butyl-ether (for
cholesterol stones only)
Bile acid-EDTA solution for pigment
stones (IfRr, experimental)
Enteral feeding Even small amounts during total
parenteral nutrition (TPN) can
decrease the risk of stone formation
Weight loss For obesity or gradual weight loss
Lovastatin and simvastatin Blockage of HMG-CoA reductase and
reduction of cholesterol synthesis
Cholecystokinin Stimulation of gallbladder
contraction while NPO
lenging in the management of childhood cholelithiasis.
In asymptomatic cases or those with gallstones of certain
sizes, only surveillance of the disease or ruling out the un-
derlying causes is recommended. It should be noted that
long periods of diagnostic and therapeutic approaches can
impose stress and tension on the patients’ families.
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