Shenoy et al.

Systematic Reviews (2022) 11:267

https://doi.org/10.1186/s13643-022-02135-8

RESEARCH Open Access

Management of symptomatic cholelithiasis:

a systematic review
Rivfka Shenoy1,2,3* , Patrick Kirkland4, Joseph E. Hadaya1, M. Wynn Tranfield5, Michael DeVirgilio1,2,
Marcia M. Russell1,2 and Melinda Maggard-Gibbons1,2,6,7

Abstract
Background: Symptomatic cholelithiasis is a common surgical disease and accounts for half of the over one mil-
lion cholecystectomies performed in the USA annually. Despite its prevalence, only one prior systematic review has
examined the evidence around treatment strategies and it contained a narrow scope. The goal of this systematic
review was to analyze the clinical effectiveness of treatment options for symptomatic cholelithiasis, including surgery,
non-surgical therapies, and ED pain management strategies.
Methods: Literature search was performed from January 2000 through June 2020, and a narrative analysis was
per- formed as studies were heterogeneous.
Results: We identified 12 publications reporting on 10 trials (9 randomized controlled trials and 1 observational
study) comparing treatment methods. The studies assessed surgery, observation, lithotripsy, ursodeoxycholic acid,
electro-acupuncture, and pain-management strategies in the emergency department. Only one compared surgery to
observation.
Conclusion: This work presents the existing data and underscores the current gap in knowledge regarding treat-
ment for patients with symptomatic cholelithiasis. We use these results to suggest how future trials may guide
comparisons between the timing of surgery and watchful waiting to create a set of standardized guidelines. Provid-
ing appropriate and timely treatment for symptomatic cholelithiasis is important to streamline care for a costly and
prevalent disease.
Trial registration: PROSPERO Protocol Number: CRD42020153153
Keywords: Symptomatic cholelithiasis, biliary colic, treatment, management, cholecystectomy, UDCA

Introduction [7–9]. Symptomatic cholelithiasis, often referred to as

Fifteen percent of Americans have gallstones and symp- biliary colic, accounts for half of these surgeries [2, 8,
toms occur in up to 10% of patients within 5 years, which 9]. Despite being a common surgical problem, there is
can progress to advanced disease such as acute cholecys- no consensus nor formal recommendations for
titis, choledocholithiasis, or gallstone pancreatitis [1–6]. eligibility criteria or optimal timing for surgery for
Gallstones lead to over one million ambulatory care vis- symptomatic cholelithiasis.
its each year, are a leading cause of hospital admissions, However, surgery for symptomatic cholelithiasis may
and result in one million cholecystectomies annually not always be warranted. The majority of patients with
gallstone disease will not experience recurrent symp-
toms or disease progression [4, 5]. Patients may opt for
*Correspondence: [email protected]
observation alone, which may in part depend on how
3
National Clinician Scholars Program, UCLA, Los Angeles, CA, USA pain is managed in the emergency department (ED) [4, 5,
Full list of author information is available at the end of the article

© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to
the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The
images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated
otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use
is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright
holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain
Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless
otherwise stated in a credit line to the data.
Shenoy et al. Systematic Reviews (2022) 11:267 Page 2 of
9

10]. Others may pursue non-surgical treatment options,

as full texts. Exclusion criteria are listed in our literature
including extracorporeal shock-wave lithotripsy or medi-
flow (Fig. 1).
cal treatments such as ursodeoxycholic acid (UDCA), but
Dual abstraction was performed including: study
success rates for such options are unclear [11]. While one
design, patient characteristics, sample size, intraoperative
prior systematic review focused on surgery as a treat-
outcomes, postoperative outcomes, long-term functional
ment modality [1], none have comprehensively analyzed
outcomes, duration of follow-up, and data needed for the
the evidence across the range of treatment options. The
Cochrane Risk of Bias tool or Cochrane Risk of Bias In
goal of this systematic review was to analyze the clini-
Non-randomized Studies—of Interventions (ROBINS-I)
cal effectiveness of treatment options for symptomatic
[12, 13]. Summary statistics (means, medians, or percent-
cholelithiasis, including surgery, non-surgical therapies,
age as appropriate) describing differences between treat-
and ED pain management strategies.
ment groups were extracted.

Materials and methods Risk of bias

This systematic review is reported using PRISMA stand- RCTs were assessed for quality (risk of bias) with the
ards and the protocol for the larger review was registered Cochrane Risk of Bias tool [12]. We used the ROBINS-I
in PROSPERO: CRD42020153153. One librarian devel- [13] for observational studies. Each outcome was meas-
oped a search strategy for comparing treatment methods ured on consistency, directness, and precision with an
for symptomatic cholelithiasis. overall certainty of evidence of high, moderate, low, or
very-low.
Literature search
All searches included PubMed, Embase, Cochrane Tri- Statistical analysis
als and Cochrane Reviews from January 2000 to 29 Due to the heterogeneity in clinical outcomes of both
June 2020, when the search was executed. The search the RCTs and the observational studies, a meta-analysis
strategy used a broad set of terms related to the was not performed, and data was synthesized narratively.
treatment out- comes of cholelithiasis, gallbladder, and Studies were grouped based on the types of treatments
biliary tract dis- ease (see Supplementary material 1 for compared: surgery, (surgery versus observation, surgery
complete search strategy). The search emphasized versus lithotripsy, urgent versus elective surgery or surgi-
terms indicating length of stay, hospital readmission, cal criteria comparisons), non-surgical therapies (UDCA
and quality adjusted life years to ascertain post- versus placebo, UDCA versus UDCA with chenodeoxy-
intervention impacts. We excluded studies published cholic acid, and electro-acupuncture versus observation),
prior to the year 2000 to cap- ture contemporary and pain management in the ED.
treatment strategies.
Results
Literature search
Study selection and data collection
The search identified 6366 publications and 12 were
All stages of title screen through data abstraction were
included in our study (see Fig. 1 for literature flow and
completed by two independent team members and disa-
breakdown by database) [14–25]. These 12 articles
greements were reconciled through discussion. Studies
reported on nine RCTs [14–17, 19–25] (several dupli-
that did not compare treatments were excluded. Stud-
cates) and one observational study [18]. Table 1 shows
ies were included if they assessed surgery (cholecystec-
the comparison arms and study characteristics for each
tomy), non-surgical therapies, or ED pain management
study including follow-up time. For surgery comparative
strategies as one of the comparison arms. Studies were
studies, seven publications reported on five trials (three
included if they had all of the following criteria: (1) stud-
reported different time-points and outcomes for one
ied adult patients with symptomatic cholelithiasis or
RCT) [14–20] Specifically, three publications reported
included a sub-group with symptomatic cholelithiasis;
on one trial that compared surgery versus observation
(2) included one group of patients treated by
[15, 16, 19], two compared timing of surgery [17, 18], one
observation or alternate treatment method; (3) had a
compared surgery to lithotripsy [14], and one compared
comparison to patients treated with a different method;
methods to select patients for surgery [20]. Three pub-
(4) measured intraoperative, perioperative, or
lications compared non-surgical therapies [21, 22, 25].
postoperative outcomes. Randomized controlled trials
Two compared UDCA to either placebo [22] or UDCA
(RCTs) and observational studies were included. We
plus chenodeoxycholic acid [21], and one compared
did not exclude studies based on follow-up time.
electro-acupuncture to observation [25]. Two publica-
Abstracts were included in the review (if there was no
tions compared types of ED pain medication [23, 24].
companion full article) and underwent the same quality
assessment and duplication exclusion
Shenoy et al. Systematic Reviews (2022) 11:267 Page 3 of
9

Fig. 1 Literature flow. *PubMed = 2575, Cochrane Trials 909, Cochrane Review 25, Embase 2838

Table 1 Characteristics of included studies by comparative arms: surgery, non-surgical, and ED pain management
Author, year Comparison Number of sites Study design Sample size Follow-up time

Vetrhus, 2002 [16], Vetrhus 2004 Surgery vs. observation Multiple Randomized 137 5 years [15, 16]
[15], and Schmidt, 2011 [19]a 14 years [19]
Ahmed, 2000 [14] Surgery vs. lithotripsy Single Randomized 144 5 years
Salman, 2005 [17] Urgent vs. elective surgery Single Randomized 75 Not specified
Anwar, 2008 [18]b Urgent vs. elective surgery Single Observational 96 Not specified
Van Dijk, 2019 [20]c Surgeon discretion vs. pre-specified criteria Multiple Randomized 1067 1 year
Petroni, 2001 [21] UDCAd vs. UDCA + bile salts Multiple Randomized 158 2 years
Venneman, 2006 [22] UDCA vs. placebo Multiple Randomized 177 Variede
Wong, 2019 [25] Electro-acupuncture vs. observation n/a Randomized 46 Not specified
Malesci, 2003 [23] ED pain managemente Single Randomized 14 48h
Antevil, 2004 [24] ED pain managementf Single Randomized 38 20 min
a
Studies looked at same population, examined different outcomes at different timepoints
b
Anwar, 2008 defined urgent cholecystectomy as early/same-day
c
Surgeon discretion defined as operation based on standard care left to the discretion of the surgeon; restrictive strategy used the fulfillment of five pre-specified
criteria as indication for operation
d
UDCA Ursodeoxycholic acid
e
Followed until they received surgery or for 12 months from start of treatment if refused surgery
e
Hyoscine-N-butyl bromide vs. Loxiglumide
f
Glycopyrrolate vs. placebo
Shenoy et al. Systematic Reviews (2022) 11:267 Page 4 of
9

Supplementary material 2 displays the full-data extrac-

The two studies looking at ED pain management were
tion tables for all 12 studies.
both single-institution and enrolled less than 50 patients
[23, 24]. They found no differences in age, sex, or dura-
tion of pain between comparison arms. Both defined
Study characteristics by comparison group
their cohort as patients with right upper quadrant
The seven publications (reporting on five trials) which
abdominal pain with gallstones on ultrasound. One study
included a surgical comparison arm had sample sizes
specifically mentioned excluding patients with acute
ranging from 75 to 1067 patients. Two trials were sin-
cholecystitis [23]. This study reported number of prior
gle institution [14–16] and the other three were multi-
episodes and pain score at enrollment and identified no
institution (Table 1) [17, 18, 20]. Four out of five trials
differences between groups [23]. The follow-up time for
reported that groups were similar in regard to age and
these studies were 48 h [23] and 20 min [24].
sex. Of these four, only one study demonstrated a
statis- tical difference between groups [16] and the
Surgical comparisons: surgery versus observation
other three did not report statistical tests of
One RCT examined surgery versus observation and
comparisons [14, 16, 20]. The fifth trial (Anwar, et al.)
published three studies (Vetrhus, 2002; Vetrhus, 2004;
which included a surgi- cal comparison only reported
Schmid, 2011) looking at different outcomes at different
age of the patients and did not comment on statistical
time-points [15, 16, 19]. Gallstone-related events includ-
significance [18]. Three out of five trials defined
ing pain attacks and complications were not different
symptomatic cholelithiasis as abdomi- nal pain with
between groups at 5 or 14 years (Table 2). Over half of
ultrasound signs of gallstones and without evidence of
the patients in the observation group received surgery
advanced biliary pathology (i.e., abnormal leukocytes,
(50.7%). Conversion rates and postoperative complica-
complicated cholelithiasis) [15–17, 19, 20]. One trial
tions were slightly higher in the patients randomized to
included patients with “symptomatic gall- stones”
observation that ultimately underwent surgery (conver-
without further specifying [14], and one included patients
sion rates: 11% versus 0; postoperative complications:
with cholelithiasis based on clinical findings from the
14% versus 5%, Table 3); however, they did not report
chart [18]. Three out of five trials reported spe- cific
whether this difference was statistically significant.
clinical disease characteristics including number of
Vetrhus, et al. (2004) examined quality of life (using the
prior episodes, severity of prior episodes, prior hospi-
Psychological General Well Being index and Nottingham
talizations and length of symptoms [14, 16, 20]. These
Health Profile Part II) and pain (pain score and visual
trials did not report statistical tests of comparison, but
analog pain scale) and found no differences between the
stated that characteristics were similar between groups.
surgery versus observation group [15].
These trials had follow-up times ranging from 1 [20] to
14 years [19]. Two trials did not specify their follow-up
time (Table 1) [17, 18]. Surgical comparisons: surgery versus lithotripsy
The two multi-institutional comparisons including Ahmed, et al. compared lithotripsy to surgery in a 5-year
UDCA had sample sizes of 158 [21] and 177 [22]. Both follow-up study to examine long-term health gains.
Open, elective cholecystectomy was compared to inpa-
groups defined symptomatic cholelithiasis as abdominal
tient lithotripsy consisting of up to four treatment ses-
pain lasting at least 30 min with gallstones, and without
sions on consecutive days with up to 3000 shocks per
advanced biliary disease [21, 22]. The first study found no
session. This study found that while both groups had
differences in age, sex, or weight between groups. This
experienced reductions in mean number of episodes of
study reported a number of different baseline disease
biliary pain and mean severity summary score, patients
characteristics such as number of biliary colic episodes
treated with surgery had larger decrease in both meas-
in the preceding year, pain localization, and pain medica-
ures as compared to the group treated with lithotripsy
tions needed in the preceding year. There were no signifi-
[14]. For example, 81.8% (N 45) of patients who under-
cant differences in these characteristics between groups
went cholecystectomy were pain-free at 5-year follow-up
[22]. The other study reported age, sex, BMI, and stone
compared to 55.2% (N 48) of patients who were rand-
characteristics, stating that groups were well-matched,
omized to lithotripsy (p < 0.05).
but did not report statistical tests of comparison [21].
The follow-up times for these studies were 1 [22] and 2
years [21]. The study examining electro-acupuncture was Surgical comparisons: elective vs. urgent
an abstract only (unknown number of institutions), did Two studies compared timing of surgery for symptomatic
not report differences in demographics between groups, cholelithiasis [17, 18]. Salman et al. compared urgent
and defined their cohort as those with “symptomatic gall- (within 24 h from presentation) versus elective surgery,
stones” [25]. This study did not specify follow-up time. and Anwar, et al. compared early or same-day (defined
Shenoy et al. Systematic Reviews (2022) 11:267 Page 5 of
9

Table 2 Outcomes of gallstone-related events and operative rate by surgical comparison

Author, year Definition of gallstone-
related events Gallstone-related events Operative rate

Surgery Observation Surgery Observation

Vetrhus, 2002 [16] and 2004 Complications of 5-year follow-up 5-year follow-up 60/68 randomized (88%) 35/69 randomized (51%)
[15] and Schmidt, 2011 [19]* gallstones: acute Pain-related Pain-related
pancreatitis, common bile admissions: 2 admission: 12
duct stone(s), acute (1%) (17%)
cholecystitis Complications: Complications:
1 (1%) 3 (4%)
14-year follow-up 14-year follow-
Pain attacks: 8 up
(12%) Pain attacks: 23
Complications: (33%)
1 (1%) Complications:
3 (4%)
Elective Urgent/early Elective surgery Urgent/early surgery
surgery surgery
Salman, 2005 [17] “Complications during the 9 (27.5%) n/a 100%
waiting time”
Anwar, 2008 [18]b “serial presentations with 1.2 visits/personc n/a 100%
symptoms of gallstones” 0.3 visits/persond
Surgeon Restrictive Surgeon discretion Restrictive strategy
discretion strategy
Van Dijk, 2019 [20] e “Gallstone complications” 38 (7%) 40 (8%) 404 (75%) 358 (68%)
a
Studies looked at same population, examined different outcomes at different timepoints
b
Anwar, 2008 defined urgent cholecystectomy as early/same-day
c
In cohort that initially presented as an emergency
d
In cohort that initially presented to outpatient
e
Surgeon discretion defined as operation based on standard care left to the discretion of the surgeon; restrictive strategy used the fulfillment of five pre-specified
criteria as indication for operation

Table 3 Operative outcomes for surgical comparisons

Author, year Wait time
mean ± Conversion rate Postoperative complications
N, (%) N, (%)
SD

Surgery Observation Surgery Observation Surgery Observation

Vetrhus, 2002 [16], 5-year follow-up 5-year 0 4 (11%) 3 (5%) 5 (14%)
2004 [15], and 3 [0–24] b follow-up
Schmidt, 2011 [19]a months 14-year 27 [0–67] months
follow-up 14-year follow-up
3 [0–168] monthsd 28 monthsb
Elective surgery Urgent/early surgery Elective surgery Urgent/early surgery Elective surgery Urgent/early
surgery
Salman, 2005 [17] 4.2 ± 1.4 months 14.2 ± 4.1 h 6 (17.2%)c 0 0e 0
Anwar, 2008 [18]f 114 days 3 days 0 e 2 (2%) 7 (8%)e 0
Surgeon discretion Restrictive strategy Surgeon discretion Restrictive strategy Surgeon discretion Restrictive strategy
Van Dijk, 2019 [20]g 6 weeks 6 weeks 7 (2%)e 7 (2%) 88 (22%)e 74 (21%)
[2, 10]c,h [3, 11]h
aStudies looked at same population, examined different outcomes at different timepoints
b
No range reported
c
p < 0.05
d
Median [range]
e
Not significantly different
f
Anwar, 2008 defined urgent cholecystectomy as early/same-day
g
Surgeon discretion defined as operation based on standard care left to the discretion of the surgeon; restrictive strategy used the fulfillment of five pre-specified
criteria as indication for operation
h
Median [IQR]
Shenoy et al. Systematic Reviews (2022) 11:267 Page 6 of
9

as an operation on the next available list) versus elec-

between groups [22]. For example, 26% (N 23) of
tive surgery. The wait times for each arm are shown in
patients receiving UDCA were colic-free compared to
Table 3. Over one quarter of patients waiting for elec-
33% (N 29) in the placebo group (p > 0.05) (follow-up
tive surgery required gallstone-related visits (Table 2). Of
time varied, see Table 1).
those patients who underwent urgent or early surgery,
One study (abstract-only) compared electro-acupunc-
none had gallstone-related events. Salman, et al. found a
ture versus observation [25]. Patient reported outcomes
reduction in conversion rates during surgery for the elec-
were only reported secondarily and they found no differ-
tive group (17.2% versus 0%, p < 0.05); however Anwar,
ences between groups. Of note, their primary outcome
et al. found no differences in conversion rates between
was proportion of patients with clearance of gallstones
the early versus elective groups (2% versus 0%, p > 0.05). (confirmed by ultrasonography), and there was no dif-
Neither study found a difference in postoperative com- ference in clearance between groups. In the electro-acu-
plications between groups with Salman, et al showing no
puncture group, 9% (N 2) of patients had full clearance,
postoperative complications in any groups, and Anwar,
compared to 4% (N 1) in the control group (p > 0.05).
et al. finding 8% complication rates in the elective group
and zero complications in the early group.
ED pain management strategies
Surgical comparisons: criteria for surgical eligibility Two trials compared medications for pain management
Van Dijk, et al. examined methods of selecting patients in the ED for patients with symptomatic cholelithiasis.
for surgery. Standard care in the participating centers Antevil et al. examined intravenous glycopyrrolate versus
(surgeon-discretion) was compared to a method using placebo and demonstrated no difference in the median
fulfillment of pre-specified criteria for eligibility in which decrease in pain (between zero and 20 min) using the
a patient had to fulfill all five criteria to be eligible for visual analog pain scale (3 [95% CI − 2–2]) versus 1
operation (restrictive). The five pre-specified criteria [95% CI − 3, 12]) [24]. Malesci et al. compared
were (1) severe pain attacks, (2) pain lasting 15–30 min loxiglumide
or longer, (3) pain located in epigastrium or right upper (CCK-1 receptor blocker) versus hyoscine-N-butyl bro-
quadrant, (4) pain radiating to the back, and (5) a posi- mide (anticholinergic) and found that the reduction in
tive pain response to simple analgesics [20]. There was no pain score as measured by visual analog scale was signifi-
difference in proportion of patients who were pain-free cantly greater with loxiglumide after 20 (88% vs 47%, p <
at 1 year (surgeon-discretion: 60% vs restrictive: 56%, p 0.05) and 30 min (92% vs 49%, p < 0.05) [23]. This study
> 0.05), or gallstone-related events (Table 2) based on also found that a second injection was needed in fewer
surgery selection method [20]. There were also no differ- patients treated with loxiglumide (14% vs 86%, p < 0.05)
ences in conversion rates (2% in both groups, p > 0.05), at 30 min.
postoperative complications (surgeon discretion 21% ver-
sus restrictive 21%, p > 0.05) or gallstone complications
between groups (surgeon discretion 7% versus restrictive Risk of bias
8%, p > 0.05) [20]. The risk of bias for the RCTs which had a surgical arm
was judged to be moderate (Supplementary material 3)
Non-surgical therapies [14–17, 19, 20]. Studies were deemed to have a moder-
Two RCTs examined the use of UDCA. Petroni et al. ate rating due to high risk of bias pertaining to blinding
compared UDCA alone with UDCA with chenodeoxy- of participants, personnel across all studies and a high
cholic acid and found that both treatments reduced the risk of bias in blinding of outcome assessment for most
frequency of biliary pain at three months and through- studies (one study had unknown risk of bias) [20]. The
out the 2-year follow-up (UDCA alone 26% versus one observational study which had a surgical arm had
UDCA with chenodeoxycholic acid 21%, p < 0.05). a moderate risk of bias using the ROBINS-I tool due to
Since this was a secondary end-point, they did not non-random assignment of treatment arms [18].
compare the difference in reduction between groups. The risk of bias for the RCTs comparing UDCA treat-
They found no substantial difference in gallstone dis- ment was low was judged to be low with one study having
solution rate (primary end-point) between groups at 2 low risk across all categories assessed [22], and the other
years (UDCA alone 28% versus UDCA with chenode- having low or unknown risk across all categories [21].
oxycholic acid 30%, p > 0.05) [21]. Venneman et al com- The RCT comparing electro-acupuncture to observation
pared UDCA to placebo in patients waiting for surgery was rated as high risk, with bias across most domains
and found no difference in the proportion of patients (Supplementary material 3) [25]. The RCTs comparing
that were colic-free or experienced complications ED pain management strategies were low risk across all
domains [23, 24].
Shenoy et al. Systematic Reviews (2022) 11:267 Page 7 of
9

Discussion better outcomes than in those who underwent the pla-

This systematic review found 12 publications reporting cebo procedure [27]. This study design may be more
on 10 trials (9 RCTs and 1 observational study) interpretable than a watchful waiting versus surgery
compar- ing treatment methods for symptomatic trial to delineate patients with symptomatic cholelithi-
cholelithiasis. The studies assessed surgery, asis who would benefit from gallbladder removal.”
observation, lithotripsy, UDCA, electro-acupuncture Despite these challenges, two studies concluded that
and pain-management strategies in the ED. We fewer complications were associated with early (within
identified only one trial that compared surgery to 24 h) or urgent cholecystectomy for symptomatic chole-
observation, one comparing surgery to lithotripsy, two lithiasis as compared to elective surgery [16, 17]. This
comparing timing of surgery and one comparing was based primarily on complications during the wait-
methods to select patients for surgery. Non- surgical ing period for patients receiving elective surgery, with
alternatives included two studies examining the use of both studies reporting mean surgery wait times of over
UDCA (either comparing to placebo or in a com- three months. Prior literature showed that prolonged
bination therapy) and one examining the use of electro- wait times for elective cholecystectomy can be associated
acupuncture compared to observation. Two studies with patient morbidity and increased hospital costs. One
looked at options for pain management in the ED. study found that while waiting for cholecystectomy, 14%
Given this heterogeneity, making conclusions across studies of patients required an unplanned presentation to the
was limited, and this review highlights challenges in hospital [28]. However, operating immediately for non-
studying treatments for a disease process that may emergent disease processes is also not ideal since urgent
present at var- ied stages of disease. procedures have higher morbidity and mortality than
When interpreting the data, the time course of elective procedures [29]. Identifying and capitalizing on
patients’ symptomatic cholelithiasis should be consid- the optimal time to operate is not easy since both urgent
ered. Prior literature demonstrated that over half of surgery and long wait times are associated with compli-
patients with symptomatic cholelithiasis will not expe- cations. Implementing strategies to minimize surgical
rience recurrence of symptoms after their first attack wait times while avoiding the need to operate urgently
[25, 26]. Thus, the patient’s disease severity is critical. may prevent complications and alleviate the costly bur-
Of the 10 studies in our review, only 6 reported on den of this disease [7, 9]. A better understanding of which
symptoms or stone characteristics at randomization or patients may be more likely to experience complications
presentation [13, 15, 19–22] and only two reported sta- can guide prioritization to reduce recurrent ED visits
tistical tests comparing these factors [21, 22]. Patients while waiting for surgery. One study examined these fac-
were enrolled at all different stages of disease presen- tors by looking at age, sex, diagnosis, and comorbidities
tation with one study including those who had zero and found that only older age was associated with longer
prior attacks along with those who had over five pain wait times for surgery [30]. However there were several
attacks a month [15]. The varied disease course of characteristics missing, such as patient’s access to care,
symptomatic cholelithiasis makes findings difficult to socioeconomic status, and information about the treat-
interpret when patients are studied at different presen- ing hospital. These characteristics may provide insight to
tations, and makes designing and performing RCTs dif- identify vulnerable groups at higher risk for experiencing
ficult in this field. Perhaps, in order to guide clinicians complications while waiting for surgery.
when counseling patients with symptomatic cholelithi- This systematic review has several limitations. Within
asis, future trials should stratify patients based on their our treatment grouping categories, there was hetero-
disease presentation of symptomatic cholelithiasis (i.e., geneity between patient factors and clinical outcomes
number of prior episodes, duration or severity of pain). assessed. Some studies primarily examined clinical out-
Such trials may then consider interventions based on comes, while others focused on quality of life or health
this stratification, for example randomizing patients to status. Studies that focused on clinical outcomes meas-
watchful waiting versus surgery early in their disease ured gallstone-related events in different ways, with some
presentation, or to urgent versus elective surgery if they focusing on pain-related admissions and complications
present after several attacks. Another consideration for separately [15, 18], and others grouping all complications
patients with mild symptoms is to utilize a placebo arm. together [16, 17]. Additionally, we were unable to test for
Such a study would randomize patients to laparoscopic publication bias and cannot make any conclusions about
cholecystectomy versus placebo procedure (no actual its possible existence. Finally, overall quality of the
surgery), and examine whether those in the placebo studies was low to moderate, given unclear blinding
arm continued to have symptoms. A similar study in mechanisms for RCTs and non-random assignment of
orthopedic surgery demonstrated that surgical inter- treatment arms for the observational study. Despite these
vention in patients with osteoarthritis did not provide limitations, our
Shenoy et al. Systematic Reviews (2022) 11:267 Page 8 of
9

work provides a current, comprehensive analysis of treat- Received: 20 December 2021 Accepted: 8 November 2022
ment strategies for symptomatic cholelithiasis.
Based on our findings, medical or alternate therapies
for symptomatic cholelithiasis such as UDCA, lithotripsy,
or electro-acupuncture as compared to surgery or References
watch- ful waiting have not been well studied. Studies 1. Gurusamy KS, Koti R, Fusai G, Davidson BR. Early versus delayed lapa-
roscopic cholecystectomy for uncomplicated biliary colic. Cochrane
compar- ing the timing of surgery or watchful waiting at
Database Syst Rev. 2013;(6):Cd007196. https://doi.org/10.1002/14651858.
particular points in patient’s disease process are CD007196.pub3.
warranted to deter- mine optimal management and 2. Stinton LM, Shaffer EA. Epidemiology of gallbladder disease: cholelithi-
asis and cancer. Gut Liver. 2012;6(2):172–87. https://doi.org/10.5009/gnl.
create a set of stand- ardized guidelines to guide 2012.6.2.172.
clinicians when counseling patients. Providing 3. Attili AF, de Santis A, Capri R, Repice AM, Maselli S, Group G. The
appropriate and timely treatment for symptomatic natural history of gallstones: The GREPCO experience. Hepatology.
1995;21(3):656–60. https://doi.org/10.1002/hep.1840210309.
cholelithiasis is important to streamline care for a 4. McSherry CK, Ferstenberg H, Calhoun WF, Lahman E, Virshup M. The
costly and prevalent disease. natural history of diagnosed gallstone disease in symptomatic and
asymptomatic patients. Ann Surg. Jul 1985;202(1):59-63. doi:https://doi.
org/10.1097/00000658-198507000-00009
Supplementary Information 5. Friedman GD. Natural history of asymptomatic and symptomatic gall-
The online version contains supplementary material available at https://doi. stones. Am J Surg. 1993;165(4):399–404. https://doi.org/10.1016/S0002-
org/10.1186/s13643-022-02135-8. 9610(05)80930-4.
6. Gurusamy KS, Davidson C, Gluud C, Davidson BR. Early versus delayed
Additional file 1: Supplementary material 1. Search strategies. laparoscopic cholecystectomy for people with acute cholecystitis.
Cochrane Database Syst Rev. 2013;(6). https://doi.org/10.1002/14651858.
Additional file 2: Supplementary material 2. Data extraction tables. CD005440.pub3.
Additional file 3: Supplementary material 3. Risk of bias for rand- 7. Shaheen NJ, Hansen RA, Morgan DR, et al. The burden of gastrointestinal
omized controlled trials and observational studies. and liver diseases, 2006. Am J Gastroenterol. 2006;101(9):2128–38. https://
doi.org/10.1111/j.1572-0241.2006.00723.x.
8. Tsui C, Klein R, Garabrant M. Minimally invasive surgery: national trends
Acknowledgements in adoption and future directions for hospital strategy. Surg
We have no additional acknowledgements. Endosc. 2013;27(7):2253–7.
https://doi.org/10.1007/s00464-013-2973-9.
Authors’ contributions 9. Glasgow RE, Cho M, Hutter MM, Mulvihill SJ. The spectrum and cost of
All authors substantially contributed to conception, design, acquisition of complicated gallstone disease in California. Arch Surg. 2000;135(9):1021–
data, and interpretation of data. RS, PK, MDV, and JH contributed to data 5. https://doi.org/10.1001/archsurg.135.9.1021.
analysis. RS, MR, and MMG drafted the manuscript. All authors critically revised 10. Altieri MS, Yang J, Zhu C, et al. What happens to biliary colic patients
the manuscript for important intellectual content and gave final approval in New York State? 10-year follow-up from emergency department
for the version to be published. visits. Surg Endosc. 2018;32(4):2058–66. https://doi.org/10.1007/
s00464-017-5902-5.
Funding 11. Portincasa P, Di Ciaula A, Wang HH, Moschetta A, Wang DQ.
Dr. Rivfka Shenoy is supposed by the VA Office of Academic Affiliations Medicinal treatments of cholesterol gallstones: old, current and new
through the VA/National Clinician Scholars Program. Funding was provided by perspectives. Curr Med Chem. 2009;16(12):1531–42.
the VA Quality Enhancement Research Initiative. The funders of the study had https://doi.org/10.2174/09298 6709787909631.
no role in design and conduct of the study; collection, management, analysis, 12. Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration’s
and interpretation of the data; and preparation, review, or approval of the tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.
manuscript or the decision to submit for publication. https://doi.org/10.1136/bmj.d5928.
13. Sterne JA, Hernán MA, Reeves BC, et al. ROBINS-I: a tool for assessing
Availability of data and materials risk of bias in non-randomised studies of interventions. BMJ.
The datasets generated and analyzed during the current study are available in 2016;355:i4919. https://doi.org/10.1136/bmj.i4919.
Supplementary material 2. The articles used to generate these evidence 14. Ahmed R, Freeman JV, Ross B, Kohler B, Nicholl JP, Johnson AG. Long term
tables are available in the PubMed, Embase, or Cochrane repository. response to gallstone treatment - problems and surprises. Eur J Surg.
2000;166(6):447–54.
15. Vetrhus M, Søreide O, Eide GE, Solhaug JH, Nesvik I, Søndenaa K. Pain
Declarations and quality of life in patients with symptomatic, non-complicated
gallblad- der stones: results of a randomized controlled trial. Clinical
Competing interests Trial; Journal Article; Randomized Controlled Trial; Research Support,
Dr. Rivfka Shenoy was supported by the VA Office of Academic Non-U.S. Gov’t. Scand J Gastroenterol. 2004;39(3):270–6.
Affiliations through the VA/National Clinician Scholars Program while https://doi.org/10.1080/00365 520310008502.
working on this study. The other authors declare that they have no 16. Vetrhus M, Søreide O, Solhaug JH, Nesvik I, Søndenaa K. Symptomatic,
competing interests. non-complicated gallbladder stone disease. Operation or observation? A
randomized clinical study. Scand J Gastroenterol. 2002;37(7):834–9.
Author details 17. Salman B, Yüksel O, Irkörücü O, et al. Urgent laparoscopic cholecystec-
1
Department of Surgery, UCLA David Geffen School of Medicine, Los Angeles, tomy is the best management for biliary colic. A prospective randomized
CA, USA. 2Veterans Health Administration, Greater Los Angeles Healthcare study of 75 cases. Dig Surg. 2005;22(1-2):95–9. https://doi.org/10.1159/
System, Los Angeles, CA, USA. 3National Clinician Scholars Program, UCLA, Los 000085300.
Angeles, CA, USA. 4Department of Surgery, Los Angeles County Harbor-UCLA 18. Anwar HA, Ahmed QA, Bradpiece HA. Removing symptomatic
Medical Center, Los Angeles, CA, USA. 5Louise M. Darling Biomedical Library, gallstones at the their first emergency presentation. Ann Royal College
UCLA Library, University of California, Los Angeles, CA, USA. 6Rand Corpora- Surgeons England. 2008;90(5):394–7.
tion, Santa Monica, CA, USA. 7Olive View-UCLA Medical Center, Sylmar, CA, https://doi.org/10.1308/003588408X301037.
USA. 19. Schmidt M, Søndenaa K, Vetrhus M, Berhane T, Eide GE. A randomized
controlled study of uncomplicated gallstone disease with a
14-year
Shenoy et al. Systematic Reviews (2022) 11:267 Page 9 of
9

follow-up showed that operation was the preferred treatment. Dig Surg.
2011;28(4):270–6. https://doi.org/10.1159/000329464.
20. van Dijk AH, Wennmacker SZ, de Reuver PR, et al. Restrictive strategy
versus usual care for cholecystectomy in patients with gallstones and
abdominal pain (SECURE): a multicentre, randomised, parallel-arm, non-
inferiority trial. Lancet. 2019;393(10188):2322–30.
https://doi.org/10.1016/ S0140-6736(19)30941-9.
21. Petroni ML, Jazrawi RP, Pazzi P, et al. Ursodeoxycholic acid alone or
with chenodeoxycholic acid for dissolution of cholesterol gallstones: a
randomized multicentre trial. The British-Italian Gallstone Study
group.
Clinical Trial; Journal Article; Multicenter Study; Randomized Con-
trolled Trial; Research Support, Non-U.S. Gov’t. Aliment Pharmacol Ther.
2001;15(1):123–8. https://doi.org/10.1046/j.1365-2036.2001.00853.x.
22. Venneman NG, Besselink MGH, Keulemans YCA, et al. Ursodeoxycholic
acid exerts no beneficial effect in patients with symptomatic gallstones
awaiting cholecystectomy. Hepatology. 2006;43(6):1276–83. https://doi.
org/10.1002/hep.21182.
23. Malesci A, Pezzilli R, D’Amato M, Rovati L. CCK-1 receptor blockade
for treatment of biliary colic: a pilot study. Aliment Pharmacol Ther.
2003;18(3):333–7. https://doi.org/10.1046/j.1365-2036.2003.01688.x.
24. Antevil JL, Buckley RG, Johnson AS, Woolf AM, Thoman DS,
Riffenburgh RH. Treatment of suspected symptomatic cholelithiasis
with glycopyr- rolate: a prospective, randomized clinical trial. Clinical Trial;
Journal Article; Randomized Controlled Trial; Research Support, U.S. Gov’t,
Non-P.H.S. Ann Emerg Med. 2005;45(2):172–6.
https://doi.org/10.1016/j.annemergmed. 2004.06.017.
25. Wong W, Wu J, Sun W, et al. A randomized, single-blind, controlled
trial of electro-acupuncture for the treatment of symptomatic gallstone
dis- eases. Adv Integrative Med. 2019;6:S50.
https://doi.org/10.1016/j.aimed. 2019.03.148.
26. Festi D, Reggiani ML, Attili AF, et al. Natural history of gallstone
disease: expectant management or active treatment? Results from a
population- based cohort study. J Gastroenterol Hepatol.
2010;25(4):719–24. https:// doi.org/10.1111/j.1440-1746.2009.06146.x.
27. Moseley JB, O’Malley K, Petersen NJ, Menke TJ, Brody BA, Kuykendall
DH, et al. A controlled trial of arthroscopic surgery for osteoarthritis
of the knee. N Engl J Med. 2002;347(2):81–8.
https://doi.org/10.1056/NEJMo a013259.
28. Lawrentschuk N, Hewitt PM, Pritchard MG. Elective laparoscopic chol-
ecystectomy: Implications of prolonged waiting times for surgery. ANZ
J Surg. 2003;73(11):890–3. https://doi.org/10.1046/j.1445-2197.2003.
02826.x.
29. Mullen MG, Michaels AD, Mehaffey JH, et al. Risk associated with com-
plications and mortality after urgent surgery vs elective and emergency
surgery: implications for defining “quality” and reporting outcomes for
urgent surgery. JAMA Surg. 2017;152(8):768–74. https://doi.org/10.1001/
jamasurg.2017.0918.
30. Lau R, Vair BA, Porter GA. Factors influencing waiting times for elective
laparoscopic cholecystectomy. Can J Surg. 2007;50(1):34–8.

Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in pub-
lished maps and institutional affiliations.

Ready to submit your researc\ ? C\oose BMC and benefit from:

• fast, convenient online submission

• thorough peer review by experienced researchers in your field
• rapid publication on acceptance
• support for research data, including large and complex data types
• gold Open Access which fosters wider collaboration and increased citations
• maximum visibility for your research: over 100M website views per year

At BMC, research is always in

progress. Learn more

biomedcentral.com/submissions