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, 9].
toms occur in up to 10% of patients within 5 years, which Despite being a common surgical problem, there is no
can progress to advanced disease such as acute cholecys- consensus nor formal recommendations for eligibility
titis, choledocholithiasis, or gallstone pancreatitis [1–6]. criteria or optimal timing for surgery for symptomatic
Gallstones lead to over one million ambulatory care vis- 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: rivfkashenoy@mednet.ucla.edu
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://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. The Creative Commons Public Domain Dedication waiver (http://​creat​iveco​
mmons.​org/​publi​cdoma​in/​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 Statistical analysis

All searches included PubMed, Embase, Cochrane Tri- Due to the heterogeneity in clinical outcomes of both
als and Cochrane Reviews from January 2000 to 29 June the RCTs and the observational studies, a meta-analysis
2020, when the search was executed. The search strategy was not performed, and data was synthesized narratively.
used a broad set of terms related to the treatment out- Studies were grouped based on the types of treatments
comes of cholelithiasis, gallbladder, and biliary tract dis- compared: surgery, (surgery versus observation, surgery
ease (see Supplementary material 1 for complete search versus lithotripsy, urgent versus elective surgery or surgi-
strategy). The search emphasized terms indicating cal criteria comparisons), non-surgical therapies (UDCA
length of stay, hospital readmission, and quality adjusted versus placebo, UDCA versus UDCA with chenodeoxy-
life years to ascertain post-intervention impacts. We cholic acid, and electro-acupuncture versus observation),
excluded studies published prior to the year 2000 to cap- and pain management in the ED.
ture contemporary treatment strategies.
Results
Study selection and data collection Literature search
All stages of title screen through data abstraction were The search identified 6366 publications and 12 were
completed by two independent team members and disa- included in our study (see Fig.  1 for literature flow and
greements were reconciled through discussion. Studies breakdown by database) [14–25]. These 12 articles
that did not compare treatments were excluded. Stud- reported on nine RCTs [14–17, 19–25] (several dupli-
ies were included if they assessed surgery (cholecystec- cates) and one observational study [18]. Table  1 shows
tomy), non-surgical therapies, or ED pain management the comparison arms and study characteristics for each
strategies as one of the comparison arms. Studies were study including follow-up time. For surgery comparative
included if they had all of the following criteria: (1) stud- studies, seven publications reported on five trials (three
ied adult patients with symptomatic cholelithiasis or reported different time-points and outcomes for one
included a sub-group with symptomatic cholelithiasis; RCT) [14–20] Specifically, three publications reported
(2) included one group of patients treated by observation on one trial that compared surgery versus observation
or alternate treatment method; (3) had a comparison to [15, 16, 19], two compared timing of surgery [17, 18], one
patients treated with a different method; (4) measured compared surgery to lithotripsy [14], and one compared
intraoperative, perioperative, or postoperative outcomes. methods to select patients for surgery [20]. Three pub-
Randomized controlled trials (RCTs) and observational lications compared non-surgical therapies [21, 22, 25].
studies were included. We did not exclude studies based Two compared UDCA to either placebo [22] or UDCA
on follow-up time. Abstracts were included in the review plus chenodeoxycholic acid [21], and one compared
(if there was no companion full article) and underwent electro-acupuncture to observation [25]. Two publica-
the same quality assessment and duplication exclusion tions compared types of ED pain medication [23, 24].
 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] ­ anagemente
ED pain m Single Randomized 14 48h
Antevil, 2004 [24] ­ anagementf
ED pain m 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 other three Surgical comparisons: surgery versus observation
did not report statistical tests of comparisons [14, 16, One RCT examined surgery versus observation and
20]. The fifth trial (Anwar, et al.) which included a surgi- published three studies (Vetrhus, 2002; Vetrhus, 2004;
cal comparison only reported age of the patients and did Schmid, 2011) looking at different outcomes at different
not comment on statistical significance [18]. Three out of time-points [15, 16, 19]. Gallstone-related events includ-
five trials defined symptomatic cholelithiasis as abdomi- ing pain attacks and complications were not different
nal pain with ultrasound signs of gallstones and without between groups at 5 or 14 years (Table  2). Over half of
evidence of advanced biliary pathology (i.e., abnormal the patients in the observation group received surgery
leukocytes, complicated cholelithiasis) [15–17, 19, 20]. (50.7%). Conversion rates and postoperative complica-
One trial included patients with “symptomatic gall- tions were slightly higher in the patients randomized to
stones” without further specifying [14], and one included observation that ultimately underwent surgery (conver-
patients with cholelithiasis based on clinical findings sion rates: 11% versus 0; postoperative complications:
from the chart [18]. Three out of five trials reported spe- 14% versus 5%, Table  3); however, they did not report
cific clinical disease characteristics including number of whether this difference was statistically significant.
prior episodes, severity of prior episodes, prior hospi- Vetrhus, et  al. (2004) examined quality of life (using the
talizations and length of symptoms [14, 16, 20]. These Psychological General Well Being index and Nottingham
trials did not report statistical tests of comparison, but Health Profile Part II) and pain (pain score and visual
stated that characteristics were similar between groups. analog pain scale) and found no differences between the
These trials had follow-up times ranging from 1 [20] to surgery versus observation group [15].
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.
groups defined symptomatic cholelithiasis as abdominal Open, elective cholecystectomy was compared to inpa-
pain lasting at least 30 min with gallstones, and without tient lithotripsy consisting of up to four treatment ses-
advanced biliary disease [21, 22]. The first study found no sions on consecutive days with up to 3000 shocks per
differences in age, sex, or weight between groups. This session. This study found that while both groups had
study reported a number of different baseline disease experienced reductions in mean number of episodes of
characteristics such as number of biliary colic episodes biliary pain and mean severity summary score, patients
in the preceding year, pain localization, and pain medica- treated with surgery had larger decrease in both meas-
tions needed in the preceding year. There were no signifi- ures as compared to the group treated with lithotripsy
cant differences in these characteristics between groups [14]. For example, 81.8% (N 45) of patients who under-
[22]. The other study reported age, sex, BMI, and stone went cholecystectomy were pain-free at 5-year follow-up
characteristics, stating that groups were well-matched, compared to 55.2% (N 48) of patients who were rand-
but did not report statistical tests of comparison [21]. omized to lithotripsy (p < 0.05).
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- Gallstone-related events Operative rate
related events

Surgery Observation Surgery Observation

Vetrhus, 2002 [16] and 2004 Complications of gallstones: 5-year follow-up 5-year follow-up 60/68 randomized (88%) 35/69 randomized (51%)
[15] and Schmidt, 2011 [19]* acute pancreatitis, common Pain-related Pain-related
bile duct stone(s), acute admissions: 2 admission: 12
cholecystitis (1%) (17%)
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 Conversion rate Postoperative complications
mean ± SD N, (%) N, (%)

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 months follow-up
Schmidt, 2011 [19]a 14-year follow-up 27 [0–67] months
3 [0–168] ­monthsd 14-year follow-up
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
f e
Anwar, 2008 [18] 114 days 3 days 0 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 [95%
operation (restrictive). The five pre-specified criteria CI − 3, 12]) [24]. Malesci et  al. compared loxiglumide
were (1) severe pain attacks, (2) pain lasting 15–30 min (CCK-1 receptor blocker) versus hyoscine-N-butyl bro-
or longer, (3) pain located in epigastrium or right upper mide (anticholinergic) and found that the reduction in
quadrant, (4) pain radiating to the back, and (5) a posi- pain score as measured by visual analog scale was signifi-
tive pain response to simple analgesics [20]. There was no cantly greater with loxiglumide after 20 (88% vs 47%, p <
difference in proportion of patients who were pain-free 0.05) and 30 min (92% vs 49%, p < 0.05) [23]. This study
at 1 year (surgeon-discretion: 60% vs restrictive: 56%, p also found that a second injection was needed in fewer
> 0.05), or gallstone-related events (Table  2) based on patients treated with loxiglumide (14% vs 86%, p < 0.05)
surgery selection method [20]. There were also no differ- at 30 min.
ences in conversion rates (2% in both groups, p > 0.05),
postoperative complications (surgeon discretion 21% ver-
sus restrictive 21%, p > 0.05) or gallstone complications Risk of bias
between groups (surgeon discretion 7% versus restrictive The risk of bias for the RCTs which had a surgical arm
8%, p > 0.05) [20]. was judged to be moderate (Supplementary material 3)
[14–17, 19, 20]. Studies were deemed to have a moder-
Non‑surgical therapies ate rating due to high risk of bias pertaining to blinding
Two RCTs examined the use of UDCA. Petroni et  al. of participants, personnel across all studies and a high
compared UDCA alone with UDCA with chenodeoxy- risk of bias in blinding of outcome assessment for most
cholic acid and found that both treatments reduced the studies (one study had unknown risk of bias) [20]. The
frequency of biliary pain at three months and through- one observational study which had a surgical arm had
out the 2-year follow-up (UDCA alone 26% versus a moderate risk of bias using the ROBINS-I tool due to
UDCA with chenodeoxycholic acid 21%, p < 0.05). non-random assignment of treatment arms [18].
Since this was a secondary end-point, they did not The risk of bias for the RCTs comparing UDCA treat-
compare the difference in reduction between groups. ment was low was judged to be low with one study having
They found no substantial difference in gallstone dis- low risk across all categories assessed [22], and the other
solution rate (primary end-point) between groups at 2 having low or unknown risk across all categories [21].
years (UDCA alone 28% versus UDCA with chenode- The RCT comparing electro-acupuncture to observation
oxycholic acid 30%, p > 0.05) [21]. Venneman et al com- was rated as high risk, with bias across most domains
pared UDCA to placebo in patients waiting for surgery (Supplementary material 3) [25]. The RCTs comparing
and found no difference in the proportion of patients ED pain management strategies were low risk across all
that were colic-free or experienced complications 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) compar- interpretable than a watchful waiting versus surgery
ing treatment methods for symptomatic cholelithiasis. trial to delineate patients with symptomatic cholelithi-
The studies assessed surgery, observation, lithotripsy, asis who would benefit from gallbladder removal.”
UDCA, electro-acupuncture and pain-management Despite these challenges, two studies concluded that
strategies in the ED. We identified only one trial that fewer complications were associated with early (within
compared surgery to observation, one comparing surgery 24 h) or urgent cholecystectomy for symptomatic chole-
to lithotripsy, two comparing timing of surgery and one lithiasis as compared to elective surgery [16, 17]. This
comparing methods to select patients for surgery. Non- was based primarily on complications during the wait-
surgical alternatives included two studies examining the ing period for patients receiving elective surgery, with
use of UDCA (either comparing to placebo or in a com- both studies reporting mean surgery wait times of over
bination therapy) and one examining the use of electro- three months. Prior literature showed that prolonged
acupuncture compared to observation. Two studies wait times for elective cholecystectomy can be associated
looked at options for pain management in the ED. Given with patient morbidity and increased hospital costs. One
this heterogeneity, making conclusions across studies was study found that while waiting for cholecystectomy, 14%
limited, and this review highlights challenges in studying of patients required an unplanned presentation to the
treatments for a disease process that may present at var- hospital [28]. However, operating immediately for non-
ied stages of disease. emergent disease processes is also not ideal since urgent
When interpreting the data, the time course of procedures have higher morbidity and mortality than
patients’ symptomatic cholelithiasis should be consid- elective procedures [29]. Identifying and capitalizing on
ered. Prior literature demonstrated that over half of the optimal time to operate is not easy since both urgent
patients with symptomatic cholelithiasis will not expe- surgery and long wait times are associated with compli-
rience recurrence of symptoms after their first attack cations. Implementing strategies to minimize surgical
[25, 26]. Thus, the patient’s disease severity is critical. wait times while avoiding the need to operate urgently
Of the 10 studies in our review, only 6 reported on may prevent complications and alleviate the costly bur-
symptoms or stone characteristics at randomization or den of this disease [7, 9]. A better understanding of which
presentation [13, 15, 19–22] and only two reported sta- patients may be more likely to experience complications
tistical tests comparing these factors [21, 22]. Patients can guide prioritization to reduce recurrent ED visits
were enrolled at all different stages of disease presen- while waiting for surgery. One study examined these fac-
tation with one study including those who had zero tors by looking at age, sex, diagnosis, and comorbidities
prior attacks along with those who had over five pain and found that only older age was associated with longer
attacks a month [15]. The varied disease course of wait times for surgery [30]. However there were several
symptomatic cholelithiasis makes findings difficult to characteristics missing, such as patient’s access to care,
interpret when patients are studied at different presen- socioeconomic status, and information about the treat-
tations, and makes designing and performing RCTs dif- ing hospital. These characteristics may provide insight to
ficult in this field. Perhaps, in order to guide clinicians identify vulnerable groups at higher risk for experiencing
when counseling patients with symptomatic cholelithi- complications while waiting for surgery.
asis, future trials should stratify patients based on their This systematic review has several limitations. Within
disease presentation of symptomatic cholelithiasis (i.e., our treatment grouping categories, there was hetero-
number of prior episodes, duration or severity of pain). geneity between patient factors and clinical outcomes
Such trials may then consider interventions based on assessed. Some studies primarily examined clinical out-
this stratification, for example randomizing patients to comes, while others focused on quality of life or health
watchful waiting versus surgery early in their disease status. Studies that focused on clinical outcomes meas-
presentation, or to urgent versus elective surgery if they ured gallstone-related events in different ways, with some
present after several attacks. Another consideration for focusing on pain-related admissions and complications
patients with mild symptoms is to utilize a placebo arm. separately [15, 18], and others grouping all complications
Such a study would randomize patients to laparoscopic together [16, 17]. Additionally, we were unable to test for
cholecystectomy versus placebo procedure (no actual publication bias and cannot make any conclusions about
surgery), and examine whether those in the placebo its possible existence. Finally, overall quality of the studies
arm continued to have symptoms. A similar study in was low to moderate, given unclear blinding mechanisms
orthopedic surgery demonstrated that surgical inter- for RCTs and non-random assignment of treatment arms
vention in patients with osteoarthritis did not provide for the observational study. Despite these 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 watch- References
1. Gurusamy KS, Koti R, Fusai G, Davidson BR. Early versus delayed lapa‑
ful waiting have not been well studied. Studies compar- roscopic cholecystectomy for uncomplicated biliary colic. Cochrane
ing the timing of surgery or watchful waiting at particular Database Syst Rev. 2013;(6):Cd007196. https://​doi.​org/​10.​1002/​14651​858.​
points in patient’s disease process are warranted to deter- CD007​196.​pub3.
2. Stinton LM, Shaffer EA. Epidemiology of gallbladder disease: cholelithi‑
mine optimal management and create a set of stand- asis and cancer. Gut Liver. 2012;6(2):172–87. https://​doi.​org/​10.​5009/​gnl.​
ardized guidelines to guide clinicians when counseling 2012.6.​2.​172.
patients. Providing appropriate and timely treatment for 3. Attili AF, de Santis A, Capri R, Repice AM, Maselli S, Group G. The
natural history of gallstones: The GREPCO experience. Hepatology.
symptomatic cholelithiasis is important to streamline 1995;21(3):656–60. https://​doi.​org/​10.​1002/​hep.​18402​10309.
care for a costly and prevalent disease. 4. McSherry CK, Ferstenberg H, Calhoun WF, Lahman E, Virshup M. The
natural history of diagnosed gallstone disease in symptomatic and
asymptomatic patients. Ann Surg. Jul 1985;202(1):59-63. doi:https://​doi.​
Supplementary Information org/​10.​1097/​00000​658-​19850​7000-​00009
The online version contains supplementary material available at https://​doi.​ 5. Friedman GD. Natural history of asymptomatic and symptomatic gall‑
org/​10.​1186/​s13643-​022-​02135-8. stones. Am J Surg. 1993;165(4):399–404. https://​doi.​org/​10.​1016/​S0002-​
9610(05)​80930-4.
Additional file 1: Supplementary material 1. Search strategies. 6. Gurusamy KS, Davidson C, Gluud C, Davidson BR. Early versus delayed
laparoscopic cholecystectomy for people with acute cholecystitis.
Additional file 2: Supplementary material 2. Data extraction tables. Cochrane Database Syst Rev. 2013;(6). https://​doi.​org/​10.​1002/​14651​858.​
Additional file 3: Supplementary material 3. Risk of bias for rand‑ CD005​440.​pub3.
omized controlled trials and observational studies. 7. Shaheen NJ, Hansen RA, Morgan DR, et al. The burden of gastrointestinal
and liver diseases, 2006. Am J Gastroenterol. 2006;101(9):2128–38. https://​
doi.​org/​10.​1111/j.​1572-​0241.​2006.​00723.x.
Acknowledgements 8. Tsui C, Klein R, Garabrant M. Minimally invasive surgery: national trends
We have no additional acknowledgements. in adoption and future directions for hospital strategy. Surg 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/​archs​urg.​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 for in New York State? 10-year follow-up from emergency department
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. Medicinal
Dr. Rivfka Shenoy is supposed by the VA Office of Academic Affiliations treatments of cholesterol gallstones: old, current and new perspectives.
through the VA/National Clinician Scholars Program. Funding was provided by Curr Med Chem. 2009;16(12):1531–42. https://​doi.​org/​10.​2174/​09298​
the VA Quality Enhancement Research Initiative. The funders of the study had 67097​87909​631.
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 risk
Availability of data and materials of bias in non-randomised studies of interventions. BMJ. 2016;355:i4919.
The datasets generated and analyzed during the current study are available in https://​doi.​org/​10.​1136/​bmj.​i4919.
Supplementary material 2. The articles used to generate these evidence tables 14. Ahmed R, Freeman JV, Ross B, Kohler B, Nicholl JP, Johnson AG. Long term
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 and
Declarations quality of life in patients with symptomatic, non-complicated gallblad‑
der stones: results of a randomized controlled trial. Clinical Trial; Journal
Competing interests Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov’t.
Dr. Rivfka Shenoy was supported by the VA Office of Academic Affiliations Scand J Gastroenterol. 2004;39(3):270–6. https://​doi.​org/​10.​1080/​00365​
through the VA/National Clinician Scholars Program while working on this 52031​00085​02.
study. The other authors declare that they have no competing interests. 16. Vetrhus M, Søreide O, Solhaug JH, Nesvik I, Søndenaa K. Symptomatic,
non-complicated gallbladder stone disease. Operation or observation? A
Author details randomized clinical study. Scand J Gastroenterol. 2002;37(7):834–9.
1
 Department of Surgery, UCLA David Geffen School of Medicine, Los Angeles, 17. Salman B, Yüksel O, Irkörücü O, et al. Urgent laparoscopic cholecystec‑
CA, USA. 2 Veterans Health Administration, Greater Los Angeles Healthcare tomy is the best management for biliary colic. A prospective randomized
System, Los Angeles, CA, USA. 3 National Clinician Scholars Program, UCLA, Los study of 75 cases. Dig Surg. 2005;22(1-2):95–9. https://​doi.​org/​10.​1159/​
Angeles, CA, USA. 4 Department of Surgery, Los Angeles County Harbor-UCLA 00008​5300.
Medical Center, Los Angeles, CA, USA. 5 Louise M. Darling Biomedical Library, 18. Anwar HA, Ahmed QA, Bradpiece HA. Removing symptomatic gallstones
UCLA Library, University of California, Los Angeles, CA, USA. 6 Rand Corpora‑ at the their first emergency presentation. Ann Royal College Surgeons
tion, Santa Monica, CA, USA. 7 Olive View-UCLA Medical Center, Sylmar, CA, England. 2008;90(5):394–7. https://​doi.​org/​10.​1308/​00358​8408X​301037.
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/​00032​9464.
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.​annem​ergmed.​
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​
a0132​59.
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/​
jamas​urg.​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 research ? Choose 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