ASYMPTOMATIC CHOLELITHIASIS: EXPECTANT OR CHOLECYSTECTOMY. A SYSTEMATIC REVIEW

Asymptomatic cholelithiasis is a highly prevalent disease, and became more evident after the currently greater access to imaging tests. Therefore, it is increasingly necessary to analyse the risks and benefits of performing a prophylactic cholecystectomy.

AIMS:

To seek the best evidence in order to indicate prophylactic cholecystectomy or conservative treatment (clinical follow-up) in patients with asymptomatic cholelithiasis.

METHODS:

A systematic review was performed using the PubMed/Medline database, according to PRISMA protocol guidelines. The review was based on studies published between April 26, 2001 and January 07, 2022, related to individuals older than 18 years., The following terms/operators were used for search standardization: (asymptomatic OR silent) AND (gallstones OR cholelithiasis).

RESULTS:

We selected 18 studies eligible for inference production after applying the inclusion and exclusion criteria. Also, the Tokyo Guideline (2018) was included for better clarification of some topics less or not addressed in these studies.

CONCLUSIONS:

Most evidence point to the safety and feasibility of conservative treatment (clinical follow-up) of asymptomatic cholelithiasis. However, in post-cardiac transplant patients and those with biliary microlithiasis with low preoperative surgical risk, a prophylactic cholecystectomy is recommended. To establish these recommendations, more studies with better levels of evidence must be conducted.

HEADINGS:
Cholecystectomy; Cholelithiasis; Gallstones; Gallbladder

Level of evidence and Degree of recommendation	Studies encompassed
1A	Systematic review of randomized clinical trials; Systematic review of prospective cohorts; Prognostic criteria validated in several populations; Systematic review of level 1 diagnostic studies.
1B	Randomized controlled clinical trials with narrow confidence interval; Cohort from disease onset, with loss <20%; Validated prognostic criteria in a single population; Validated cohort with a good baseline.
1C	All-or-nothing therapeutic results.
2A	Systematic review of cohort studies; Systematic review of retrospective or follow-up cohorts of untreated cases from a randomized clinical trial control group; Systematic review of diagnostic studies level >2.
2B	Cohort study (including randomized clinical trial of lower quality; e.g., <80% follow-up); Retrospective cohort study or follow-up of untreated control patients in randomized clinical trials.
2C	Observation of therapeutic outcomes (outcomes research); Ecological study.
3A	Systematic review of case-control studies; Systematic review of diagnostic studies level >3B.
3B	Case-control study; Non-consecutive study or no consistently applied benchmarks; Non-consecutive cohort study or very limited population.
4	Case report; Case series; Low-quality cohort and case-control studies.
5	Expert opinion without explicit critical appraisal or based on physiology, bench research, or “first principles”.

Studies	Presence of Randomization	Appropriate randomization method	Study was double-blind	Appropriate double-blind method	Sample Loss Description	Total
Ahmed et al.¹1 Ahmed I, Innes K, Brazzelli M, Gillies K, Newlands R, Avenell A, et al. Protocol for a randomised controlled trial comparing laparoscopic cholecystectomy with observation/conservative management for preventing recurrent symptoms and complications in adults with uncomplicated symptomatic gallstones (C-Gall trial). BMJ Open. 2021;11(3):e039781. https://doi.org/10.1136/bmjopen-2020-039781 https://doi.org/10.1136/bmjopen-2020-039...	+1	+1	0	0	+1	+3
Bencini et al.²2 Bencini L, Marchet A, Alfieri S, Rosa F, Verlato G, Marrelli D, et al. The Cholegas trial: long-term results of prophylactic cholecystectomy during gastrectomy for cancer-a randomized-controlled trial. Gastric Cancer. 2019;22(3):632-9. https://doi.org/10.1007/s10120-018-0879-x https://doi.org/10.1007/s10120-018-0879-...	+1	+1	+1	+1	+1	+5
Habeeb et al.⁹9 Habeeb TAAM, Kermansaravi M, Giménez ME, Manangi MN, Elghadban H, Abdelsalam SA, et al. Sleeve gastrectomy and cholecystectomy are safe in obese patients with asymptomatic cholelithiasis. a multicenter randomized trial. World J Surg. 2022;46(7):1721-33. https://doi.org/10.1007/s00268-022-06557-2. https://doi.org/10.1007/s00268-022-06557...	+1	0	0	0	+1	+2
Hyun et al.¹¹11 Howick J, Chalmers I, Glasziou P, Greenhalgh T, Heneghan C, Liberati A, et al. The Oxford Levels of Evidence. 2011. Available at: https://www.cebm.ox.ac.uk/resources/levels-of-evidence/ocebm-levels-of-evidence. Accessed: Jun. 25, 2022 https://www.cebm.ox.ac.uk/resources/leve...	0	0	0	0	+1	+1

Section/topic		Checklist item	Reported on page #
TITLE
	Title	Identify the report as a systematic review, meta-analysis, or both.	1
ABSTRACT
	Structured summary	Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.	1
INTRODUCTION
	Rationale	Describe the rationale for the review in the context of what is already known.	1–2
	Objectives	Provide an explicit statement of questions being addressed with reference to PICOS.	2
METHODS
	Protocol and registration	Indicate if a review protocol exists, if and where it can be accessed (e.g., web address), and, if available, provide registration information including registration number.	N/A
	Eligibility criteria	Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.	3
	Information sources	Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.	3
	Search	Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.	3
	Study selection	State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).	3
	Data collection process	Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.	3
	Data items	List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.	N/A
	Risk of bias in individual studies	Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.	N/A
	Summary measures	State the principal summary measures (e.g., risk ratio, difference in means).	2–3
	Synthesis of results	Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I2) for each meta-analysis.	3
	Risk of bias across studies	Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).	N/A
	Additional analyses	Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified.	N/A
RESULTS
	Study selection	Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.	3
	Study characteristics	For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.	N/A
	Risk of bias within studies	Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12).	3–8
	Results of individual studies	For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.	N/A
	Synthesis of results	Present results of each meta-analysis done, including confidence intervals and measures of consistency.	N/A
	Risk of bias across studies	Present results of any assessment of risk of bias across studies (see Item 15).	N/A
	Additional analysis	Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]).	N/A
DISCUSSION
	Summary of evidence	Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).	3–8
	Limitations	Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).	3–8
	Conclusions	Provide a general interpretation of the results in the context of other evidence, and implications for future research.	3–8
FUNDING
	Funding	Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.	8

Level of Evidence	Advantages of surgical treatment	Disadvantages of surgical treatment	Advantages of clinical follow-up	Disadvantages of clinical follow-up
I B	Prophylactic cholecystectomy during gastrectomies did not represent significant extra operative time and was associated with minimal additional risks²2 Bencini L, Marchet A, Alfieri S, Rosa F, Verlato G, Marrelli D, et al. The Cholegas trial: long-term results of prophylactic cholecystectomy during gastrectomy for cancer-a randomized-controlled trial. Gastric Cancer. 2019;22(3):632-9. https://doi.org/10.1007/s10120-018-0879-x https://doi.org/10.1007/s10120-018-0879-... . Prophylactic cholecystectomy concomitant with oncologic gastrectomies had no significant impact on the natural history of cancer²2 Bencini L, Marchet A, Alfieri S, Rosa F, Verlato G, Marrelli D, et al. The Cholegas trial: long-term results of prophylactic cholecystectomy during gastrectomy for cancer-a randomized-controlled trial. Gastric Cancer. 2019;22(3):632-9. https://doi.org/10.1007/s10120-018-0879-x https://doi.org/10.1007/s10120-018-0879-... .	The complication rate up to 30 days after cholecystectomy is 10.8%, the two main ones being reported as collection formation and infection of the operative wound¹1 Ahmed I, Innes K, Brazzelli M, Gillies K, Newlands R, Avenell A, et al. Protocol for a randomised controlled trial comparing laparoscopic cholecystectomy with observation/conservative management for preventing recurrent symptoms and complications in adults with uncomplicated symptomatic gallstones (C-Gall trial). BMJ Open. 2021;11(3):e039781. https://doi.org/10.1136/bmjopen-2020-039781 https://doi.org/10.1136/bmjopen-2020-039... .	The natural course of the disease is benign and presents low lifetime mortality (less than 1% of people will die from gallstone-related causes)¹1 Ahmed I, Innes K, Brazzelli M, Gillies K, Newlands R, Avenell A, et al. Protocol for a randomised controlled trial comparing laparoscopic cholecystectomy with observation/conservative management for preventing recurrent symptoms and complications in adults with uncomplicated symptomatic gallstones (C-Gall trial). BMJ Open. 2021;11(3):e039781. https://doi.org/10.1136/bmjopen-2020-039781 https://doi.org/10.1136/bmjopen-2020-039... .	About 20% of AC will become symptomatic in a mean follow-up time of 8.7 years, causing pain or complications (acute cholecystitis, empyema, choledocholithiasis, cholangitis, and pancreatitis)¹1 Ahmed I, Innes K, Brazzelli M, Gillies K, Newlands R, Avenell A, et al. Protocol for a randomised controlled trial comparing laparoscopic cholecystectomy with observation/conservative management for preventing recurrent symptoms and complications in adults with uncomplicated symptomatic gallstones (C-Gall trial). BMJ Open. 2021;11(3):e039781. https://doi.org/10.1136/bmjopen-2020-039781 https://doi.org/10.1136/bmjopen-2020-039... .
II B	Laparoscopic cholecystectomy has a mortality rate of less than 0.2% and a morbidity rate of less than 5.0%⁶6 Festi D, Reggiani ML, Attili AF, Loria P, Pazzi P, Scaioli E, 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 https://doi.org/10.1111/j.1440-1746.2009... . Prophylactic cholecystectomy performed electively is associated with lower morbidity and mortality than when the surgery is emergency⁶6 Festi D, Reggiani ML, Attili AF, Loria P, Pazzi P, Scaioli E, 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 https://doi.org/10.1111/j.1440-1746.2009... .	After laparoscopic cholecystectomy, 9% of asymptomatic patients before surgery developed biliary-type pain after surgery; 27.3% of those with mild symptoms before surgery persisted with these symptoms after the procedure; 14.1% of patients with severe symptoms persisted with symptoms after surgery, although four of them evolved with decreased intensity⁶6 Festi D, Reggiani ML, Attili AF, Loria P, Pazzi P, Scaioli E, 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 https://doi.org/10.1111/j.1440-1746.2009... .	22% of previously asymptomatic patients developed symptoms during the follow-up period, but these disappeared in 58% and 52%, respectively, when they were mild and intense⁶6 Festi D, Reggiani ML, Attili AF, Loria P, Pazzi P, Scaioli E, 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 https://doi.org/10.1111/j.1440-1746.2009... . 1 to 4% of AC cases become symptomatic annually, reaching 20% in 20 years, and almost always had symptoms before a complication set in²¹21 Nascimento JHFD, Tomaz SC, Souza-Filho BM, Vieira ATS, Andrade AB, Gusmão-Cunha A. A population study on gender and ethnicity differences in gallbladder disease in Brazil. Arq Bras Cir Dig. 2022;35:e1652. https://doi.org/10.1590/0102-672020210002e1652 https://doi.org/10.1590/0102-67202021000... .	–
III A	Prophylactic cholecystectomy after heart transplantation is recommended because it reduces mortality and costs, according to a quality-adjusted life-year assessment⁴4 Choi SY, Kim TS, Kim HJ, Park JH, Park DI, Cho YK, et al. Is it necessary to peorm prophylactic cholecystectomy for asymptomatic subjects with gallbladder polyps and gallstones? J Gastroenterol Hepatol. 2010;25(6):1099-104. https://doi.org/10.1111/j.1440-1746.2010.06288.x https://doi.org/10.1111/j.1440-1746.2010... .	Emergency cholecystectomy in post-transplant recipients is associated with significantly higher morbidity and mortality, respectively: 44 and 37% in heart transplant recipients; 33 and 5.6% in kidney transplant recipients⁴4 Choi SY, Kim TS, Kim HJ, Park JH, Park DI, Cho YK, et al. Is it necessary to peorm prophylactic cholecystectomy for asymptomatic subjects with gallbladder polyps and gallstones? J Gastroenterol Hepatol. 2010;25(6):1099-104. https://doi.org/10.1111/j.1440-1746.2010.06288.x https://doi.org/10.1111/j.1440-1746.2010... .	In cases of pancreas or kidney transplantation, the management of AC is recommended to be conservative since there has been no increase in AC-related morbidity in the post-transplant period⁴4 Choi SY, Kim TS, Kim HJ, Park JH, Park DI, Cho YK, et al. Is it necessary to peorm prophylactic cholecystectomy for asymptomatic subjects with gallbladder polyps and gallstones? J Gastroenterol Hepatol. 2010;25(6):1099-104. https://doi.org/10.1111/j.1440-1746.2010.06288.x https://doi.org/10.1111/j.1440-1746.2010... .	–
III B	–		–	During their lifetime, 25 to 33% of patients with AC develop symptoms or complications related to the disease¹⁵15 Kim SB, Kim KH, Kim TN, Heo J, Jung MK, Cho CM, et al. Sex differences in prevalence and risk factors of asymptomatic cholelithiasis in Korean health screening examinee: A retrospective analysis of a multicenter study. Medicine (Baltimore). 2017;96(13):e6477. https://doi.org/10.1097/MD.0000000000006477 https://doi.org/10.1097/MD.0000000000006... . In patients with AC, the rate of acute cholecystitis at 5-year follow-up was significantly higher in patients with coronary artery disease (CAD) (10.9%) compared to those without CAD (1.6%)¹⁵15 Kim SB, Kim KH, Kim TN, Heo J, Jung MK, Cho CM, et al. Sex differences in prevalence and risk factors of asymptomatic cholelithiasis in Korean health screening examinee: A retrospective analysis of a multicenter study. Medicine (Baltimore). 2017;96(13):e6477. https://doi.org/10.1097/MD.0000000000006477 https://doi.org/10.1097/MD.0000000000006... .
IV C	Asymptomatic biliary microlithiasis is present in 74% of cases of acute idiopathic pancreatitis, and prophylactic cholecystectomy would eliminate the possibility of recurrence of pancreatitis²²22 Pineda O, Maydón HG, Amado M, Sepúlveda EM, Guilbert L, Espinosa O, et al. A prospective study of the conservative management of asymptomatic preoperative and postoperative gallbladder disease in bariatric surgery. Obes Surg. 2017;27(1):148-53. https://doi.org/10.1007/s11695-016-2264-3 https://doi.org/10.1007/s11695-016-2264-... .	Cholecystectomy concomitant to bariatric surgery had higher morbidity and mortality rates (higher occurrence of infections, pulmonary and gastrointestinal complications), more re-interventions, and longer hospital stays compared to bariatric surgery without cholecystectomy²⁰20 Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4(1):1. https://doi.org/10.1186/2046-4053-4-1 https://doi.org/10.1186/2046-4053-4-1... .	Few patients with AC after bariatric surgery developed gallstone symptoms in the first 12 months of postoperative follow-up. The overall rate of cholecystectomy when the patient became symptomatic or developed a complication 12 months after bariatric surgery was 3.4%²⁰20 Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4(1):1. https://doi.org/10.1186/2046-4053-4-1 https://doi.org/10.1186/2046-4053-4-1... .	–
V D	–	Cirrhotic patients have higher mortality rates when undergoing surgery and anesthesia (overall mortality rate of 11.6%) and even higher in those with Child-Pugh C liver function (mortality rate of 17%)²³23 Quintana JM, Cabriada J, Aróstegui I, Oribe V, Perdigo L, Varona M, et al. Health-related quality of life and appropriateness of cholecystectomy. Ann Surg. 2005;241(1):110-8. https://doi.org/10.1097/01.sla.0000149302.32675.22 https://doi.org/10.1097/01.sla.000014930... . The morbidity rate for cirrhotic patients after laparoscopic cholecystectomy is higher (21% of cases)²³23 Quintana JM, Cabriada J, Aróstegui I, Oribe V, Perdigo L, Varona M, et al. Health-related quality of life and appropriateness of cholecystectomy. Ann Surg. 2005;241(1):110-8. https://doi.org/10.1097/01.sla.0000149302.32675.22 https://doi.org/10.1097/01.sla.000014930... . Cirrhotic patients have a higher conversion rate from laparoscopic to open surgery²³23 Quintana JM, Cabriada J, Aróstegui I, Oribe V, Perdigo L, Varona M, et al. Health-related quality of life and appropriateness of cholecystectomy. Ann Surg. 2005;241(1):110-8. https://doi.org/10.1097/01.sla.0000149302.32675.22 https://doi.org/10.1097/01.sla.000014930... .		When symptoms appear, morbidity and mortality are higher in patients with cirrhosis compared to non-cirrhotic patients²³23 Quintana JM, Cabriada J, Aróstegui I, Oribe V, Perdigo L, Varona M, et al. Health-related quality of life and appropriateness of cholecystectomy. Ann Surg. 2005;241(1):110-8. https://doi.org/10.1097/01.sla.0000149302.32675.22 https://doi.org/10.1097/01.sla.000014930... .

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[1] Correspondence: José Roberto Alves. E-mail: joserobertoalves1980@gmail.com