Gallbladder stones (GS) are reported in 5% to 25% of the global adult population^1,2 and are usually asymptomatic. Symptomatic GS may manifest as recurrent episodes of right upper quadrant abdominal pain or as acute cholecystitis.³ However, up to 20% of patients with GS have concomitant common bile duct (CBD) stones, which are believed to originate in the gallbladder.^4,5 Unlike GS, CBD stones can lead to life-threatening conditions such as obstructive jaundice, acute ascending cholangitis, and acute pancreatitis (AP). Long-term cohort studies of GS have revealed a relatively low rate of biliary complications after 20 years of follow-up, ranging from 3% to 15%.^6–9 Risk factors for complications of GS include older age, a history of complicated disease, and the presence of multiple stones.^7,9,10 Additionally, gallbladder sludge (GBS) is considered a risk factor for biliary complications, particularly AP.^11,12 Recently, Venneman et al¹⁰ demonstrated that small GS are associated with an increased risk of pancreatitis, but not of other biliary complications. In this study, we aimed to investigate whether small GS size is associated with the overall development of biliary complications.

Study population and design

This retrospective comparative cohort study was conducted at Meir Medical Center from January 2010 to December 2014. The study group comprised consecutive patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) for complicated biliary disease. The indications for ERCP were categorized as obstructive jaundice, acute ascending cholangitis, and AP (see Fig. 1). The control group consisted of consecutive patients with sonographic evidence of GS and non-specific abdominal symptoms who were discharged from the emergency department and did not develop biliary complications during the study period. Both groups were matched for sex and age. Data were retrieved from electronic patient files, including age, sex, and medical history. Laboratory tests included measurements of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, bilirubin, albumin, and serum cholesterol. Transabdominal ultrasonography images from both groups were reviewed by a trained radiologist. The number and size of the GS and the presence of GBS were documented. Exclusion criteria encompassed patients younger than 18 years, those with previous cholecystectomy (CCY), those with a follow-up period of less than 5 years or inadequate follow-up, and those with inconclusive sonographic findings.

Figure 1. Biliary complications stratified by ERCP indication. ERCP, endoscopic retrograde cholangiopancreatography.

Statistical analysis

Sample size calculations indicated an expected 30% difference in stone size between the two groups, necessitating a total of 60 patients in each group. The groups were matched for age and sex. Data were presented as means ± standard deviations for continuous variables and as counts and percentages for nominal variables. The normality of continuous data was assessed using the Shapiro-Wilk test. Statistical analyses were conducted as follows: continuous data were analyzed using the t-test or Mann-Whitney U test, while nominal data were analyzed using the chi-square test. Logistic regression was used to identify which independent variables, if any, influenced the differences between the groups. A P-value of less than 0.05 was considered to indicate statistical significance. All analyses were performed using SPSS version 25 (IBM Corp.).

Ethical considerations

This study was approved by the ethics committee of Meir Medical Center (approval No. 309-16-MMC) and conformed to the tenets of the Declaration of Helsinki. Informed consent was waived for this retrospective analysis.

From January 2010 to December 2014, 141 patients underwent ERCP at the Gastroenterology and Hepatology Department of Meir Medical Center due to biliary complications. The study group comprised 57 of these patients, selected after matching for age and sex. The control group consisted of 60 patients who were followed for an average of 7.00 ± 3.51 years. Demographic data, medical history, and laboratory test results for both groups are presented in Table 1.

Table 1 . Demographic Data, Medical Background, and Laboratory Results of Study and Control Groups.

Parameter	Study group (n = 57)	Control group (n = 60)	P-value
Age (yr)	51.5 ± 18.9	51.1 ± 18.5	0.887
Sex, male	21 (36.8)	20 (33.3)	0.691
Diabetes mellitus	10 (17.5)	7 (11.7)	0.367
Hypertension	19 (33.3)	15 (25.0)	0.321
Dyslipidemia	12 (21.1)	9 (15.0)	0.394
Ischemic heart disease	2 (3.5)	4 (6.7)	0.189
Laboratory result
AST (7–37 IU/L)	249.3 ± 204.5	85.7 ± 59.4	< 0.01
ALT (0–40 IU/L)	338.1 ± 259.2	95.5 ± 57.1	< 0.01
ALP (30–120 IU/L)	262.0 ± 123.5	116.1 ± 121.1	< 0.01
GGT (7–49 IU/L)	464.0 ± 344.2	206.1 ± 130.1	< 0.01
Bilirubin (0.2–1.5 mg/dL)	4.3 ± 3.1	2.7 ± 1.3	< 0.01
Albumin (3.3–5.5 g/dL)	3.9 ± 0.4	3.9 ± 0.4	0.30
Cholesterol (110–200 mg/dL)	165.0 ± 43.7	159.0 ± 61.0	0.59

Values are presented as mean ± standard deviation or number (%)..

AST, aspartate transaminase; ALT, alanine transaminase; ALP, alkaline phosphatase; GGT, gamma-glutamyl transferase..

Relative to the control participants, the study group exhibited significantly smaller GS (3.93 ± 3.14 mm vs. 5.45 ± 3.64 mm, P < 0.01), a greater number of GS (8.30 ± 6.24 vs. 6.42 ± 5.63, P < 0.01), and a higher rate of GBS (29.8% vs. 15.0%, P = 0.054). Sonographic findings of the two groups are compared in Table 2.

Table 2 . Comparison of Sonographic Characteristics Between Groups.

Sonographic parameter	Study group (n = 57)	Control group (n = 60)	P-value
GS size (mm)	3.93 ± 3.14	5.45 ± 3.64	< 0.01
GS number	8.30 ± 6.24	6.42 ± 5.63	< 0.01
GBS	17 (29.8)	9 (15.0)	0.054

Values are presented as mean ± standard deviation or number (%)..

GS, gallbladder stones; GBS, gallbladder sludge..

As shown in Table 3, the three study subgroups displayed significantly smaller GS than the control group (control, 5.45 ± 3.64 mm; obstructive jaundice, 4.6 ± 3.4 mm [P < 0.01], acute ascending cholangitis, 3.2 ± 2.9 mm [P < 0.006]; AP, 2.7 ± 1.1 mm [P = 0.036]). Both the obstructive jaundice and AP subgroups exhibited a higher number of GS than the control group (7.2 ± 6.8 and 7.4 ± 1.1 vs. 6.42 ± 5.63; P < 0.001 and P = 0.038, respectively). GBS rates were statistically similar between the three study subgroups and the control group (control, 15.0%; obstructive jaundice, 27.8% [P = 0.095]; acute ascending cholangitis, 35.7% [P = 0.075]; AP, 28.6% [P = 0.323]).

Table 3 . Comparison of Sonographic Parameters Between Study Subgroups and Control Group.

Sonographic parameter	Study group (n = 57)						Control group (n = 60)
	Obstructive jaundice (n = 36)	P-value	Acute ascending cholangitis (n = 14)	P-value	Acute pancreatitis (n = 7)	P-value
GS size (mm)	4.6 ± 3.4	< 0.01	3.2 ± 2.9	< 0.006	2.7 ± 1.1	0.036	5.45 ± 3.64
GS number	7.2 ± 6.8	< 0.001	8.0 ± 5.9	0.096	7.4 ± 1.1	0.038	6.42 ± 5.63
GBS	10 (27.8)	0.095	5 (35.7)	0.075	2 (28.6)	0.323	9 (15.0)

Values are presented as mean ± standard deviation or number (%)..

GS, gallbladder stones; GBS, gallbladder sludge..

Our study demonstrated that patients with biliary complications exhibited smaller and more numerous GS than those without biliary complications.

Previous studies have evaluated the influence of GS size and number on the occurrence of complications, yielding inconsistent results. Persson⁹ prospectively assigned patients with documented symptomatic GS to either early CCY or expectant management, concluding that the latter is justified. Their data indicated that GS size and number were not associated with the development of biliary complications.⁹ However, we believe that the incidence of biliary complications in that prospective study was low, making risk stratification based on sonographic characteristics inadequate.

A large retrospective Danish cohort study documented a biliary complication rate of 8% after 17.4 years of follow-up. In that study, a GS diameter larger than 10 mm was associated with acute cholecystitis, CCY, and uncomplicated symptomatic disease. However, consistent with our results, numerous GS were associated with complicated disease, including AP.⁷

Diehl et al¹³ recorded the size and number of GS retrieved during surgery in patients who underwent CCY due to cholecystitis, AP, or symptomatic but uncomplicated biliary colic. Their multivariate analysis revealed that patients with at least one GS smaller than 5 mm had a fourfold increase in the risk of developing AP.¹³ Overall, these results are comparable to those of our research, although the studies had some methodological differences. In the present investigation, we measured the stones sonographically rather than directly. Additionally, we compared sonographic parameters across subgroups of biliary complications, not just in an overall group. Furthermore, our findings indicated that the number of stones, in addition to their size, was associated with the development of biliary complications.

Venneman et al¹⁰ compared GS characteristics among four patient groups: AP, obstructive jaundice, cholecystitis, and uncomplicated biliary disease. Patients with obstructive jaundice and AP exhibited more and smaller GS compared to the other two groups. However, multivariate analysis revealed that only advanced age and small GS size were independent risk factors for AP. In comparison, our findings indicate that smaller GS are associated not only with AP but also with biliary complications overall.

The presence of GBS plays a key role in the development of biliary complications.^12,14,15 The natural history of GBS varies, with outcomes ranging from spontaneous resolution over time to the formation of small GS.¹⁶ Lee et al¹⁴ reported comparatively high rates of cholecystitis, acute ascending cholangitis, and AP in symptomatic patients with GBS. Another study suggested that GBS is an underrecognized cause of acute idiopathic pancreatitis.¹¹ Our findings indicated that the rates of GBS were higher in the study group, albeit with borderline significance.

The prevalence of CBD stones in patients with GS ranges from 15% to 20%.^17–21 Compared to GS, the natural history of CBD stones is less well understood. The frequency and risk factors associated with GS migrating into the CBD remain unclear. Furthermore, it is uncertain which GS will pass silently into the duodenum or cause complications due to their retention in the CBD. CBD stones may lead to partial or complete biliary obstruction, resulting in complications such as obstructive jaundice, acute ascending cholangitis, hepatic abscesses, and AP.²² While these complications impact a minority of patients, they are associated with high morbidity and mortality.^23,24

The current guidelines suggest that patients who are symptomatic or have developed biliary complications should undergo CCY. Conversely, those who are asymptomatic should receive conservative management. However, the approach to patients presenting with mild or non-specific symptoms remains unclear.^25,26

A study conducted in the United States demonstrated that patients who remain asymptomatic after 5 years following an initial mild presentation have a low rate of symptom recurrence.²⁷ Furthermore, a meaningful number of patients who undergo CCY continue to experience abdominal pain, which suggests that their symptoms may be attributable to other etiologies.²⁸ Criteria guiding the decision to perform CCY are limited.^7,9,24 Consequently, we consider the inclusion of the sonographic characteristics of GS in this decision-making process to be appropriate.

Our study had several limitations due to its retrospective design. For instance, the sample size was relatively small and lacked the power to detect statistical significance between the subgroups and the control group. Additionally, the follow-up period for the control group was 7.00 ± 3.51 years, which may have been insufficient to identify long-term complications. Sonographic measurements are also subjective and could introduce observer bias. Finally, as advanced imaging techniques such as magnetic resonance imaging and computed tomography were not utilized in the control group, we lacked information on the potential presence of concurrent asymptomatic CBD stones in these participants.

To our knowledge, this is the first study to compare GS size and number in patients with and without biliary complications. Recently, patients with mild GS symptoms have not been automatically referred for surgery; instead, a “watch and wait” strategy is recommended. Our findings indicate that small and numerous GS are risk factors for all types of biliary complications. Consequently, the “watch and wait” approach for these patients should be conducted with greater vigilance, and a lower threshold for surgical referral is advisable. Incorporating sonographic parameters, such as GS size and number, into the decision-making process may be beneficial. However, further research is necessary to confirm our findings.

None.

The datasets generated and analyzed during the current study are not publicly available due to privacy and ethical restrictions. However, they are available from the corresponding author upon reasonable request.

No potential conflict of interest relevant to this article was reported.