The clinical significance of bile duct sludge: is it different from bile duct stones?

Surg Endosc (2007) DOI: 10.1007/s00464-006-9153-0  Springer Science+Business Media, Inc. 2007 The clinical significance of bile duct sludge: is it di...
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Surg Endosc (2007) DOI: 10.1007/s00464-006-9153-0  Springer Science+Business Media, Inc. 2007

The clinical significance of bile duct sludge: is it different from bile duct stones? D. Keizman,* M. Ish-Shalom,* F. M. Konikoff Department of Gastroenterology, Tel Aviv Sourasky Medical Center, and the Minerva Center for Cholesterol Gallstones and Lipid Metabolism in the Liver, Tel Aviv University, Tel Aviv, Israel Received: 22 August 2006/Accepted: 30 August 2006

Abstract Background: Some patients with suspected common bile duct (CBD) stones are found to have sludge and no stones. Although sludge in the gallbladder is a precursor of gallbladder stones, the significance of bile duct sludge (BDS) is poorly defined. This study aimed to compare BDS with bile duct stones in terms of frequency, associated risk factors, and clinical outcome after endoscopic therapy. Methods: The study enrolled 228 patients who underwent therapeutic endoscopic retrograde cholangiopancreatography (ERCP) for suspected choledocholithiasis. The patients were divided into two groups: patients with BDS but no stones on ERCP and patients with CBD stones. The presence of risk factors for bile duct stones (age, periampullary diverticulum, ductal dilation or angulation, previous open cholecystectomy) were assessed at ERCP. Follow-up data (36 ± 19 months) were obtained from medical records and by patient questioning. Results: Bile duct sludge occurred in 14% (31/228) of patients and was more common in females. After endoscopic clearance, CBD stones recurred in 17% (33/197) of the patients with CBD stones, and in 16% (5/31) of the patients with BDS (p = 0.99). Common bile duct dilation was less common in the sludge group. The other known risk factors for recurrent CBD stones (age, previous open cholecystectomy, bile duct angulation, and the presence of a peripampullary diverticulum) were not statistically different between the two groups. Conclusions: The findings indicate that the clinical significance of symptomatic BDS is similar to that of CBD stones. Bile duct sludge seems to be an early stage of choledocholithiasis.

* Both authors have equally contributed to this study Correspondence to: F. M. Konikoff

Key words: Common bile duct sludge — ERCP — Recurrent bile duct stones

Some patients who present with a clinical picture of bile duct stones are found by endoscopic retrograde cholangiopancreatography (ERCP) to have bile duct sludge (microlithiasis) without any stones [1–8]. Most of the literature dealing with biliary sludge relates to gallbladder sludge, whereas bile duct sludge (BDS) has received little, if any, consideration, and its clinical significance remains unclear. Biliary sludge was first described with the advent of ultrasonography in the early 1970s [9]. On ultrasonography, sludge appears as low-level echoes [10]. On microscopy, it has been defined as a mixture of particulate matter that occurs when various solutes in bile precipitate [11–13]. Biliary sludge is most commonly composed of cholesterol monohydrate crystals and calcium bilirubinate granules or other calcium salts embedded in strands of gallbladder mucus, in addition to a large proportion of undefined residue and protein– lipid complexes [1, 11]. Sludge formation depends on the physical–chemical interactions of all of these constituents, abnormalities of gallbladder mucosal function, and bile stasis [9]. The criteria for differentiating between sludge (microlithiasis) and small stones are not entirely clear, but it has been suggested that a stone be defined as a particle with a diameter exceeding 2 mm that cannot be crushed by digital compression [1, 12]. Clinically, biliary sludge is almost always an imaging diagnosis. Natural history studies and case reports about gallbladder or BDS usually are based on ultrasonographic or endoscopic visualization (flow of sandlike bile without evidence of stones) without microscopic or chemical confirmation, which is less clinically applicable [9]. Most investigators think the pathogenesis of sludge is similar to that of gallstones [1, 14–16]. It has been

hypothesized that gallstones are formed from sludge by further precipitate aggregation, and it is generally thought that sludge is a necessary precursor to gallstones [1, 17]. Although gallbladder sludge can resolve spontaneously, it may develop into gallstones with significant clinical consequences identical to those of cholecystolithiasis, such as biliary colic [2–4], ‘‘acalculous’’ cholecystitis [5–6], and acute pancreatitis [7–8]. Thus, symptomatic gallbladder sludge is treated in the same manner as gallstone disease, by cholecystectomy. Endoscopic sphincterotomy is a well-established therapeutic procedure for symptomatic bile duct stones [18–21]. Complications after the procedure are divided into early (within 3 months after the procedure) or late (more than 3 months after the procedure) [20–22]. Among late complications are recurrent bile duct stones that occur in 4% to 24% of patients, despite increasing experience and success with the procedure [21–23]. Common bile duct (CBD) stones found 6 months or more after the ERCP generally are considered recurrent, as opposed to retained [21, 24, 25]. Although a considerable amount of literature concerning biliary sludge in the gallbladder exists, it is difficult to find literature about BDS. Therefore, we performed a retrospective clinical study to assess BDS in symptomatic patients by comparing it with the more common and familiar condition of bile duct stones. We compared these two entities in a cohort of patients that underwent ERCP due to symptoms of suspected choledocholithiasis. This comparison considered frequency, associated risk factors for the formation of bile duct stones, and future development of recurrent symptomatic choledocholithiasis after endoscopic duct clearance. Patients and methods Patients The study group consisted of patients who underwent endoscopic sphincterotomy (EST) for suspected CBD stones in our gastroenterology unit between 1997 and 2004. The procedure was indicated by the presence of clinical symptoms (i.e., abdominal pain, jaundice), laboratory tests (i.e., direct hyperbilirubinemia, elevated liver function tests), or both complemented by an imaging procedure (i.e., ultrasound or magnetic resonance cholangiopancreatography [MRCP]) before the procedure. The presence of bile duct stones or sludge (microlithiasis) was diagnosed during the procedure. The examiner diagnosed CBD sludge by endoscopic visualization as the flow of sandlike bile without evidence of stones. Only patients with evidence of bile duct stones or sludge during the procedure were included in the study. The follow-up period was at least 1 year after the ERCP. Patients with stenosis (benign or malignant) of the CBD, loss of medical or endoscopic information, or gallbladder in situ were excluded from the study. All patients included had undergone a cholecystectomy either before the ERCP or soon (within a month) thereafter. Patients with a dilated CBD during the initial ERCP also had an intraoperative cholangiogram (during the cholecystectomy) to exclude retained stones. The patients were divided into two groups: patients with CBD sludge (no stones) and patients with CBD stones during the ERCP. After the ERCP, all patients were contacted by the same investigator (D.K.) for updated clinical follow-up data to be obtained at the time of this study. Patients who were symptomatic during the follow-up evaluation underwent clinical, biochemical (liver function tests), and

radiologic (sonography, MRCP) evaluation, for diagnosis or exclusion of recurrent CBD stones. The presence of recurrent bile duct stones was confirmed endoscopically during a second ERCP. Recurrence of symptomatic CBD stones was defined as the development of symptomatic stones not earlier than 1 year after the complete removal of the initial CBD stones or sludge.

Preprocedure data Before the procedure, each patientÕs medical data, including age, sex, and prior cholecystectomy (a risk factor for bile duct stones formation) [26, 27] were recorded.

Endoscopic procedure Endoscopic sphincterotomy was performed by an experienced endoscopist using a side-viewing Pentax duodenoscope (ED-3440T; Asahi Optical Co., Tokyo, Japan) and a standard pull-type papillotome. All sphincterotomies were complete, resulting in the appearance of air in the biliary tree. Sludge or CBD stones were extracted with a retrieval balloon or basket. During the first ERCP, the presence of CBD stones, sludge, or a periampullary diverticulum (a risk factor for stone recurrence) [18–19, 23] were recorded. After stone removal, contrast material was injected, and an inflated balloon catheter (up to 15 mm in diameter) was withdrawn along the CBD to the duodenum to confirm clearance of the biliary tree.

Assessment of CBD course: angulation and diameter The CBD course (CBD in the study relates to the entire bile duct, from the ampulla to the bifurcation) was analyzed from the postprocedure cholangiogram with the patient in the prone position. The CBD angulation was measured as the sharpest angle along the CBD from 1 cm below the bifurcation to 1 cm above the papilla [26]. An angle of 145 or less was considered a sharp angle, and a risk factor for bile duct stone formation [17, 26]. The CBD diameter was measured at its widest point, corrected for magnification in relation to the known diameter of the endoscope. A diameter of 13 mm or more was considered a significant dilation, and a risk factor for recurrent bile duct stone [18–19, 23–24]. To ensure reproducibility of the measurements and to lower the possibility of bias, cholangiogram analysis was performed by two independent investigators not involved in the patientÕs treatment and blinded to the data as well as the other investigatorsÕ measurements.

Statistical analysis Categorical variables (gender, presence of a periampullary diverticulum, and type of cholecystectomy, whether open or laparoscopic) were compared by PearsonÕs chi-square test, or when both variables were dichotomous, by FisherÕs exact test. Continuous variables (age, angulation of the bile duct, and bile duct diameter) were analyzed using the StudentÕs t-test when the variables were normally distributed, or by the Mann–Whitney U test when the variables had no normal distribution. All tests were two sided, and a p value of 0.05 or less was considered statistically significant. Curves based on the Kaplan–Meier method were used to estimate the proportion of patients free of recurrence during follow-up evaluation, and these were compared using the log rank test. Statistical analysis was conducted using the SPSS package 11 (SSPS Inc., Chicago, IL, USA). The research was conducted in accordance with the Helsinki declaration, and the study was approved by the ethical committee of our institution.

Results Patients During the study period, 415 consecutive patients underwent EST for suspected CBD stones in our gas-

both groups, 13% of the patients had recurrent CBD stones after 3 years (Fig. 1). Moreover, there was no statistically significant difference between the two groups in the mean length of time from cholecystectomy until stone recurrence. Risk factors for recurrence

Fig. 1. Recurrence rate for patients with common bile duct (CBD) stones versus that for patients with CBD sludge.

troenterology unit. Of these, 187 were excluded due to lack of evidence for stones or sludge during the procedure (n = 31), stenosis (benign or malignant) of the CBD (n = 43), unavailability for follow-up assessment (n = 45), loss of medical or endoscopic information (n = 47), or a retained gallbladder with stones or sludge (1 month or more after the EST) (n = 21). Altogether, a total of 228 patients (143 women, 63%) for whom sphincterotomy and bile duct clearance were achieved were included in the analysis. The mean age was 64.1 ± 18.3 years (median, 69 years; range, 8–93 years). Most procedures (61%, n = 140) were performed for hospitalized patients. The mean follow-up time after the initial ERCP was 36 ± 19 months (median, 33 months; range, 12–86 months). There was no significant difference in the follow-up time between the study groups (CBD sludge vs CBD stones). The findings showed that CBD sludge (without stones) occurred in 14% (31/228) of the patients with suspected symptomatic choledocholithiasis, and was more common in females (26/143, 18%) than in males (5/85, 6%) (p = 0.009). The prevalence of both stones and sludge was 16% (32/197) in all patients with stones and 18% (11/62) in the patients with stones who underwent intraoperative cholangiogram at the time of cholecystectomy. This difference was not statistically significant (p = 0.8). Stone recurrence The rate of symptomatic bile duct stones recurrence was 17% (33/197) for the patients with CBD stones, and 16% (5/31) for the patients with CBD sludge. This difference between the two groups was not statistically significant (p = 0.99). The mean length of time until recurrence was 22 ± 10 months (range, 12–59 months) for the patients with CBD stones and 18 ± 6 months (range, 12–36 months) for the patients with CBD sludge (p = 0.4). The time until recurrence also was not different between the groups on Kaplan–Meier analysis. In

Patient characteristics and the results from univariate analysis of known risk factors for recurrence of CBD stones are given in Table 1. Age, previous open cholecystectomy, bile duct angulation (mean, 150.3 ± 16.2 in the sludge group and 147.6 ± 17.7 in the CBD stones group), and the presence of a peripampullary diverticulum were not statistically different between the two groups. A dilated CBD (diameter, ‡13 mm) was more common among the patients with CBD stones (p = 0.001). The mean CBD diameter was 14.6 ± 5.3 mm among the patients with CBD stones and 12.3 ± 2.9 mm among the patients with CBD sludge. Discussion In the current study, we have found that patients with suspected symptomatic choledocholithiasis have a 14% frequency (31/228) of biliary sludge (without stones). Moreover, 16% of the patients with CBD sludge will develop future symptomatic CBD stones. This figure resembles that described in the literature on recurrent CBD stones after EST in patients with choledocholithiasis [21–23], and does not differ significantly from the rate of recurrent stones among the patients with choledocholithiasis in the current study (17% of patients) (p = 0.99). Furthermore, this figure also resembles the risk of gallbladder stones developing in patients with gallbladder sludge [2, 9]. Among the known risk factors for the development of primary CBD stones or their recurrence after EST, we have found a similar prevalence for age, previous open cholecystectomy, CBD angulation, and the presence of periampullary diverticulum between the sludge group and the stone group. However, CBD dilation was more common among the patients with CBD stones. This difference in CBD diameter strengthens the hypothesis that sludge is significant for future stone development because despite the lack of an important risk factor for recurrent stones (CBD dilation) in the sludge group, the recurrence rate was not different from that for the stones group. Although an abundance of literature can be found concerning biliary sludge in the gallbladder, it is difficult to find literature about CBD sludge. To the best of our knowledge, the current study is the first to describe the frequency of CBD sludge among symptomatic patients with suspected choledocholithiasis who underwent endoscopic bile duct clearance. The current study also is the first to examine the known risk factors for bile duct stones development, and to assess the future development of symptomatic CBD stones among patients with BDS.

Table 1. Univariate analysis of patient characteristics Variable/group

Preprocedure data: n (%) Gender Admission: n (%) Elective Urgent Mean age Past open cholecystectomy: n (%) Procedure data: n (%) Periampullary diverticulum Common bile duct diameter ‡ 13 mm Angulated common bile duct (angle £ 145)

Sludge (n = 31)

Stones (n = 197)

p Value

Female: 26 (84) Men: 5 (16)

Female: 117 (60) Men: 80 (40)

0.009

16 (52) 15 (48) 64.5 ± 15.4 6 (19)

72 (36) 125 (64) 64 ± 18.7 60 (31)

0.11 0.89 0.21

7 (23) 7 (23) 10 (32)

53 (27) 83 (42) 89 (45)

0.83 0.001 0.24

Biliary sludge and gallstones have a similar pathogenesis [1, 9, 14–16], which is related to bile stasis [11, 14–15, 28]. Sludge in the gallbladder is believed to be a precursor of bladder stones [9, 28]. Thus, CBD sludge also could be a predisposing condition to the formation of CBD stones. Indeed, as shown in the current study, CBD sludge is formed under the same predisposing risk factors as CBD stones. In particular, CBD angulation and the presence of a periampullary diverticulum may predispose to bile stasis, leading to the formation of bile duct stones. In our study, CBD sludge was found to be more common in females. Previous studies have shown that gender is not a risk factor for recurrent primary CBD stones [18–19, 22, 24]. Whether gender indeed has an influence on sludge and stone formation needs to be studied in larger, prospective studies. In conclusion, our findings suggest that the presence of sludge in the bile ducts of symptomatic patients has clinical significance similar to that for ductal stones. Careful follow-up evaluation is advisable for patients after endoscopic clearance of BDS because BDS may predispose to recurrent choledocholithiasis. Due to the retrospective nature of our study and the endoscopic definition of bile duct sludge, future prospective studies with microscopic or chemical diagnosis of sludge are needed to confirm our results.

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