World J Surg (2010) 34:2915–2921 DOI 10.1007/s00268-010-0771-2
Pancreaticobiliary Reflux in Patients with and without Cholelithiasis: Is It a Normal Phenomenon? Marcelo A. Beltra´n • Mario A. Contreras Karina S. Cruces
•
Published online: 1 September 2010 Ó Socie´te´ Internationale de Chirurgie 2010
Abstract Background Pancreaticobiliary reflux is a pathologic phenomenon occurring in patients with gallstones. However, the occurrence of pancreaticobiliary reflux has not been studied in patients without gallstones. The objective of the present study was to measure the bile levels of amylase and lipase in patients without gallstones submitted to cholecystectomy as part of another surgical procedure, and to compare these values with the bile levels of amylase and lipase of patients submitted to cholecystectomy for gallstone disease. Patients and methods A prospective observational and comparative study was designed. A sample of 136 consecutive patients was included. Amylase and lipase levels were measured in bile. At our institution, normal plasma concentrations of amylase are 28–100 IU/l and lipase 13–60 IU/l. Normal values for pancreatic enzyme concentrations in bile have not been established. Therefore, bile amylase and lipase concentrations exceeding normal plasma concentrations were deemed to be elevated. Results Of the patients in the present study, 103 (76%) had gallstones and 33 (24%) had healthy gallbladders without gallstones. According to normal plasma levels for amylase and lipase, these enzymes in bile were elevated in 83.5% patients with gallstones, compared to elevated levels of amylase in 6% patients and lipase in 3% patients without gallstones (P \ 0.0001).
M. A. Beltra´n (&) K. S. Cruces Department of Surgery, Hospital de la Serena, P.O. Box 912, La Serena, IV Regio´n, Chile e-mail:
[email protected] M. A. Contreras Balmaceda 916, La Serena, IV Regio´n, Chile
Conclusions Pancreaticobiliary reflux is a common phenomenon in patients with gallstones and an uncommon phenomenon in patients with healthy gallbladders without gallstone disease.
Introduction Pancreaticobiliary reflux has been traditionally associated with pancreaticobiliary maljunction, which is defined as the union of pancreatic and biliary ducts outside the duodenal wall forming a long common channel where the sphincteric mechanism provided by the sphincter of Oddi does not exist, and as a consequence, allows the reflux of pancreatic enzymes into the biliary tree and gallbladder [1–3]. Recently, it has become evident that pancreaticobiliary reflux can occur in the absence of an anomalous pancreaticobiliary junction in patients with a morphologically normal pancreaticobiliary junction [1–4]. The importance of pancreatic enzymes refluxing into the biliary tree and gallbladder is that it has been related to the development of precancerous changes of the gallbladder mucosa and gallbladder cancer, mediated by induction of genetic changes such as K-ras point mutations and p53 overexpression [1–10]. In a previous study we have found an elevated incidence of pancreaticobiliary reflux in patients with benign and malignant gallbladder diseases and suggested that the inflammation of the biliary mucosa caused by active pancreatic enzymes, such as amylase and lipase, could be the cause of biliary symptoms, gallstone development, precancerous changes, and, ultimately, gallbladder cancer [4]. However, the presence of pancreaticobiliary reflux has not been studied in patients with healthy gallbladders without gallstones. At present there are no published studies measuring the levels of active pancreatic
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enzymes—amylase and lipase—in patients with diseased gallbladders with gallstones and patients with healthy gallbladders without gallstones. Based in our previous research, we suggest that pancreaticobiliary reflux is a pathologic phenomenon occurring only in patients with gallstone diseases and that the occurrence of pancreaticobiliary reflux in patients without gallstones may be just an uncommon occasional phenomenon. To address this hypothesis this study was designed. The objective was to measure the levels of gallbladder amylase and lipase in bile of patients submitted to cholecystectomy for gallstone disease and patients without gallstones in whom cholecystectomy was performed as part of another surgical procedure, such as total gastrectomy for gastric cancer.
Patients and methods Study design The ethics committee of our institution approved the protocol. All patients signed an informed consent form accepting the performance of intraoperative cholangiography when undergoing cholecystectomy and the performance of any necessary preoperative blood tests. A prospective observational and comparative study was designed. The primary outcome measure was the values of amylase and lipase in gallbladder bile from healthy gallbladders without gallstones and in bile from chronically diseased gallbladders with gallstones, in patients with a normal pancreaticobiliary junction evidenced by intraoperative cholangiography. Eligibility criteria and sample size Patients were included according to the following criteria: patients older than 15 years of age with symptomatic gallstone disease submitted to elective cholecystectomy, and patients older than 15 years of age with healthy gallbladders without gallstones submitted to total elective gastrectomy for gastric cancer, in whom 24 h before surgery serum levels of amylase and lipase were measured, which must have been within the accepted normal range of our institutional laboratory, and who had a normal intraoperative cholangiography. Patients were excluded based on the following criteria: diabetes, acute cholecystitis, cholangitis, acute or chronic pancreatic disease, common bile duct stones preoperatively diagnosed or evidenced during surgery, abnormal preoperative amylase and lipase values, abnormal preoperative hepatic function tests, and anatomic biliary tract anomalies or pancreaticobiliary maljunction evidenced by intraoperative cholangiography. None of the included patients had undergone preoperative
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endoscopic cholangiography or sphincterotomy. Sampling of bile was performed only in patients in whom the gallbladder was filled with clear liquid bile. Any patient with a small shrunken and atrophic gallbladder or a gallbladder filled with thick sticky bile or no bile content at all, or any patient in whom the cystic duct was occluded and the gallbladder was hydropic, was also excluded. Only patients with chronic benign alterations of the gallbladder mucosa or with healthy normal gallbladders according to the biopsy report were included in the analysis. Any patient with dysplastic changes or gallbladder carcinoma incidentally found was also excluded. At our institution we operate on 200 elective patients older than age 15 with gallstone disease, who would meet the inclusion criteria of this study, every year. For the purposes of this study we included a non-probability convenience sample of 136 consecutive patients 15 years old and older. Most patients with gallstone disease are female, whereas most patients with gastric cancer and without gallstone disease are male; we acknowledge this difference as a source of possible bias. Interventions and procedures Eligible patients submitted to elective cholecystectomy for symptomatic gallstone disease, and eligible patients scheduled for elective total gastrectomy for gastric cancer without gallstone disease, in whom cholecystectomy was planned as part of the procedure, were included. The day before surgery a blood sample was drawn to measure amylase, lipase, and hepatic function test values. The procedure during surgery was similar for patients with and without gallstones. Before dissection of the Calot triangle was performed, and before the cystic duct was clipped or ligated, 5 cc of bile was aspirated from the gallbladder with a syringe. That sample was kept in a sterile tube at room temperature (21–25°C), and delivered for processing as soon as the operation was over. All bile samples were processed during the following 2 h by laboratory technicians unaware of the study, and consequently blinded to the origin of the sample. Before the cholecystectomy was completed, intraoperative cholangiography was performed to confirm a normal pancreaticobiliary junction, and any anomalies were recorded. Definitions and normal values Anomalies of the biliary tree were defined as any alteration of the expected normal anatomy. To classify choledocal cysts, we used the Todani classification modified by Lenriot et al. [11]. To classify an anomalous pancreaticobiliary junction, we used the Kimura et al. classification [12]. In the present series we did not find any patient with these anomalies or any other biliary tract anatomy alterations.
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Amylase and lipase levels were measured in bile by a colorimetric method using an automatic Roche/Hitachi 917 analyzer (Mannheim, Germany). The normal range of serum amylase with this system is 28–100 U/l, and that for lipase is 13–60 U/l. Although there are no known or established normal levels for pancreatic enzymes in bile, and there is no known evidence of absorption, filtration, or secretion of amylase and lipase across the biliary or hepatic epithelium, for the purposes of analysis and reporting the results of this study, we considered elevated any bile amylase and lipase levels that were higher than the accepted normal plasma levels [4].
Table 2 Comparison of amylase and lipase levels Gallstone disease
Healthy 95% CI gallbladders
P value
Amylase: mean ± SD (range)
181.2 ± 352 (3–2,450)
5.5 ± 16.4 (0–80)
0.001
Lipase: mean ± SD (range)
434.8 ± 1224 (10–8,460)
9.5 ± 16.6 (0–71)
85.1–192
148.6–514.7 0.048
Confidence intervals (95% CI): difference between the means of the two groups
Table 3 Highly elevated amylase and lipase levels
Statistics
Total
Categorical variables were expressed as proportions and continuous variables as mean, standard deviation, and range. Simple comparisons between groups were performed with the t-test. Comparative analysis was performed with one-way analysis of variance (ANOVA) to compare amylase and lipase means between groups. A probability value \0.05 was considered significant. The analysis was performed using the statistical software SSPS version 11.0 (Chicago, IL).
Results Of 136 patients who met the inclusion criteria, 103 (76%) had chronic symptomatic gallstone disease and 33 (24%) had healthy gallbladders. Most patients with gallstones were female (86%) and were younger than patients with healthy gallbladders. Body mass index (BMI) was similar between the two groups. Patients with healthy gallbladders were mostly male (64%) and older than patients with gallstones (Table 1). Amylase and lipase levels were significantly elevated in most patients with gallstones and were negligible in patients with healthy gallbladders
Table 1 Demography and clinical characteristics Total
Gallstone disease
Healthy gallbladders
P value
Patients (%)
136 (100)
103 (76)
33 (24)
–
Female/male (%)
101 (74)/35 (26)
89 (86)/14 (14)
12 (36)/21 (64)
0.002
Age: mean ± SD (years)
46.3 ± 13 (17–80)
43.4 ± 12.6 (17–74)
55.4 ± 10 (34–80)
0.036
BMI: mean ± SD (kg/m2)
24.6 ± 1.3 24.8 ± 1.3 24.1 ± 1.4 0.753 (19.1–33.8) (19.1–33.8) (22.5–27.3)
SD standard deviation, BMI body mass index
Patients (%)
Gallstone disease
136 (100) 103 (100)
Healthy gallbladders 33 (100)
P value –
Amylase [100 U/l (%)
88 (65)
86 (83.5)
2 (6)
\0.0001
Lipase [60 U/l (%)
87 (64)
86 (83.5)
1 (3)
\0.0001
(Table 2). According to normal plasma levels for amylase and lipase, these pancreatic enzymes in bile were coincidently elevated in the same 83.5% patients with gallstones. Elevated levels of amylase and lipase were found in only 1 patient, and lipase alone was elevated in another patient without gallstones and a healthy gallbladder; consequently, in this group of patients, amylase levels were elevated in 2 patients (6%; P \ 0.0001) and lipase was elevated in 1 patient (3%; P \ 0.0001) (Table 3). Error bar graphics illustrate the difference between amylase and lipase values in patients with and without gallstones; the 95% CI range is lower and has a very small spread for patients without gallstones compared to patients with gallstone disease, who have higher 95% CI range with a wider variation (Fig. 1). Histogram graphics show that although there is some reflux of pancreatic enzymes into the gallbladder of patients with healthy gallbladders, the values reached in those patients are mostly within the normal range of plasma amylase and lipase values, whereas the values of pancreatic enzymes in patients with gallstones exceeded the normal plasma values for these enzymes (Figs. 2 and 3).
Discussion There are no published data on reflux of pancreatic enzymes in patients without gallstone disease or with healthy gallbladders; consequently the occurrence and incidence of biliary amylase or lipase levels among individuals without biliary pathology is unknown [13]. What
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World J Surg (2010) 34:2915–2921 800
95% CI Gallbladder Lipase (IU/L)
300
95% CI Gallbladder Amylase (IU/l)
Fig. 1 Error bars (95% Confidence Intervals) comparing gallbladder amylase and lipase levels between gallstone disease and healthy gallbladders. Amylase and lipase levels were significantly elevated (P \ 0.0001) compared to the slight elevation and narrow range of the levels of these pancreatic enzymes in patients without gallstones
200
100
0
-100 N=
600
400
200
0
-200 103 Gallstones
33 Healthy Gallbladders
N=
103 Gallstones
Diagnostic
33 Healthy Gallbladders
Diagnostic
Gallstone disease
Healthy gallbladders 40
70
60
30
Number of cases
Number of cases
50
40
30
20
20
10 10 0 ,0 00 24 ,0 00 22 ,0 00 20 ,0 00 18 ,0 00 16 ,0 00 14 ,0 00 12 ,0 00 10 0 0, 80 0 0, 60 0 0, 40 0 0, 20 0 0,
Amylase (IU/l)
0 0,0
20,0
40,0
60,0
80,0
Amylase (IU/l)
Fig. 2 Histogram showing the differences between various levels of gallbladder amylase in gallstone disease and in healthy gallbladders, 17 patients (16.5%) with gallstones had amylase values between 3 IU/ l and 100 IU/l. Other 41 patients had amylase levels between 101 IU/l and 200 IU/l, and 5 patients had amylase values between 201 IU/l and
2450 IU/l. Regarding amylase levels in patients without gallstones 30 patients (94%) had values between 0 IU/l and 20 IU/l, of them 25 patients had a amylase value of 0 IU/l. The other 3 patients (6%) had the following amylase values: 27 IU/l, 43 IU/l and 80 IU/l
has become clear and currently accepted is the occurrence of pancreaticobiliary reflux in patients with a normal pancreaticobiliary junction [1–4, 13–16]. Diverse methods have been used to demonstrate this reflux: magnetic resonance cholangiopancreatography (MRCP) stimulating pancreatic secretion with intravenous injection of Secretin [1, 3], sampling bile from the bile duct and gallbladder with endoscopic retrograde cholangiopancreatography (ERCP) [2, 3, 16], and sampling bile direct from the gallbladder during cholecystectomy [4, 14, 15]. Of these methods, the sampling of bile by ERCP seems to be an inadequate method to demonstrate pancreaticobiliary reflux, because in the process of taking the sample of bile, the sphincter of Oddi must necessarily be disrupted, potentially causing reflux of enzymes into the bile duct and gallbladder, which
would invalidate both the sample and the method. Secretin injection MRCP is an indirect method of proving pancreaticobiliary reflux, and in patients that should be submitted to surgery it seems to be an unnecessary preoperative study. We believe that the most accurate method for measuring pancreaticobiliary reflux is to sample bile directly from the gallbladder during cholecystectomy, before any manipulation in the triangle of Calot area or over the common bile duct has been performed. Through sampling bile with this method in the present study, we have found an incidence of 83.5% of pancreaticobiliary reflux in patients with gallstone disease compared to an incidence of 3%–6% for patients without gallstones. This incidence was similar to the incidence of 66%–87% reported by Anderson et al. [14], and to our previous
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World J Surg (2010) 34:2915–2921 Gallstone disease
Healthy gallbladders 30
100
Number of cases
Number of cases
80
60
40
20
10
20
0 ,0 00 83 ,0 00 74 ,0 00 65 ,0 00 56 ,0 00 47 ,0 00 38 0 , 00 29 ,0 00 20 0 , 00 11 0 0,
20
Fig. 3 Histogram showing the differences between various levels of gallbladder lipase in gallstone disease and in healthy gallbladders, 91 patients (88.3%) with gallstones had lipase levels from 10 IU/l to 200 IU/l, of them 74 patients had values over 60 IU/l. The other 12 patients (11.7%) had lipase levels from 201 IU/l to 8460 IU/l. Only 1 patient without cholelithiasis had a lipase value over 60 IU/l, the other had lipase levels from 0 IU/l to 52 IU/l, and most of them (21 patients) had a lipase value of 0 IU/l
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Lipase (IU/l)
experience where we found an incidence of 82.6% of pancreaticobiliary reflux in patients with chronic calculous cholecystitis, 87.5% in acute calculous cholecystitis, and 100% in patients with cholelithiasis and associated common bile duct stones, acalculous cholecystitis, and gallbladder cancer [4]. Furthermore, amylase levels in patients with gallbladder cancer were extremely elevated compared to patients with other gallbladder diseases [1, 2, 4]. Given the facts that this is not a dynamic study and that bile samples were taken in fasting individuals undergoing surgery as a point prevalence estimate of elevated pancreatic enzyme concentration in diseased gallbladders, it is possible that pancreaticobiliary reflux may be different under physiologic conditions.Nevertheless, the important finding of the present study is the absence of lipase and amylase in the bile of most patients with healthy gallbladders. The reflux of active pancreatic enzymes into the biliary tree and the gallbladder induces chronic inflammation and increased cellular proliferation of the biliary epithelium, leading to hyperplasia, metaplasia, and carcinoma of the biliary tract and gallbladder [1]. Initial and chronic inflammatory changes of the gallbladder mucosa induced by active pancreatic enzymes could play a role in gallstone formation [4, 14, 17]. Chronic inflammation of the biliary mucosa modifies the hepatic bile in ways other than the reabsorption of fluids and electrolytes with the addition of total proteins, such as mucin and albumin, which increase the nucleation time leading to formation of biliary sludge, microlithiasis, and, ultimately, gallstones [18]. Gallstones may cause chronic abrasion and inflammation of the mucosa [19], leading to inflammatory changes induced by pancreatic enzymes, and genetic mutations such as the loss of heterozygosity of the p53 gene, overexpression of p53 encoding protein, K-ras point mutations, Bcl-2 expression, microsatellite instability, telomerase activity, and inactivation of
0 0,0
10,0
20,0
30,0
40,0
50,0
60,0
70,0
Lipase (IU/l)
p16INK4/CDK2 genes, all of which could result in malignant transformation of the gallbladder mucosa [4, 6, 8, 9, 19–22]. Age was similar in both groups of patients in the present study; although gastric cancer patients were older, the difference was not significant. Cholelithiasis is not an agerelated phenomenon. In fact patients in the present study with gallstones were younger than patients presenting with gastric cancer without gallstones, indicating that older patients do not necessarily have a greater chance of developing cholelithiasis. The reflux of pancreatic enzymes into the gallbladder as a consequence of a motility disorder of the biliary tree may combine with the biliary tree motility disorder to cause biliary symptoms and gallstone disease in young children. Indirect evidence of this possibility lies in the secretion of pancreatic enzymes directly in the gallbladder, an anomaly that has been demonstrated in children with functional endocrine and exocrine heterotopic pancreas located in the gallbladder wall undergoing operation for symptomatic gallstone disease [17]. Consequently, in patients in whom the sphincter of Oddi does not function properly or in patients with an anomalous pancreaticobiliary maljunction outside of the duodenal wall where the sphincter of Oddi does not exist, the reflux of pancreatic enzymes could explain biliary symptoms [23]. A functional disorder of the sphincter of Oddi is the currently proposed explanation for pancreaticobiliary reflux in patients with a normal pancreaticobiliary junction [1, 4, 7, 23–31]. Sphincter of Oddi dysfunction has been classified in two separate categories: sphincter of Oddi stenosis and sphincter of Oddi dyskinesia. Disorders in the sphincter of Oddi cyclic motility are the cause of biliary-type pain in the absence of organic diseases of the pancreaticobiliary system [29, 31–34]. Furthermore, intermittent spasm of the sphincter of Oddi not related to the migrating myoelectric
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complex could be the cause of pancreaticobiliary reflux [4]. Patients with motility disorders of the biliary tree experience biliary-type symptoms and develop chronic acalculous cholecystitis [35–37]; also, motility disorders of the gallbladder leading to biliary stasis are contributing factors for the development of gallstones and chronic gallbladder disease. Based on this evidence, we suggest that motility disorders of the biliary tree—including spastic episodes of the sphincter of Oddi that could be influenced by gender, hormones, and genetic predisposition, and associated to pancreaticobiliary reflux leading to bile tract and gallbladder mucosa chronic injury—could play a role in the etiology of gallstones, chronic gallbladder disease, and, ultimately, gallbladder cancer, as continuous stages of a common pathologic entity. Moreover, gallbladder cancer could represent the final stage of a severe motility disorder of the biliary tract that begins with biliary stasis and leads to pancreaticobiliary reflux secondary to sphincter of Oddi dysfunction, gallstone development, hyperplastic and metaplastic changes of the gallbladder mucosa induced by pancreatic enzymes, and chronic inflammation caused by the continuous mechanical injury induced by the presence of gallstones. This hypothesis might explain why patients with healthy gallbladders without gallstones experience minimal reflux of pancreatic enzymes into the gallbladder, episodes likely representing an uncommon phenomenon or occasional sphincter of Oddi spasm, which also could be influenced by age, gender, medications, and hormonal stimulus.
Conclusions The results of the present study shown that pancreaticobiliary reflux is a common phenomenon in patients with chronic gallstone disease and an uncommon phenomenon in patients with healthy gallbladders without gallstone disease. Acknowledgments This work is registered as Clinicaltrials.Gov— Protocol Registration System—Nct00890201.
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