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Endoscopic papillary balloon dilation causes transient pancreatobiliary and duodenobiliary reflux
Endoscopic papillary balloon dilation causes transient pancreatobiliary and duodenobiliary reflux Masanori Sugiyama, MD, Yutaka Atomi, MD Tokyo, Japan
Background: Endoscopic papillary balloon dilation reduces sphincter function at least transiently or partially, which may allow pancreatobiliary and duodenobiliary reflux to occur. This study prospectively evaluated pancreatobiliary and duodenobiliary reflux after endoscopic papillary balloon dilation. Methods: In 12 patients with choledocholithiasis, ductal bile was sampled for amylase concentration and bacterial culture during ERCP, before and at 7 days to 5 years after endoscopic papillary balloon dilation. To provide comparative and control data, ductal bile was sampled in 12 patients with gallbladder cholesterol polyps and 6 with anomalous pancreaticobiliary junction who did not undergo endoscopic papillary balloon dilation. Results: Amylase concentrations in ductal bile from patients with choledocholithiasis before endoscopic papillary balloon dilation were marginally significantly higher (before Bonferroni correction) compared with concentrations in bile from patients with gallbladder polyps. The concentration of amylase in bile was significantly increased at 7 days after endoscopic papillary balloon dilation compared with that before endoscopic papillary balloon dilation; the level was comparable with that of patients with an anomalous pancreaticobiliary junction. Subsequently, the amylase concentration gradually decreased and was approximately equal to the pre-endoscopic papillary balloon dilation level at 1 year. Bacteriocholia was frequent (67%-92%) for up to 3 months after endoscopic papillary balloon dilation but was rare thereafter. Conclusions: Endoscopic papillary balloon dilation causes transient pancreatobiliary and duodenobiliary reflux. However, reflux is no longer present at 1 year after endoscopic papillary balloon dilation. (Gastrointest Endosc 2004;60:186-90.)
Endoscopic papillary balloon dilation (EPBD) is an alternative to endoscopic sphincterotomy (ES) for treatment of bile duct stones.1-7 EPBD is presumed to preserve papillary function, at least partially, in the long term. In manometric studies, EPBD produced transient papillary dysfunction, but normal function was substantially restored by 1 month to 1 year after the procedure.3,8,9 Although preserved papillary function may prevent late complications, such as recurrent choledocholithiasis and cholangitis, few data are available on the long-term results of EPBD. Furthermore, the development of biliary tract carcinoma after EPBD has not been thoroughly studied. The sphincter of Oddi prevents reflux of pancreatic juice into the bile duct as well as duodenobiliary reflux. In patients with an anomalous pancreaticoReceived October 27, 2003. For revision February 24, 2004. Accepted April 23, 2004. Current affiliations: Department of Surgery, Kyorin University School of Medicine, Tokyo, Japan. Reprint requests: Masanori Sugiyama, MD, Department of Surgery, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan. Copyright Ó 2004 by the American Society for Gastrointestinal Endoscopy 0016-5107/$30.00 PII: S0016-5107(04)01571-8 186
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biliary junction (APBJ), the pancreatic and biliary ducts unite outside the duodenal wall to form a long common channel proximal to the sphincter of Oddi.10,11 Intraductal pressure in the pancreatic duct is higher than that in the bile duct.12 Therefore, APBJ allows free pancreatobiliary reflux, which is considered to be a factor in the development of biliary-tract carcinoma (relative frequency of occurrence being 15.6%-36.0%).13,14 Transduodenal sphincteroplasty ablates sphincter function, and, in one study, it was associated with a 7.4% relative frequency of occurrence of bile duct carcinoma during a median follow-up of 18 years.15 The development of carcinoma after sphincteroplasty is likely a result of reflux of intestinal contents with activated pancreatic juice and bacterial flora into the bile duct.15 The loss of sphincter function with EPBD, even though transient or partial, may allow pancreatobiliary reflux and duodenobiliary reflux. This reflux, if it occurs and is prolonged, could be a risk factor for biliary-tract carcinoma, as occurs with APBJ and transduodenal sphincteroplasty. However, pancreatobiliary and duodenobiliary reflux after EPBD has not been studied. In the present study, amylase concentration and bacterial contamination in ductal bile were serially measured for up to 5 years after VOLUME 60, NO. 2, 2004
Papillary balloon dilation: transient pancreatobiliary, duodenobiliary reflux
EPBD to determine whether EPBD results in pancreatobiliary and/or duodenobiliary reflux. PATIENTS AND METHODS A series of 12 patients (5 men, 7 women; mean age 63 years, range 39-74 years) who underwent EPBD for removal of bile duct stones was studied prospectively. The number of stones ranged from one to 6 (mean 2). Stone size (of the largest, if multiple stones) ranged from 3 to 11 mm (mean 6 mm). The measured diameter of the common bile duct ranged from 6 to 15 mm (mean 11 mm). Five patients had undergone cholecystectomy before EPBD. Of the remaining 7 patients with a gallbladder in situ, 6 had gallbladder stones. None of the 12 patients had acute or chronic pancreatitis, either at study entry or in the past. At the time of initial ERCP, none had clinical signs of acute cholangitis. None had periampullary diverticulum. During ERCP, ductal bile was sampled by selective insertion of a sterile catheter into the bile duct and aspiration at approximately 5 cm from the papilla, before injection of contrast material or EPBD. Selective cannulation was confirmed by bile aspiration, not cholangiography. Bile amylase concentrations were measured enzymatically. The sampled bile also was cultured for aerobic and anaerobic bacteria. After obtaining the bile sample, cholangiography and EPBD were performed. For EPBD, a balloon-tipped catheter with a maximum expanded diameter of 8 mm (PET; Bard Interventional Products, Billerica, Mass.) was inserted and fully expanded for 2 minutes. The bile duct stones were extracted immediately by using a basket, retrieval balloon, or mechanical lithotriptor. All 12 patients received antibiotics for 3 days after EPBD. ERCP was repeated at 7 days, 3 months, 1 year, and 5 years after EPBD to obtain samples of ductal bile for measurement of amylase concentration and bacterial culture, to verify complete clearance of bile duct stones, and to assess the presence of pneumobilia. To provide comparative and control data, amylase concentration and bacterial contamination of ductal bile were investigated in a similar manner in 6 patients (2 men, 4 women; mean age 47 years, range 27-59 years) with APBJ without congenital choledochal cyst and 12 asymptomatic patients (7 men, 5 women; mean age 54 years, range 35-70 years) with cholesterol polyps of the gallbladder who underwent diagnostic ERCP without EPBD. In these patients, ERCP was performed to visualize the biliary tract and the pancreaticobiliary junction. None had a history of biliary surgery, periampullary diverticulum, gallstones, or chronic pancreatitis. Anomalous pancreaticobiliary junction was defined as a common channel that measured 15 mm or longer at ERCP.11 The diagnosis of cholesterol polyp was by US.16 In patients with gallbladder polyp, ERCP was performed mainly for bile duct dilation or because bile duct stones or APBJ was suspected. The measured diameter of the common bile duct ranged from 5 to 13 mm (mean 9 mm) in patients with APBJ and 7 to 14 mm (mean 10 mm) in those with gallbladder polyp. After ERCP, all 6 patients with APBJ underwent surgical treatment, which VOLUME 60, NO. 2, 2004
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revealed gallbladder carcinoma in one and gallbladder hyperplasia in 5. The patients included in the study were randomly selected from among those undergoing EPBD or ERCP. The study was performed in accordance with the Declaration of Helsinki. The protocol was approved by the Department of Surgery of our university. Informed consent was obtained from all 30 patients. All values are expressed as mean (standard deviation[SD]). Results were analyzed by means of the Fisher exact test or by the paired or unpaired t test, when appropriate. Differences were considered significant when p < 0.05. It is recognized that there was multiple testing of outcome data. The p values presented are without correction, and it is noted wherever correction by the method of Bonferroni removes statistical significance. Results that are nominally significant in a single test, but when significance is removed by the Bonferroni correction for multiple testing, are termed ‘‘marginally significant’’ before Bonferroni correction.
RESULTS After EPBD, an early complication occurred in one patient (mild pancreatitis requiring treatment for 2 days). At initial EPBD, the bile duct stones were completely extracted in all 12 patients. Clearance was confirmed by ERCP 7 days after EPBD. Five patients underwent elective cholecystectomy for gallbladder stones after EPBD. During a 5-year followup, none of the 12 patients developed recurrent bile duct stones or a papillary stricture as determined at ERCP. None developed acute cholecystitis, acute cholangitis, or biliary tract carcinoma. Ductal bile amylase concentration before EPBD was marginally significantly higher before Bonferroni correction in patients with bile duct stones compared with those with gallbladder cholesterol polyps and was significantly lower than that in patients with APBJ (Fig. 1, Table 1). For patients with choledocholithiasis, the ductal bile amylase concentration was not significantly different between those with and those without a gallbladder (1230 [352] IU/L vs. 1126 [499] IU/L, respectively). The amylase concentration in ductal bile was significantly increased at 7 days and at 3 months after EPBD, compared with that before EPBD, but the concentration at 1 year and 5 years after EPBD was approximately the same as the pre-EPBD level. The amylase concentration peaked at 7 days after EPBD and did not differ significantly from that in patients with APBJ (although the uncorrected p value neared significance). Before EPBD, 9 (75%) of the 12 patients with bile duct stones had bile cultures positive for bacteria (Table 1). The relative frequency of occurrence of bacteriocholia at 7 days and 1 month after EPBD did GASTROINTESTINAL ENDOSCOPY
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Figure 1. Ductal bile amylase concentrations in patients with bile duct stones, before and at 7 days, 3 months, 1 year, and 5 years after EPBD, in patients with gallbladder cholesterol polyp (GB polyp), and in patients with anomalous pancreaticobiliary junction (APBJ). Results are expressed as mean (SD). *p < 0.05; **p < 0.001 vs. patients before EPBD. For the comparison involving patients with GB polyps, correction by the method of Bonferroni removes statistical significance.
not differ significantly from those before EPBD. The relative frequencies of occurrence at 1 and 5 years were 8% and 0%, respectively, both being significantly lower than that before EPBD. The bacterial species did not differ between bile samples obtained before and after EPBD. The predominant species were Escherichia coli, Enterococcus, Klebsiella oxytoca, and Klebsiella pneumoniae. Pneumobilia was found in 33% of patients at 7 days after EPBD and in none at 1 and 5 years after EPBD. None of patients with APBJ or gallbladder polyps had bacteriocholia or pneumobilia. DISCUSSION In the present study, the ductal bile amylase concentration increased immediately after EPBD but returned to the pre-EPBD level at 1 year after the procedure. Bacterobilia frequently persisted until 1 month after EPBD but was rarely observed thereafter. The concentration of amylase in ductal bile obtained during ERCP is considered to be a marker for the presence and the degree of pancreatobiliary reflux, although cannulation itself may cause such reflux. The ductal bile amylase concentration in patients with bile duct stones before EPBD was marginally significantly higher before Bonferroni correction compared with that in ductal bile from patients with gallbladder polyps, who were assumed to have normal papillary function and to have normal 188
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ductal bile amylase levels. Patients with bile duct stones have mild papillary dysfunction.17,18 This appears to allow a modest degree of pancreatobiliary reflux.19 Pancreatobiliary reflux also can be associated with periampullary diverticulum and acute biliary pancreatitis for the same reason.19 Therefore, patients with a diverticulum or biliary pancreatitis were excluded from the present study. Although the etiology of biliary tract carcinoma is not fully elucidated, risk factors for biliary carcinogenesis have been proposed. In patients with APBJ, there is severe reflux of proteolytic pancreatic enzymes and phospholipase A2, which are activated in the biliary tract.20 Phospholipase A2, which has a direct proliferative effect on biliary tract mucosa, produces lysophosphatidylcholine, which has a cytotoxic effect.20,21 These agents may induce hyperplasia, dysplasia, and carcinoma of the biliary tract. Transduodenal sphincteroplasty results in permanent reflux of intestinal contents with activated pancreatic juice and bacterial flora into the bile duct, possibly producing an environment that favors the development of bile duct carcinoma. Hakamada et al.15 found a high relative frequency of occurrence (7.4%) of bile duct carcinoma after sphincteroplasty. In that study, all patients who developed carcinoma had free reflux of barium into the bile duct, as demonstrated by barium contrast radiography. All of these patients had clinical and histopathologic findings of cholangitis, in contrast to a low relative frequency of occurrence of cholangitis after ES. Cholangitis or biliary infection are thought to be factors in the development of bile duct carcinoma.15 Manometric studies have demonstrated marked impairment of sphincter of Oddi function immediately after ES.22,23 It also has been shown that partial function may return by 2 years after ES.23 Nevertheless, ES results in duodenobiliary reflux over the long term.24,25 Furthermore, in a previous study in which ductal bile amylase concentrations were measured by us, ES resulted in transient but marked pancreatobiliary reflux for up to 3 months.25 However, reflux disappeared by 1 year after ES. Long term, ES actually was associated with an extremely low relative frequency of occurrence of biliary tract carcinoma: 0% to 0.6% during a follow-up of 8 to 14 years. The low relative frequency of occurrence of biliary tract carcinoma after ES, in contrast to that reported after transduodenal sphincteroplasty, may be attributed at least partly to early cessation of pancreatobiliary reflux. It has been demonstrated that papillary function is impaired at 1 week after EPBD.3,8,9 Whether function is restored after EPBD over the long term is controversial: studies have demonstrated complete VOLUME 60, NO. 2, 2004
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Table 1. Ductal bile amylase concentration, bacteriocholia and pneumobilia in patients with gallbladder cholesterol polyp, anomalous pancreatobiliary junction, or bile duct stones Bile duct stones (n = 12) Time after EPBD
Ductal bile amylase concentration (IU/L), mean (SD) Bacteriobilia Pneumobilia
GB polyp* (n = 12)
APBJ (n = 6)
Before EPBD
7 days
3 mo
1y
5y
833y
21364z
1169
12593z
2951y
1521
1404
(272) 0z 0
(12655) 0§ 0
(428) 9 0
(5389) 11 4y
(2028) 8 2
(425) 1§ 0
(380) 0z 0
GB polyp, Gallbladder cholesterol polyp; APBJ, anomalous pancreatobiliary junction; EPBD, endoscopic papillary balloon dilation; SD, standard deviation. *For the comparison involving patients with GB polyps, correction by the method of Bonferroni removes the p < 0.05. yp < 0.05. zp < 0.001 vs. before EPBD. §p < 0.01.
recovery to the pre-EPBD level by 1 month3,8 or partial restoration by 1 year.9 The present study found an extremely high concentration of amylase in ductal bile samples obtained at 7 days after EPBD, which reached the level observed in patients with APBJ. After 7 days, the concentration gradually decreased, returning approximately to the level before EPBD by 1 year. Although pancreatobiliary reflux occurs immediately after EPBD, recovery of sphincter function with a gradual reduction in reflux begins approximately 3 months after the procedure. Thus, exposure of the biliary tract to an extremely high concentration of pancreatic juice persists for no more than 3 months after EPBD. These findings are similar to those observed after ES.25 Therefore, EPBD is unlikely to increase the risk for development of biliary tract carcinoma. Endoscopic papillary balloon dilation results in duodenobiliary reflux, as evidenced by bacteriocholia at 7 days and 3 months after the procedure. However, duodenobiliary reflux was rarely observed thereafter, because of recovery of papillary function. This is in contrast to the prolonged bacteriocholia demonstrated in other studies after ES or transduodenal sphincteroplasty.24,25 Pneumobilia was less frequent than bacteriocholia after EPBD, probably because papillary dysfunction and duodenobiliary reflux were mild. In conclusion, EPBD results in transient pancreatobiliary and duodenobiliary reflux, which are no longer present after 1 year. REFERENCES 1. May G, Cotton PB, Edmunds SE, Chong W. Removal of stones from the bile duct at ERCP without sphincterotomy. Gastrointest Endosc 1993;39:749-54. VOLUME 60, NO. 2, 2004
2. Mac Mathuna P, White P, Clarke E, Lennon J, Crowe J. Endoscopic sphincteroplasty: a novel and safe alternative to papillotomy in the management of bile duct stones. Gut 1994;35:127-9. 3. Minami A, Nakatsu T, Uchida N, Hirabayshi S, Fukuma H, Morshed SA, et al. Papillary dilation vs sphincterotomy in endoscopic removal of bile duct stones. A randomized trial with manometric function. Dig Dis Sci 1995;40:2550-4. 4. Bergman JJGHM, Rauws EAJ, Foskens P, van Berkel AM, Bossuyt PM, Tijssen JG, et al. Randomised trial of endoscopic balloon dilation versus endoscopic sphincterotomy for removal of bileduct stones. Lancet 1997;349:1124-9. 5. Komatsu Y, Kawabe T, Toda N, Ohashi M, Isayama M, Tateishi K, et al. Endoscopic papillary balloon dilation for the management of common bile duct stones: experience of 226 cases. Endoscopy 1998;30:12-7. 6. Fujita N, Maguchi H, Komatsu Y, Yasuda I, Hasebe O, Igarashi Y, et al. Endoscopic sphincterotomy and endoscopic papillary balloon dilatation for bile duct stones: a prospective randomized controlled multicenter trial. Gastrointest Endosc 2003;57:151-5. 7. Sugiyama M, Izumisato Y, Abe N, Masaki T, Mori T, Atomi Y. Predictive factors for acute pancreatitis and hyperamylasemia after endoscopic papillary balloon dilation. Gastrointest Endosc 2003;57:531-5. 8. Sato H, Kodama T, Takaaki J, Tatsumi Y, Maeda T, Fujita S, et al. Endoscopic papillary balloon dilatation may preserve sphincter of Oddi function after common bile duct stone management: evaluation from the viewpoint of endoscopic manometry. Gut 1997;41:541-4. 9. Yasuda I, Tomita E, Enya M, Kato T, Moriwaki H. Can endoscopic papillary balloon dilation really preserve sphincter of Oddi function? Gut 2001;49:686-91. 10. Babitt DP. Congenital choledochal cyst: new etiological concept based on anomalous relationships of the common bile duct and pancreatic bulb. Annales de Radiologie 1969;12:231-40. 11. Kimura K, Ohto M, Saisho H, Unozawa T, Tsuchiya Y, Morita M, et al. Association of gallbladder carcinoma and anomalous pancreatobiliary ductal union. Gastroenterology 1985;89:1258-65. 12. Csendes A, Kruse A, Funch-Jensen P, Oster MJ, Ornsholt J, Amdrup E. Pressure measurements in the biliary and pancreatic duct systems in controls and in patients with GASTROINTESTINAL ENDOSCOPY
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13.
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15.
16.
17.
18.
Papillary balloon dilation: transient pancreatobiliary, duodenobiliary reflux
gallstones, previous cholecystectomy, or common bile duct stones. Gastroenterology 1979;77:1203-10. Komi N, Tamura T, Miyoshi Y, Kunitomo K, Udaka H, Takehara H. Nationwide survey of cases of choledochal cyst. Analysis of coexistent anomalies, complications and surgical treatment in 645 cases. Surg Gastroenterol 1984;3:69-73. Aoki H, Sugatani H. Shimizu M. A clinical study on cancer of the bile duct associated with anomalous arrangements of pancreaticobiliary ductal system. Analysis of 569 cases collected in Japan [Japanese]. Journal of Biliary Tract and Pancreas 1987;8:1539-51. Hakamada K, Sasaki M, Endoh M, Itoh T, Morita T, Konn M. Late development of bile duct cancer after sphincteroplasty: a ten- to twenty-two-year follow-up study. Surgery 1997; 121:488-92. Sugiyama M, Atomi Y, Yamato T. Endoscopic ultrasonography for differential diagnosis of polypoid gall bladder lesions: analysis in surgical and follow up series. Gut 2000;46:250-4. Toouli J, Geenen JE, Hogan WJ, Dodds WJ, Arndorfer RC. Sphincter of Oddi motor activity: a comparison between patients with common bile duct stones and controls. Gastroenterology 1982;82:111-7. De Masi E, Corazziari E, Habib FI, Fontana B, Gatti V, Fegiz GF, et al. Manometric study of the sphincter of Oddi in patients with and without common bile duct stones. Gut 1984;25:275-8.
19. Sugiyama M, Atomi Y. Periampullary diverticula cause pancreatobiliary reflux. Scand J Gastroenterol 2001;36: 994-7. 20. Shimada K, Yanagisawa J, Nakayama F. Increased lysophosphatidylcholine and pancreatic enzyme content in bile of patients with anomalous pancreaticobiliary ductal junction. Hepatology 1991;13:438-44. 21. Hanada K, Itoh M, Fujii K, Tsuchida A, Hirata M, Ishimaru S, et al. Pathology and cellular kinetics of gallbladder with an anomalous junction of the pancreaticobiliary duct. Am J Gastroenterol 1996;91:1007-11. 22. Funch-Jensen P, Csendes A, Kruse A, Oster MJ, Amdrup E. Common bile duct and Oddi sphincter pressure before and after endoscopic papillotomy in patients with common bile duct stones. Ann Surg 1979;190:176-8. 23. Geenen JE, Toouli J, Hogan WJ, Dodds WJ, Stewart ET, Mavrelis P, et al. Endoscopic sphincterotomy: follow-up evaluation of effects on the sphincter of Oddi. Gastroenterology 1984;87:754-8. 24. Gregg JA, de Girolami P, Carr-locke DL. Effects of sphincteroplasty and endoscopic sphincterotomy on the bacteriologic characteristics of the common bile duct. Am J Surg 1985;149:668-71. 25. Sugiyama M, Atomi Y. Does endoscopic sphincterotomy cause prolonged pancreatobiliary reflux? Am J Gastroenterol 1999;94:795-8.
By the Numbers All of the previously published biostatistical articles are now available in a grouped format through a link, By the Numbers, under Features at www.mosby.com/gie.
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VOLUME 60, NO. 2, 2004
Background: Endoscopic papillary balloon dilation reduces sphincter function at least transiently or partially, which may allow pancreatobiliary and duodenobiliary reflux to occur. This study prospectively evaluated pancreatobiliary and duodenobiliary reflux after endoscopic papillary balloon dilation. Methods: In 12 patients with choledocholithiasis, ductal bile was sampled for amylase concentration and bacterial culture during ERCP, before and at 7 days to 5 years after endoscopic papillary balloon dilation. To provide comparative and control data, ductal bile was sampled in 12 patients with gallbladder cholesterol polyps and 6 with anomalous pancreaticobiliary junction who did not undergo endoscopic papillary balloon dilation. Results: Amylase concentrations in ductal bile from patients with choledocholithiasis before endoscopic papillary balloon dilation were marginally significantly higher (before Bonferroni correction) compared with concentrations in bile from patients with gallbladder polyps. The concentration of amylase in bile was significantly increased at 7 days after endoscopic papillary balloon dilation compared with that before endoscopic papillary balloon dilation; the level was comparable with that of patients with an anomalous pancreaticobiliary junction. Subsequently, the amylase concentration gradually decreased and was approximately equal to the pre-endoscopic papillary balloon dilation level at 1 year. Bacteriocholia was frequent (67%-92%) for up to 3 months after endoscopic papillary balloon dilation but was rare thereafter. Conclusions: Endoscopic papillary balloon dilation causes transient pancreatobiliary and duodenobiliary reflux. However, reflux is no longer present at 1 year after endoscopic papillary balloon dilation. (Gastrointest Endosc 2004;60:186-90.)
Endoscopic papillary balloon dilation (EPBD) is an alternative to endoscopic sphincterotomy (ES) for treatment of bile duct stones.1-7 EPBD is presumed to preserve papillary function, at least partially, in the long term. In manometric studies, EPBD produced transient papillary dysfunction, but normal function was substantially restored by 1 month to 1 year after the procedure.3,8,9 Although preserved papillary function may prevent late complications, such as recurrent choledocholithiasis and cholangitis, few data are available on the long-term results of EPBD. Furthermore, the development of biliary tract carcinoma after EPBD has not been thoroughly studied. The sphincter of Oddi prevents reflux of pancreatic juice into the bile duct as well as duodenobiliary reflux. In patients with an anomalous pancreaticoReceived October 27, 2003. For revision February 24, 2004. Accepted April 23, 2004. Current affiliations: Department of Surgery, Kyorin University School of Medicine, Tokyo, Japan. Reprint requests: Masanori Sugiyama, MD, Department of Surgery, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan. Copyright Ó 2004 by the American Society for Gastrointestinal Endoscopy 0016-5107/$30.00 PII: S0016-5107(04)01571-8 186
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biliary junction (APBJ), the pancreatic and biliary ducts unite outside the duodenal wall to form a long common channel proximal to the sphincter of Oddi.10,11 Intraductal pressure in the pancreatic duct is higher than that in the bile duct.12 Therefore, APBJ allows free pancreatobiliary reflux, which is considered to be a factor in the development of biliary-tract carcinoma (relative frequency of occurrence being 15.6%-36.0%).13,14 Transduodenal sphincteroplasty ablates sphincter function, and, in one study, it was associated with a 7.4% relative frequency of occurrence of bile duct carcinoma during a median follow-up of 18 years.15 The development of carcinoma after sphincteroplasty is likely a result of reflux of intestinal contents with activated pancreatic juice and bacterial flora into the bile duct.15 The loss of sphincter function with EPBD, even though transient or partial, may allow pancreatobiliary reflux and duodenobiliary reflux. This reflux, if it occurs and is prolonged, could be a risk factor for biliary-tract carcinoma, as occurs with APBJ and transduodenal sphincteroplasty. However, pancreatobiliary and duodenobiliary reflux after EPBD has not been studied. In the present study, amylase concentration and bacterial contamination in ductal bile were serially measured for up to 5 years after VOLUME 60, NO. 2, 2004
Papillary balloon dilation: transient pancreatobiliary, duodenobiliary reflux
EPBD to determine whether EPBD results in pancreatobiliary and/or duodenobiliary reflux. PATIENTS AND METHODS A series of 12 patients (5 men, 7 women; mean age 63 years, range 39-74 years) who underwent EPBD for removal of bile duct stones was studied prospectively. The number of stones ranged from one to 6 (mean 2). Stone size (of the largest, if multiple stones) ranged from 3 to 11 mm (mean 6 mm). The measured diameter of the common bile duct ranged from 6 to 15 mm (mean 11 mm). Five patients had undergone cholecystectomy before EPBD. Of the remaining 7 patients with a gallbladder in situ, 6 had gallbladder stones. None of the 12 patients had acute or chronic pancreatitis, either at study entry or in the past. At the time of initial ERCP, none had clinical signs of acute cholangitis. None had periampullary diverticulum. During ERCP, ductal bile was sampled by selective insertion of a sterile catheter into the bile duct and aspiration at approximately 5 cm from the papilla, before injection of contrast material or EPBD. Selective cannulation was confirmed by bile aspiration, not cholangiography. Bile amylase concentrations were measured enzymatically. The sampled bile also was cultured for aerobic and anaerobic bacteria. After obtaining the bile sample, cholangiography and EPBD were performed. For EPBD, a balloon-tipped catheter with a maximum expanded diameter of 8 mm (PET; Bard Interventional Products, Billerica, Mass.) was inserted and fully expanded for 2 minutes. The bile duct stones were extracted immediately by using a basket, retrieval balloon, or mechanical lithotriptor. All 12 patients received antibiotics for 3 days after EPBD. ERCP was repeated at 7 days, 3 months, 1 year, and 5 years after EPBD to obtain samples of ductal bile for measurement of amylase concentration and bacterial culture, to verify complete clearance of bile duct stones, and to assess the presence of pneumobilia. To provide comparative and control data, amylase concentration and bacterial contamination of ductal bile were investigated in a similar manner in 6 patients (2 men, 4 women; mean age 47 years, range 27-59 years) with APBJ without congenital choledochal cyst and 12 asymptomatic patients (7 men, 5 women; mean age 54 years, range 35-70 years) with cholesterol polyps of the gallbladder who underwent diagnostic ERCP without EPBD. In these patients, ERCP was performed to visualize the biliary tract and the pancreaticobiliary junction. None had a history of biliary surgery, periampullary diverticulum, gallstones, or chronic pancreatitis. Anomalous pancreaticobiliary junction was defined as a common channel that measured 15 mm or longer at ERCP.11 The diagnosis of cholesterol polyp was by US.16 In patients with gallbladder polyp, ERCP was performed mainly for bile duct dilation or because bile duct stones or APBJ was suspected. The measured diameter of the common bile duct ranged from 5 to 13 mm (mean 9 mm) in patients with APBJ and 7 to 14 mm (mean 10 mm) in those with gallbladder polyp. After ERCP, all 6 patients with APBJ underwent surgical treatment, which VOLUME 60, NO. 2, 2004
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revealed gallbladder carcinoma in one and gallbladder hyperplasia in 5. The patients included in the study were randomly selected from among those undergoing EPBD or ERCP. The study was performed in accordance with the Declaration of Helsinki. The protocol was approved by the Department of Surgery of our university. Informed consent was obtained from all 30 patients. All values are expressed as mean (standard deviation[SD]). Results were analyzed by means of the Fisher exact test or by the paired or unpaired t test, when appropriate. Differences were considered significant when p < 0.05. It is recognized that there was multiple testing of outcome data. The p values presented are without correction, and it is noted wherever correction by the method of Bonferroni removes statistical significance. Results that are nominally significant in a single test, but when significance is removed by the Bonferroni correction for multiple testing, are termed ‘‘marginally significant’’ before Bonferroni correction.
RESULTS After EPBD, an early complication occurred in one patient (mild pancreatitis requiring treatment for 2 days). At initial EPBD, the bile duct stones were completely extracted in all 12 patients. Clearance was confirmed by ERCP 7 days after EPBD. Five patients underwent elective cholecystectomy for gallbladder stones after EPBD. During a 5-year followup, none of the 12 patients developed recurrent bile duct stones or a papillary stricture as determined at ERCP. None developed acute cholecystitis, acute cholangitis, or biliary tract carcinoma. Ductal bile amylase concentration before EPBD was marginally significantly higher before Bonferroni correction in patients with bile duct stones compared with those with gallbladder cholesterol polyps and was significantly lower than that in patients with APBJ (Fig. 1, Table 1). For patients with choledocholithiasis, the ductal bile amylase concentration was not significantly different between those with and those without a gallbladder (1230 [352] IU/L vs. 1126 [499] IU/L, respectively). The amylase concentration in ductal bile was significantly increased at 7 days and at 3 months after EPBD, compared with that before EPBD, but the concentration at 1 year and 5 years after EPBD was approximately the same as the pre-EPBD level. The amylase concentration peaked at 7 days after EPBD and did not differ significantly from that in patients with APBJ (although the uncorrected p value neared significance). Before EPBD, 9 (75%) of the 12 patients with bile duct stones had bile cultures positive for bacteria (Table 1). The relative frequency of occurrence of bacteriocholia at 7 days and 1 month after EPBD did GASTROINTESTINAL ENDOSCOPY
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Papillary balloon dilation: transient pancreatobiliary, duodenobiliary reflux
Figure 1. Ductal bile amylase concentrations in patients with bile duct stones, before and at 7 days, 3 months, 1 year, and 5 years after EPBD, in patients with gallbladder cholesterol polyp (GB polyp), and in patients with anomalous pancreaticobiliary junction (APBJ). Results are expressed as mean (SD). *p < 0.05; **p < 0.001 vs. patients before EPBD. For the comparison involving patients with GB polyps, correction by the method of Bonferroni removes statistical significance.
not differ significantly from those before EPBD. The relative frequencies of occurrence at 1 and 5 years were 8% and 0%, respectively, both being significantly lower than that before EPBD. The bacterial species did not differ between bile samples obtained before and after EPBD. The predominant species were Escherichia coli, Enterococcus, Klebsiella oxytoca, and Klebsiella pneumoniae. Pneumobilia was found in 33% of patients at 7 days after EPBD and in none at 1 and 5 years after EPBD. None of patients with APBJ or gallbladder polyps had bacteriocholia or pneumobilia. DISCUSSION In the present study, the ductal bile amylase concentration increased immediately after EPBD but returned to the pre-EPBD level at 1 year after the procedure. Bacterobilia frequently persisted until 1 month after EPBD but was rarely observed thereafter. The concentration of amylase in ductal bile obtained during ERCP is considered to be a marker for the presence and the degree of pancreatobiliary reflux, although cannulation itself may cause such reflux. The ductal bile amylase concentration in patients with bile duct stones before EPBD was marginally significantly higher before Bonferroni correction compared with that in ductal bile from patients with gallbladder polyps, who were assumed to have normal papillary function and to have normal 188
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ductal bile amylase levels. Patients with bile duct stones have mild papillary dysfunction.17,18 This appears to allow a modest degree of pancreatobiliary reflux.19 Pancreatobiliary reflux also can be associated with periampullary diverticulum and acute biliary pancreatitis for the same reason.19 Therefore, patients with a diverticulum or biliary pancreatitis were excluded from the present study. Although the etiology of biliary tract carcinoma is not fully elucidated, risk factors for biliary carcinogenesis have been proposed. In patients with APBJ, there is severe reflux of proteolytic pancreatic enzymes and phospholipase A2, which are activated in the biliary tract.20 Phospholipase A2, which has a direct proliferative effect on biliary tract mucosa, produces lysophosphatidylcholine, which has a cytotoxic effect.20,21 These agents may induce hyperplasia, dysplasia, and carcinoma of the biliary tract. Transduodenal sphincteroplasty results in permanent reflux of intestinal contents with activated pancreatic juice and bacterial flora into the bile duct, possibly producing an environment that favors the development of bile duct carcinoma. Hakamada et al.15 found a high relative frequency of occurrence (7.4%) of bile duct carcinoma after sphincteroplasty. In that study, all patients who developed carcinoma had free reflux of barium into the bile duct, as demonstrated by barium contrast radiography. All of these patients had clinical and histopathologic findings of cholangitis, in contrast to a low relative frequency of occurrence of cholangitis after ES. Cholangitis or biliary infection are thought to be factors in the development of bile duct carcinoma.15 Manometric studies have demonstrated marked impairment of sphincter of Oddi function immediately after ES.22,23 It also has been shown that partial function may return by 2 years after ES.23 Nevertheless, ES results in duodenobiliary reflux over the long term.24,25 Furthermore, in a previous study in which ductal bile amylase concentrations were measured by us, ES resulted in transient but marked pancreatobiliary reflux for up to 3 months.25 However, reflux disappeared by 1 year after ES. Long term, ES actually was associated with an extremely low relative frequency of occurrence of biliary tract carcinoma: 0% to 0.6% during a follow-up of 8 to 14 years. The low relative frequency of occurrence of biliary tract carcinoma after ES, in contrast to that reported after transduodenal sphincteroplasty, may be attributed at least partly to early cessation of pancreatobiliary reflux. It has been demonstrated that papillary function is impaired at 1 week after EPBD.3,8,9 Whether function is restored after EPBD over the long term is controversial: studies have demonstrated complete VOLUME 60, NO. 2, 2004
Papillary balloon dilation: transient pancreatobiliary, duodenobiliary reflux
M Sugiyama, Y Atomi
Table 1. Ductal bile amylase concentration, bacteriocholia and pneumobilia in patients with gallbladder cholesterol polyp, anomalous pancreatobiliary junction, or bile duct stones Bile duct stones (n = 12) Time after EPBD
Ductal bile amylase concentration (IU/L), mean (SD) Bacteriobilia Pneumobilia
GB polyp* (n = 12)
APBJ (n = 6)
Before EPBD
7 days
3 mo
1y
5y
833y
21364z
1169
12593z
2951y
1521
1404
(272) 0z 0
(12655) 0§ 0
(428) 9 0
(5389) 11 4y
(2028) 8 2
(425) 1§ 0
(380) 0z 0
GB polyp, Gallbladder cholesterol polyp; APBJ, anomalous pancreatobiliary junction; EPBD, endoscopic papillary balloon dilation; SD, standard deviation. *For the comparison involving patients with GB polyps, correction by the method of Bonferroni removes the p < 0.05. yp < 0.05. zp < 0.001 vs. before EPBD. §p < 0.01.
recovery to the pre-EPBD level by 1 month3,8 or partial restoration by 1 year.9 The present study found an extremely high concentration of amylase in ductal bile samples obtained at 7 days after EPBD, which reached the level observed in patients with APBJ. After 7 days, the concentration gradually decreased, returning approximately to the level before EPBD by 1 year. Although pancreatobiliary reflux occurs immediately after EPBD, recovery of sphincter function with a gradual reduction in reflux begins approximately 3 months after the procedure. Thus, exposure of the biliary tract to an extremely high concentration of pancreatic juice persists for no more than 3 months after EPBD. These findings are similar to those observed after ES.25 Therefore, EPBD is unlikely to increase the risk for development of biliary tract carcinoma. Endoscopic papillary balloon dilation results in duodenobiliary reflux, as evidenced by bacteriocholia at 7 days and 3 months after the procedure. However, duodenobiliary reflux was rarely observed thereafter, because of recovery of papillary function. This is in contrast to the prolonged bacteriocholia demonstrated in other studies after ES or transduodenal sphincteroplasty.24,25 Pneumobilia was less frequent than bacteriocholia after EPBD, probably because papillary dysfunction and duodenobiliary reflux were mild. In conclusion, EPBD results in transient pancreatobiliary and duodenobiliary reflux, which are no longer present after 1 year. REFERENCES 1. May G, Cotton PB, Edmunds SE, Chong W. Removal of stones from the bile duct at ERCP without sphincterotomy. Gastrointest Endosc 1993;39:749-54. VOLUME 60, NO. 2, 2004
2. Mac Mathuna P, White P, Clarke E, Lennon J, Crowe J. Endoscopic sphincteroplasty: a novel and safe alternative to papillotomy in the management of bile duct stones. Gut 1994;35:127-9. 3. Minami A, Nakatsu T, Uchida N, Hirabayshi S, Fukuma H, Morshed SA, et al. Papillary dilation vs sphincterotomy in endoscopic removal of bile duct stones. A randomized trial with manometric function. Dig Dis Sci 1995;40:2550-4. 4. Bergman JJGHM, Rauws EAJ, Foskens P, van Berkel AM, Bossuyt PM, Tijssen JG, et al. Randomised trial of endoscopic balloon dilation versus endoscopic sphincterotomy for removal of bileduct stones. Lancet 1997;349:1124-9. 5. Komatsu Y, Kawabe T, Toda N, Ohashi M, Isayama M, Tateishi K, et al. Endoscopic papillary balloon dilation for the management of common bile duct stones: experience of 226 cases. Endoscopy 1998;30:12-7. 6. Fujita N, Maguchi H, Komatsu Y, Yasuda I, Hasebe O, Igarashi Y, et al. Endoscopic sphincterotomy and endoscopic papillary balloon dilatation for bile duct stones: a prospective randomized controlled multicenter trial. Gastrointest Endosc 2003;57:151-5. 7. Sugiyama M, Izumisato Y, Abe N, Masaki T, Mori T, Atomi Y. Predictive factors for acute pancreatitis and hyperamylasemia after endoscopic papillary balloon dilation. Gastrointest Endosc 2003;57:531-5. 8. Sato H, Kodama T, Takaaki J, Tatsumi Y, Maeda T, Fujita S, et al. Endoscopic papillary balloon dilatation may preserve sphincter of Oddi function after common bile duct stone management: evaluation from the viewpoint of endoscopic manometry. Gut 1997;41:541-4. 9. Yasuda I, Tomita E, Enya M, Kato T, Moriwaki H. Can endoscopic papillary balloon dilation really preserve sphincter of Oddi function? Gut 2001;49:686-91. 10. Babitt DP. Congenital choledochal cyst: new etiological concept based on anomalous relationships of the common bile duct and pancreatic bulb. Annales de Radiologie 1969;12:231-40. 11. Kimura K, Ohto M, Saisho H, Unozawa T, Tsuchiya Y, Morita M, et al. Association of gallbladder carcinoma and anomalous pancreatobiliary ductal union. Gastroenterology 1985;89:1258-65. 12. Csendes A, Kruse A, Funch-Jensen P, Oster MJ, Ornsholt J, Amdrup E. Pressure measurements in the biliary and pancreatic duct systems in controls and in patients with GASTROINTESTINAL ENDOSCOPY
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Papillary balloon dilation: transient pancreatobiliary, duodenobiliary reflux
gallstones, previous cholecystectomy, or common bile duct stones. Gastroenterology 1979;77:1203-10. Komi N, Tamura T, Miyoshi Y, Kunitomo K, Udaka H, Takehara H. Nationwide survey of cases of choledochal cyst. Analysis of coexistent anomalies, complications and surgical treatment in 645 cases. Surg Gastroenterol 1984;3:69-73. Aoki H, Sugatani H. Shimizu M. A clinical study on cancer of the bile duct associated with anomalous arrangements of pancreaticobiliary ductal system. Analysis of 569 cases collected in Japan [Japanese]. Journal of Biliary Tract and Pancreas 1987;8:1539-51. Hakamada K, Sasaki M, Endoh M, Itoh T, Morita T, Konn M. Late development of bile duct cancer after sphincteroplasty: a ten- to twenty-two-year follow-up study. Surgery 1997; 121:488-92. Sugiyama M, Atomi Y, Yamato T. Endoscopic ultrasonography for differential diagnosis of polypoid gall bladder lesions: analysis in surgical and follow up series. Gut 2000;46:250-4. Toouli J, Geenen JE, Hogan WJ, Dodds WJ, Arndorfer RC. Sphincter of Oddi motor activity: a comparison between patients with common bile duct stones and controls. Gastroenterology 1982;82:111-7. De Masi E, Corazziari E, Habib FI, Fontana B, Gatti V, Fegiz GF, et al. Manometric study of the sphincter of Oddi in patients with and without common bile duct stones. Gut 1984;25:275-8.
19. Sugiyama M, Atomi Y. Periampullary diverticula cause pancreatobiliary reflux. Scand J Gastroenterol 2001;36: 994-7. 20. Shimada K, Yanagisawa J, Nakayama F. Increased lysophosphatidylcholine and pancreatic enzyme content in bile of patients with anomalous pancreaticobiliary ductal junction. Hepatology 1991;13:438-44. 21. Hanada K, Itoh M, Fujii K, Tsuchida A, Hirata M, Ishimaru S, et al. Pathology and cellular kinetics of gallbladder with an anomalous junction of the pancreaticobiliary duct. Am J Gastroenterol 1996;91:1007-11. 22. Funch-Jensen P, Csendes A, Kruse A, Oster MJ, Amdrup E. Common bile duct and Oddi sphincter pressure before and after endoscopic papillotomy in patients with common bile duct stones. Ann Surg 1979;190:176-8. 23. Geenen JE, Toouli J, Hogan WJ, Dodds WJ, Stewart ET, Mavrelis P, et al. Endoscopic sphincterotomy: follow-up evaluation of effects on the sphincter of Oddi. Gastroenterology 1984;87:754-8. 24. Gregg JA, de Girolami P, Carr-locke DL. Effects of sphincteroplasty and endoscopic sphincterotomy on the bacteriologic characteristics of the common bile duct. Am J Surg 1985;149:668-71. 25. Sugiyama M, Atomi Y. Does endoscopic sphincterotomy cause prolonged pancreatobiliary reflux? Am J Gastroenterol 1999;94:795-8.
By the Numbers All of the previously published biostatistical articles are now available in a grouped format through a link, By the Numbers, under Features at www.mosby.com/gie.
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