The most outstanding feature of the normal anatomy of the extrahepatic biliary system is its high degree of variability. In the rare studies about this subject, abnormal opening of the common bile duct (CBD) is reported at a wide range of 5.6 to 23% due to the limited number of cases [[1,5] and [6]]. Lindner et al. examined 1,000 intraoperative cholangiograms and they found that the rate of distal opening versus the normal anatomic site was 13.1%; however, no proximal opening was indicated [7]. As can be seen, the distal opening is not rare, but a proximal opening, especially into the duodenal bulb, is reported rarely, consisting of only a few cases [8]. Lee et al. recently reported a large series concerning clinical implications of this abnormality [9].

The etiology of this anomalous opening is not known, but it has been argued that developmental errors formed during embryogenesis, which are not yet understood, could be a causative factor. The liver originates from the hepatic diverticulum, the cranial part (pars hepatica) of which gives rise to the intrahepatic and common hepatic ducts and the caudal part (the pars cystica) gives rise to the gall bladder and the cystic duct [10]. The most commonly adopted hypothesis about the ectopic opening of the CBD was proposed by Boyden [8], who explained that the ectopic CBD opening was formed by coincidental subdivision of the primary hepatic furrow, as it becomes pars hepatica and pars cystica. He summarized the process as follows; "In the first weeks of embryogenesis, if subdivision occurs very early, leaving the pars hepatica above the zone of growth that separates stomach from duodenum, then the pars hepatica will develop into a duct emptying into the region of the pylorus".

To date, in those cases with ectopic opening of CBD into the duodenal bulb, the relation of embryonal defects with sex has not been discussed in the published literature, but evident male predominance is remarkable according to case reports. In one series, fifteen of 18 patients, and in another series, seven of eight patients were male [9,11]. In the presented series, the male to female (m/f) ratio was 49/4. When the ectopic openings of CBD to the other sites of the digestive tract were evaluated, there was no significant difference according to sex, whereas male predominance in patients with ectopic opening to the duodenal bulb is indicative, and warrants explanation.

Although the age range of patients in this study was between 36–78 years, the median age at diagnosis was 55. The most frequent symptom was biliary pain and was present in 95% of patients during admission. However, since the diagnosis was made in their fifth decade, it is obvious that some of the patients were asymptomatic for a long period. Indeed, two patients (5%) in this series were diagnosed coincidentally. One of these patients was 78 years old and diagnosed during the etiological search of elevated cholestatic enzyme levels; another patient had been evaluated for diarrhea.

When the past medical history of some of these patients was questioned, a history of cholecystectomy (64%) and/or ulcer (20.5%) operations because of biliary and duodenal diseases was revealed in a significant number of patients, as well as of medical treatment due to recurring duodenal ulcer (61.4%) and/or frequent cholangitis attacks.

In fact, diseases related with the biliary system are reported frequently in patients with ectopic CBD opening[2-4,9,11-18]. In this study, CBD dilatation was found in 94% of the cases with or without intrahepatic biliary dilatation. Additionally, 51% of the patients had CBD stone and 59% of the patients had cholangitis attacks. Liver function tests were abnormal in 97.4% of the patients, and 76.9% had evident jaundice. In our opinion, duodenal mucosal diseases (ulcer and deformation/stenosis) and the biliary system diseases are strongly related with the site and structure of the ectopic opening. In the literature, histological examination of double CBD cases with openings into the stomach demonstrated that there was no sphincteric structure at the site of the openings [19-22].

In a presentation with two cases, one of the cases who had an anomalous opening at the third part of the duodenum had intact sphincteric function manometrically, whereas there was no sphinteric function in the other case with opening into the duodenal bulb[23]. In all of our cases, there was a loose, cleft-like opening instead of a normal papillary structure, through which bile could easily flow into the duodenal bulb.

This situation causes a two-sided interaction between the duodenum and biliary tract:

Duodenal content will pass through the biliary tract easily (duodenobiliary reflux) and Bile can flow into the duodenal bulb without sphincteric control. In our opinion, the first of these actions causes biliary tract diseases and the second causes ulcer and complications. Duodenobiliary reflux was examined in the literature. Bacterial contamination continues for months even years in approximately 30–70% of patients after endoscopic or surgical sphincteroplasty [24,25]. However, occurrence of cholangitis together with sphincteroplasty is rare, and if the orifice is open, the rate is less than 3% [26]. There are, however, cases reported in the literature with recurrent cholangitis attacks after choledochoduodenostomy[27] and endocopic sphincterotomy (EST)[28]. It is proposed that duodenobiliary reflux and temporary obstructions cause the cholangitis attacks without restenosis. This idea is supported by evidences like barium or air reflux (pneumobilia) through the biliary tract [29] and extraction of food debris in some cases from the CBD[25].

In our series, air was seen in the intrahepatic bile ducts in 35.8% of patients by transabdominal USG, in 28% of patients fluoroscopically during ERCP and in two of the patients by CT. Barium passage through the biliary tract was indicated in three patients in whom upper gastrointestinal tract barium series were taken, and food debris was extracted from the pancreatic duct in one case. Similar findings were reported in the literature in patients with ectopic bilioenteric openings [[2,3], and [30]]. Although not demonstrated to date, there is possibly bacteriobilia in those cases that would not cause any problem as long as bile flux continues just like in sphincterotomy or choledochoduodenostomy cases. It is possible that duodenal content refluxing into the biliary system would cause temporary obstructions at times that might lead to bacterial growth triggering cholangitis attacks. The improvement in more than two-thirds of our patients with dilated CBD but without stone with only medical treatment supports this idea. Furthermore, temporary obstruction at the biliary opening site due to edema in the duodenal bulb caused by chronic ulceration and/or inflammation is another possibility in many patients. Bacterial overgrowth resulting from stasis in the biliary tract due to temporary obstructions or distal stricture is likely to cause the bile to gain lithogenic characteristics. Moreover, the reflux material itself also causes stone formation. It has been reported in the literature that medical materials like sutures [31] and metalic clips [32], vegetable debris such as cherry stalk [33] and tomato skin [34], and foods like fish bones [35] form a nidus for biliary stone formation.

The second most common finding in these patients was ulcer disease and its complications like deformation and stenosis. Duodenal bulb deformation was found in 49% of the cases. There was active duodenal or gastric ulceration in 31% and 1.8% of these patients, respectively. Eight cases (31%) had a gastric by-pass operation because of duodenal obstruction. As mentioned above, the second result of the absence of a sphincteric structure in the ectopic biliary opening site is the free bile flux into the duodenal bulb and stomach without control. Bile is very ionic and can lead to mucosal damage by deteriorating the surfactant characteristics of the protective mucous layer [36]. Deformation of the duodenal bulb can develop after chronic exposure to the noxious effects of ionic bile acids and alkaline pH causing mucosal damage and ulceration, which cannot be prevented by cytoprotective mechanisms. Similar effects might also occur in gastric mucosa with the duodenal content's passage through the stomach[37]. In some patients, opening of the pancreatic duct into the duodenal bulb was seen as a loose cleft, similar to the CBD opening. Similar to the bile, flowing of the pancreatic fluid that has a high pH and contains proteolytic enzymes and bicarbonate may contribute to ulcer formation. Furthermore, these patients had significantly higher cholelithiasis (28%) and cholecystectomy (64%) rate. It is known that adding one of those two situations increases the duodenogastric reflux caused by biliary sphincter ablation [38]. A similar situation might occur in these cases.

Although the bulbus was deformed in half of the cases, ERCP success rate in diagnosis was 96%. Cannulation was not possible in only two (4%) patients due to advanced deformity in the bulbus, and these patients were diagnosed by PTC. In all cases, the CBD made a sharp curve and was tapered at the distal end entering the duodenal bulb at a right angle (Figure 3). This finding is called "hook or sickle-shaped" in the literature and was seen in all of our cases. In our opinion, the tapered end of the CBD is due to the sharp right angle on its way to the duodenal bulb. It is a relative tapering when compared to the proximal part of the CBD and does not mean "real stricture". The authors of this study use the phrase "real stricture" because the tapered distal end which is a characteristic feature of these patients, together with the dilated proximal bile ducts, creates a stricture-like appearance caused by the relative diameter difference of the proximal and distal ends. We pulled out an 11.5 mm stone extraction balloon in each case to control whether a stone was present. When the balloon could not be extracted easily, in the case of there is no stone; we accepted that these patients had a "real stenosis"(Figure 5). It is not known why a stricture develops at the distal end of CBD. Lee et al. found fibrofatty proliferation in the peribulbar area on CT in three of eight patients with ectopic biliary openings [11]. Although the authors made no comment in their study, the increase in the reactive connective tissue around the bulb was possibly due to duodenal ulceration and deformation. We conclude that it can be a finding that can explain "real stricture" formation in the opening site including the distal end of the CBD in some cases. In contrast to the literature, the distal stenosis rate in our series was very low (two cases), probably due to our different definition of the situation.

The pancreatic duct, which was visualized in 12 cases, had an opening similar to the CBD's cleft-like opening, and opened into the duodenal bulb 1 to 2 cm next to it. (Figure 2 and 3) Pancreatic duct dilatation was found in four cases (33%), but none of these patients had any history or finding of pancreatic disease. In the literature, there is limited data about the pancreatic duct in those patients. Lee et al. visualized the pancreatic channel in seven patients. All of the patients had pancreatic channel openings into the duodenal bulb; channel dilatation was seen in two patients, but it was not clarified whether the CBD opening was together with the pancreatic opening [9]. In another large series, the pancreatic canal was visualized in one of the eight patients and was opened to the papillary orifice in the bulbus, which also appeared normal [11]. The pancreatic channels of 11 patients who had CBD opening into the duodenal bulb were visualized in the literature [4,9,11,15]. Acute pancreatitis was diagnosed in only one case (there was no finding supporting pancreatitis other than elevated amylase level in this case, who was also a heavy alcohol user) [15]. Adding our 12 cases to the literature, there are 23 cases in total, and pancreatic duct dilatation was found in a total of six (26%) patients. This may be due to possible obstructions in the pancreatic channel in some cases from time to time. There is a great possibility of reflux of the duodenal content into the pancreatic duct, because the structure of the pancreatic opening in our patients was very loose, without a sphincter, and even food debris could easily reflux into the canal.

Although it is a rare situation, since most of the patients have deformity and stenosis in the duodenal bulb, anomalous CBD opening into the duodenal bulb should be considered in intractable and recurrent ulcer cases. Surgeons are cautioned to use extreme care during the surgery of peptic ulcer disease in order to avoid biliary injury, which can be fatal[39,40]. The surgeons in our eight cases with peptic ulcer operation must have exerted extreme care because they performed only gastric by-pass operation (simple gastroenterostomy) and not operations like Billroth I or II, which could damage the biliary system. Although the patients were not diagnosed at that time, the surgeons no doubt realized the anomaly, possibly during the releasing of the duodenum (Kocher maneuver), and abandoned the decision to apply the Billroth procedure.

Choledochoduodenal fistulas, surgical or spontaneous, which also cause free bile flux from an orifice into the duodenum, must be considered in the differential diagnosis.

Biliodigestive fistulas are rare and 70% of these are choledochoduodenal fistulas [41]. Those fistulas can develop in only choledocholithiasis without a history of any biliary surgery, ERCP, pancreatitis or ulcer [42]. Especially the proximal type of choledochoduodenal fistulas, which have a relation with the duodenum from the more proximal to the distal 2 cm end of the CBD, can be confused with anomalous biliary opening. This situation might occur due to fistulization of duodenal ulcer to the CBD [43], and can cause an endoscopic appearance similar to ectopic opening anomaly with ulcer. A distinction can easily be made in these cases by seeing normal papilla in the second part of the duodenum distal to the orifice and by imaging of the more distal part of the CBD to the catheter entry point when the contrast material is delivered from the orifice.

Periampullary tumors must also be differentiated because the dilatation of the pancreatic duct and CBD together, and a sudden ending of the CBD, are common features of the anomalous opening of CBD and of the periampullary tumor (pancreatic carcinoma must also be differentiated). In our series, one of the patients who was referred as periampullary tumor due to dilatation of CBD and pancreatic duct was diagnosed as anomalous opening, and there was food debris in the pancreatic duct. The patient was also evaluated by different visualization techniques and no malignancy was found. During the follow-up period, there was no malignancy development. In the literature, two cases with anomalous opening of the CBD to the duodenal bulb had pancreatoduodenectomy operation for the suspicion of periampular tumor. Afterwards it was reported that there was no tumoral mass in the specimens[9,11].

As to the therapy, surgery is the main treatment modality in most of the case reports in the literature. Choledochoenterostomy, surgical stone extraction by choledochotomy and rarely, pancreatoduodenectomy are the surgical procedures reported thus far. Lee et al. preferred surgical treatment in 13 (72%) of 18 patients [9]. In another series, seven of eight patients (87.5%) underwent surgical treatment [11]. Primary endoscopic treatment is reported rarely [14]. There are two cases in the literature that improved spontaneously or by supportive medical treatment without any invasive procedure[11,15].

In the presented series, endoscopic approach was our primary diagnostic and therapeutic modality. ERCP was performed successfully in 96% (51/53) of the cases and 52% (26/50) of the patients with a dilated CBD (with or without stone) was treated endoscopically. Stone extraction was successful in 59% (16/27) of the patients with stone in CBD. In the vast majority (14/16; %87.5), it is performed by papillary baloon dilatation. Stenting was preferred in three (11%) cases with stones due to advanced age and comorbidities. The total endoscopic treatment success rate was 70% (19/27) in the patients with CBD stone. Surgery was considered in only 16% (8/50) of the patients whose stones could not be retrieved endoscopically due to the size (>2 cm) with or without a real stricture distal to the CBD which has been described previously in this article. Nasobiliary drainage was another endoscopic treatment option in the cases with cholangitis and without any stone in the CBD. Interestingly, in 32% (16/50) of the patients who were symptomatic with a dilated CBD but without stone, symptoms improved via supportive medical treatment solely or spontaneously. Overall, half of the cases improved by endoscopic treatment, one-third improved by supportive treatment or healed spontaneously, and only a few patients needed surgery.

Surgery was the major treatment modality in the past because it was thought that endoscopic sphincterotomy (ES) could cause bleeding and perforation due to absence of the sphincteric structure and intramural part of the CBD, which was oblique to the duodenum. Two perforations (3.7%), one of which occurred in a different center, were seen during ES in our series. The perforation rate was higher than in ES performed on normal papilla, in which one patient had bleeding (1.8%). After our perforation experience, during EST in these specific patient groups, we performed the Endoscopic Papillary Balloon Dilatation (EPBD) method successfully. We used "Through The Scope" (TTS) biliary dilatation balloon (6–8 mm in diameter) or 10–12 mm diameter TTS pyloric dilatation balloon for larger CBD stones. The orifice was dilated using standard dilatation procedure under fluoroscopy and then CBD stones were extracted using stone

extraction balloon and/or dormia basket. It was shown that the perforation and bleeding rate of EPBD in normal papilla was lower than in ES [44,45]. In those cases with anomalous opening of the CBD into the bile duct, or in whom the sphincteric structure is absent or very weak, the procedure was not a real sphincteroplasty, but rather a dilatation procedure of the opening as far as the duodenal wall flexibility allowed. For some of the patients, this process is dilatation of a stricture that developed in the ectopic orifice over time because of mucosal edema, ulceration and duodenal deformation. Due to deformation/stenosis in the bulbus, CBD cannulation was possible in 12 patients (22.6%) only after duodenal bulb dilatation. There were no complications during bulbar and biliary orifice balloon dilatations. Two cases who suffered from perforation during EST improved with supportive treatment without any surgery, and endoscopic CBD stone extraction was carried out later. Bleeding spontaneously stopped in a patient who bled during EST, and neither blood transfusion nor endoscopic operation was needed to stop the bleeding.

During an average of 31-month of follow-up, there were no deaths due to the biliary system disease. No GIS-related cancer case was found. In the literature, only a single case of pancreatic cancer was reported among cases with double CBD dilatation [12]. In double CBD cases that open into the stomach, cancer was reported in one case, but no cancer was reported in patients whose CBD opened to the duodenal bulb[12,46].

Symptoms of seven patients recurred during follow-up (2 cases with CBD stone, 5 cases with recurrent cholangitis). The recurrence rate (13.2% of all cases), the number of attacks and period between the attacks were within acceptable limits (11 episodes in a total of 7 patients, 14–47 months, average 20 months). The minimal period for cholangitis attack in recurrent cases is 14 months, and for stone development 16 months, but it could be as long as 47 months for cholangitis attacks and as long as 27 months for stone formation. An interesting finding is that in five (71%) of seven cases, duodenal deformation was present, and in one case there was also an active duodenal ulcer. Duodenal bulb stenosis was so severe in two patients with CBD stones that balloon dilatation was needed in order to reach the biliary opening. A higher rate of duodenal damage in recurrent patients, when compared to the duodenal deformation rate in all cases (49%), supports the opinion that edema, ulceration and deformation in the duodenum are sometimes effective in causing formation of biliary pathologies in these patients. Another factor for the recurrence is the real stricture at the distal end of the CBD in two of five patients who were admitted with recurrent cholangitis attacks. In comparison to the three cases who had only one attack, those two cases with three attacks had shorter attack duration (mean 15.5 months vs. 28.3 months). This is also a determinant for the treatment approach because while the other three patients' clinical situation was improving with only supportive treatment; these two patients with stricture needed dilatation and/or stent application.

In conclusion, based on these findings, presence of duodenal deformation and/or ulcer and its severity play a significant role in the patient's long-term follow-up and the treatment strategy. The patients with distal, "real stricture" may be considered as suitable candidates for surgery. Each patient must be evaluated individually and the surgery must be decided weighing risks and benefits of the operation. Given the low recurrence rate in the long-term follow-up and acceptable period of time to recurrence, endoscopic therapy should primarily be considered in all but those patients who has "real stricture" at the end of the CBD. Surgery should be reserved for the patients in whom endoscopic treatment is failed or for those with the stricture in the distal CBD.