The clinical analysis of endoscopic pancreaticobiliary separation in the treatment of occult pancreaticobiliary reflux

doi:10.21203/rs.3.rs-20110/v1

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The clinical analysis of endoscopic pancreaticobiliary separation in the treatment of occult pancreaticobiliary reflux

https://doi.org/10.21203/rs.3.rs-20110/v1

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Objective To investigate the aetiology of occult pancreaticobiliary reflux (OPBR) and the curative effect of EST in patients with cholecystolithiasis.

Methods The clinical data of 47 OPBR patients with cholecystolithiasis from October 2013 to October 2016 were analyzed retrospectively.

Results The average gallbladder bile amylase (GBA) of 47 patients was 864 ± 575 U/L. Forty patients underwent endoscopic retrograde cholangiopancreatography (ERCP), among which 26 patients were diagnosed with papillitis, 16 patients with peripapillary diverticulum, 14 patients with nipple overlength, five patients with nipple atrophy, three patients with ampullary calculi and two patients with papillary tumour. Thirty-three patients underwent endoscopic sphincterotomy (EST), after the operation, 16 patients reexamined GBA, in which 15 patients had normal GBA, and the difference of GBA was statistically significant (1161 ± 764 U/L vs 47 ± 17 U/L, t=5.641, P<0.05). After following up of 1 to 4 years, 27 patients without cholecystectomy who underwent EST had no recurrence of calculus, and in 9 patients who did not undergo EST, two patients had a recurrence of calculus. There was a significant difference in the recurrence rate of calculus (χ²=21.340, P<0.05).

Conclusion Pancreaticobiliary junction disease is an essential cause of OPBR and cholecystolithiasis formation. EST can reduce the retention of pancreatic reflux juice both in gallbladder and bile duct and can reduce the recurrence rate of cholecystolithiasis after choledochoscopic lithotomy.

General Surgery

Surgery

Occult pancreaticobiliary reflux

Cholecystolithiasis

EST

SOD

Pancreaticobiliary maljunction (PBM) is caused by the absence of sphincter control at the pancreaticobiliary junction, which leads to the reflux of pancreatic juice and bile. The pressure of the pancreatic duct is higher than that of the bile duct, which is the main reason for pancreaticobiliary reflux (PBR). Recently, studies have reported that PBR also exists in a part of normal pancreaticobiliary junction, which is called occult pancreaticobiliary reflux (OPBR)[1]. It was reported that the incidence rate of OPBR in benign gallbladder diseases was 25.8%~84.2%, while 40.0%~100% in gallbladder carcinoma[2]. At present, the treatment principle for PBR is to performing cholecystectomy to avoid gallbladder carcinoma, but for OPBR, the treatment principle has not been established so far. Some scholars suggested prophylactic cholecystectomy, while others advocated endoscopic sphincterotomy (EST) or duodenal papilloplasty[3]. The treatment efficacy of EST in patients with cholecystolithiasis accompanied by OPBR still needs to be determined. Therefore, in this study, we retrospectively collected and analyzed the clinical data of 47 patients with cholecystolithiasis accompanied by OPBR from October 2013 to October 2016, to explore the aetiology of OPBR in patients with cholecystolithiasis and the therapeutic effect of EST.

1. Participants

Forty-seven patients with cholecystolithiasis from October 2013 to October 2016 were included in this study. They all showed normal pancreaticobiliary junction by examination of magnetic resonance cholangiopancreatography (MRCP), and they also underwent percutaneous transhepatic gallbladder drainage (PTGD), laparoscopy or open cholecystectomy, with elevated gallbladder bile amylase. Twenty-six patients were male, and 21 patients were female, aged from 32 to 77 years old, with an average age of 54.5 years.

2. Inclusion and exclusion criteria

Inclusion criteria: (1) Normal pancreaticobiliary junction showed in MRCP; (2) Cholecystolithiasis; (3) Normal blood amylase; (4) Gallbladder bile amylase >110U/L; (5) Without neoplastic diseases in liver, gallbladder or pancreases; (6) Without dilatation of extra-hepatic bile duct; (7) The data was complete.

Exclusion criteria: (1) History of EST or endoscopic papillary balloon dilation (EPBD) treatment; (2) History of biliary tract exploration; (3) Low junction of the biliary duct and common hepatic duct; (4) Acute and chronic pancreatitis; (5) Intrahepatic or common bile duct stones; (6) Obstructive jaundice; (7) Acute cholangitis; (8) Biliary duct stones; (9) White bile in the gallbladder.

3. Therapeutic method:

1) Bile collection: For patients with external drainage tube, after their condition was stable, the drainage tube was clamped for 24 hours, and next morning, fresh bile of 5ml was collected through the external drainage tube. For patients who underwent general anaesthesia, the bile of 5ml was extracted by puncturing gallbladder bottom during anaesthesia. For patients without external drainage tube after EST, the bile of 5ml was extracted by gallbladder puncture under the guidance of ultrasound.

2) EST: After successful retrograde intubation of bile duct and pancreatic duct under duodenoscope, using dual-wire or pancreatic duct stent occupation method, we used hybrid-current ablation to cut papillary sphincter step by step until exposing the opening of pancreatic duct sphincter, and the length of the common passage of pancreaticobiliary duct was less than 5 mm. Using biliary cylindrical balloon dilatation for patients whose duodenal papilla stenosis failed to be relieved (diameter of balloon ≤ diameter of the common bile duct).

3) Gallbladder bile amylase (GBA) detection: Amylase was detected within half an hour after bile samples were collected, with the same detection method of blood amylase.

4. Evaluation criterion:

1) Normal pancreaticobiliary junction: MRCP showed that the main pancreatic duct joined with the common bile duct in the wall of the duodenum, with the joint angle less than 45°, and the length of common passage was 4~10mm.

2) PBM(Pancreaticobiliary maljunction): MRCP showed that the contractile segment of ampulla was wholly located at the distal end of the pancreaticobiliary junction, or the length of common passage ≥ 15mm.

3) OPBR: MRCP showed that pancreaticobiliary junction was normal, serum amylase was normal, and GBA was greater than 110U/L [4].

5. Follow-up

Following up in the outpatient department. Retaking ultrasound examination of liver, gallbladder, spleen and pancreas every year to clear cholecystolithiasis recurrence or hepatolithiasis formation.

6. Statistical analysis

Data analyses were performed by using SPSS 21.0 software. Measurement data with normal distribution were represented by mean ± standard deviation (±S) and analyzed by performing t-test. Fisher's exact test analyzed the recurrence rate of stones via a χ² test. P<0.05 indicated that the difference was statistically significant.

Forty-seven patients received PTGD, choledochofiberscopy under general anaesthesia, endoscopic retrograde cholangiopancreatography (ERCP) or EST. Among them, two patients with papillary tumour were pathologically diagnosed as duodenal papillary adenoma by ERCP. Moreover, after pancreaticoduodenectomy, their postoperative pathological diagnosis was duodenal adenocarcinoma. The specific treatment scheme and number of cases were shown in Table 1.
Bile collection and gallbladder operation: The average value of GBA and serum amylase in 47 patients were 864±575U/L and 44±16U/L, respectively. There was a significant difference between two groups (t=5.641, P=0.000). Method and number of cases for bile collection were shown in Table 2.
Aetiology of OPBR in patients with cholecystolithiasis: 40 cases performed ERCP, all these patients had one or more diseases of the pancreaticobiliary junction, including 26 cases of papillitis, 16 cases of the peripapillary diverticulum, 14 cases of papillary overlength, 5 cases of papillary atrophy, 3 cases of stone inside the ampullary and 2 cases of the papillary tumour.
Results of EST and postoperative GBA changes: 8 patients with PTGD all received EST. Among 39 patients who underwent general anaesthesia, 32 patients received ERCP, of which 25 patients were treated with EST. Thirty-three patients with EST developed no complications such as biliary bleeding, bile leakage or acute pancreatitis. 2 patients with developed pancreatic duct underwent anterograde cholangiography again, but pancreatic duct was not shown. Bile examination was performed in 16 of 33 patients after EST, and GBA of 1 case decreased from 527U/L before the operation to 227U/L, and GBA of the remaining 15 cases returned to normal, as shown in Table 3.
Follow-up: 47 patients were followed up for 1~4 years. Among these patients, 11 cases had no intrahepatic or extra-hepatic stone after cholecystectomy. In 36 cases without cholecystectomy, 27 cases with EST had no recurrence of calculus. In 9 cases without EST, 2 cases had a recurrence of calculus. The difference in the recurrence rate of calculus between the two groups was statistically significant (χ²=21.340, P=0.000), as shown in Table 4. Cholecystectomy was performed in 2 patients with recurrence. Before the operation, extracting bile and their GBA was 368U/L and 857U/L respectively. Besides, they were diagnosed as papillitis, peripapillary diverticulum or papillary overlength by ERCP. (Table 4)

The natural incidence rate of OPBR is as high as 5.5%. However, the recognition of this phenomenon is relatively low, with a still unclear mechanism [4]. At present, OPBR is believed to be the result of gallbladder activity and pressure difference in the pancreaticobiliary duct and is regulated by the Sphincter of Oddi (SO) [5]. If SO spasms, contracted reversely and loses function, or common passage of pancreaticobiliary duct obstructs, OPBR may occur based on the pressure difference between pancreatic juice and bile [6]. In this study, duodenoscopy and cholangiopancreatography were performed in 40 patients with elevated GBA, and the results showed that there was more than one pancreaticobiliary junction disease in patients with OPBR, such as papillitis, peripapillary diverticulum, and papillary overlength. Moreover, these diseases can lead to different degrees of dysfunction of SO, resulting in the pancreaticobiliary duct or common passage obstruction, so OPBR is more likely to occur [7]. Combined with the anatomy of SO and the characteristics of pancreaticobiliary hydrodynamics, we believe that the occurrence of OPBR needs to meet the following conditions: (1) Existence of common passage; (2) Dysplasia or dysfunction of bile duct sphincter; (3) Loss or functional defect of ampulla septum; (4) Obstruction, stenosis and overlength of common passage, or diastolic dysfunction of the ampullary sphincter.

One classic disease of pancreaticobiliary reflux is PBM, which has an obvious correlation with benign and malignant tumours of the biliary tract. Laparoscopic cholecystectomy is recommended for PBM patients without congenital choledochal dilatation. In contrast, for patients with choledochal dilatation, Roux-Y choledochojejunostomy should be performed to reduce the incidence of gallbladder carcinoma or cholangiocarcinoma in PBM patients [9]. At present, it is generally believed that OPBR, like PBM, is also a high-risk factor for benign and malignant biliary diseases [10]. The activated pancreatin in OPBR patients’ bile can cause pathological changes such as gallbladder mucosal hyperplasia, metaplasia and atypical hyperplasia, leading to cholecystitis, gallbladder adenomyomatosis and gallbladder carcinoma. Chronic inflammation of gallbladder can increase mucin and albumin in bile, then shortens nucleation time and leads to cholestasis and muddy stone of gallbladder, and finally forms gallstone. Damage to bile duct mucosa can also trigger cholangitis, choledocholithiasis, choledochal dilatation and cholangiocarcinoma [4,5]. Since the incidence rate of OPBR in patients with gallbladder carcinoma is as high as 40%~100%, if PBR cannot be terminated fundamentally, cholecystectomy may, after all, be accepted as an ideal treatment method to prevent gallbladder cancerization in gallstone patients with OPBR [2]. However, prophylactic cholecystectomy for gallstone patients with OPBR is still controversial due to the potential risk of cholangiocarcinoma in a later stage, although cholecystectomy can effectively avoid the occurrence of gallbladder carcinoma [5].

Studies have shown that [11] activated pancreatin in bile will harm gallbladder or bile duct mucosa through a series of cascade reactions, and the countercurrent pancreatic juice cannot be removed in time due to cholestasis, which will aggravate the damage to bile duct mucosa. Therefore, a mixture of pancreatic juice and bile, and cholestasis are the two main conditions for biliary mucosal damage in PBR. The damage degree depends on the degree of PBR and the local retention time of reflux fluid [12]. Based on this theory, if pancreatic juice which enters gallbladder and bile duct can be discharged freely through duodenal papilla without deposition, it will not cause severe damage to bile duct mucosa. For clinical treatment, we do not have to choose cholecystectomy but choose EST to reduce the retention of countercurrent pancreatic juice in the gallbladder, and then further reduce its damage to the gallbladder. Besides, the curative effect of EST on OPBR can be verified by measuring GBA. Conventional EST is to cut the distal part of the papillary sphincter and common bile duct, in this way, duodenal reflux is quite evident after the operation. However, in our study, we firstly cut papillary sphincter, and then stopped until exposing the opening of the pancreatic duct, to ensure that the length of the common passage of pancreaticobiliary duct is less than or equal to 5cm. The lower segment of the bile duct should not be cut too much to avoid the injury of lower bile duct sphincter and to prevent intestinal severe fluid reflux after the operation. To be different from conventional EST, we called this method endoscopic pancreaticobiliary separation (EPBS).

In this study, we compared GBA of 16 patients before and after EST, and the results showed that 93.8% of patients' GBA returned to normal. Although the GBA of 1 patient was still increased, it was significantly lower than that before EST. This result suggested that the severity of PBR in OPBR decreased after EST, this was because resistance effect of SO decreased due to papilla incision by EST, and thus reflux fluid could be discharged quickly without deposition. Although EST could not reduce countercurrent, it could reduce the harm caused by reflux fluid. This result was consistent with the view of Sugiyama [13]. Although EST can cause duodenal juice reflux to the bile duct, results of long-term follow-up (8~14 years) showed that EST significantly reduced the relative incidence rate of bile duct cancer by 0%~0.6%, which might be attributed to the short duration of PBR. In clinical studies of pancreaticobiliary junction disease, we found that when performing anterograde cholangiography, the incidence rate of pancreatitis in patients with developed pancreatic duct was as high as 27.5%. After the implementation of EST, the development rate of pancreatic duct reduced only to 17.2%. However, there was no pancreatitis recurrence during follow-up, which also confirmed that EST could reduce pancreatitis incidence by reducing bile duct pressure and reflux fluid retention (article to be published).

The integrity of anatomical structure and function of SO is the key to maintain biliary leakproofness, which can effectively prevent the occurrence of cholangitis, cholelithiasis, biliary tumour and other complications caused by duodenal-biliary reflux [5]. The pathogenesis of OPBR may be related to oddi sphincter disfunction (SOD) [6,14], which refers to structural abnormalities of SO (such as chronic inflammation and fibrosis) causes complete or partial sphincter stenosis, or primary dyskinesis of SO causes uncoordinated movements between the terminal sphincter of bile and pancreatic duct, and distal ampullary sphincter. In this study, there were 40 patients performing ERCP, each of whom had one or more diseases of the pancreaticobiliary junction. Among them, two patients with developed preoperative pancreatic duct after EST underwent anterograde cholangiography again, but their pancreatic duct was not developed. These results suggested that although EST was an invasive operation, this treatment was still necessary due to the intrinsic lesions of SO in OPBR patients.

What is more, part of the lower ampullary sphincter of the bile duct was preserved during EST implementation, and the function of pancreatic duct sphincter was not damaged [11]. Also, after follow-up for 1~4 years, our study found that in 36 cases without cholecystectomy, 27 cases with EST had no recurrence of calculus. In 9 cases without EST, 2 cases had a recurrence of calculus. Cholecystectomy was performed in 2 patients with recurrence. Before the operation, extracting bile and their GBA (368U/L and 857U/L) was significantly higher than the average value. Besides, they were diagnosed as papillitis, peripapillary diverticulum or papillary overlength by ERCP, indicating that the cause of cholecystolithiasis recurrence was related to SOD. The recurrence rate of postoperative stones in OPBR patients with EST was significantly lower than those without EST; the probable reason was that EST could relieve biliary obstruction caused by SOD, improve gallbladder emptying and then further reduce cholestasis inside the gallbladder [15,16]. The results of our studies were consistent with those of Sharma et al. [17]. EST can enhance gallbladder contractility, prolong bile nucleation time, decrease the concentration of cholesterol in bile, and reduce the inducement of gallstone recurrence. The results of Taskin et al. [18] also believed that EST had no adverse side effects on gallbladder dynamics, and had a tendency to enhance gallbladder motor function. However, this trend was not statistically significant.

pancreaticobiliary junction disease is an essential cause of OPBR and cholecystolithiasis formation. EST can reduce the retention of pancreatic juice and bile and decrease the recurrence rate of cholecystolithiasis after choledochofiberscopy. However, our study is a retrospective study with small sample size. Thus the results need to be further verified by multicenter and large-sample randomized controlled trials. Meanwhile, more clinical trials are urgently needed to explore the indications selection for OPBR and the prevention of EST complications.

EPBS: endoscopic pancreaticobiliary separation

OPBR: occult pancreaticobiliary reflux

GBA: gallbladder bile amylase

EST: endoscopic sphincterotomy

MRCP: magnetic resonance cholangiopancreatography

PTSD: percutaneous transhepatic gallbladder drainage

EPBD: endoscopic papillary balloon dilation

PBM: pancreaticobiliary maljunction

ERCP: Endoscopic retrograde cholangiopancreatography

SO: sphincter of Oddi

SOD: Oddi sphincter disfunction

Acknowledgements

The authors acknowledge the staff and doctors of the Cholelithiasis Centre affiliated with the Shanghai-East Hospital of Tongji University for their Kind Assistance in this study.

Authors’ contributions

ZG designed the research and facilitated the data collection. ZC and CH performed the statistical analysis. XA, LD and HQ contributed to the follow-up, ZG, GA and YL contributed to the manuscript revision. All authors contributed to the drafting and final writing of the manuscript. YL and all co-authors approved the article’s submission for publication.

Funding

This work was supported by the Natural Science Foundation of Liaoning Province (2017, Grand No. 13)

Availability of data and materials

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

The institutional review board approved the study involving human participants of Tongji University Affiliated Shanghai East Hospital (No 2013-032). Written consent was obtained from all the participants. The methods were carried out following the approved guidelines. All clinical research was performed based on the principles expressed in the Declaration of Helsinki.

Consent for publication

Not applicable.

Competing interests

The authors ZG, ZC, CX, XA, LD, HQ, GA and YL declare that they have no conflict of interest financial or otherwise to disclose

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Table 1 Distribution table of specific operation scheme of 47 patients
Operation scheme	Number of cases	PTGD	ERCP	EST	Cholecystectomy	Non- Cholecystectomy
PTGD + Cholecystectomy + ERCP + EST	3	3	3	3	3
PTGD+ Choledochofiberscopy + ERCP+EST	5	5	5	5		5
Cholecystectomy	3				3
Cholecystectomy + ERCP + EST	3		3	3	3
Choledochofiberscopy	4					4
Choledochofiberscopy + ERCP	5		5			5
Choledochofiberscopy + ERCP + EST	22		22	22		22
Choledochofiberscopy+ ERCP+ Pancreaticoduodenectomy	2		2		2
Total	47	8	40	33	11	36

Table 2 Distribution table of bile collection and operation scheme specific of 47 patients
Bile collection	Surgery procedure	Number of cases	Total number
PTGD	PTGD	8	8
Gallbladder puncture under general anesthesia	Cholecystectomy	6	39
	Choledochofiberscopy + Cholecystostomy	3
	Choledochofiberscopy + Primary suture of gallbladder	30

Table 3 Comparison of GBA before and after EST in 15 patients
Group	PTGD (7 cases)	Cholecystostomy (3 cases)	Gallbladder puncture (5 cases)	All patients (15 cases)
GBA before EST (U/L)	788±501	1640±501	1396±582	1161±764
GBA after EST (U/L)	40±15	63±9	48±18	47±17
t value	3.944	2.101	5.181	5.641
P-value	0.002	0.003	0.001	0.000

Table 4 Follow-up condition of 36 patients without cholecystectomy
Group	Number of follow-ups	Number of recurrent calculus
With EST	27	0
Without EST	9	2
χ²		21.340
P		0.000

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The clinical analysis of endoscopic pancreaticobiliary separation in the treatment of occult pancreaticobiliary reflux

Status:

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Abstract

Background

Methods

Results

Discussion

Conclusion

Abbreviations

Declarations

References

Tables

Status:

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