Acute pancreatitis： Etiology and common pathogenesis

Acute pancreatitis is an inflammatory disease of the pancreas. The etiology and pathogenesis of acute pancreatitis have been intensively investigated for centuries worldwide. Many causes of acute pancreatitis have been discovered, but the pathogenetic theories are controversial. The most common cause of acute pancreatitis is gallstone impacting the distal common bile-pancreatic duct. The majority of investigators accept that the main factors for acute billiary pancreatitis are pancreatic hyperstimulation and bile-pancreatic duct obstruction which increase pancreatic duct pressure and active trypsin reflux.Acute pancreatitis occurs when intracellular protective mechanisms to prevent trypsinogen activation or reduce trypsin activity are overwhelmed. However, little is known about the other acute pancreatitis. We hypothesize that acute biliary pancreatitis and other causes of acute pancreatitis possess a common pathogenesis. Pancreatic hyperstimulation and pancreatic duct obstruction increase pancreatic duct pressure, active trypsin reflux, and subsequent unregulated activation of trypsin within pancreatic acinar cells. Enzyme activation within the pancreas leads to auto-digestion of the gland and local inflammation. Once the hypothesis is confirmed, traditional therapeutic strategies against acute pancreatitis may be improved. Decompression of pancreatic duct pressure should be advocated in the treatment of acute pancreatitits which may greatly improve its outcome.     

Etiological analysis of chronic pancreatitis in 215 cases

OBJECTIVE: To investigate the etiology of chronic pancreatitis in China. METHODS: The causes of 215 cases of chronic pancreatitis treated at Peking Union Medical College Hospital between 1990 and 2000 were analyzed retrospectively. RESULTS: The causes of chronic pancreatitis were biliary diseases (36.7%), alcoholic (26.5%), idiopathic (30.2%), and other uncommon causes such as auto­immune disease, recurrent acute pancreatitis, trauma and heredity. Among biliary diseases, the most common cause was cholecystolithiasis, followed by bile duct stone and cholecystitis. CONCLUSIONS: The main cause of chronic pancreatitis in China is biliary disease. That caused by ethanol is increasing, and autoimmune disease is also receiving increasing attention.     

Idiopathic recurrent pancreatitis: long-term results after ERCP, endoscopic sphincterotomy, or ursodeoxycholic acid treatment

OBJECTIVE: In about 30% of cases, the etiology of acute recurrent pancreatitis remains unexplained, and the term "idiopathic" is currently used to define such disease. We aimed to evaluate the long-term outcome of patients with idiopathic recurrent pancreatitis who underwent endoscopic cholangiopancreatography (ERCP) followed by either endoscopic biliary (and seldom pancreatic) sphincterotomy or ursodeoxycholic acid (UDCA) treatment, in a prospective follow-up study. METHODS: A total of 40 consecutive patients with intact gallbladder entered the study protocol after a 24-month observation period during which at least two episodes of pancreatitis occurred. All patients underwent diagnostic ERCP, followed by biliary or minor papilla sphincterotomy in cases of documented or suspected bile duct microlithiasis and sludge, type 2 sphincter of Oddi dysfunction, or pancreas divisum with dilated dorsal duct. Patients with no definite anatomical or functional abnormalities received long-term treatment with UDCA. After biliary sphincterotomy, patients with further episodes of pancreatitis underwent main pancreatic duct stenting followed by pancreatic sphincterotomy if the stent had proved to be effective. RESULTS: ERCP found an underlying cause of pancreatitis in 70% of cases. Patients were followed-up for a period ranging from 27 to 73 months. Effective therapeutic ERCP or UDCA oral treatment proved that occult bile stone disease and type 2 or 3 sphincter of Oddi dysfunction (biliary or pancreatic segment) had been etiological factors in 35 of the 40 cases (87.5%) After therapeutic ERCP or UDCA, only three patients still continued to have episodes of pancreatitis. CONCLUSIONS: Diagnostic and therapeutic ERCP and UDCA were effective in 92.5% of our cases, over a long follow-up, indicating that the term "idiopathic" was justified only in a few patients with acute recurrent pancreatitis.     

215例慢性胰腺炎病因学分析

目的：探讨我国慢性胰腺炎的病因。方法：回顾性分析1990－2000年北京协和医院215例慢性胰腺炎患者的病因。结果：215例慢性胰腺炎患者的病因中,胆道系统疾病占36．7％,酒精中毒占26．5％,特发性占30．2％,其他病因包括自身免疫性疾病、急性胰腺炎、外伤和遗传等。胆道系统疾病中以胆囊结石最为多见,其次为胆管结石和胆囊炎。结论：我国慢性胰腺炎的病因以胆道系统疾病为主,而酒精性因素呈上升趋势,自身免疫性疾病作为慢性胰腺炎的病因正逐渐受到重视。     

Relationship between acute pancreatitis and ACE inhibitors

Most of the acute pancreatitis cases are due to cholelithiasis and alcohol intake.Two percent of the cases are related to medications. Drugs including ACE (angiotensin-converting enzyme) inhibitors and thiazide diuretics may cause acute pancreatitis. Patients with biliary system disorders using certain drugs may develop acute pancreatitis and this may be confusing when considering the aetiology. We report a patient without any known risk factor who developed acute pancreatitis shortly after the intake of lisinopril and hydrochlorothiazide. Common bile duct stone and biliary sludge were diagnosed after physical and radiological evaluation.     

ERCP在不明原因复发性急性胰腺炎诊治中的作用

目的探讨ERCP在不明原因复发性急性胰腺炎(RAP)诊治中的作用。方法收集15例不明原因RAP患者。其中男5例,女10例,年龄25～65岁,中位年龄38岁,病程1～2年,发病次数2～5次。10例在急性发作期,5例在发作间期行ERCP诊治。结果15例患者经ERCP明确病因者6例(3例胆管微结石,1例胆总管末端小囊肿,1例胰管小结石,1例胰管蛋白栓子),可疑病因者6例(乳头旁憩室2例,十二指肠乳头炎4例),未明确病因者3例。根据ERCP检查结果,9例行乳头括约肌切开术(EST),6例行胰管括约肌切开术。术后随访2年,15例患者均未复发胰腺炎。ERCP和EST术后2例出现一过性高淀粉酶血症,无其他并发症。结论ERCP对不明原因RAP有明确病因和指导治疗的作用。     

Pancreatographic findings in idiopathic acute pancreatitis

Background/purpose

Despite extensive evaluation based on clinical history, biochemical tests, and noninvasive imaging studies, the cause of acute pancreatitis cannot be determined in 10 to 30% of patients, and a diagnosis of idiopathic acute pancreatitis is made. The purpose of this study was to clarify the pancreatographic findings in patients with idiopathic acute pancreatitis.

Methods

Endoscopic retrograde cholangiopancreatography (ERCP) was performed in 34 patients with idiopathic acute pancreatitis, and the pancreatographic findings were examined. Patency of the accessory pancreatic duct was examined by dye-injection endoscopic retrograde pancreatography (ERP) in 16 of the 34 patients.

Results

In 11 patients (32%), the following anatomic abnormalities of the pancreatic or biliary system were demonstrated: complete pancreas divisum (n = 5), incomplete pancreas divisum (n = 2), high confluence of pancreaticobiliary ducts (n = 2), choledochocele (n = 1), and giant periampullary diverticulum (n = 1). Pancreatographic findings were normal in 17 patients. Eleven of these patients were examined by dye-injection ERP, and all were found to have nonpatent accessory pancreatic duct.

Conclusions

Anatomic abnormality of the pancreatic or biliary system is one of the major causes of idiopathic acute pancreatitis. Closure of the accessory pancreatic duct may play a role in the development of idiopathic acute pancreatitis in patients with a normal pancreaticobiliary ductal system.     

Role of ERCP and endoscopic sphincterotomy in acute pancreatitis.

When assessing the indications for interventional endoscopy, obstructive and non-obstructive causes of acute pancreatitis should be distinguished. In non-obstructive (e.g. alcoholic) pancreatitis, no data are available proving any benefit for endoscopic retrograde cholangiopancreatography (ERCP) and sphincterotomy. In obstructive (e.g. biliary) pancreatitis, the pathogenetic role of gallstones is controversial. The vast majority of gallstones initiating biliary pancreatitis pass spontaneously through the papilla of Vater into the duodenum without causing cholangitis or obstructive jaundice. Three prospective randomized published studies have attempted to answer the question of whether urgent removal of the stone improves the prognosis of patients suffering from acute pancreatitis. From these studies it can be concluded that the use of ERCP in acute biliary pancreatitis should depend on biliary symptoms: in cases of obstructive jaundice or cholangitis, bile duct stones should be removed as soon as possible; in patients without biliary complications, emergency ERCP is neither beneficial nor cost-effective; if retained stones (without biliary complications) are suspected, they can be removed electively.     

Acute idiopathic pancreatitis: does it really exist or is it a myth?

BACKGROUND: Acute pancreatitis is a severe disease with considerable morbidity and mortality. Gallstones and alcohol abuse are the most frequent causes (75% of patients). Other well-known causes are: hyperlipidemia, hypercalcaemia, abdominal surgery and drugs. In 10%-40% of patients however, no cause is identified after initial diagnostic evaluation: acute idiopathic pancreatitis. Identifying a cause in these patients is important, since the recurrence rate is high. METHODS: A systematic review of the current literature was performed to identify possible causes, diagnoses and treatment options of acute idiopathic pancreatitis. Relevant literature was found via Pubmed. RESULTS: The presence of microlithiasis or biliary sludge is an important cause of acute 'idiopathic' pancreatitis (up to 80% of patients). Microlithiasis and sludge can be detected by transabdominal/endoscopic ultrasonography, ERCP or polarizing light microscopy of bile. Cholecystectomy is the treatment of choice, whereas endoscopic sphincterotomy and ursodeoxycholic acid maintenance therapy are effective alternatives. Sphincter of Oddi dysfunction can be identified as the cause of acute 'idiopathic' pancreatitis in up to 30% of patients. Manometry of Oddi's sphincter is the gold standard for its diagnosis. Endoscopic sphincterotomy prevents recurrence in most patients. Anatomic abnormalities such as major papilla stenosis, pancreas divisum, pancreatic duct strictures and tumours may also cause acute 'idiopathic' pancreatitis. Endoscopic sphincterotomy and surgery are effective treatments. Finally, genetic screening may reveal gene mutations as the cause of acute 'idiopathic' pancreatitis. CONCLUSIONS: Acute 'idiopathic' pancreatitis is a severe disease with a high recurrence rate. Extensive diagnostic investigations may lead to a cause in >90% of patients.     

Biliary pancreatic reflux-induced acute pancreatitis--myth or possibility?

OBJECTIVE: The mechanism whereby gallstone passage through the choledochoduodenal junction initiates acute pancreatitis is not known. We mimicked different patterns of stone impaction at the choledochoduodenal junction in a rabbit model and studied whether these result in biliary pancreatic reflux and the initiation of pancreatic inflammation. METHODS: In rabbits, catheters were introduced into the common bile duct (CBD) and the pancreatic duct. In five experiments, obstruction of these catheters at various time intervals mimicked different patterns of stone obstruction of both ducts prior to a stone impaction at the papilla of Vater: experiment I--no obstruction of the pancreatic duct and the CBD; experiment II--separate obstruction of the CBD and the pancreatic duct; experiment III--selective obstruction of the CBD; experiment IV--separate obstruction of the CBD and the pancreatic duct and subsequent decompression of the pancreatic duct; experiment V--obstruction pattern as in experiment IV associated with a bacterial infection of bile (10(8) E. coli/ml). Ductal pressures were recorded for 24 h. In order to study the effects of a subsequent impaction of the stone at the papilla of Vater, the catheters in the CBD and in the pancreatic duct were connected and mimicked a common channel behind a papillary stone. The flow direction of bile and pancreatic juice was directly observed. Pancreatic histology was analysed 24 h later. RESULTS: In experiments I-III, neither biliary pancreatic reflux nor acute pancreatitis was observed. In experiments IV and V, obstruction of the CBD caused an increase in the biliary pressure to 17 +/- 3 cm H2O, whereas the pancreatic duct pressure dropped to subnormal levels following obstruction and selective decompression (2 +/- 0.5 cm H2O). After the creation of a 'common channel', biliary pancreatic reflux was observed for 118 +/- 21 min. Flow of sterile bile into the pancreas was not harmful to the gland. Infected biliary pancreatic reflux initiated acute pancreatitis. CONCLUSIONS: 1. Bile flow into the pancreas may occur. 2. Biliary pancreatic reflux may initiate acute pancreatitis. 3. Bile reflux-induced acute pancreatitis requires previous biliary hypertension, temporary pancreatic duct obstruction, and the bacterial infection of choledochal secretions.     

胆总管结石与胆源性胰腺炎的相关性研究

目的 探讨胆总管结石的大小、部位等相关因素与胆源件胰腺炎的相关性.方法 回顾性分析2002年1月至2008年12月收治的3497例胆总管结石患者的临床资料,并根据胆总管结石的大小,结石部位分组,比较各组并发胰腺炎的发病率.结果 胆总管结石患者并发胆源性胰腺炎时,以发热、腹痛、黄疸等症状更为明显,血清淀粉酶显著增高,其中胆总管结石的大小与胆源性胰腺炎严重程度呈负相关,位于胆总管下段与壶腹部的结石者易并发胰腺炎.结论 对位于胆总管下段或壶腹部的小结石应早期行内镜下取石治疗,以预防急性胆源性胰腺炎的发生.     

急性胰腺炎与胆管结石相关因素探讨及内镜治疗

目的探讨胆管结石与急性胰腺炎的相关因素及内镜治疗。方法回顾性分析了我院196例胆管结石患者的临床资料。根据结石梗阻部位和结石大小分组,比较各组的急性胰腺炎发病率。结果各组胰腺炎发病率有明显差异。结论小结石是胆源性胰腺炎的危险因素,结石梗阻于乳头部,易引起胰腺炎。早期内镜综合治疗效果明显。     

Sphincter of Oddi dysfunction and bile duct microlithiasis in acute idiopathic pancreatitis

Although there are numerous causes of acute panc-reatitis, an etiology cannot always be found. Two potential etiologies, microlithiasis and sphincter of Oddi dysfunction, are discussed in this review. Gallbladder microlithiasis, missed on transcutaneous ultrasound, is reported as the cause of idiopathic acute pancreatitis in a wide frequency range of 6%-80%. The best diagnostic technique for gallbladder microlithiasis is endoscopic ultrasound although biliary crystal analysis and empiric cholecystectomy remain as reasonable options. In contrast, in patients who are post-cholecystectomy, bile duct microlithiasis does not appear to have a role in the pathogenesis of acute pancreatitis. Sphincter of Oddi dysfunction is present in 30%-65% of patients with idiopathic acute recurrent pancreatitis in whom other diagnoses have been excluded. It is unclear if this sphincter dysfunction was the original etiology of the first episode of pancreatitis although it appears to have a causative role in recurring episodes since sphincter ablation decreases the frequency of recurrent attacks. Unfortunately, this conclusion is primarily based on small retrospective case series; larger prospective studies of the outcome of pancreatic sphincterotomy for SOD-associated acute pancreatitis are sorely needed. Another problem with this diagnosis and its treatment is the concern over potential procedure related complications from endoscopic retrograde cholangiopancreatography （ERCP）, manometry and pancreatic sphincterotomy. For these reasons, patients should have recurrent acute pancreatitis, not a single episode, and have a careful informed consent before assessment of the sphincter of Oddi is undertaken.     

Computed tomographic differentiation between alcoholic and gallstone pancreatitis： Significance of distribution of infiltration or fluid collection

AIM: To evaluate the usefulness of various computed tomography (CT) findings including distribution of infiltration or fluid collection in differentiating the major etiologies of acute pancreatitis. METHODS: We reviewed 75 relatively severe cases of acute pancreatitis of alcoholic (n = 43) or biliary stone (n = 32) etiology having infiltration or fluid collection on CT. We compared the pancreatic size, CT grading, presence or absence of biliary calculi, and dilatation of pancreatic or bile duct. We also evaluated degree and the distribution of infiltration and fluid collection in each group. RESULTS: The sizes of pancreas were not different between alcohol group and stone group. Alcohol group showed higher CT grading than stone group (P < 0.05). Presence of biliary stone and duct dilatation was statistically significant in differentiating etiology (P < 0.05). Alcohol group showed significantly prominent peripancreatic pathology than stone group only in left peritoneal compartment (P = 0.020). CONCLUSION: Alcoholic pancreatitis tends to form more prominent peripancreatic changes than gallstone pancreatitis in relatively severe cases. This is evident on the anterior aspect of left abdomen. Although clinical history and some CT findings usually are a major determinant of the etiology, this pattern of peripancreatic pathology may have an ancillary role in determining the etiologies of acute pancreatitis in the equivocal cases.     

Pathophysiology of acute pancreatitis

Recent experiments in different animal models of acute pancreatitis have improved our understanding of the pathophysiology of this disease. The present review discusses the individual steps and mechanisms and puts them into a pathophysiologic concept for the two most important forms of acute pancreatitis (alcoholic and biliary form). In biliary acute pancreatitis a temporary occlusion of the common channel by impacted stones may be followed by a reflux into the pancreatic duct. This reflux results in an increase of ductal permeability and extravasation of cytotoxic agents into the surrounding tissue. As consequences, disturbances of compartimentation and faulty activation of enzymes occur in pancreatic cells. Long-term cellular damage, obstruction of pancreatic ducts and increase of ductal permeability with leakage of noxious agents play a substantial role in pathophysiology of alcoholic pancreatitis. Sustained abuse of alcohol usually leads to chronic pancreatitis. Additional, as yet unknown factors are necessary to induce acute alcoholic pancreatitis. Following its initiation by different etiological sources, pathophysiology of acute pancreatitis may take a similar course. Digestive enzymes are activated and set free into intracellular, intraductal and interstitial spaces. Trypsin as the trigger-enzyme of activation cascade is thought to play a major role. In addition, lipolytic enzymes may be involved in the pathophysiologic process. Phospholipase A is known to release lysolecithin which causes membrane damage. Recent studies indicate that the release of fatty acids by lipase causes acinar cell necrosis. New insights into the pathophysiology may lead to a rational and more successful therapy of acute pancreatitis.     

Acute recurrent pancreatitis: Etiopathogenesis,diagnosis and treatment

Acute recurrent pancreatitis(ARP)refers to a clinical entity characterized by episodes of acute pancreatitis which occurs on more than one occasion.Recurrence of pancreatitis generally occurs in a setting of normal morpho-functional gland,however,an established chronic disease may be found either on the occasion of the first episode of pancreatitis or during the follow-up.The aetiology of ARP can be identified in the majority of patients.Most common causes include common bile duct stones or sludge and bile crystals;sphincter of oddi dysfunction;anatomical ductal variants interfering with pancreatic juice outflow;obstruction of the main pancreatic duct or pancreatico-biliary junction;genetic mutations;alcohol consumption.However,despite diagnostic technologies,the aetiology of ARP still remains unknown in up to 30%of cases:in these cases the term“idiopathic”is used.Because occult bile stone disease and sphincter of oddi dysfunction account for the majority of cases,cholecystectomy,and eventually the endoscopic biliary and/or pancreatic sphincterotomy are curative in most of cases.Endoscopic biliary sphincterotomy appeared to be a curative procedure per se in about 80%of patients.Ursodeoxycholic acid oral treatment alone has also been reported effective for treatment of biliary sludge.In uncertain cases toxinbotulin injection may help in identifying some sphincter of oddi dysfunction,but this treatment is not widely used.In the last twenty years,pancreatic endotherapy has been proven effective in cases of recurrent pancreatitis depending on pancreatic ductal obstruction,independently from the cause of obstruction,and has been widely used instead of more aggressive approaches.     

急性胰腺炎994例病因与治疗分析

目的 探讨急性胰腺炎(AP)的病因及其治疗方法 的选择.方法 回顾性分析2003年1月至2007年1月瑞金医院胰腺普外科收治的994例AP患者资料,根据病因及治疗方式进行分类统计.结果 994例AP患者中,胆源性AP 825例(83.0%),酒精性AP 24例(2.41%),高脂血症性AP29例(2.92%),妊娠性AP16例(1.61%),特发性AP 71例(7.14%),外伤性4例(0.40%),两种病因以上的混合性AP 25例(2.52%).轻症急性胰腺炎(MAP)767例(77.2%),重症急性胰腺炎(SAP)227例(22.8%).总的治愈好转率91.2%,病亡87例,病死率8.8%,其中酒精性AP的病死率达37.5%,显著高于胆源性AP.对胆源性AP患者分别采用非手术治疗、内镜逆行胰胆管造影+乳头括约肌切开(ERCP+EST)、胆囊切除术+胆总管探查或ERCP术后腹腔镜下胆囊切除术及清创引流术.采用清创引流术的患者均为SAP患者,术后病死率高达25.0%,显著高于其他治疗方法 者(P＜0.01).其他3种治疗方法 间的SAP病例比及病死率均无显著差异.结论胆道因素仍是AP的首要病因.酒精性AP病情较危重,预后较差.对胆源性AP,多种治疗方法 的疗效无显著差异.     

Biliary microcrystals in idiopathic acute pancreatitis: clue for occult underlying biliary etiology

The main causes of pancreatic inflammation worldwide are biliary lithiasis and alcoholism. However, 10 to 30% of patients have been considered to have "idiopathic" acute pancreatitis. Recently, some studies showed that a significant rate of the so called idiopathic pancreatitis are caused by microlithiasis and/or biliary sludge, identified by the presence of cholesterol monohidrate and/or calcium bilirubinate microcrystals in the biliary sediment. In the present study, the analysis of microcrystals from bile obtained during endoscopic retrograde cholangiopancreatography was done in patients with pancreatitis (idiopathic, biliary or alcoholic--20 in each group). Patients with idiopathic pancreatitis and microcrystals in the bile underwent cholecystectomy whenever possible. Those who refused or were inapt to surgery underwent endoscopic sphincterotomy or received continuous therapy with ursodeoxycholic acid. Patients with idiopathic pancreatitis without biliary crystals did not receive any specific treatment. The prevalence of biliary microcrystals in patients with idiopathic pancreatitis (75%) and biliary pancreatitis (90%) was significantly higher than in those with alcoholic pancreatitis (15%). In the identification of the etiology of biliary pancreatitis, the presence of microcrystals had a sensitivity of 90%, specificity of 85%, positive predictive value of 85.7%, negative predictive value of 89.4% and accuracy of 87.5%. In the patients with recurrent idiopathic pancreatitis, with biliary crystals, there was an statistically significant reduction in the number of pancreatitis episodes after specific treatment. In the follow-up of this group during 23.3 +/- 4.8 months, recurrence of pancreatitis occurred only in patients with "persistent biliary factor" (choledocholithiasis and/or persistence of cholesterol monohidrate). All patients with idiopathic pancreatitis who underwent cholecystectomy had chronic cholecystitis. Moreover, cholelithiasis was present in one case. In the ultrassonographic follow-up of the patients with idiopathic acute pancreatitis with microcrystals in the bile, cholelithiasis was detected in one case. In the subgroup of five patients with idiopathic pancreatitis without biliary microcrystals recurrence occurred in one case. Ultrassonographic study during follow-up did not reveal biliary stones in any of these patients. We concluded that the detection of biliary microcrystals in "idiopathic" pancreatitis suggested an underlying biliary etiology, even if occult. What's more, early specific therapeutic procedure (cholecystectomy, endoscopic sphincterotomy or ursodeoxycholic acid) in patients with recurrent idiopathic pancreatitis with microcrystals in the bile reduced significantly the recurrence during the follow-up. Finally, acute pancreatitis (specially recurrent) should not be called idiopathic before the microscopic analysis of the bile, aiming to detect or exclude the presence of microcrystals.     

Acute cholangitis after endoscopic sphincterotomy: Complications of expectant treatment

Two elderly patients who had endoscopic sphincterotomy (EST) for their common duct stones developed acute cholangitis and, one of them also developed acute pancreatitis after the procedure. Despite the presence of an adequate sphincterotomy which allows subsequent spontaneous stone elimination, transient ductal obstruction during stone migration through the sectioned papilla is probably accountable for their complications. From the present reported experience, it is clear that expectant treatment of common duct stone after EST can be associated with definite hazards. Immediate biliary decompression with either active instrumental extraction or, when not feasible, insertion of nasobiliary catheter, should be performed to prevent these complications in selected patients.     

Migrated endoclip and stone formation after cholecystectomy： A new danger of acute pancreatitis

Endoclip migration into the common bile duct following laparoscopic cholecystectomy (LC) is an extremely rare complication. Migrated endoclip into the common bile duct can cause obstruction,serve as a nidus for stone formation,and cause cholangitis. We report a case of obstructive jaundice and acute biliary pancreatitis due to choledocholithiasis caused by a migrated endoclip 6 mo after LC. The patient underwent early endoscopic retrog-rade cholangiopancreatography (ERCP) with endoscopic sphincterotomy and stone extraction.