Pancreas VOI. 5, NO. 3, pp. 248-254 8 1990 Raven Press, Ltd., New York
Pancreas Divisum is a Probable Cause of Acute Pancreatitis: A Report of 137 Cases J. P. Bernard, J. Sahel, M. Giovannini, and H. Sarles Clinique des Maladies de 1’Appareil Digestif et de la Nutrition, Hbpital Sainte Marguerite, and Unite‘ de Recherches de Pathologie Digestive, INSERM U 315, Marseille, France
Summary: The incidence of pancreas divisum (PD) was evaluated in a retrospective series of 1,825 successful consecutive ERCPs. One hundred thirtyseven pancreas divisums (7.5%) were found in 80 males and 57 females at a mean age of 49.2 years. The ventral ducts were visualized in 82.5% and the dorsal ducts in 74.1% of attempted cannulations of the minor papilla. Pancreas divisum was significantly more frequent in patients presenting with acute idiopathic pancreatitis (50.0%) or acute biliary pancreatitis (23.7%) than in controls or in the general population. This difference was not found in acute pancreatitis due to other etiologies. Acute pancreatitis associated with PD is generally recurrent, is not severe, but may be complicated by necrotic pseudocysts. The frequency of PD was also significantly increased in patients with gallbladder stones but not with common bile duct stones. In other pathological groups-chronic pancreatitis and pancreatic cancer-the frequency of pancreas divisum was not statistically different from that observed in controls andor in the general population. We conclude that on a statistical basis, PD is a probable cause of acute pancreatitis, especially in its idiopathic recurrent variety, and that its frequency is increased in patients with gallbladder stones. Key Words: Pancreas divisum-Endoscopic retrograde cholangiopancreatography-Acute pancreatitis-Gallbladder stones.
others were strongly opposed to this hypothesis (24-27). This work aims to evaluate the frequency of PD in various well-defined pancreatic diseases, in order to try to understand the differences reported in the recent literature related to the correlation or the absence of correlation of PD with pancreatitis.
Pancreas divisum (PD) is the most frequent ductal embryological anomaly of the pancreas. It is characterized by the absence of fusion of the ducts draining the ventral and dorsal pancreatic buds (14). The two independent ducts reach the duodenum at two distinct orifices: the dorsal duct at the minor papilla, and the ventral duct together with the main bile duct at the major papilla (33-10). Its discovery in patients suffering from acute pancreatitis without usual etiology prompted some authors to admit its responsiveness in this disease (1 1-23). However,
MATERIALS AND METHODS From 1980 to 1987, 1,825 endoscopic retrograde cholangiopancreatographies (ERCPs) were successfully performed in our institution. All interpretable ERCPs were considered, whatever the indication of the examination. ERCPs were performed with lateral viewing duodenoscopes (Olympus JF
Manuscript received June 5, 1989; revised manuscript accepted September 29, 1989. Address correspondenceand reprint requests to Dr. J. Sahel, Clinique des Maladies de 1’Appareil Digestif et de la Nutrition, Hap. Ste Marguerite, bd Ste Marguerite, 13274 Marseille Cedex 09, France.
248
PANCREAS DIVISUM AND ACUTE PANCREATITIS
1T or JF IT lo). The main papilla was always cannulated; when PD was suspected or in case of failure of visualisation of the pancreatic ducts after cannulation of the papilla of Vater, the accessory papilla was sought and catheterized when possible. Definitions of patients Patients were classified into seven groups (Table 1). Particular attention was paid to distinguish acute pancreatitis from acute episodes superimposed on chronic pancreatitis. More than 90% of patients had their first ERCP in the service. Patients were mostly referred for failure by other gastroenterologists in cases of main bile duct stones. Group 1 :chronic pancreatitis The diagnosis was based on either the existence of pancreatic stones visible on plain films of the abdomen or on CT scan, or typical histological lesions on resected specimens, or a typical clinical symptomatology associated with one of the following criteria: (a) characteristic ductal changes on ERCP; (b) exocrine pancreatic insufficiency; pancreatic function was assessed by duodenal suction samples obtained after stimulation by i.v. secretin (1 CU/kg) and cholecystokinin (3 CHR U/kg). Lipase, chymotrypsin, bicarbonate, and calcium concentrations were measured.
249
Group 2: acute pancreatitis The diagnosis was established based on clinical signs associated with both paroxysmal hyperamylasemia or hyperlipasemia and typical changes demonstrated at ultrasonography or CT scans. In some cases, it was confirmed by laparotomy. The usual causes of acute pancreatitis were carefully looked for: biliary stones, alcoholism, hyperlipidemia, postoperation, ERCP, drugs, infections, allergy, hypercalcemia, and congenital malformations of the main bile duct. When no cause was found, acute pancreatitis was called idiopathic. The recurrent character of acute pancreatitis is defined by the recurrence of painful attacks associated with a rise in serum amylase and lipase, without pancreatic exocrine and endocrine insufficiency or ductal changes characteristic of chronic pancreatitis. In this group, no patient was referred for failure of ERCP in another center. Therefore, the diagnosis of pancreas divisum was made based on the first pancreatography realized in our service. Group 3: pancreatic, bile duct, and ampullary carcinoma Diagnosis was made by clinical presentation (obstructivejaundice, persistent epigastric pain, loss of weight) associated with typical ultrasonic, CT, and ERCP signs, and histological or cytological evi-
TABLE l. Relationship between pancreas divisum and various pathological conditions Pancreas divisum Diseases (1) Chronic pancreatitis (n = 303)
(2) Acute pancreatitis All cases (n = 162) Biliary (n = 59) Other causes (n = 47) Idiopathic (n = 56) (3) Pancreatic cancer + bile duct cancer -+ ampullary cancer (n = 273) (4) Liver diseases (n = 159) (5) Benign biliary diseases Gallbladder stones (n = 106) MBD stones (n = 300) Benign stenosis of the sphincter of Oddi (n = 29) (6) Miscellaneous (n = 8) (7) Control patients (n = 485) Total 1825
Normally fused pancreas
n
%
n
15
5.0
45 14 3 28
%
Significance
288
95.0
NS
27.8 23.7 6.4 50.0
117 45 44 28
72.2 76.3 93.6 50.0
12 17
4.4 10.7
26 1 142
95.6 89.3
17 10
16.0 3.3
89 290
84.0 96.7
3" 18 137
37.5 3.7 7.5
56
467 1,688
< 0.001 < 0.001
p
< 0.001
p*
< 0.001
NS NS
p < 0.001 NS
NS
29
0
p p
62.5 96.3 92.5
p : significantly different from both control patients and total population. p*: significant only versus control but not versus total population. a One perihepatitis, one venous mesenteric infarction, and one duodenal ulcer perforated into the pancreas. Four parasites in the MBD, and one choledococele.
Pancreas, Vol. 5 , No. 3, 1990
J . P . BERNARD ET AL.
250
dence (endoscopic or percutaneous or perioperative cytopuncture or microbiopsy and/or microscopic examination of resected samples). Groups 4-7 Groups 4 and 5 included liver diseases such as hepatitis, cirrhosis, and primary and secondary carcinoma of the liver, and biliary lithiasis. Group 6 included miscellaneous diseases different of one of the above groups (see Table 1). Group 7 included controls without organic lesions. These patients had been referred to the service because a pancreatic disease had been suspected for different reasons. However, after a careful clinical, biological, endoscopic, and radiological evaluation, an organic disease or a detectable functional trouble had been ruled out.
Statistical methods The x2 test in a 2 x 2 contingency table was used. The frequency of PD in each disease group was compared to that observed in control subjects and in all patients. RESULTS Frequency of PD in the total population of patients One hundred thirty-seven PD were diagnosed during 1,825 consecutive ERCPs (7.5%). The success rate of visualization of ERCP was not recorded since only successful pancreatographies were considered. In our experience (unpublished results), ERCP was obtained in 92% of pancreatic indications and in 74% of biliary indications. There were 80 males and 57 females. The mean age was 49.2 years (range of 17-96 years). The major papilla was cannulated in all cases and the bile ducts were visualized. The ventral pancreas was seen 113 times (82.5%);in 11 cases, it was considered to be atrophic (8.0%), presenting usually as a very small submucosal injection; the ventral pancreatogram could not be obtained in 13 patients (9.5%). In these 1 1 cases of “atrophic” ventral pancreas and 13 cases without ventral pancreatography, the diagnosis of PD was confirmed by a successful cannulation of the minor papilla demonstrating the main pancreatic duct. The ventral ducts were normal in 94 cases (83.2%) and abnormal in 19 cases (16.8%). Abnormalities consisted of changes due to either chronic pancreatitis in 15 cases, or obstructive pancreatitis secondary to ampullary carcinoma in 4 cases.
Pancreas, Vol. 5 , No. 3, 1990
Cannulation of the accessory papilla was attempted on 116 occasions (84.7%) and was successful in 86 cases (74.1%). Cannulation was performed by using either fine-tipped catheters or needle catheters (28) or a standard 5 F catheter following resection of the accessory papilla with a diathermic loop. The dorsal duct was normal in 62 cases (72.1%) and was the site of abnormalities in 24 patients (27.9%): 15 chronic pancreatitis, 7 pancreatic cancers localized in the dorsal pancreas, and 2 pseudocysts secondary to acute pancreatitis. Frequency of PD according to diagnostic classes Chronic pancreatitis (CP) CP was diagnosed 303 times during 1,825 ERCPs. CP was due to alcohol abuse in 290 patients; 15 patients, all alcoholics, presented with PD. Ductal changes involved both the ventral and dorsal parts of the pancreas (Fig. 1). The frequency of CP associated with PD (5.0%) was not significantly different from the incidence of PD in control subjects (3.7%) and in the whole population (7.5%) (x2of 0.714 and 2 S60, respectively). Acute pancreatitis ERCPs were performed in order to find a cause for 162 cases of acute pancreatitis (AP). Acute pancreatitis complicating chronic pancreatitis or tumor was not treated in this group. PD was found in 45 patients; there were 31 cases of recurrent acute pancreatitis and 14 isolated cases of AP. When comparing the incidence of PD and normally fused pancreas in AP of all causes, it appeared that the frequency of PD was statistically higher in AP patients than in control patients (x2 = 80.026, p < 0.001) and in the total population (x2 = 73.481, p < 0.001). In 106 cases, a commonly admitted etiology to AP was found (65.9%). Biliary stones were found in 59 cases (36.4%): among these, there were 14 patients with PD, (23.7%), i.e., a frequency significantly higher than in control subjects (x2 = 38.071, p < 0.001) and in the total population (x2 = 20.400, p < 0.001). Other causes of AP were alcoholism (21 casesamong which 2 had PD). Although these patients had no detectable signs of chronic pancreatitis, it is possible that they presented with early chronic calcifying pancreatitis. As in this last disease, the frequency of pancreas divisum was not different from that of controls or of the total population. The other
PANCREAS DIVIS U M AND ACUTE PANCREATITIS
FIG. 1. ERCP in a patient with pancreas divisum presenting with alcoholic chronic pancreatitis. Ductal changes (microcystic dilatation of ducts) are visible on both the ventral (A) and dorsal (B) pancreas, but predominate on the dorsal ductal system.
causes were hyperlipidemia (seven cases), ERCP (seven cases), trauma (one case), drugs (two cases), hypercalcemia (two cases), annular pancreas (one case), postoperation (four cases of which one had PD), infection (one case), and allergy (one case). The frequency of PD in this group (3/47) was not significantly different from that observed in control subjects (x2 = 0.807) and in the whole population (x2 = 0.084). In 56 cases, AP was classified as idiopathic (IAP) before ERCP (34.7%). In 28 cases, ERCP demonstrated PD. The other cases remained of unknown origin and were followed in a long-term survey in order to rule out chronic pancreatitis revealed by acute pancreatitis as the initial presentation.
251
The frequency of PD in IAP (50%) was significantly higher than in control subjects (x2 = 138.265, p < 0.001) and in the whole population (x2 = 122.596, p < 0.001). In no instance was PD-associated idiopathic AP severe from a clinical point of view. The generally recurrent painful episodes were always well tolerated with neither loss of weight nor deterioration of general condition. In four cases, IAP associated with PD was complicated by necrotic pseudocysts that disappeared either spontaneously or following percutaneous puncture under ultrasonic guidance. Pancreatic exocrine function was normal except in three patients who underwent a dorsal sphincterotomy and presented during follow-up with a stenosis of the accessory orifice, of a total of 10 sphincterotomies of the minor papilla. The 31 patients who presented with recurrent acute pancreatitis had suffered two to nine episodes per year, with symptomfree intervals of 1 to 24 months (Fig. 1). When performed at the time of painful episodes, ultrasonography showed either a normal or a hypoechoic pancreas with an enlargement of the head of the gland. In cases of AP, ERCP showed normal dorsal pancreatic ducts except when pseudocysts were present (four cases); in three cases, there was a regular dilation of the dorsal duct secondary to stenosis of the endoscopic section of the accessory papilla. Carcinoma of the pancreas, bile ducts, and the papillary region One hundred fifty-one pancreatic cancers, 68 bile duct carcinomas, and 54 ampullary carcinomas were diagnosed. In each group, there were seven, one, and four cases of PD, respectively. In cases of PD, ductal changes typical of pancreatic carcinoma were all located in the dorsal part, the ventral ducts being normal. There was no significant difference in the frequency of PD in the cancer patients compared to the control subjects and all patients (x2of 0.091 and 0.024, respectively). Liver diseases The incidence of PD in patients presenting with liver diseases (10.7%) was higher than in control subjects (x2 = 11.353, p < 0.001) but not significantly different from that observed in the whole population (x2 = 2.072); therefore, this difference will not be taken into consideration. Benign biliary diseases Benign biliary diseases were diagnosed on 435 occasions (23.8%): common bile duct stones in 300 Pancreas, Vol. 5, No. 3, 1990
J . P . BERNARD ET AL.
252
cases (68.9%), isolated gallbladder stones in 106 cases (24.4%), and benign stenosis of the sphincter of Oddi in 29 cases (6.7%). The incidence of biliary lithiasis (in the main and accessory ducts) was statistically higher in PD patients (x2 = 9.934, p < 0.01 and x2 = 6.970, p < 0.01) than in the total population. When comparing the frequency of PD in patients with either gallbladder stones, common bile duct stones, or benign vaterian stenosis to control subjects, the difference remained significant for gallbladder stones only (x2 = 23.723, p < 0.001). In cases of miscellaneous diseases, the small number of cases does not allow a comparison. DISCUSSION In 1977, Gregg (14) and Cotton (12) postulated that PD was a cause of acute pancreatitis or pancreatic pain, these troubles being secondary to a retention of pancreatic juice at the level of the minor papilla. Retention would be caused by the diameter of the papilla being too small to accommodate permanently or occasionally the major portion of pancreatic secretion. In fact, objective clinical and morphological arguments supporting the validity of this hypothesis are rare. Actually, when ERCP demonstrates obvious signs of obstructive pancreatitis, selectively located on the dorsal pancreas, the ventral part being normal, the responsibility of an obstacle at the minor papilla can be accepted. However, in most patients presenting with pancreatic pain or acute recurrent pancreatitis, dorsal pancreatography is normal (7,19-21). The test proposed by Warshaw et al. (29), consisting of the ultrasonographic evaluation of the increase in the diameter of the dorsal duct following intravenous injection of secretin, could be considered useful if the results obtained by these authors were confirmed. Although the positivity of the test allowed the prediction of good results after surgical sphincterotomy in 90% of cases, 25% were false-negative results; moreover, there was no asymptomatic PD in the control group. Staritz et al. (30) were able to measure the pressure in the dorsal duct in six patients with PD presenting with unexplained abdominal pain associated with hyperamylasemia. They found that the dorsal intraductal pressure was significantly higher (23.7 k 1.3 mm Hg) than in the normally fused pancreas, both in the Wirsung duct (10.0 ? 1.0 mm Hg) and in the Santorini duct (10.5 k 0.9 mm Hg). According to Warshaw et al. (23), the minimal size (measured by Pancreas, Val. 5, No. 3, 1990
lacrymal probes during laparotomy) of the accessory orifice was 0.75 mm; when the caliber is less, these authors admit the existence of a stenosis and the indication of ’sphincteroplasty that deserves to be confirmed. The results of endoscopic sections and surgical sphincterotomies and sphincteroplasties also argue for the existence of an obstruction of the accessory papilla (7,13,20,23,31,32,33). In cases of secondary stricture, one assists the recurrence of painful attacks concomitant with the dilation of the pancreatic dorsal duct system that did not exist before sphincterotomy. Finally, the pathological examination of the accessory papilla can demonstrate the presence of submucosal fibrosis (19,20). The reason why an embryological anomaly leads to pancreatic troubles at an adult age in some patients remains unknown; a possible explanation could be that some fibrosis of the accessory papilla develops with aging. The clinical relevance of PD remains controversial. For Mitchell et al. (25), Delaye et al. (24), and Sugawa et al. (26), PD is a simple anatomical variant without any relation to pancreatic disease and especially pancreatitis. These conclusions have to be taken with some reservations. In the study of Mitchell et al., the diagnostic criteria are not the same in cases of PD in which the diagnosis of pancreatic disease was done based on clinical data and in cases of normally fused pancreas in which the diagnosis of pancreatitis was made on the basis of pancreatographic data. Yet, the lack of consistency of radiographic changes in cases of AP or chronic pancreatitis at early stages is well documented. Moreover, in this study, acute pancreatitis and chronic pancreatitis were not individualized. In the paper from Cremer’s group (24), the frequency of PD in acute idiopathic and acute gallbladder stone pancreatitis could be underestimated because these groups were not individualized but studied together with acute pancreatitis of other causes that were not different from controls. On the contrary, the frequency of PD is probably overestimated in the control group because it includes diseases such as gallbladder stones that are associated, according to our data, with increased frequency of PD. The success in achieving a dorsal pancreatography was only 97 in 304 cases (33%) compared to 74% in our series. In the paper of Sugawa et al. (26), the frequency of PD was low (41/1,529 patients: 2.7%) and ranged from 1.7 to 3.7% in the four following groups: biliary diseases + pancreatic carcinoma, unexplained
PANCREAS DIVISUM AND ACUTE PANCREATITIS
abdominal pain, alcoholic pancreatitis, and idiopathic pancreatitis. Because of the low incidence of PD in this series, compared to that reported in the literature and in our own series, one can question the possibility of an underestimation of PD or a bias in the recruitment of patients. On the contrary, a majority of authors admit, on statistical bases, that PD can be responsible for acute pancreatitis and particularly for recurrent acute pancreatitis (11,12,14- 16,1%23,32). The results of the present study, dealing with a large number of cases, agree with other papers (11,13,14,16,17,19,32).Furthermore, it shows that the highest frequency of pancreas divisum is observed in idiopathic acute pancreatitis, where it reached 50% of 58 cases, which is very significantly higher than in both normal controls and the whole population. Pancreas divisum was found in 23.7% of patients with biliary pancreatitis, which is also highly significantly greater than in normal controls and in the whole population. However, the frequency of PD was not increased in acute pancreatitis of other etiologies (alcoholism, hyperlipidemia, ERCP, trauma, drugs, surgery, etc.). In this study, we did not confirm our initial observation (19) that PD was less frequently observed in cases of chronic pancreatitis. The frequency of PD was 16.0% in patients presenting with gallbladder stones, which is a significantly higher percentage than in both normal controls and the whole population. Such a correlation was previously reported in one paper (16). This is in agreement with the recent observation of an increased incidence of gallstones in cases of separated opening of the bile and pancreatic ducts at the major papilla (34). Although PD was found statistically more frequently in liver diseases (cirrhosis, hepatitis, and carcinoma of the liver) than in controls, when this group of patients was compared to the general population, this difference was no longer significant. Therefore, it will not be discussed. The symptoms of idiopathic acute pancreatitis due to pancreas divisum are characterized by painful episodes associated with transient increases in serum levels of pancreatic enzyme, and most frequently is recurring. Although the recurrence could suggest chronic pancreatitis, there is neither loss of weight nor deterioration of general condition nor exocrine pancreatic insufficiency as judged by duodenal suction after secretin and cholecystokinin in-
253
jection. The only complications were four patients with necrotic pseudocysts following acute episodes that disappeared spontaneously or following percutaneous punctures. In conclusion, the frequency of PD compared to normally fused pancreatic ducts is highly significantly increased in idiopathic acute pancreatitis (50% of 58 cases) but also in biliary acute pancreatitis, but not in acute pancreatitis due to other causes. This is a strong argument proving the role of this congenital anomaly in the pathogenesis of acute, generally recurrent, and benign pancreatitis. Acute idiopathic pancreatitis associated with PD is frequently recurrent but does not lead to pancreatic insufficiency (acute recurrent pancreatitis). The frequency of PD is also increased in gallbladder lithiasis. REFERENCES 1. Baldwin WM. An adult human pancreas showing an embryological condition. Anat Rec 1910;4:21-2. 2. Belber JP, Bill K. Fusion anomalies of the pancreas ductal system: differentiation from pathologic states. Radiology
1977;123:637-42. 3. McLean JM. Embryology of the pancreas. In: Howat HT, Sarles H, eds. The exocrine pancreas. Philadelphia: W.B. Saunders, 1979:3-4. 4. Milbourn E. On the excretory ducts of the pancreas in man, with special reference to their relations to each other, to the common bile duct and to the duodenum. Acta Anat 1950;
9:1-34.
A study of the pancreatic duct system in man by the use of vinyl acetate cats of post mortem preparations. Surg Gynecol Obstet
5 . Berman LG, Prior JT, Abranow W, Seigler DD.
1960;110:391-403. 6. Birnstlingl M. A study of pancreatography. Br J Surg 1959;47:128-39. 7. Blair AJ, Russell CG, Cotton PB. Resections for pancreatitis in patients with pancreas divisum. Ann Surg 1984;5:59&4. 8. Dawson W , Langman J. An anatomical radiological study on the pancreatic duct pattern in man. Anat Rec 1961;139:59-
68. 9. Phillips J, Koch H, Classen M. Variations and anomalies of the papilla of Vater, the pancreas and the biliary duct system. Endoscopy 1974;6:70-7. 10. Rienhoff WF, Pickrell KL. Pancreatitis: an anatomical study of the pancreatic and extrahepatic biliary system. Arch Surg 1945;5 1 :205-19. 11. Chevillotte G, Sahel J, Pietri H, Sarles H. Pancreatites aigues B rechutes associees au pancreas divisum. etude clinique de 12 cas. Gastroenterol Clin Biol 1984;8:352-8. 12. Cotton PB, Kizu M. Malfusion of dorsal and ventral pancreas: a cause of pancreatitis? Gut 1977;18:A-400(Abstract). 13. Cotton PB. Congenital anomaly of pancreas divisum as cause of obstructive pain and pancreatitis. Gut 1980;21:105-
14. 14. Gregg JA.Pancreas divisum: its association with pancreatitis. Am J Surg 1977;134:539-43. 15. Kruse A. Pancreas divisum: a significantly higher incidence in chronic pancreatitis. Scand J Gustroenterol1977;12(suppl 45):52. Pancreas, Vol. 5 , No. 3, 1990
J . P. BERNARD ET AL.
254
16. Liguory C, Lefebvre JF, Canard JM, Bonnel D, Fritsch J, fitienne JP. Le pancrkas divisum: Btude clinique et therapeutique chez l'homme. A propos de 87 cas. Gastroenterol Clin Biol 1986;10:820-5. 17. Rex DK, O'Connor KW, Hawes RH, Winchester M, Lehman GA. Idiopathic pancreatitis. ERCP findings and association with pancreas divisum (P div). Gastrointest Endosc 1987;33:159(Abstract). 18. Rosch W, Koch H, Schfanner 0, Demling L. The clinical significance of the pancreas divisum. Gastrointest Endosc 1976;22:206-7. 19. Sahel J, Cros RC, Bouny J, Sarles H. Clinicopathological massociated with pancreas divisum. Digestion 1982; conditions
.
26. 27. 28. 29,
0
L3:l-D.
20. Sahel J, Boustiere C, Sarles JC, Chevillotte G, Sarles H. Le traitement du pancrkas divisum. Rksultats preliminaires. Gastroenterol Clin Biol 1983;7:293-8. 21. Thompson MH, Williamson RCH, Salmon PR. The clinical relevance of isolated ventral pancreas. Br J Surg 1981; 68:101-4. 22. Tulassay Z, Papp J. New clinical aspects of pancreas divisum. Gastrointest Endosc 1980;26:143-6. 23. Warschaw AL, Richter JM, Schapiro RH. Cause and treatment of pancreatitis associated with pancreas divisum. Ann Surg 1983;4:443-52. 24. Delhaye M, Engelholm L, Cremer M. Pancreas divisum. Congenital anatomic variant or anomaly? Contribution of endoscopic retrograde dorsal pancreatography. Gastroenterology 1985;89:951-8. 25. Mitchell CJ, Lintott DJ, Ruddel WSJ, Losowsky MS, Axon
Pancreas, Vol. 5 , No. 3, 1990
30. 31. 32. 33.
34.
RT. Clinical relevance of an unfused pancreatic duct system. Gut 1979;20:1066-71. Sugawa C, Walt AJ, Nunez DC, Masuyama H. Pancreas divisum: is it a normal anatomic variant? Am J Surg 1987; 153:62-7. Delhaye M, Engelholm L, Cremer M. Pancreas divisum: controversial clinical significance. Dig Dis 1988;6:30-9. Dunham F, Deltenre M, Jeanmart J, Toussaint J, Cremer M. Special catheters for ERCP. Endoscopy 1981;13:81-5. Warshaw AL, Simeone J, Schapiro RH, Hedberg SE, Mueller PE, Fenvcci JT. Objective evaluation of arnpullary stenosis with ultrasonography and pancreatic stimulation. Am J Surg 1985;149:65-78. S t a t 2 M, Weyerzum Buschenfelde KH. Elevated pressure in the dorsal part of pancreas divisum: the cause of chronic pancreatitis? Pancreas 1988;3:10110. Gregg JA, Monaco AM, McDennott WV. Pancreas divisum: results of surgical intervention. Am J Surg 1982;145:488-92. Keith RG, Shapero TF, Saibil FG. Treatment of pancreatitis associated with pancreas divisum by dorsal duct sphincterotomy alone. Can J Surg 1982;25:622-6. Richter JM, Schapiro RH, Mulley AL, Warshaw AL. Association of pancreas divisum and pancreatitis and its treatment by sphincteroplasty of the accessory ampulla. Gastroenterology 1981;81:1104-5. Misra SP, Gulatti P, Thorat VK, Vij JC, Anand BS. Pancreaticobiliary ductal union in biliary diseases. An endoscopic retrograde cholangiopancreatographicstudy. Gastroenterology 1989;96:9O7-12.
Pancreas Divisum is a Probable Cause of Acute Pancreatitis: A Report of 137 Cases J. P. Bernard, J. Sahel, M. Giovannini, and H. Sarles Clinique des Maladies de 1’Appareil Digestif et de la Nutrition, Hbpital Sainte Marguerite, and Unite‘ de Recherches de Pathologie Digestive, INSERM U 315, Marseille, France
Summary: The incidence of pancreas divisum (PD) was evaluated in a retrospective series of 1,825 successful consecutive ERCPs. One hundred thirtyseven pancreas divisums (7.5%) were found in 80 males and 57 females at a mean age of 49.2 years. The ventral ducts were visualized in 82.5% and the dorsal ducts in 74.1% of attempted cannulations of the minor papilla. Pancreas divisum was significantly more frequent in patients presenting with acute idiopathic pancreatitis (50.0%) or acute biliary pancreatitis (23.7%) than in controls or in the general population. This difference was not found in acute pancreatitis due to other etiologies. Acute pancreatitis associated with PD is generally recurrent, is not severe, but may be complicated by necrotic pseudocysts. The frequency of PD was also significantly increased in patients with gallbladder stones but not with common bile duct stones. In other pathological groups-chronic pancreatitis and pancreatic cancer-the frequency of pancreas divisum was not statistically different from that observed in controls andor in the general population. We conclude that on a statistical basis, PD is a probable cause of acute pancreatitis, especially in its idiopathic recurrent variety, and that its frequency is increased in patients with gallbladder stones. Key Words: Pancreas divisum-Endoscopic retrograde cholangiopancreatography-Acute pancreatitis-Gallbladder stones.
others were strongly opposed to this hypothesis (24-27). This work aims to evaluate the frequency of PD in various well-defined pancreatic diseases, in order to try to understand the differences reported in the recent literature related to the correlation or the absence of correlation of PD with pancreatitis.
Pancreas divisum (PD) is the most frequent ductal embryological anomaly of the pancreas. It is characterized by the absence of fusion of the ducts draining the ventral and dorsal pancreatic buds (14). The two independent ducts reach the duodenum at two distinct orifices: the dorsal duct at the minor papilla, and the ventral duct together with the main bile duct at the major papilla (33-10). Its discovery in patients suffering from acute pancreatitis without usual etiology prompted some authors to admit its responsiveness in this disease (1 1-23). However,
MATERIALS AND METHODS From 1980 to 1987, 1,825 endoscopic retrograde cholangiopancreatographies (ERCPs) were successfully performed in our institution. All interpretable ERCPs were considered, whatever the indication of the examination. ERCPs were performed with lateral viewing duodenoscopes (Olympus JF
Manuscript received June 5, 1989; revised manuscript accepted September 29, 1989. Address correspondenceand reprint requests to Dr. J. Sahel, Clinique des Maladies de 1’Appareil Digestif et de la Nutrition, Hap. Ste Marguerite, bd Ste Marguerite, 13274 Marseille Cedex 09, France.
248
PANCREAS DIVISUM AND ACUTE PANCREATITIS
1T or JF IT lo). The main papilla was always cannulated; when PD was suspected or in case of failure of visualisation of the pancreatic ducts after cannulation of the papilla of Vater, the accessory papilla was sought and catheterized when possible. Definitions of patients Patients were classified into seven groups (Table 1). Particular attention was paid to distinguish acute pancreatitis from acute episodes superimposed on chronic pancreatitis. More than 90% of patients had their first ERCP in the service. Patients were mostly referred for failure by other gastroenterologists in cases of main bile duct stones. Group 1 :chronic pancreatitis The diagnosis was based on either the existence of pancreatic stones visible on plain films of the abdomen or on CT scan, or typical histological lesions on resected specimens, or a typical clinical symptomatology associated with one of the following criteria: (a) characteristic ductal changes on ERCP; (b) exocrine pancreatic insufficiency; pancreatic function was assessed by duodenal suction samples obtained after stimulation by i.v. secretin (1 CU/kg) and cholecystokinin (3 CHR U/kg). Lipase, chymotrypsin, bicarbonate, and calcium concentrations were measured.
249
Group 2: acute pancreatitis The diagnosis was established based on clinical signs associated with both paroxysmal hyperamylasemia or hyperlipasemia and typical changes demonstrated at ultrasonography or CT scans. In some cases, it was confirmed by laparotomy. The usual causes of acute pancreatitis were carefully looked for: biliary stones, alcoholism, hyperlipidemia, postoperation, ERCP, drugs, infections, allergy, hypercalcemia, and congenital malformations of the main bile duct. When no cause was found, acute pancreatitis was called idiopathic. The recurrent character of acute pancreatitis is defined by the recurrence of painful attacks associated with a rise in serum amylase and lipase, without pancreatic exocrine and endocrine insufficiency or ductal changes characteristic of chronic pancreatitis. In this group, no patient was referred for failure of ERCP in another center. Therefore, the diagnosis of pancreas divisum was made based on the first pancreatography realized in our service. Group 3: pancreatic, bile duct, and ampullary carcinoma Diagnosis was made by clinical presentation (obstructivejaundice, persistent epigastric pain, loss of weight) associated with typical ultrasonic, CT, and ERCP signs, and histological or cytological evi-
TABLE l. Relationship between pancreas divisum and various pathological conditions Pancreas divisum Diseases (1) Chronic pancreatitis (n = 303)
(2) Acute pancreatitis All cases (n = 162) Biliary (n = 59) Other causes (n = 47) Idiopathic (n = 56) (3) Pancreatic cancer + bile duct cancer -+ ampullary cancer (n = 273) (4) Liver diseases (n = 159) (5) Benign biliary diseases Gallbladder stones (n = 106) MBD stones (n = 300) Benign stenosis of the sphincter of Oddi (n = 29) (6) Miscellaneous (n = 8) (7) Control patients (n = 485) Total 1825
Normally fused pancreas
n
%
n
15
5.0
45 14 3 28
%
Significance
288
95.0
NS
27.8 23.7 6.4 50.0
117 45 44 28
72.2 76.3 93.6 50.0
12 17
4.4 10.7
26 1 142
95.6 89.3
17 10
16.0 3.3
89 290
84.0 96.7
3" 18 137
37.5 3.7 7.5
56
467 1,688
< 0.001 < 0.001
p
< 0.001
p*
< 0.001
NS NS
p < 0.001 NS
NS
29
0
p p
62.5 96.3 92.5
p : significantly different from both control patients and total population. p*: significant only versus control but not versus total population. a One perihepatitis, one venous mesenteric infarction, and one duodenal ulcer perforated into the pancreas. Four parasites in the MBD, and one choledococele.
Pancreas, Vol. 5 , No. 3, 1990
J . P . BERNARD ET AL.
250
dence (endoscopic or percutaneous or perioperative cytopuncture or microbiopsy and/or microscopic examination of resected samples). Groups 4-7 Groups 4 and 5 included liver diseases such as hepatitis, cirrhosis, and primary and secondary carcinoma of the liver, and biliary lithiasis. Group 6 included miscellaneous diseases different of one of the above groups (see Table 1). Group 7 included controls without organic lesions. These patients had been referred to the service because a pancreatic disease had been suspected for different reasons. However, after a careful clinical, biological, endoscopic, and radiological evaluation, an organic disease or a detectable functional trouble had been ruled out.
Statistical methods The x2 test in a 2 x 2 contingency table was used. The frequency of PD in each disease group was compared to that observed in control subjects and in all patients. RESULTS Frequency of PD in the total population of patients One hundred thirty-seven PD were diagnosed during 1,825 consecutive ERCPs (7.5%). The success rate of visualization of ERCP was not recorded since only successful pancreatographies were considered. In our experience (unpublished results), ERCP was obtained in 92% of pancreatic indications and in 74% of biliary indications. There were 80 males and 57 females. The mean age was 49.2 years (range of 17-96 years). The major papilla was cannulated in all cases and the bile ducts were visualized. The ventral pancreas was seen 113 times (82.5%);in 11 cases, it was considered to be atrophic (8.0%), presenting usually as a very small submucosal injection; the ventral pancreatogram could not be obtained in 13 patients (9.5%). In these 1 1 cases of “atrophic” ventral pancreas and 13 cases without ventral pancreatography, the diagnosis of PD was confirmed by a successful cannulation of the minor papilla demonstrating the main pancreatic duct. The ventral ducts were normal in 94 cases (83.2%) and abnormal in 19 cases (16.8%). Abnormalities consisted of changes due to either chronic pancreatitis in 15 cases, or obstructive pancreatitis secondary to ampullary carcinoma in 4 cases.
Pancreas, Vol. 5 , No. 3, 1990
Cannulation of the accessory papilla was attempted on 116 occasions (84.7%) and was successful in 86 cases (74.1%). Cannulation was performed by using either fine-tipped catheters or needle catheters (28) or a standard 5 F catheter following resection of the accessory papilla with a diathermic loop. The dorsal duct was normal in 62 cases (72.1%) and was the site of abnormalities in 24 patients (27.9%): 15 chronic pancreatitis, 7 pancreatic cancers localized in the dorsal pancreas, and 2 pseudocysts secondary to acute pancreatitis. Frequency of PD according to diagnostic classes Chronic pancreatitis (CP) CP was diagnosed 303 times during 1,825 ERCPs. CP was due to alcohol abuse in 290 patients; 15 patients, all alcoholics, presented with PD. Ductal changes involved both the ventral and dorsal parts of the pancreas (Fig. 1). The frequency of CP associated with PD (5.0%) was not significantly different from the incidence of PD in control subjects (3.7%) and in the whole population (7.5%) (x2of 0.714 and 2 S60, respectively). Acute pancreatitis ERCPs were performed in order to find a cause for 162 cases of acute pancreatitis (AP). Acute pancreatitis complicating chronic pancreatitis or tumor was not treated in this group. PD was found in 45 patients; there were 31 cases of recurrent acute pancreatitis and 14 isolated cases of AP. When comparing the incidence of PD and normally fused pancreas in AP of all causes, it appeared that the frequency of PD was statistically higher in AP patients than in control patients (x2 = 80.026, p < 0.001) and in the total population (x2 = 73.481, p < 0.001). In 106 cases, a commonly admitted etiology to AP was found (65.9%). Biliary stones were found in 59 cases (36.4%): among these, there were 14 patients with PD, (23.7%), i.e., a frequency significantly higher than in control subjects (x2 = 38.071, p < 0.001) and in the total population (x2 = 20.400, p < 0.001). Other causes of AP were alcoholism (21 casesamong which 2 had PD). Although these patients had no detectable signs of chronic pancreatitis, it is possible that they presented with early chronic calcifying pancreatitis. As in this last disease, the frequency of pancreas divisum was not different from that of controls or of the total population. The other
PANCREAS DIVIS U M AND ACUTE PANCREATITIS
FIG. 1. ERCP in a patient with pancreas divisum presenting with alcoholic chronic pancreatitis. Ductal changes (microcystic dilatation of ducts) are visible on both the ventral (A) and dorsal (B) pancreas, but predominate on the dorsal ductal system.
causes were hyperlipidemia (seven cases), ERCP (seven cases), trauma (one case), drugs (two cases), hypercalcemia (two cases), annular pancreas (one case), postoperation (four cases of which one had PD), infection (one case), and allergy (one case). The frequency of PD in this group (3/47) was not significantly different from that observed in control subjects (x2 = 0.807) and in the whole population (x2 = 0.084). In 56 cases, AP was classified as idiopathic (IAP) before ERCP (34.7%). In 28 cases, ERCP demonstrated PD. The other cases remained of unknown origin and were followed in a long-term survey in order to rule out chronic pancreatitis revealed by acute pancreatitis as the initial presentation.
251
The frequency of PD in IAP (50%) was significantly higher than in control subjects (x2 = 138.265, p < 0.001) and in the whole population (x2 = 122.596, p < 0.001). In no instance was PD-associated idiopathic AP severe from a clinical point of view. The generally recurrent painful episodes were always well tolerated with neither loss of weight nor deterioration of general condition. In four cases, IAP associated with PD was complicated by necrotic pseudocysts that disappeared either spontaneously or following percutaneous puncture under ultrasonic guidance. Pancreatic exocrine function was normal except in three patients who underwent a dorsal sphincterotomy and presented during follow-up with a stenosis of the accessory orifice, of a total of 10 sphincterotomies of the minor papilla. The 31 patients who presented with recurrent acute pancreatitis had suffered two to nine episodes per year, with symptomfree intervals of 1 to 24 months (Fig. 1). When performed at the time of painful episodes, ultrasonography showed either a normal or a hypoechoic pancreas with an enlargement of the head of the gland. In cases of AP, ERCP showed normal dorsal pancreatic ducts except when pseudocysts were present (four cases); in three cases, there was a regular dilation of the dorsal duct secondary to stenosis of the endoscopic section of the accessory papilla. Carcinoma of the pancreas, bile ducts, and the papillary region One hundred fifty-one pancreatic cancers, 68 bile duct carcinomas, and 54 ampullary carcinomas were diagnosed. In each group, there were seven, one, and four cases of PD, respectively. In cases of PD, ductal changes typical of pancreatic carcinoma were all located in the dorsal part, the ventral ducts being normal. There was no significant difference in the frequency of PD in the cancer patients compared to the control subjects and all patients (x2of 0.091 and 0.024, respectively). Liver diseases The incidence of PD in patients presenting with liver diseases (10.7%) was higher than in control subjects (x2 = 11.353, p < 0.001) but not significantly different from that observed in the whole population (x2 = 2.072); therefore, this difference will not be taken into consideration. Benign biliary diseases Benign biliary diseases were diagnosed on 435 occasions (23.8%): common bile duct stones in 300 Pancreas, Vol. 5, No. 3, 1990
J . P . BERNARD ET AL.
252
cases (68.9%), isolated gallbladder stones in 106 cases (24.4%), and benign stenosis of the sphincter of Oddi in 29 cases (6.7%). The incidence of biliary lithiasis (in the main and accessory ducts) was statistically higher in PD patients (x2 = 9.934, p < 0.01 and x2 = 6.970, p < 0.01) than in the total population. When comparing the frequency of PD in patients with either gallbladder stones, common bile duct stones, or benign vaterian stenosis to control subjects, the difference remained significant for gallbladder stones only (x2 = 23.723, p < 0.001). In cases of miscellaneous diseases, the small number of cases does not allow a comparison. DISCUSSION In 1977, Gregg (14) and Cotton (12) postulated that PD was a cause of acute pancreatitis or pancreatic pain, these troubles being secondary to a retention of pancreatic juice at the level of the minor papilla. Retention would be caused by the diameter of the papilla being too small to accommodate permanently or occasionally the major portion of pancreatic secretion. In fact, objective clinical and morphological arguments supporting the validity of this hypothesis are rare. Actually, when ERCP demonstrates obvious signs of obstructive pancreatitis, selectively located on the dorsal pancreas, the ventral part being normal, the responsibility of an obstacle at the minor papilla can be accepted. However, in most patients presenting with pancreatic pain or acute recurrent pancreatitis, dorsal pancreatography is normal (7,19-21). The test proposed by Warshaw et al. (29), consisting of the ultrasonographic evaluation of the increase in the diameter of the dorsal duct following intravenous injection of secretin, could be considered useful if the results obtained by these authors were confirmed. Although the positivity of the test allowed the prediction of good results after surgical sphincterotomy in 90% of cases, 25% were false-negative results; moreover, there was no asymptomatic PD in the control group. Staritz et al. (30) were able to measure the pressure in the dorsal duct in six patients with PD presenting with unexplained abdominal pain associated with hyperamylasemia. They found that the dorsal intraductal pressure was significantly higher (23.7 k 1.3 mm Hg) than in the normally fused pancreas, both in the Wirsung duct (10.0 ? 1.0 mm Hg) and in the Santorini duct (10.5 k 0.9 mm Hg). According to Warshaw et al. (23), the minimal size (measured by Pancreas, Val. 5, No. 3, 1990
lacrymal probes during laparotomy) of the accessory orifice was 0.75 mm; when the caliber is less, these authors admit the existence of a stenosis and the indication of ’sphincteroplasty that deserves to be confirmed. The results of endoscopic sections and surgical sphincterotomies and sphincteroplasties also argue for the existence of an obstruction of the accessory papilla (7,13,20,23,31,32,33). In cases of secondary stricture, one assists the recurrence of painful attacks concomitant with the dilation of the pancreatic dorsal duct system that did not exist before sphincterotomy. Finally, the pathological examination of the accessory papilla can demonstrate the presence of submucosal fibrosis (19,20). The reason why an embryological anomaly leads to pancreatic troubles at an adult age in some patients remains unknown; a possible explanation could be that some fibrosis of the accessory papilla develops with aging. The clinical relevance of PD remains controversial. For Mitchell et al. (25), Delaye et al. (24), and Sugawa et al. (26), PD is a simple anatomical variant without any relation to pancreatic disease and especially pancreatitis. These conclusions have to be taken with some reservations. In the study of Mitchell et al., the diagnostic criteria are not the same in cases of PD in which the diagnosis of pancreatic disease was done based on clinical data and in cases of normally fused pancreas in which the diagnosis of pancreatitis was made on the basis of pancreatographic data. Yet, the lack of consistency of radiographic changes in cases of AP or chronic pancreatitis at early stages is well documented. Moreover, in this study, acute pancreatitis and chronic pancreatitis were not individualized. In the paper from Cremer’s group (24), the frequency of PD in acute idiopathic and acute gallbladder stone pancreatitis could be underestimated because these groups were not individualized but studied together with acute pancreatitis of other causes that were not different from controls. On the contrary, the frequency of PD is probably overestimated in the control group because it includes diseases such as gallbladder stones that are associated, according to our data, with increased frequency of PD. The success in achieving a dorsal pancreatography was only 97 in 304 cases (33%) compared to 74% in our series. In the paper of Sugawa et al. (26), the frequency of PD was low (41/1,529 patients: 2.7%) and ranged from 1.7 to 3.7% in the four following groups: biliary diseases + pancreatic carcinoma, unexplained
PANCREAS DIVISUM AND ACUTE PANCREATITIS
abdominal pain, alcoholic pancreatitis, and idiopathic pancreatitis. Because of the low incidence of PD in this series, compared to that reported in the literature and in our own series, one can question the possibility of an underestimation of PD or a bias in the recruitment of patients. On the contrary, a majority of authors admit, on statistical bases, that PD can be responsible for acute pancreatitis and particularly for recurrent acute pancreatitis (11,12,14- 16,1%23,32). The results of the present study, dealing with a large number of cases, agree with other papers (11,13,14,16,17,19,32).Furthermore, it shows that the highest frequency of pancreas divisum is observed in idiopathic acute pancreatitis, where it reached 50% of 58 cases, which is very significantly higher than in both normal controls and the whole population. Pancreas divisum was found in 23.7% of patients with biliary pancreatitis, which is also highly significantly greater than in normal controls and in the whole population. However, the frequency of PD was not increased in acute pancreatitis of other etiologies (alcoholism, hyperlipidemia, ERCP, trauma, drugs, surgery, etc.). In this study, we did not confirm our initial observation (19) that PD was less frequently observed in cases of chronic pancreatitis. The frequency of PD was 16.0% in patients presenting with gallbladder stones, which is a significantly higher percentage than in both normal controls and the whole population. Such a correlation was previously reported in one paper (16). This is in agreement with the recent observation of an increased incidence of gallstones in cases of separated opening of the bile and pancreatic ducts at the major papilla (34). Although PD was found statistically more frequently in liver diseases (cirrhosis, hepatitis, and carcinoma of the liver) than in controls, when this group of patients was compared to the general population, this difference was no longer significant. Therefore, it will not be discussed. The symptoms of idiopathic acute pancreatitis due to pancreas divisum are characterized by painful episodes associated with transient increases in serum levels of pancreatic enzyme, and most frequently is recurring. Although the recurrence could suggest chronic pancreatitis, there is neither loss of weight nor deterioration of general condition nor exocrine pancreatic insufficiency as judged by duodenal suction after secretin and cholecystokinin in-
253
jection. The only complications were four patients with necrotic pseudocysts following acute episodes that disappeared spontaneously or following percutaneous punctures. In conclusion, the frequency of PD compared to normally fused pancreatic ducts is highly significantly increased in idiopathic acute pancreatitis (50% of 58 cases) but also in biliary acute pancreatitis, but not in acute pancreatitis due to other causes. This is a strong argument proving the role of this congenital anomaly in the pathogenesis of acute, generally recurrent, and benign pancreatitis. Acute idiopathic pancreatitis associated with PD is frequently recurrent but does not lead to pancreatic insufficiency (acute recurrent pancreatitis). The frequency of PD is also increased in gallbladder lithiasis. REFERENCES 1. Baldwin WM. An adult human pancreas showing an embryological condition. Anat Rec 1910;4:21-2. 2. Belber JP, Bill K. Fusion anomalies of the pancreas ductal system: differentiation from pathologic states. Radiology
1977;123:637-42. 3. McLean JM. Embryology of the pancreas. In: Howat HT, Sarles H, eds. The exocrine pancreas. Philadelphia: W.B. Saunders, 1979:3-4. 4. Milbourn E. On the excretory ducts of the pancreas in man, with special reference to their relations to each other, to the common bile duct and to the duodenum. Acta Anat 1950;
9:1-34.
A study of the pancreatic duct system in man by the use of vinyl acetate cats of post mortem preparations. Surg Gynecol Obstet
5 . Berman LG, Prior JT, Abranow W, Seigler DD.
1960;110:391-403. 6. Birnstlingl M. A study of pancreatography. Br J Surg 1959;47:128-39. 7. Blair AJ, Russell CG, Cotton PB. Resections for pancreatitis in patients with pancreas divisum. Ann Surg 1984;5:59&4. 8. Dawson W , Langman J. An anatomical radiological study on the pancreatic duct pattern in man. Anat Rec 1961;139:59-
68. 9. Phillips J, Koch H, Classen M. Variations and anomalies of the papilla of Vater, the pancreas and the biliary duct system. Endoscopy 1974;6:70-7. 10. Rienhoff WF, Pickrell KL. Pancreatitis: an anatomical study of the pancreatic and extrahepatic biliary system. Arch Surg 1945;5 1 :205-19. 11. Chevillotte G, Sahel J, Pietri H, Sarles H. Pancreatites aigues B rechutes associees au pancreas divisum. etude clinique de 12 cas. Gastroenterol Clin Biol 1984;8:352-8. 12. Cotton PB, Kizu M. Malfusion of dorsal and ventral pancreas: a cause of pancreatitis? Gut 1977;18:A-400(Abstract). 13. Cotton PB. Congenital anomaly of pancreas divisum as cause of obstructive pain and pancreatitis. Gut 1980;21:105-
14. 14. Gregg JA.Pancreas divisum: its association with pancreatitis. Am J Surg 1977;134:539-43. 15. Kruse A. Pancreas divisum: a significantly higher incidence in chronic pancreatitis. Scand J Gustroenterol1977;12(suppl 45):52. Pancreas, Vol. 5 , No. 3, 1990
J . P. BERNARD ET AL.
254
16. Liguory C, Lefebvre JF, Canard JM, Bonnel D, Fritsch J, fitienne JP. Le pancrkas divisum: Btude clinique et therapeutique chez l'homme. A propos de 87 cas. Gastroenterol Clin Biol 1986;10:820-5. 17. Rex DK, O'Connor KW, Hawes RH, Winchester M, Lehman GA. Idiopathic pancreatitis. ERCP findings and association with pancreas divisum (P div). Gastrointest Endosc 1987;33:159(Abstract). 18. Rosch W, Koch H, Schfanner 0, Demling L. The clinical significance of the pancreas divisum. Gastrointest Endosc 1976;22:206-7. 19. Sahel J, Cros RC, Bouny J, Sarles H. Clinicopathological massociated with pancreas divisum. Digestion 1982; conditions
.
26. 27. 28. 29,
0
L3:l-D.
20. Sahel J, Boustiere C, Sarles JC, Chevillotte G, Sarles H. Le traitement du pancrkas divisum. Rksultats preliminaires. Gastroenterol Clin Biol 1983;7:293-8. 21. Thompson MH, Williamson RCH, Salmon PR. The clinical relevance of isolated ventral pancreas. Br J Surg 1981; 68:101-4. 22. Tulassay Z, Papp J. New clinical aspects of pancreas divisum. Gastrointest Endosc 1980;26:143-6. 23. Warschaw AL, Richter JM, Schapiro RH. Cause and treatment of pancreatitis associated with pancreas divisum. Ann Surg 1983;4:443-52. 24. Delhaye M, Engelholm L, Cremer M. Pancreas divisum. Congenital anatomic variant or anomaly? Contribution of endoscopic retrograde dorsal pancreatography. Gastroenterology 1985;89:951-8. 25. Mitchell CJ, Lintott DJ, Ruddel WSJ, Losowsky MS, Axon
Pancreas, Vol. 5 , No. 3, 1990
30. 31. 32. 33.
34.
RT. Clinical relevance of an unfused pancreatic duct system. Gut 1979;20:1066-71. Sugawa C, Walt AJ, Nunez DC, Masuyama H. Pancreas divisum: is it a normal anatomic variant? Am J Surg 1987; 153:62-7. Delhaye M, Engelholm L, Cremer M. Pancreas divisum: controversial clinical significance. Dig Dis 1988;6:30-9. Dunham F, Deltenre M, Jeanmart J, Toussaint J, Cremer M. Special catheters for ERCP. Endoscopy 1981;13:81-5. Warshaw AL, Simeone J, Schapiro RH, Hedberg SE, Mueller PE, Fenvcci JT. Objective evaluation of arnpullary stenosis with ultrasonography and pancreatic stimulation. Am J Surg 1985;149:65-78. S t a t 2 M, Weyerzum Buschenfelde KH. Elevated pressure in the dorsal part of pancreas divisum: the cause of chronic pancreatitis? Pancreas 1988;3:10110. Gregg JA, Monaco AM, McDennott WV. Pancreas divisum: results of surgical intervention. Am J Surg 1982;145:488-92. Keith RG, Shapero TF, Saibil FG. Treatment of pancreatitis associated with pancreas divisum by dorsal duct sphincterotomy alone. Can J Surg 1982;25:622-6. Richter JM, Schapiro RH, Mulley AL, Warshaw AL. Association of pancreas divisum and pancreatitis and its treatment by sphincteroplasty of the accessory ampulla. Gastroenterology 1981;81:1104-5. Misra SP, Gulatti P, Thorat VK, Vij JC, Anand BS. Pancreaticobiliary ductal union in biliary diseases. An endoscopic retrograde cholangiopancreatographicstudy. Gastroenterology 1989;96:9O7-12.
