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Pancreas divisum, an evidence-based review: part I, pathophysiology
REVIEW ARTICLE Pancreas divisum, an evidence-based review: part I, pathophysiology Steven D. Klein, MD, John P. Affronti, MS, MD Atlanta, Georgia
Pancreas divisum (PD) occurs when the ventral and dorsal ducts of the embryonic pancreas fail to fuse during organogenesis. It is the most common congenital variant of pancreatic ductal development, occurring in approximately 10% of individuals.1 The frequency of PD in series of patients undergoing ERCP is lower, varying from 0.3%2 to 7.5%,3 depending on the success of minor papilla cannulation. Although recognized by anatomists hundreds of years ago,4 it was not until the 1970s and the advent of ERCP that several investigators proposed an association between PD and pancreatitis.5-7 However, investigators quickly divided into two camps, because several failed to find a significantly increased frequency of pancreatic disease among patients with PD compared with control patients.3,8 Yet, even most skeptics acknowledge that a small minority of patients with PD may develop pancreatic disease, so that the more relevant issue becomes the clinical significance of such an association. This review is divided into two parts. The first evaluates the evidence supporting a pathophysiologic role for PD, and the second assesses the outcomes of surgical and endoscopic therapy in patients with this anomaly. METHODS A search for published data was performed by using the MEDLINE database (1966 to March 2004) with ‘‘pancreas divisum’’ as a keyword. The search was limited to publications in English. Publications that discussed pathophysiology, epidemiology, diagnosis, therapeutic trials, and outcomes were deemed relevant, and were reviewed in full. Further relevant articles then were obtained by using citations in the publications identified by the initial search. Current affiliation: Department of Medicine, Emory University, Atlanta, Georgia. Reprint requests: John Affronti, MS, MD, The Emory Clinic Suite 4100, Clinic Building A, 1365 Clifton Rd., Atlanta, GA 30322. Copyright Ó 2004 by the American Society for Gastrointentinal Endoscopy 0016-5107/$30.00 PII: S0016-5107(04)01815-2 VOLUME 60, NO. 3, 2004
EMBRYOLOGY The normal adult pancreas results from the fusion of dorsal and ventral pancreatic buds during the second month of fetal development. The ventral bud arises with the hepatobiliary system and will form the postero-inferior aspect of the head of the pancreas as it rotates to fuse with the dorsal bud, which ultimately constitutes the remainder of the gland (Fig. 1). Normally, the duct of the dorsal bud fuses with that of the ventral bud to form the main pancreatic duct. In approximately 30% of people, the portion of the dorsal duct nearest the minor papilla does not regress. This residual segment of the dorsal duct becomes the accessory duct, which may or may not be patent. This congenital variant has no known clinical consequence. It appears that proper fusion of the dorsal and ventral ducts occurs in just over 90% of individuals.1 However, when the two ducts fail to fuse, the dorsal duct remains and drains the majority of the pancreas via the minor papilla, and the short ventral duct drains the inferior portion of the head via the major papilla, the condition termed PD. Several variations of PD exist, including incomplete PD, in which there is a thin ductal communication between the two ducts and complete absence of a ventral duct (Fig. 2). The frequency at which these variants occur varies, depending on the patient group, but the clinical implications appear to be similar for each variant,9 because the dorsal duct drains the majority of the gland in all three instances. PATHOPHYSIOLOGY The earliest investigators first found an increased frequency of PD in patients with idiopathic pancreatitis. Cotton5 found that 3.6% of patients undergoing pancreatography for biliary tract disease had an incidental finding of PD. Moreover, among patients undergoing pancreatography for unexplained pancreatitis, the proportion of patients with PD was much higher, at 25.6%. Subsequently, several other studies found a significantly increased frequency of PD among patients with pancreatitis.10-13 These observational studies led investigators to search for more direct evidence of an association between PD and pancreatitis. It was first proposed that the small diameter of the minor papilla represented an obstruction relative to the large volume flow of pancreatic juice, because the dorsal duct drains the majority of the pancreas. However, this explanation is inconsistent with the observation that the vast majority of individuals with PD are asymptomatic. The most commonly accepted hypothesis for the development of acute recurrent pancreatitis (ARP), GASTROINTESTINAL ENDOSCOPY
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Figure 1. Development of the pancreas. (From The Netter Collection, Volume 3, Part 3. Illustrations by Frank H. Netter, MD. Used with permission from Icon Learning Systems, a division of MediMedia USA, Inc. All rights reserved.)
chronic pancreatitis, or pancreatic-type pain in association with PD is that some patients with this anomaly have a stenotic minor papilla. It is extremely difficult to demonstrate pathologic changes in the dorsal pancreas and a coexistent normal ventral pancreas. However, surgical specimens from multiple patients with PD and pancreatitis have been shown to exhibit pathologic changes confined to the dorsal duct distribution,5 thereby lending support to the stenotic minor papilla theory. Yet, most patients with PD and recurrent pancreatitis have a non-dilated dorsal duct, and some investigators, therefore, have suggested that the obstruction must be transient in nature and be related to intermittent plugging of the minor papilla with proteinic material, flow being normal most of the time.14 What evidence exists to support the hypothesis of obstruction at the minor papilla? Staritz and Meyer zum Buschenfelde15 measured intraductal pressures in both the dorsal and ventral ducts in 14 patients with upper abdominal pain, 6 with PD, and 8 with normal pancreatic ductal anatomy. The mean dorsal 420
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duct pressure in PD was 23.7 mm Hg, and the mean ventral duct pressure was 10.8 mm Hg, whereas in the control group the mean ventral duct pressure was 10.5 mm Hg. The clinical significance of this observation is unclear, but Staritz and Meyer zum Buschenfelde15 proposed that the association of PD with another risk factor, such as excessive ingestion of alcohol, may increase the viscosity of the pancreatic juice and thereby increase the risk of pancreatitis. Perhaps another risk factor could be hereditary in nature. Muzaffar et al.16 described a family in which the mother, son, and daughter presented with recurrent pancreatitis, and, at ERCP, the mother and son had PD, while the daughter had normal ductal anatomy with a distal stricture. These investigators propose an interesting hypothesis: that the presentation of hereditary pancreatitis may be affected by anatomic variations, with those having PD presenting at a much younger age. Given the incomplete penetrance of hereditary pancreatitis, perhaps several factors, such as abnormal ductal anatomy and viscous pancreatic juice, must interact. VOLUME 60, NO. 3, 2004
Pancreas divisum, an evidence-based review: part I, pathophysiology
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Figure 2. Drawings illustrating pancreatic ductal variations including pancreas divisum. A, A common variant with patent main and accessory ducts and patent major and minor papillae. B, Typical pancreas divisum. C, Incomplete pancreas divisum; a tiny branch connects dorsal and ventral ducts. D, Accessory duct absent; minor papilla not patent. E, Drainage of entire ductal system drains through minor papilla. F, Isolated accessory duct draining through minor papilla. (From Lehman, Feldman’s GastroAtlas Online. Available from: URL:http://www.gastroatlas.com.)
Focal dilatation of the terminal portion the dorsal duct, coined ‘‘santorinicele,’’ is described in association with PD and obstruction at the minor papilla. Eisen et al.17 described 4 patients with ARP who had a web-like membrane on the surface of the minor papilla. All four responded to endoscopic intervention, either papillotomy or balloon dilation. Because PD is a congenital variant, childhood cases would be of considerable interest. Pancreatitis is uncommon in children, therefore, large series are lacking. A retrospective study of 25 pediatric patients VOLUME 60, NO. 3, 2004
with either ARP or chronic pancreatitis found that 4 patients had no pancreatic disease other than PD.18 These patients were between 5 and 13 years of age, and all were managed conservatively. There are other reports of pancreatitis in children with PD, including several who appeared to respond to surgery.19,20 There also is evidence for the absence of a true association between PD and pancreatic disease. A large retrospective review, involving over 6000 patients undergoing ERCP, found a similar frequency of PD among a heterogeneous group of GASTROINTESTINAL ENDOSCOPY
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patients with different pancreatic and biliary disorders. In those with acute and chronic pancreatitis, as well as patients with pancreatic neoplasms and nonpancreatic disorders, the mean frequency of PD was 5.9%.21 When patients were grouped by disorder, the frequency of PD was similar in each group and within the range for the general population. Similar findings are reported for smaller case series.22-26 Why are there such large discrepancies in the frequency of PD between case series? Delhaye and Cremer3 argue that referral bias plays a large role, with PD being diagnosed with greater frequency at tertiary centers in patients referred for endoscopic retrograde pancreatography after unsuccessful attempts to visualize the pancreatic ductal system in community institutions. They also cite additional observations as evidence against the obstructive hypothesis, including the absence of ductal dilation in most patients, and the mixed results in surgical and endoscopic series. PATIENT CHARACTERISTICS In the large retrospective series of Cotton,5 patients with PD undergoing evaluation for pancreatic disease were divided into groups based on clinical presentation and the likelihood of another explanation for pancreatitis. Nineteen patients had ARP and no other evident cause of pancreatitis, and 9 had pancreatictype pain, with no serologic or radiographic evidence of acute pancreatitis. Of the 19 patients with ARP, 9 had abnormal dorsal pancreatograms, with most having a normal ventral pancreatogram. By definition, those with pain alone had normal pancreatograms. Most patients with ARP and PD present during their adult life. The average age in the series of Cotton5 was 53 years, whereas, the average age of patients with pancreatic-type pain was 43 years. The length of time that patients had abdominal pain varied widely, from 1 to 20 years, but, on average, symptoms had been present for approximately 6 years before the diagnosis of PD. Because approximately a third of the patients with ARP had ductal changes by pancreatography, these patients could be classified as having chronic pancreatitis. Thus, possible clinical presentations of pancreatic disease associated with PD include ARP, chronic pancreatitis, and, finally, pancreatic-type pain with no objective findings of organic disease. These differences in patient characteristics are important when evaluating response to therapy, because there are significant differences in outcome in relation to presentation. Based on the series of Cotton,5 it appears that patients with pancreatic disease related to PD usually present with chronic symptoms during adult life. 422
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Pancreas divisum, an evidence-based review: part I, pathophysiology
EVALUATION ERCP is the reference standard for the diagnosis of PD (Figs. 3 and 4). When cannulation of the major papilla reveals a short ventral duct, the possibility of PD must be considered. In patients with PD, the ventral duct is from 1 to 4 cm in length; the duct does not cross the midline.1 There generally is prompt drainage of contrast, and the morphology of the duct, including ductal branches, should appear normal. Aggressive injection of contrast medium may result in acinarization (widespread visualization of ductal structure to the level of the acinus). In about a third of cases, the ventral duct may be absent.27 In these cases, the ventral portion of the pancreas is drained by a branch of the dorsal duct. It is essential to rule out secondary ductal obstruction, especially that caused by malignancy, and, therefore, identification and cannulation of the minor papilla should be pursued to demonstrate the presence of a dominant dorsal duct. The technical aspects of minor papilla cannulation are outlined in detail in the review of Lehman and Sherman.1 The minor papilla generally is located superior and anterior to the major papilla, which corresponds to the upper right quadrant of the view field of a side-viewing duodenoscope. Placing the duodenoscope in the so-called long position, in which the insertion tube forms a large loop in the stomach, often facilitates cannulation. Although a standard tapered 5F catheter can be used, ideally, the catheter should be highly tapered; a 5F catheter with a much smaller diameter blunt needle at the tip is often useful, because the orifice of the minor papilla may be extremely small. Deep cannulation may be accomplished with a thin (0.018 inch) guidewire. The latter usually is necessary when therapeutic maneuvers are intended. When difficulty locating the minor papilla is encountered, secretin can be administered intravenously (0.25-1 IU) to stimulate the flow of pancreatic juice, with consequent widening of the papillary orifice. However, Lehman and Sherman1 caution that vigorous flow of pancreatic juice may make it difficult to inject contrast to the tail of the pancreas; they recommend that secretin be given only if necessary for identification of the minor papilla. If it is still difficult to locate the papilla, a dilute solution of methylene blue dye can be sprayed in the area likely to contain the papilla; with extended observation, the location may be revealed as the flow of pancreatic juice washes the dye away from the orifice. With use of the techniques and devices described above, cannulation is successful in the majority of patients. Failure is generally a result of VOLUME 60, NO. 3, 2004
Pancreas divisum, an evidence-based review: part I, pathophysiology
Figure 3. Retrograde pancreatogram showing typical normal dorsal pancreatic ductogram in patient with pancreas divisum. The appearance is similar to that of a normal ductogram obtained via injection of contrast at major papilla. Note endoscope in ‘‘long’’ position. (From Lehman, Feldman’s GastroAtlas Online. Available from: http://www.gastroatlas. com/.)
papillary and anatomical distortion caused by prior surgery or the presence of a diverticulum or malignancy. There was a correlation between ductal morphology and clinical presentation in the series of Lehman and Sherman.1 For example, among patients who presented with pancreatitis, 53% had an abnormal dorsal pancreatic ductogram. By comparison, 13% and 6% of patients who presented with pancreatictype pain alone and symptoms referable to the biliary tract, respectively, had abnormal dorsal pancreatic ducts. EUS can be used to evaluate the pancreas for evidence of PD. With the echoendoscope in the second portion of the duodenum, the uncinate process, the papilla, and the distal aspects of the bile and the pancreatic ducts may be visualized; the remainder of the head of the pancreas comes into view as the instrument tip is withdrawn to the duodenal bulb. If continuity cannot be demonstrated between the duct in the ventral portion of the gland and that in the dorsal aspect, PD may be present.28 In addition, a dominant dorsal duct also may be visualized. Conversely, if the ventral duct can be traced from the major papilla through the body and the tail, PD usually can be excluded.29 PD can be demonstrated noninvasively by MRCP, which has an accuracy similar to that of ERCP (Fig. 5).30 Imaging studies in the majority of patients with PD will demonstrate normal-appearing dorsal and ventral ducts, with no sign of pancreatitis. One strategy for the evaluation of these patients has been VOLUME 60, NO. 3, 2004
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Figure 4. Retrograde pancreatogram showing short ventral pancreatic duct, consistent with pancreas divisum; slight acinarization has occurred. (From Lehman, Feldman’s GastroAtlas Online. Available from: http://www.gastroatlas. com/.)
Figure 5. MRCP showing separate dorsal (arrowhead) and ventral (arrow) pancreatic ducts, consistent with pancreas divisum (from Matos C, Metens T, Deviere J, Delhaye M, Le Moine O, Cremer M. Pancreas divisum: evaluation with secretin-enhanced magnetic resonance cholangiopancreatography. Gastrointest Endosc 2001;53:728-33).
to identify the small subset with obstruction at the level of the minor papilla. Initially, there was substantial enthusiasm for measurement of the diameter of the dorsal duct ultrasonographically before and after secretin stimulation. When secretin is administered, the diameter of the pancreatic duct increases. However, prolongation of this widening could, in theory, be indicative of obstruction. Warshaw et al.31 defined prolonged dilation of the GASTROINTESTINAL ENDOSCOPY
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duct as that which persists from 15 to 30 minutes after secretin administration. These investigators then examined the ability of this test to predict the outcome of surgical sphincteroplasty in patients with recurrent pancreatitis and pancreatic-type pain. Among patients with a positive secretin stimulated US test, 92% had a satisfactory response to surgery. Unfortunately, these results were not reproducible in subsequent studies. Lowes et al.32 evaluated a heterogeneous group of 44 patients that included healthy control subjects and patients with PD who either had pancreatic symptoms or were asymptomatic. No correlation was found between ductal anatomy and the response to secretin. In fact, half of the normal control subjects had a positive test result. More recently, secretin-enhanced MRCP (SMRCP) has been used to evaluate patients with probable pancreatic disease. Matos et al.30 compared the results of S-MRCP in a heterogeneous group of patients suspected to have pancreatic disease. Not only was the frequency of PD similar across all subgroups, so was the response to secretin. S-MRCP did provide better images, but ductal dilation occurred with a similar frequency among the various patients, including those with and without PD. Sphincter manometry also has been used in an effort to better understand the function of the minor papilla. Satterfield et al.33 described 4 patients with PD and ARP who had minor papilla basal and phasic pressures that were similar to those recorded from the major papilla. These results differed from those of a prior study that found that pressures measured at the minor papilla were elevated in relation to those recorded from the major papilla.14 Unfortunately, there are few manometric studies of the minor papilla, largely because these are technically difficult to perform and parameters of ‘‘normal’’ have not been established. In summary, individuals with PD constitute a heterogeneous group. Most are asymptomatic, with PD being found only incidentally. However, some may develop an outflow obstruction at the minor papilla, with resulting pancreatitis. Although the diagnosis of PD is fairly straightforward, the demonstration of a causal relationship between the anomaly and pancreatic disease is more challenging but extremely important when evaluating potential candidates for invasive therapy. Patient selection and the outcomes of therapy will be discussed in part II of this review.
REFERENCES 1. Lehman GA, Sherman S. Diagnosis and therapy of pancreas divisum. Gastrointest Endosc Clin N Am 1998;8:55-77. 424
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2. Kasugai T, Kuno N, Kobayashi S, Hattori K. Endoscopic pancreatocholangiopathy. I. The normal endoscopic pancreatocholangiogram. Gastroenterology 1972;63:217-26. 3. Delhaye M, Cremer M. Clinical significance of pancreas divisum. Acta Gastroenterol Belg 1992;55:306-13. 4. Stern CD. A historical perspective on the discovery of the accessory duct of the pancreas, the ampulla of vater and pancreas divisum. Gut 1986;27:203-12. 5. Cotton PB. Congenital anomaly of pancreas divisum as cause of obstructive pain and pancreatitis. Gut 1980;21:105-14. 6. Gregg JA. Pancreas divisum: its association with pancreatitis. Am J Surg 1977;134:539-43. 7. Rosch W, Koch H, Schaffner O, Demling L. The clinical significance of the pancreas divisum. Gastrointest Endosc 1976;22:206-7. 8. Burtin P, Person B, Charneau J, Boyer J. Pancreas divisum and pancreatitis: a coincidental association? Endoscopy 1991; 23:55-8. 9. Kim MH, Lee SS, Kim CD, Lee SK, Kim HJ, Park HJ, et al. Incomplete pancreas divisum: is it merely a normal anatomic variant without clinical implication? Endoscopy 2001;33: 778-85. 10. Richter JM, Schapiro RH, Mulley AG, Warshaw AL. Association of pancreas divisum and pancreatitis and its treatment by sphincteroplasty of the accessory ampulla. Gastroenterology 1981;81:1104-10. 11. Sahel J, Cros RC, Bourry J, Sarles H. Clinico- pathological conditions associated with pancreas divisum. Digestion 1982;23:1-8. 12. Bernard JP, Sahel J, Giovannini M, Sarles H. Pancreas divisum is a probable cause of acute pancreatitis: a report of 137 cases. Pancreas 1990;5:248-54. 13. Schnelldorfer T, Adams DB. Outcome after lateral pancreaticojejunostomy in patients with chronic pancreatitis associated with pancreas divisum. Am Surg 2003;69:1041-6. 14. Cotton PB. Pancreas divisum [editorial]. Pancreas 1988;3: 245-7. 15. Staritz M, Meyer zum Buschenfelde KH. Elevated pressure in the dorsal part of pancreas divisum: the cause of chronic pancreatitis?. Pancreas 1988;3:108-10. 16. Muzaffar AR, Moyer MS, Dobbins J, Calhow CE, Gryboski JD, Shneider BL. Pancreas divisum in a family with hereditary pancreatitis. J Clin Gastroenterol 1996;22:16-20. 17. Eisen G, Schutz S, Metzler D, Baille J, Cotton PB. Santorinicele: new evidence for obstruction in pancreas divisum. Gastrointest Endosc 1994;40:73-6. 18. Forbes A, Leung JW, Cotton PB. Relapsing acute and chronic pancreatitis. Arch Dis Child 1984;59:927-34. 19. Shukri N, Wasa M, Hasegawa T, Okada A. Diagnostic significance of pancreas divisum in early life. Eur J Pediatr Surg 2000;10:12-6. 20. Yedlin ST, Dubois RS, Phillippart AI. Pancreas divisum: a cause of pancreatitis in childhood. J Pediatr Surg 1984;19: 793-4. 21. Delhaye M, Engelholm L, Cremer M. Pancreas divisum: controversial clinical significance. Dig Dis 1988;6:30-9. 22. Delhaye M, Engelholm L, Cremer M. Pancreas divisum: congenital anatomic variant or anomaly? Contribution of endoscopic retrograde dorsal pancreatograpy. Gastroenterology 1985;89:951-8. 23. Hayakawa T, Kondo T, Shibata T, Sugimoto Y, Kita-Gawa M, Suzuki T, et al. Pancreas divisum: a predisposing factor to pancreatitis? Int J Pancreatol 1989;5:317-26. VOLUME 60, NO. 3, 2004
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24. Mitchell CJ, Lintott DJ, Ruddell WSJ, Losowsky MS, Axon ATR. Clinical relevance of an unfused duct system. Gut 1979;20:1066-71. 25. Ott H, Ro¨sch W. The divided pancreas: a cause of pancreatitis? [German]. Med Welt 1983;34:466-8. 26. Sugawa C, Walt AJ, Nunez DC, Masuyama H. Pancreas divisum: is it a normal anatomic variant? Am J Surg 1987;153:62-7. 27. Benage D, McHenry R, Hawes RH, O’Connor KW, Lehman GA. Minor papilla cannulation and dorsal ductography in pancreas divisum. Gastrointest Endosc 1990;36:553-7. 28. Bhutani MS, Hoffman BJ, Hawes RH. Diagnosis of pancreas divisum by endoscopic ultrasonography. Endoscopy 1999;31: 550-3. 29. Sahai AV. EUS and chronic pancreatitis. Gastrointest Endosc 2002;56(Suppl 4):S76-81.
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30. Matos C, Metens T, Deviere J, Delhaye M, Le Moine O, Cremer M. Pancreas divisum: evaluation with secretinenhanced magnetic resonance cholangiopancreatography. Gastrointest Endosc 2001;53:728-33. 31. Warshaw AL, Simeone JF, Schapiro RH, Warshaw BF. Evaluation and treatment of the dominant dorsal duct syndrome (pancreas divisum redefined). Am J Surg 1990; 159:59-66. 32. Lowes JR, Lees WR, Cotton PB. Pancreatic duct dilatation after secretin stimulation in patients with pancreas divisum. Pancreas 1989;4:371-4. 33. Satterfield ST, McCarthy JH, Geenen JE, Hogan WJ, Venu RP, Dodds WJ, et al. Clinical experience in 82 patients with pancreas divisum: preliminary results of manometry and endoscopic therapy. Pancreas 1988;3:248-53.
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Pancreas divisum (PD) occurs when the ventral and dorsal ducts of the embryonic pancreas fail to fuse during organogenesis. It is the most common congenital variant of pancreatic ductal development, occurring in approximately 10% of individuals.1 The frequency of PD in series of patients undergoing ERCP is lower, varying from 0.3%2 to 7.5%,3 depending on the success of minor papilla cannulation. Although recognized by anatomists hundreds of years ago,4 it was not until the 1970s and the advent of ERCP that several investigators proposed an association between PD and pancreatitis.5-7 However, investigators quickly divided into two camps, because several failed to find a significantly increased frequency of pancreatic disease among patients with PD compared with control patients.3,8 Yet, even most skeptics acknowledge that a small minority of patients with PD may develop pancreatic disease, so that the more relevant issue becomes the clinical significance of such an association. This review is divided into two parts. The first evaluates the evidence supporting a pathophysiologic role for PD, and the second assesses the outcomes of surgical and endoscopic therapy in patients with this anomaly. METHODS A search for published data was performed by using the MEDLINE database (1966 to March 2004) with ‘‘pancreas divisum’’ as a keyword. The search was limited to publications in English. Publications that discussed pathophysiology, epidemiology, diagnosis, therapeutic trials, and outcomes were deemed relevant, and were reviewed in full. Further relevant articles then were obtained by using citations in the publications identified by the initial search. Current affiliation: Department of Medicine, Emory University, Atlanta, Georgia. Reprint requests: John Affronti, MS, MD, The Emory Clinic Suite 4100, Clinic Building A, 1365 Clifton Rd., Atlanta, GA 30322. Copyright Ó 2004 by the American Society for Gastrointentinal Endoscopy 0016-5107/$30.00 PII: S0016-5107(04)01815-2 VOLUME 60, NO. 3, 2004
EMBRYOLOGY The normal adult pancreas results from the fusion of dorsal and ventral pancreatic buds during the second month of fetal development. The ventral bud arises with the hepatobiliary system and will form the postero-inferior aspect of the head of the pancreas as it rotates to fuse with the dorsal bud, which ultimately constitutes the remainder of the gland (Fig. 1). Normally, the duct of the dorsal bud fuses with that of the ventral bud to form the main pancreatic duct. In approximately 30% of people, the portion of the dorsal duct nearest the minor papilla does not regress. This residual segment of the dorsal duct becomes the accessory duct, which may or may not be patent. This congenital variant has no known clinical consequence. It appears that proper fusion of the dorsal and ventral ducts occurs in just over 90% of individuals.1 However, when the two ducts fail to fuse, the dorsal duct remains and drains the majority of the pancreas via the minor papilla, and the short ventral duct drains the inferior portion of the head via the major papilla, the condition termed PD. Several variations of PD exist, including incomplete PD, in which there is a thin ductal communication between the two ducts and complete absence of a ventral duct (Fig. 2). The frequency at which these variants occur varies, depending on the patient group, but the clinical implications appear to be similar for each variant,9 because the dorsal duct drains the majority of the gland in all three instances. PATHOPHYSIOLOGY The earliest investigators first found an increased frequency of PD in patients with idiopathic pancreatitis. Cotton5 found that 3.6% of patients undergoing pancreatography for biliary tract disease had an incidental finding of PD. Moreover, among patients undergoing pancreatography for unexplained pancreatitis, the proportion of patients with PD was much higher, at 25.6%. Subsequently, several other studies found a significantly increased frequency of PD among patients with pancreatitis.10-13 These observational studies led investigators to search for more direct evidence of an association between PD and pancreatitis. It was first proposed that the small diameter of the minor papilla represented an obstruction relative to the large volume flow of pancreatic juice, because the dorsal duct drains the majority of the pancreas. However, this explanation is inconsistent with the observation that the vast majority of individuals with PD are asymptomatic. The most commonly accepted hypothesis for the development of acute recurrent pancreatitis (ARP), GASTROINTESTINAL ENDOSCOPY
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Pancreas divisum, an evidence-based review: part I, pathophysiology
Figure 1. Development of the pancreas. (From The Netter Collection, Volume 3, Part 3. Illustrations by Frank H. Netter, MD. Used with permission from Icon Learning Systems, a division of MediMedia USA, Inc. All rights reserved.)
chronic pancreatitis, or pancreatic-type pain in association with PD is that some patients with this anomaly have a stenotic minor papilla. It is extremely difficult to demonstrate pathologic changes in the dorsal pancreas and a coexistent normal ventral pancreas. However, surgical specimens from multiple patients with PD and pancreatitis have been shown to exhibit pathologic changes confined to the dorsal duct distribution,5 thereby lending support to the stenotic minor papilla theory. Yet, most patients with PD and recurrent pancreatitis have a non-dilated dorsal duct, and some investigators, therefore, have suggested that the obstruction must be transient in nature and be related to intermittent plugging of the minor papilla with proteinic material, flow being normal most of the time.14 What evidence exists to support the hypothesis of obstruction at the minor papilla? Staritz and Meyer zum Buschenfelde15 measured intraductal pressures in both the dorsal and ventral ducts in 14 patients with upper abdominal pain, 6 with PD, and 8 with normal pancreatic ductal anatomy. The mean dorsal 420
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duct pressure in PD was 23.7 mm Hg, and the mean ventral duct pressure was 10.8 mm Hg, whereas in the control group the mean ventral duct pressure was 10.5 mm Hg. The clinical significance of this observation is unclear, but Staritz and Meyer zum Buschenfelde15 proposed that the association of PD with another risk factor, such as excessive ingestion of alcohol, may increase the viscosity of the pancreatic juice and thereby increase the risk of pancreatitis. Perhaps another risk factor could be hereditary in nature. Muzaffar et al.16 described a family in which the mother, son, and daughter presented with recurrent pancreatitis, and, at ERCP, the mother and son had PD, while the daughter had normal ductal anatomy with a distal stricture. These investigators propose an interesting hypothesis: that the presentation of hereditary pancreatitis may be affected by anatomic variations, with those having PD presenting at a much younger age. Given the incomplete penetrance of hereditary pancreatitis, perhaps several factors, such as abnormal ductal anatomy and viscous pancreatic juice, must interact. VOLUME 60, NO. 3, 2004
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Figure 2. Drawings illustrating pancreatic ductal variations including pancreas divisum. A, A common variant with patent main and accessory ducts and patent major and minor papillae. B, Typical pancreas divisum. C, Incomplete pancreas divisum; a tiny branch connects dorsal and ventral ducts. D, Accessory duct absent; minor papilla not patent. E, Drainage of entire ductal system drains through minor papilla. F, Isolated accessory duct draining through minor papilla. (From Lehman, Feldman’s GastroAtlas Online. Available from: URL:http://www.gastroatlas.com.)
Focal dilatation of the terminal portion the dorsal duct, coined ‘‘santorinicele,’’ is described in association with PD and obstruction at the minor papilla. Eisen et al.17 described 4 patients with ARP who had a web-like membrane on the surface of the minor papilla. All four responded to endoscopic intervention, either papillotomy or balloon dilation. Because PD is a congenital variant, childhood cases would be of considerable interest. Pancreatitis is uncommon in children, therefore, large series are lacking. A retrospective study of 25 pediatric patients VOLUME 60, NO. 3, 2004
with either ARP or chronic pancreatitis found that 4 patients had no pancreatic disease other than PD.18 These patients were between 5 and 13 years of age, and all were managed conservatively. There are other reports of pancreatitis in children with PD, including several who appeared to respond to surgery.19,20 There also is evidence for the absence of a true association between PD and pancreatic disease. A large retrospective review, involving over 6000 patients undergoing ERCP, found a similar frequency of PD among a heterogeneous group of GASTROINTESTINAL ENDOSCOPY
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patients with different pancreatic and biliary disorders. In those with acute and chronic pancreatitis, as well as patients with pancreatic neoplasms and nonpancreatic disorders, the mean frequency of PD was 5.9%.21 When patients were grouped by disorder, the frequency of PD was similar in each group and within the range for the general population. Similar findings are reported for smaller case series.22-26 Why are there such large discrepancies in the frequency of PD between case series? Delhaye and Cremer3 argue that referral bias plays a large role, with PD being diagnosed with greater frequency at tertiary centers in patients referred for endoscopic retrograde pancreatography after unsuccessful attempts to visualize the pancreatic ductal system in community institutions. They also cite additional observations as evidence against the obstructive hypothesis, including the absence of ductal dilation in most patients, and the mixed results in surgical and endoscopic series. PATIENT CHARACTERISTICS In the large retrospective series of Cotton,5 patients with PD undergoing evaluation for pancreatic disease were divided into groups based on clinical presentation and the likelihood of another explanation for pancreatitis. Nineteen patients had ARP and no other evident cause of pancreatitis, and 9 had pancreatictype pain, with no serologic or radiographic evidence of acute pancreatitis. Of the 19 patients with ARP, 9 had abnormal dorsal pancreatograms, with most having a normal ventral pancreatogram. By definition, those with pain alone had normal pancreatograms. Most patients with ARP and PD present during their adult life. The average age in the series of Cotton5 was 53 years, whereas, the average age of patients with pancreatic-type pain was 43 years. The length of time that patients had abdominal pain varied widely, from 1 to 20 years, but, on average, symptoms had been present for approximately 6 years before the diagnosis of PD. Because approximately a third of the patients with ARP had ductal changes by pancreatography, these patients could be classified as having chronic pancreatitis. Thus, possible clinical presentations of pancreatic disease associated with PD include ARP, chronic pancreatitis, and, finally, pancreatic-type pain with no objective findings of organic disease. These differences in patient characteristics are important when evaluating response to therapy, because there are significant differences in outcome in relation to presentation. Based on the series of Cotton,5 it appears that patients with pancreatic disease related to PD usually present with chronic symptoms during adult life. 422
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EVALUATION ERCP is the reference standard for the diagnosis of PD (Figs. 3 and 4). When cannulation of the major papilla reveals a short ventral duct, the possibility of PD must be considered. In patients with PD, the ventral duct is from 1 to 4 cm in length; the duct does not cross the midline.1 There generally is prompt drainage of contrast, and the morphology of the duct, including ductal branches, should appear normal. Aggressive injection of contrast medium may result in acinarization (widespread visualization of ductal structure to the level of the acinus). In about a third of cases, the ventral duct may be absent.27 In these cases, the ventral portion of the pancreas is drained by a branch of the dorsal duct. It is essential to rule out secondary ductal obstruction, especially that caused by malignancy, and, therefore, identification and cannulation of the minor papilla should be pursued to demonstrate the presence of a dominant dorsal duct. The technical aspects of minor papilla cannulation are outlined in detail in the review of Lehman and Sherman.1 The minor papilla generally is located superior and anterior to the major papilla, which corresponds to the upper right quadrant of the view field of a side-viewing duodenoscope. Placing the duodenoscope in the so-called long position, in which the insertion tube forms a large loop in the stomach, often facilitates cannulation. Although a standard tapered 5F catheter can be used, ideally, the catheter should be highly tapered; a 5F catheter with a much smaller diameter blunt needle at the tip is often useful, because the orifice of the minor papilla may be extremely small. Deep cannulation may be accomplished with a thin (0.018 inch) guidewire. The latter usually is necessary when therapeutic maneuvers are intended. When difficulty locating the minor papilla is encountered, secretin can be administered intravenously (0.25-1 IU) to stimulate the flow of pancreatic juice, with consequent widening of the papillary orifice. However, Lehman and Sherman1 caution that vigorous flow of pancreatic juice may make it difficult to inject contrast to the tail of the pancreas; they recommend that secretin be given only if necessary for identification of the minor papilla. If it is still difficult to locate the papilla, a dilute solution of methylene blue dye can be sprayed in the area likely to contain the papilla; with extended observation, the location may be revealed as the flow of pancreatic juice washes the dye away from the orifice. With use of the techniques and devices described above, cannulation is successful in the majority of patients. Failure is generally a result of VOLUME 60, NO. 3, 2004
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Figure 3. Retrograde pancreatogram showing typical normal dorsal pancreatic ductogram in patient with pancreas divisum. The appearance is similar to that of a normal ductogram obtained via injection of contrast at major papilla. Note endoscope in ‘‘long’’ position. (From Lehman, Feldman’s GastroAtlas Online. Available from: http://www.gastroatlas. com/.)
papillary and anatomical distortion caused by prior surgery or the presence of a diverticulum or malignancy. There was a correlation between ductal morphology and clinical presentation in the series of Lehman and Sherman.1 For example, among patients who presented with pancreatitis, 53% had an abnormal dorsal pancreatic ductogram. By comparison, 13% and 6% of patients who presented with pancreatictype pain alone and symptoms referable to the biliary tract, respectively, had abnormal dorsal pancreatic ducts. EUS can be used to evaluate the pancreas for evidence of PD. With the echoendoscope in the second portion of the duodenum, the uncinate process, the papilla, and the distal aspects of the bile and the pancreatic ducts may be visualized; the remainder of the head of the pancreas comes into view as the instrument tip is withdrawn to the duodenal bulb. If continuity cannot be demonstrated between the duct in the ventral portion of the gland and that in the dorsal aspect, PD may be present.28 In addition, a dominant dorsal duct also may be visualized. Conversely, if the ventral duct can be traced from the major papilla through the body and the tail, PD usually can be excluded.29 PD can be demonstrated noninvasively by MRCP, which has an accuracy similar to that of ERCP (Fig. 5).30 Imaging studies in the majority of patients with PD will demonstrate normal-appearing dorsal and ventral ducts, with no sign of pancreatitis. One strategy for the evaluation of these patients has been VOLUME 60, NO. 3, 2004
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Figure 4. Retrograde pancreatogram showing short ventral pancreatic duct, consistent with pancreas divisum; slight acinarization has occurred. (From Lehman, Feldman’s GastroAtlas Online. Available from: http://www.gastroatlas. com/.)
Figure 5. MRCP showing separate dorsal (arrowhead) and ventral (arrow) pancreatic ducts, consistent with pancreas divisum (from Matos C, Metens T, Deviere J, Delhaye M, Le Moine O, Cremer M. Pancreas divisum: evaluation with secretin-enhanced magnetic resonance cholangiopancreatography. Gastrointest Endosc 2001;53:728-33).
to identify the small subset with obstruction at the level of the minor papilla. Initially, there was substantial enthusiasm for measurement of the diameter of the dorsal duct ultrasonographically before and after secretin stimulation. When secretin is administered, the diameter of the pancreatic duct increases. However, prolongation of this widening could, in theory, be indicative of obstruction. Warshaw et al.31 defined prolonged dilation of the GASTROINTESTINAL ENDOSCOPY
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duct as that which persists from 15 to 30 minutes after secretin administration. These investigators then examined the ability of this test to predict the outcome of surgical sphincteroplasty in patients with recurrent pancreatitis and pancreatic-type pain. Among patients with a positive secretin stimulated US test, 92% had a satisfactory response to surgery. Unfortunately, these results were not reproducible in subsequent studies. Lowes et al.32 evaluated a heterogeneous group of 44 patients that included healthy control subjects and patients with PD who either had pancreatic symptoms or were asymptomatic. No correlation was found between ductal anatomy and the response to secretin. In fact, half of the normal control subjects had a positive test result. More recently, secretin-enhanced MRCP (SMRCP) has been used to evaluate patients with probable pancreatic disease. Matos et al.30 compared the results of S-MRCP in a heterogeneous group of patients suspected to have pancreatic disease. Not only was the frequency of PD similar across all subgroups, so was the response to secretin. S-MRCP did provide better images, but ductal dilation occurred with a similar frequency among the various patients, including those with and without PD. Sphincter manometry also has been used in an effort to better understand the function of the minor papilla. Satterfield et al.33 described 4 patients with PD and ARP who had minor papilla basal and phasic pressures that were similar to those recorded from the major papilla. These results differed from those of a prior study that found that pressures measured at the minor papilla were elevated in relation to those recorded from the major papilla.14 Unfortunately, there are few manometric studies of the minor papilla, largely because these are technically difficult to perform and parameters of ‘‘normal’’ have not been established. In summary, individuals with PD constitute a heterogeneous group. Most are asymptomatic, with PD being found only incidentally. However, some may develop an outflow obstruction at the minor papilla, with resulting pancreatitis. Although the diagnosis of PD is fairly straightforward, the demonstration of a causal relationship between the anomaly and pancreatic disease is more challenging but extremely important when evaluating potential candidates for invasive therapy. Patient selection and the outcomes of therapy will be discussed in part II of this review.
REFERENCES 1. Lehman GA, Sherman S. Diagnosis and therapy of pancreas divisum. Gastrointest Endosc Clin N Am 1998;8:55-77. 424
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2. Kasugai T, Kuno N, Kobayashi S, Hattori K. Endoscopic pancreatocholangiopathy. I. The normal endoscopic pancreatocholangiogram. Gastroenterology 1972;63:217-26. 3. Delhaye M, Cremer M. Clinical significance of pancreas divisum. Acta Gastroenterol Belg 1992;55:306-13. 4. Stern CD. A historical perspective on the discovery of the accessory duct of the pancreas, the ampulla of vater and pancreas divisum. Gut 1986;27:203-12. 5. Cotton PB. Congenital anomaly of pancreas divisum as cause of obstructive pain and pancreatitis. Gut 1980;21:105-14. 6. Gregg JA. Pancreas divisum: its association with pancreatitis. Am J Surg 1977;134:539-43. 7. Rosch W, Koch H, Schaffner O, Demling L. The clinical significance of the pancreas divisum. Gastrointest Endosc 1976;22:206-7. 8. Burtin P, Person B, Charneau J, Boyer J. Pancreas divisum and pancreatitis: a coincidental association? Endoscopy 1991; 23:55-8. 9. Kim MH, Lee SS, Kim CD, Lee SK, Kim HJ, Park HJ, et al. Incomplete pancreas divisum: is it merely a normal anatomic variant without clinical implication? Endoscopy 2001;33: 778-85. 10. Richter JM, Schapiro RH, Mulley AG, Warshaw AL. Association of pancreas divisum and pancreatitis and its treatment by sphincteroplasty of the accessory ampulla. Gastroenterology 1981;81:1104-10. 11. Sahel J, Cros RC, Bourry J, Sarles H. Clinico- pathological conditions associated with pancreas divisum. Digestion 1982;23:1-8. 12. Bernard JP, Sahel J, Giovannini M, Sarles H. Pancreas divisum is a probable cause of acute pancreatitis: a report of 137 cases. Pancreas 1990;5:248-54. 13. Schnelldorfer T, Adams DB. Outcome after lateral pancreaticojejunostomy in patients with chronic pancreatitis associated with pancreas divisum. Am Surg 2003;69:1041-6. 14. Cotton PB. Pancreas divisum [editorial]. Pancreas 1988;3: 245-7. 15. Staritz M, Meyer zum Buschenfelde KH. Elevated pressure in the dorsal part of pancreas divisum: the cause of chronic pancreatitis?. Pancreas 1988;3:108-10. 16. Muzaffar AR, Moyer MS, Dobbins J, Calhow CE, Gryboski JD, Shneider BL. Pancreas divisum in a family with hereditary pancreatitis. J Clin Gastroenterol 1996;22:16-20. 17. Eisen G, Schutz S, Metzler D, Baille J, Cotton PB. Santorinicele: new evidence for obstruction in pancreas divisum. Gastrointest Endosc 1994;40:73-6. 18. Forbes A, Leung JW, Cotton PB. Relapsing acute and chronic pancreatitis. Arch Dis Child 1984;59:927-34. 19. Shukri N, Wasa M, Hasegawa T, Okada A. Diagnostic significance of pancreas divisum in early life. Eur J Pediatr Surg 2000;10:12-6. 20. Yedlin ST, Dubois RS, Phillippart AI. Pancreas divisum: a cause of pancreatitis in childhood. J Pediatr Surg 1984;19: 793-4. 21. Delhaye M, Engelholm L, Cremer M. Pancreas divisum: controversial clinical significance. Dig Dis 1988;6:30-9. 22. Delhaye M, Engelholm L, Cremer M. Pancreas divisum: congenital anatomic variant or anomaly? Contribution of endoscopic retrograde dorsal pancreatograpy. Gastroenterology 1985;89:951-8. 23. Hayakawa T, Kondo T, Shibata T, Sugimoto Y, Kita-Gawa M, Suzuki T, et al. Pancreas divisum: a predisposing factor to pancreatitis? Int J Pancreatol 1989;5:317-26. VOLUME 60, NO. 3, 2004
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24. Mitchell CJ, Lintott DJ, Ruddell WSJ, Losowsky MS, Axon ATR. Clinical relevance of an unfused duct system. Gut 1979;20:1066-71. 25. Ott H, Ro¨sch W. The divided pancreas: a cause of pancreatitis? [German]. Med Welt 1983;34:466-8. 26. Sugawa C, Walt AJ, Nunez DC, Masuyama H. Pancreas divisum: is it a normal anatomic variant? Am J Surg 1987;153:62-7. 27. Benage D, McHenry R, Hawes RH, O’Connor KW, Lehman GA. Minor papilla cannulation and dorsal ductography in pancreas divisum. Gastrointest Endosc 1990;36:553-7. 28. Bhutani MS, Hoffman BJ, Hawes RH. Diagnosis of pancreas divisum by endoscopic ultrasonography. Endoscopy 1999;31: 550-3. 29. Sahai AV. EUS and chronic pancreatitis. Gastrointest Endosc 2002;56(Suppl 4):S76-81.
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30. Matos C, Metens T, Deviere J, Delhaye M, Le Moine O, Cremer M. Pancreas divisum: evaluation with secretinenhanced magnetic resonance cholangiopancreatography. Gastrointest Endosc 2001;53:728-33. 31. Warshaw AL, Simeone JF, Schapiro RH, Warshaw BF. Evaluation and treatment of the dominant dorsal duct syndrome (pancreas divisum redefined). Am J Surg 1990; 159:59-66. 32. Lowes JR, Lees WR, Cotton PB. Pancreatic duct dilatation after secretin stimulation in patients with pancreas divisum. Pancreas 1989;4:371-4. 33. Satterfield ST, McCarthy JH, Geenen JE, Hogan WJ, Venu RP, Dodds WJ, et al. Clinical experience in 82 patients with pancreas divisum: preliminary results of manometry and endoscopic therapy. Pancreas 1988;3:248-53.
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