After all these years of SOD and endotherapy – how far have we come? The role of endoscopic treatment for acute recurrent pancreatitis (ARP) with sphincter of Oddi dysfunction (SOD)

• Retrospective endoscopic studies
• Prospective endoscopic studies
• References

The etiology of acute pancreatitis can be determined in the majority of patients. Alcohol and gallstones account for 60 % – 90 % of cases. Other causes include hypertriglyceridemia, hypercalcemia, drug reactions, trauma, genetics, neoplasia, surgery, endoscopic retrograde cholangiopancreatography (ERCP), etc. However, despite a careful history, physical examination, laboratory testing, and radiological evaluation, 10 % – 30 % of cases will have no obvious etiology and will be labeled as idiopathic acute pancreatitis (IAP) [1] [2] [3]. Patients with recurrent episodes of IAP are classified as having idiopathic acute recurrent pancreatitis (IARP). A structural cause for IARP will be found in the majority of patients who are further investigated with endoscopic ultrasound (EUS), ERCP with sphincter of Oddi manometry (SOM), bile crystal analysis (for those with the gallbladder in situ), and magnetic resonance imaging/cholangiopancreatography. The literature shows that sphincter of Oddi dysfunction (SOD) is the most frequent cause of IARP. Using ERCP with SOM as the gold standard for diagnosis, SOD has been manometrically documented in 15 % – 72 % of such patients [4] [5] [6] [7] [8] [9] [10] [11].

The pathogenesis of SOD relates to either an anatomic obstruction at the sphincter of Oddi caused by fibrosis and/or inflammation, or to a functional (”dyskinetic”) obstruction caused by sphincter muscle spasm. This results in elevation of pancreatic sphincter pressure and has been shown to correlate with increased intrapancreatic ductal pressure, presumably playing a role in the pathogenesis of pancreatitis [12]. However, elevated pancreatic basal sphincter of Oddi pressure and concomitant elevated pancreatic duct pressure are found in patients with pain only and no prior evidence of pancreatitis, arguing that it is not the sole determinant of pancreatitis.

Previous studies in which biliary (BES), pancreatic (PES) or dual biliary and pancreatic sphincter ablation (DES) were performed surgically [6] [13] [14] or endoscopically [9] [10] [15] [16] [17] [18] [19] [20] [21] for IARP due to SOD have shown a decreased incidence of future attacks of pancreatitis, and it appears that pancreatic SOD plays a role in the pathogenesis of recurrent attacks even if it was not the original cause. In recent years endoscopic therapy has become the treatment of choice over surgery for SOD. The decision on whether to perform BES alone, PES alone or DES was based on results of the SOM findings and/or the discretion of the physician in both the retrospective and prospective studies. Overall data in these studies seem to suggest that DES resulted in a lower recurrence rate compared with BES or PES ablation alone.

Retrospective endoscopic studies

Sherman et al. [9] reported no recurrence of pancreatitis after biliary sphincterotomy alone in 44 % of SOD patients with IARP who were followed up for 5 years. In the endoscopy arm, Toouli et al. [6] found that only two out of seven patients (29 %) were asymptomatic at 24 months following BES. Guelrud et al. [16] showed that BES alone may be an insufficient therapy for IARP patients with pancreatic SOD as a result of residual pancreatic sphincter hypertension. Sherman et al. have shown that biliary sphincteroplasty does not alter the pancreatic sphincter pressure. This makes anatomic sense, as the pancreatic and biliary sphincters are separate. In the study by Guelrud, 28 % of IARP patients with pancreatic SOD treated by BES alone had no further episodes of pancreatitis during a 1-year follow-up period compared with 77 % treated by BES followed by PES in separate sessions, and 86 % treated by DES in the same session. Okolo et al. [17] followed up patients who had undergone PES for IARP and pancreatic SOD for a median of 16 months (range 3 – 52 months) and reported a 73 % response to therapy in patients with normal pancreatogram and 58 % of patients with chronic pancreatitis on pancreatography. Park et al. examined the outcome of endoscopic therapy in SOD patients with initial pancreatic sphincter hypertension (with or without biliary sphincter hypertension) [20]. Patients were followed for a mean of 43.1 months (range 11 – 77 months); re-intervention was offered for sustained or recurrent symptoms at a median of 8 months after initial therapy. Performance of an initial dual pancreatobiliary sphincterotomy was associated with a lower re-intervention rate (70 / 285, 24.6 %) compared with biliary sphincterotomy alone (31 / 95, 33 %; P < 0.05). However, this study did not mention the number of patients with documented acute pancreatitis

Prospective endoscopic studies

Wehrmann et al. [18] showed that eight of nine patients (89 %) treated with DES for pancreatic SOD and IARP had improvement over a median period of 21 months (range 6 – 33 months). Kaw and Brodmerkel [10] showed that 42 of 52 patients (81 %) treated with DES (some had BES alone) were asymptomatic after a mean of 32 months (range 18 – 33 months).

Wehrmann et al. [21] prospectively evaluated the feasibility of botulinum toxin injection in 15 patients with SOD and IARP. A total of 12 patients (80 %) remained asymptomatic at 3-month follow-up but 11 developed a relapse at a follow-up period of 6 ± 2 months. These patients underwent PES or DES with subsequent remission after a median follow-up of 15 months. This study showed that injection of botulinum toxin is safe, may be effective in the short term, and may predict the outcome from pancreatic sphincter ablation in patients having frequent episodes of pancreatitis; however, the need for definitive sphincter ablation in most patients limits its clinical use.

Jacob et al. [22] postulated that SOD might cause recurrent episodes of pancreatitis, even when SOM was normal, and pancreatic stent placement might prevent further attacks. In a randomized study, 34 patients with IARP, normal SOM and pancreatic duct on ERCP, secretin testing, and no biliary crystals were treated with pancreatic stents (n = 19; 5 – 7 Fr, with stents exchanged three times over a 1-year period) or conservative therapy (n = 15). During a 3-year follow-up, pancreatitis recurred in 53 % of the patients in the control group and in only 11 % of the stented patients (P < 0.02). This study suggests that SOM may be an imperfect test because patients with SOD may not be detected at the time of SOM. However, long-term studies are needed to evaluate the outcome after removal of stents, and concern remains regarding stent-induced ductal and parenchymal changes.

Although the above studies suggest that endoscopic therapy may benefit a majority of patients with IARP due to SOD, there are many limitations that need to be emphasized.

(1) The majority of published studies are retrospective and suffer from incomplete follow-up, lack homogeneity of patient selection for therapy, and are not blinded or compared with an untreated group.

(2) Uncontrolled prospective studies are prone to bias. The natural history of recurrent acute pancreatitis is variable without a predictable onset or severity. Without a control group it is uncertain whether treatment has truly improved the course of the disease. Thus, the best study design to determine the true efficacy of endoscopic therapy for SOD would be a randomized controlled trial.

(3) The length of follow-up of most studies is less than 3 years. As noted, the natural history of IARP is unpredictable. If a patient has an attack at 12 years and 2 weeks prior to an endoscopic intervention and is asymptomatic at 1-year follow-up, it would not be possible to say the patient is ”cured.” That patient may have an attack the next week, the next year or never. Thus, the short follow-up may result in an underestimate of the true recurrence rates.

(4) There are differences in defining study outcomes. Authors have used different outcomes including, documented recurrent pancreatitis, need for re-intervention or a grading system of no relief, good relief to complete relief of symptoms. This makes assessing response to endoscopic therapy difficult to analyze.

(5) Lack of a homogeneous population of IARP patients treated may impact the results of therapy. There is significant variability among (and within) studies as to how detailed the pre-treatment evaluation was. Were serum triglyceride levels routinely drawn on admission? Was a genetic evaluation done (e. g. were patients assessed for mutations of the CFTR, PRSS1, and SPINK1 genes)? How detailed was the evaluation in patients with the gallbladder in situ – was bile evaluated by microscopy for crystals; was an EUS done? Patients with suspected IARP who actually have microlithiasis should have resolution of their pancreatitis with a BES. This may in part explain why earlier studies showed that biliary sphincterotomy alone was effective in preventing recurrent acute pancreatitis in some patients, as EUS was not used routinely to exclude the presence of microlithiasis or sludge. Was SOM done to define the endoscopic approach? Many studies did not use SOM so it is unclear whether or not pancreatic sphincter hypertension was present. Other factors that may impact the outcome of therapy include the presence of chronic pancreatitis. Some studies describe poorer response rates in patients with chronic pancreatitis (based on pancreatogram findings) and SOD who undergo endoscopic therapy. There is a possibility that some patients with IARP may actually have early chronic pancreatitis. Finally it is unlikely that IARP patients with a dilated pancreatic duct are the ”same” as patients with normal-diameter pancreatic ducts. Confounding factors such as alcohol and tobacco use are not controlled for in the reported retrospective and prospective studies.

(6) Variable interventions are utilized. As noted, the studies varied as to whether a BES, PES or DES was done. In fact, in several studies patients underwent one or more of these therapies and it is not clear why the particular therapy was chosen. The completeness of sphincter ablation is often not determined; if the sphincter is not ablated then a suboptimal outcome can be anticipated.

In this issue of Endoscopy, Wehrmann [23] attempts to clarify the issue of long-term follow-up after endoscopic therapy in IARP patients with manometrically documented pancreatic SOD. A total of 48 patients with at least two prior episodes of IARP during a 12-month period were entered into a prospective study of endoscopic therapy of SOD and followed for 2 years when the study was terminated. In total, 37 of these patients were successfully contacted more than 10 years later to assess their benefit from therapy, using a written structured questionnaire and information provided by their primary physician. Patients underwent a variety of therapies including BES (n = 3), PES (n = 10), and DES (n = 24). During the prospective portion of the study, five of 37 patients (14 %) experienced a recurrent attack of pancreatitis during a mean duration of 32.4 months (range 24 – 53 months). In the retrospective re-evaluation of these patients 19 of 37 (51 %) had at least one further episode of pancreatitis during the follow-up period of 11.5 ± 1.6 years. The frequency of pancreatitis episodes, however, was lower after therapy (0.65 ± 0.7; range 0 – 2) than prior to endoscopic therapy (2.5 ± 0.5; range 2 – 4). The authors concluded that endoscopic sphincter ablation seems to be an effective treatment strategy in patients with documented SOD by slowing the natural progression of the disease.

The authors should be complimented on their efforts to try to clarify whether the short-term benefits of endoscopic sphincterotomy reported in prior studies are durable. However, this study suffers from many of the limitations highlighted above. This was a retrospective study and the patients treated were not homogeneous: 34 of the original 48 still had their gallbladders; the pancreatic ducts were dilated in 20 of 37 patients; the endoscopic therapies varied. It is unclear how the author excluded microlithiasis. Early chronic pancreatitis was not excluded – EUS was not routinely carried out and other testing that was used to exclude chronic pancreatitis are relatively insensitive to detect early-stage disease. Genetic testing was done on only eight patients. At the very least we learned from Wehrmann that there is a high rate of recurrent pancreatitis during long-term follow-up in patients treated by endoscopic sphincter ablation.

We are left with many unanswered questions that are fertile for research. Such questions include: 1) What is the natural history of this disease? Is it a precursor of chronic pancreatitis in many patients? 2) What evaluation should be done before taking on the significant risks of ERCP, manometry, and sphincterotomy? [24] 3) What is the best therapy for these patients? 4) Should patients have their gallbladder removed before endoscopic interventions are done? 5) Do the results of SOM predict outcome from sphincter ablation? Only well-designed randomized controlled trials with long-term follow-up will help answer some of these questions. Until then, the benefits of endoscopic sphincter ablation therapy should be considered unproven.

Competing interests: None

References

• 1 Grendell J H. Idiopathic acute pancreatitis.  Gastroenterol Clin North Am. 1990;  19 843-848
  PubMedSearch in Google Scholar
• 2 Ballinger A B, Barnes E, Alstead E M et al. Is intervention necessary after a first episode of acute idiopathic pancreatitis?.  Gut. 1996;  38 293-295
  CrossrefPubMedSearch in Google Scholar
• 3 Levy M J, Geenen J E. Idiopathic acute recurrent pancreatitis.  Am J Gastroenterol. 2001;  96 2540-2555
  CrossrefPubMedSearch in Google Scholar
• 4 Choudari C P, Fogel E L, Sherman S et al. Idiopathic pancreatitis: yield of ERCP correlated with patient age.  Am J Gastroenterol. 1998;  93 1654A
  PubMedSearch in Google Scholar
• 5 Venu R P, Geenen J E, Hogan W et al. Idiopathic recurrent pancreatitis: an approach to diagnosis and treatment.  Dig Dis Sci. 1989;  34 56-60
  CrossrefPubMedSearch in Google Scholar
• 6 Toouli J, Francesco V, Saccone G et al. Division of sphincter of Oddi for treatment of dysfunction associated with recurrent pancreatitis.  Br J Surg. 1996;  83 1205-1210
  CrossrefPubMedSearch in Google Scholar
• 7 Guelrud M, Mendoz S, Viera L. Idiopathic recurrent pancreatitis and hypercontractile sphincter of Oddi. Treatment with endoscopic sphincterotomy and pancreatic duct dilation.  Gastroenterology. 1986;  90 1443
  PubMedSearch in Google Scholar
• 8 Gregg J A. Function and dysfunction of the sphincter of Oddi.. In: Jacobson I M, ed. ERCP: diagnostic and therapeutic applications.. New York: Elsevier; 1989: 137-170
  Search in Google Scholar
• 9 Sherman S, Jamidar P, Reber H. Idiopathic acute pancreatitis (IAP): endoscopic diagnosis and therapy.  Am J Gastroenterol. 1993;  88 1541A
  PubMedSearch in Google Scholar
• 10 Kaw M, Brodmerkel G J. ERCP, biliary crystal analysis, and sphincter of Oddi manometry in idiopathic pancreatitis.  Gastrointest Endosc. 2002;  55 157-162
  CrossrefPubMedSearch in Google Scholar
• 11 Fischer M, Hassan A, Sipe B W et al. Endoscopic retrograde cholangiopancreatography and manometry findings in 1,241 idiopathic pancreatitis patients.  Pancreatology. 2010;  10 444-452
  CrossrefPubMedSearch in Google Scholar
• 12 Fazel A, Geenen J E, MoezArdalan K, Catalano M F. Intrapancreatic ductal pressure in sphincter of Oddi dysfunction.  Pancreas. 2005;  30 359-362
  CrossrefPubMedSearch in Google Scholar
• 13 Sherman S, Hawes R H, Madura J A, Lehman G A. Comparison of intraoperative and endoscopic manometry of the sphincter of Oddi.  Surg Gynecol Obstet. 1992;  175 410-418
  PubMedSearch in Google Scholar
• 14 Madura J A, Madura 2nd J A, Sherman S, Lehman G A. Surgical sphincteroplasty in 446 patients.  Arch Surg. 2005;  140 504-511; discussion 511 – 513
  CrossrefPubMedSearch in Google Scholar
• 15 Lans J L, Parikh N P, Geenen J E. Applications of sphincter of Oddi manometry in routine clinical investigations.  Endoscopy. 1991;  23 139-143
  Thieme ConnectPubMedSearch in Google Scholar
• 16 Guelrud M, Plaz J, Mendoza S et al. Endoscopic treatment in Type II pancreatic sphincter dysfunction.  Gastrointest Endosc. 1995;  41 A398
  PubMedSearch in Google Scholar
• 17 Okolo P I, Pasricha P J, Kalloo A N. What are the long-term results of endoscopic pancreatic sphincterotomy.  Gastrointest Endosc. 2000;  52 15-19
  Search in Google Scholar
• 18 Wehrmann T, Zipf A, Caspary W F, Jung M. [Sphincter of Oddi dysfunction in ”idiopathic” recurrent pancreatitis.] Article in German.  Dtsch Med Wochenschr. 1996;  121 781-787
  Thieme ConnectPubMedSearch in Google Scholar
• 19 Coyle W J, Pineau B C, Tarnasky P R et al. Evaluation of unexplained acute and acute recurrent pancreatitis using endoscopic retrograde cholangiopancreatography, sphincter of Oddi manometry, and endoscopic ultrasound.  Endoscopy. 2002;  34 617-623
  Thieme ConnectPubMedSearch in Google Scholar
• 20 Park S H, Watkins J L, Fogel E L et al. Long-term outcome of endoscopic dual sphincterotomy in patients with manometry-documented sphincter of Oddi dysfunction and normal pancreatogram.  Gastrointest Endosc. 2003;  57 483-491
  CrossrefPubMedSearch in Google Scholar
• 21 Wehrmann T, Schmitt T H, Arndt A et al. Endoscopic botulinum toxin injection for treatment of idiopathic recurrent pancreatitis due to sphincter of Oddi dysfunction.  Aliment Pharmacol Therap. 2000;  14 1469-1477
  CrossrefPubMedSearch in Google Scholar
• 22 Jacob L, Geenen J E, Catalano M F et al. Prevention of pancreatitis in patients with idiopathic recurrent pancreatitis: a prospective, non-blinded randomized study using endoscopic stents.  Endoscopy. 2001;  33 559-562
  Thieme ConnectPubMedSearch in Google Scholar
• 23 Wehrmann T. Long-term results (≥ 10 years) of endoscopic therapy for sphincter of Oddi dysfunction in patients with acute recurrent pancreatitis.  Endoscopy. 2011;  43 202-207
  Thieme ConnectPubMedSearch in Google Scholar
• 24 Freeman M L, DiSario J A, Nelson D B et al. Risk factors for post-ERCP pancreatitis: a prospective multicenter study.  Gastrointest Endosc. 2001;  54 425-434
  CrossrefPubMedSearch in Google Scholar

Stuart ShermanMD 

Division of Gastroenterology and Hepatology
Indiana University School of Medicine

550N University Boulevard
UH 4100
Indianapolis
Indiana
USA

Fax: +1-317-9681066

Email: ssherman@iupui.edu

References

• 1 Grendell J H. Idiopathic acute pancreatitis.  Gastroenterol Clin North Am. 1990;  19 843-848
  PubMedSearch in Google Scholar
• 2 Ballinger A B, Barnes E, Alstead E M et al. Is intervention necessary after a first episode of acute idiopathic pancreatitis?.  Gut. 1996;  38 293-295
  CrossrefPubMedSearch in Google Scholar
• 3 Levy M J, Geenen J E. Idiopathic acute recurrent pancreatitis.  Am J Gastroenterol. 2001;  96 2540-2555
  CrossrefPubMedSearch in Google Scholar
• 4 Choudari C P, Fogel E L, Sherman S et al. Idiopathic pancreatitis: yield of ERCP correlated with patient age.  Am J Gastroenterol. 1998;  93 1654A
  PubMedSearch in Google Scholar
• 5 Venu R P, Geenen J E, Hogan W et al. Idiopathic recurrent pancreatitis: an approach to diagnosis and treatment.  Dig Dis Sci. 1989;  34 56-60
  CrossrefPubMedSearch in Google Scholar
• 6 Toouli J, Francesco V, Saccone G et al. Division of sphincter of Oddi for treatment of dysfunction associated with recurrent pancreatitis.  Br J Surg. 1996;  83 1205-1210
  CrossrefPubMedSearch in Google Scholar
• 7 Guelrud M, Mendoz S, Viera L. Idiopathic recurrent pancreatitis and hypercontractile sphincter of Oddi. Treatment with endoscopic sphincterotomy and pancreatic duct dilation.  Gastroenterology. 1986;  90 1443
  PubMedSearch in Google Scholar
• 8 Gregg J A. Function and dysfunction of the sphincter of Oddi.. In: Jacobson I M, ed. ERCP: diagnostic and therapeutic applications.. New York: Elsevier; 1989: 137-170
  Search in Google Scholar
• 9 Sherman S, Jamidar P, Reber H. Idiopathic acute pancreatitis (IAP): endoscopic diagnosis and therapy.  Am J Gastroenterol. 1993;  88 1541A
  PubMedSearch in Google Scholar
• 10 Kaw M, Brodmerkel G J. ERCP, biliary crystal analysis, and sphincter of Oddi manometry in idiopathic pancreatitis.  Gastrointest Endosc. 2002;  55 157-162
  CrossrefPubMedSearch in Google Scholar
• 11 Fischer M, Hassan A, Sipe B W et al. Endoscopic retrograde cholangiopancreatography and manometry findings in 1,241 idiopathic pancreatitis patients.  Pancreatology. 2010;  10 444-452
  CrossrefPubMedSearch in Google Scholar
• 12 Fazel A, Geenen J E, MoezArdalan K, Catalano M F. Intrapancreatic ductal pressure in sphincter of Oddi dysfunction.  Pancreas. 2005;  30 359-362
  CrossrefPubMedSearch in Google Scholar
• 13 Sherman S, Hawes R H, Madura J A, Lehman G A. Comparison of intraoperative and endoscopic manometry of the sphincter of Oddi.  Surg Gynecol Obstet. 1992;  175 410-418
  PubMedSearch in Google Scholar
• 14 Madura J A, Madura 2nd J A, Sherman S, Lehman G A. Surgical sphincteroplasty in 446 patients.  Arch Surg. 2005;  140 504-511; discussion 511 – 513
  CrossrefPubMedSearch in Google Scholar
• 15 Lans J L, Parikh N P, Geenen J E. Applications of sphincter of Oddi manometry in routine clinical investigations.  Endoscopy. 1991;  23 139-143
  Thieme ConnectPubMedSearch in Google Scholar
• 16 Guelrud M, Plaz J, Mendoza S et al. Endoscopic treatment in Type II pancreatic sphincter dysfunction.  Gastrointest Endosc. 1995;  41 A398
  PubMedSearch in Google Scholar
• 17 Okolo P I, Pasricha P J, Kalloo A N. What are the long-term results of endoscopic pancreatic sphincterotomy.  Gastrointest Endosc. 2000;  52 15-19
  Search in Google Scholar
• 18 Wehrmann T, Zipf A, Caspary W F, Jung M. [Sphincter of Oddi dysfunction in ”idiopathic” recurrent pancreatitis.] Article in German.  Dtsch Med Wochenschr. 1996;  121 781-787
  Thieme ConnectPubMedSearch in Google Scholar
• 19 Coyle W J, Pineau B C, Tarnasky P R et al. Evaluation of unexplained acute and acute recurrent pancreatitis using endoscopic retrograde cholangiopancreatography, sphincter of Oddi manometry, and endoscopic ultrasound.  Endoscopy. 2002;  34 617-623
  Thieme ConnectPubMedSearch in Google Scholar
• 20 Park S H, Watkins J L, Fogel E L et al. Long-term outcome of endoscopic dual sphincterotomy in patients with manometry-documented sphincter of Oddi dysfunction and normal pancreatogram.  Gastrointest Endosc. 2003;  57 483-491
  CrossrefPubMedSearch in Google Scholar
• 21 Wehrmann T, Schmitt T H, Arndt A et al. Endoscopic botulinum toxin injection for treatment of idiopathic recurrent pancreatitis due to sphincter of Oddi dysfunction.  Aliment Pharmacol Therap. 2000;  14 1469-1477
  CrossrefPubMedSearch in Google Scholar
• 22 Jacob L, Geenen J E, Catalano M F et al. Prevention of pancreatitis in patients with idiopathic recurrent pancreatitis: a prospective, non-blinded randomized study using endoscopic stents.  Endoscopy. 2001;  33 559-562
  Thieme ConnectPubMedSearch in Google Scholar
• 23 Wehrmann T. Long-term results (≥ 10 years) of endoscopic therapy for sphincter of Oddi dysfunction in patients with acute recurrent pancreatitis.  Endoscopy. 2011;  43 202-207
  Thieme ConnectPubMedSearch in Google Scholar
• 24 Freeman M L, DiSario J A, Nelson D B et al. Risk factors for post-ERCP pancreatitis: a prospective multicenter study.  Gastrointest Endosc. 2001;  54 425-434
  CrossrefPubMedSearch in Google Scholar

Stuart ShermanMD 

Division of Gastroenterology and Hepatology
Indiana University School of Medicine

550N University Boulevard
UH 4100
Indianapolis
Indiana
USA

Fax: +1-317-9681066

Email: ssherman@iupui.edu