Pancreatic Ductal Hypertension Research Articles

EUS 2008 Working Group document: evaluation of EUS-guided pancreatic-duct drainage (with video)

The principle of endotherapy in chronic pancreatitis is based on the premise that obstruction to the flow of pancreatic juice causes pancreatic-duct hypertension and increased pancreatic parenchymal pressures, which, in turn, induces pain. Strictures, stones, and a disrupted duct are the 3 main causes of obstruction in chronic pancreatitis. Apart from chronic pancreatitis, anastomotic stricture after a Whipple procedure can cause pancreatic-duct obstruction and lead to pain. Decompression of the obstructive pancreatic duct at ERCP leads to complete or partial relief of symptoms in 60% to 80% of patients. Patients who fail treatment by ERCP and those in whom ERCP is technically unsuccessful undergo surgery or are conservatively managed. Recently, EUS has been advocated as a rescue technique for management of patients in whom ERCP is technically unsuccessful. This section of the EUS 2008 Working Group Proceedings evaluates the current evidence and potential role of EUS in the management of symptomatic patients with obstructive pancreatic duct from benign causes in whom ERCP is technically unsuccessful.

Evidence of Notch pathway activation in the ectatic ducts of chronic pancreatitis

Ductal concretions in chronic pancreatitis (CP) are one of the causes of ductal obstruction, resulting in pancreatic ductal hypertension (PDH) and duct ectasia. Ductal epithelium subjected to chronic stress by PDH may undergo molecular alterations, thereby not only initiating and sustaining the inflammatory process but also activating molecules that have transforming potential. Acino-ductal metaplasia and pancreatic intraepithelial neoplasia (PanIN) are frequently seen in CP. Using laser capture microdissection, cDNA microarrays and Ingenuity Pathways Analysis, we found an altered Notch pathway in the ectatic ducts of CP. The microarray data was further validated by real-time PCR. We also found elevated transcripts of Notch receptors, Notch1 and Notch3 in microdissected ectatic ducts of CP. The Notch pathway ligands, Jagged/Delta-like and a Notch target, HES-related repressor protein (HERP), were up-regulated in ectatic compared to normal pancreatic ducts, while another target of Notch, hairy/enhancer of split (HES), was down-regulated. The transcripts of Delta-like1 and Jagged1 were increased 3.7-fold and 1.3-fold, respectively, while those of HERP1 were elevated 2.4-fold in the ectatic ducts of CP, compared to normal ducts. Immunohistochemistry showed that Jagged1 was not expressed in normal pancreatic ducts, while it was highly expressed in ectatic ducts. This pattern of Notch component alteration in ectatic ducts was mimicked to some extent in vitro in a human pancreatic duct epithelial (HPDE) cell line, when subjected to a pressure of 200 mmHg for 24 h. Therefore, we conclude that in the ectatic ducts of CP, PDH activates signalling pathways such as Notch, which have transforming potential.

EUS-guided pancreatogastrostomy and pancreatobulbostomy for the treatment of pain in patients with pancreatic ductal dilatation inaccessible for transpapillary endoscopic therapy

EUS-guided pancreatogastrostomy (EPG) is described as an alternative to surgery for ductal decompression in symptomatic patients when endoscopic transpapillary access of the main pancreatic duct (MPD) is impossible. To present the midterm clinical response and follow-up of a larger group of patients treated with EPG and a new transbulbar approach, EUS-guided pancreatobulbostomy (EPB). Retrospective case review. Two tertiary referral centers in Brussels and Marseille. From 2000 to 2004, 36 patients (51 years old; range, 14-71 years) were seen. EPG or EPB. Pain relief, technical aspects, complications, and clinical follow-up. Indications were chronic pancreatitis, with complete obstruction (secondary to a tight stenosis, a stone, or MPD rupture); inaccessible papilla or impossible cannulation (n = 20); anastomotic stenosis after a Whipple procedure (n = 12); complete MPD rupture after acute pancreatitis (AP); or trauma (n = 4). EPG or EPB was unsuccessful in 3 patients; 1 was lost to follow-up. Major complications occurred in 2 patients and included 1 hematoma and 1 severe AP. The median follow-up was 14.5 months (range, 4-55 months). Pain relief was complete or partial in 25 patients (69%, intention to treat). Eight patients treated had no improvement of their symptoms (4 were subsequently diagnosed with cancer). Stent dysfunction occurred in 20 patients (55%) and required a total of 29 repeat endoscopies. Technically demanding and requires careful pretherapeutic evaluation. EPG or EPB appears to be an effective and relatively safe treatment for the management of pain secondary to pancreatic ductal hypertension in patients with an MPD not accessible by a transpapillary route.

A new model of chronic pancreatitis in rats

This study was designed to examine whether continuous pancreatic ductal hypertension (PDH) plays an important role in the onset and development of chronic pancreatitis (CP). Pancreatic, biliary, and duodenal cannulas were implanted in male Wistar rats. PDH was induced by vertically raising the free end of the pancreatic duct cannula to exert a hydrostatic pressure and maintained for 2 wk. PDH was gradually increased, but when the pancreatic juice (PJ) flow was interrupted, PDH was decreased to restore PJ flow. The induction of PDH resulted in a marked reduction of amylase activity in PJ and an increase in serum amylase activity. At 2 wk after persistent PDH, pancreatic exocrine function was markedly decreased in response to a bolus injection of secretin (100 pmol/kg) compared with the control group. Histological examination revealed interlobular as well as intralobular fibrosis in the form of nodular pancreatitis at 2 wk after the induction of PDH. Immunohistochemistry revealed the expression of fibronectin and collagen types I and III. Quantitative real-time RT-PCR showed an increase in transforming growth factor-beta(1) mRNA expression in the pancreas during PDH. The present results suggest that PDH plays an important role in the onset and development of CP. Furthermore, our animal model seems useful for investigating the mechanisms of CP in rats.

ENDOSCOPIC APPROACH TO THE MINOR DUODENAL PAPILLA: SPECIAL EMPHASIS ON ENDOSCOPIC MANAGEMENT ON PANCREAS DIVISUM

Diagnostic and therapeutic approach to the minor duodenal papilla including standardized technique was reviewed. In cases in which a pancreatogram is not achieved or those in which only a small portion of the ductal anatomy is visualized via the major duodenal papilla, cannulation of the minor papilla provides a second route of access to the ductal system. Successful minor papilla cannulation requires meticulous attention to technique. As the orifice of the minor papilla is usually of pinpoint size, needle‐tipped catheters are useful. As minor papilla cannulation in pancreas divisum carries the risk of severe pancreatitis, the procedure should be performed with more caution. In some patients with pancreas divisum, an increased resistance to flow across the small orifice results in dorsal pancreatic duct hypertension and clinical symptoms including acute recurrent pancreatitis, chronic pancreatitis, and pancreatic‐type pain. Pancreas divisum patients with acute recurrent pancreatitis are the best candidates for endoscopic management for dorsal‐duct decompression including endoscopic minor papilla sphincterotomy and stenting.

Drainage operations in chronic pancreatitis.

If pancreatic ductal hypertension explained the pain of chronic pancreatitis, adequate decompression of ectatic ducts should provide lasting relief. We have analysed a personal series of 20 patients (14 men and 6 women) with chronic pancreatitis undergoing one or more drainage procedures. Alcohol was the main aetiological factor, and symptoms had been present for a median of 2.5 years. Pancreatic ductal decompression was achieved by pancreatic sphincteroplasty (n = 4) or longitudinal pancreaticojejunostomy (11). Thirteen patients underwent incidental or additional procedures to decompress the biliary tree: sphincteroplasty (5), choledochal bypass (7) and T-tube drainage (1). Cysts were either drained (7) or resected (3). Two patients required re-operation for subphrenic abscess. Some pancreatic insufficiency was detected preoperatively in 11 patients (exocrine 10, endocrine 4) and was essentially unchanged in all but one patient who came to total pancreatectomy. Two other patients required a coeliac plexus block, but the remaining 17 patients had good pain relief at a median follow-up of 30 months. Ductal drainage procedures effectively relieve the pain of chronic pancreatitis without further compromising pancreatic function.

Pancreatic duct pressure, duct permeability and acute pancreatitis

The relationship between pancreatic duct pressure, duct permeability to macromolecules and the development of acute pancreatitis was studied in a cat model. Perfusion of the pancreatic duct with 15 mM glycodeoxycholic acid, ethanol administration, or secretagogue-stimulated pancreatic secretion against greater than 50 per cent duct obstruction resulted in an increase in peak pancreatic duct pressure in all animals. Duct permeability to 20,000 molecular weight dextran molecules was increased in 22 of 29 experimental animals compared with two of 22 control animals (P less than 0.01). Perfusion of the pancreatic duct with activated pancreatic enzymes resulted in acute pancreatitis in 24 of 29 experimental animals compared with three of 22 control animals (P less than 0.01). These results suggest that pancreatic ductal hypertension, resulting in increased ductal permeability to large molecules, may be a common early event in gallstone and alcoholic pancreatitis.

Pancreatic Duct Stenting for Chronic Pancreatitis Pain

In patients with chronic pancreatitis, the aim of endoscopic therapy is to relieve pancreatic duct hypertension by decompressing the duct. In this

EUS-Guided Pancreatogastrostomy for the Treatment of Pain in Patients with Pancreatic Ductal Dilation Inaccessible for Transpapillary Endoscopic Therapy

Background and Aim: EUS guided-pancreatogastrostomy (EPG) has been described as an alternative to surgery for ductal decompression in symptomatic patients in whom endoscopic transpapillary access of the main pancreatic duct (MPD) is impossible. The aim of this study is to present the clinical response and follow-up of patients treated with EPG. Methods: Between 04/2000 and 07/2004, 28 patients underwent EPG for pancreatic ductal decompression in two interventional endoscopy referral centres. Technical aspects, pain relief, and follow up were retrospectively reviewed. Results: The indications for EPG were: chronic pancreatitis with complete obstruction secondary to stenosis or rupture of the MPD (n=15), anastomotic stenosis post- duodenopancreatectomy (n=12) and post-traumatic MPD rupture (n=1). The technique was unsuccessful in three patients one of which was lost to follow-up. Major complications occurred in three patients and included one hematoma and two episodes of acute pancreatitis. The median follow-up was 11 months (range 1-50 months). Pain relief was complete or partial in 20 patients (71%). Eight patients had no improvement of their symptoms but four were subsequently diagnose with cancer. Prosthesis dysfunction (migration, stenosis or fracture) occurred in ten (35%) patients. We were able to change the prosthesis in four of these cases. In the other four patients, two underwent repeat drainage procedure (one EPG and one EUS-guided pancreatobulbostomy) and two had the stents removed definitively due to lack of MPD dilation. Conclusion: EPG appears to be a safe and effective treatment for the management of pain and/or recurrent pancreatitis secondary to pancreatic ductal hypertension in patients with chronic pancreatitis or anastomotic stenosis post-duodenopancreatectomy. Background and Aim: EUS guided-pancreatogastrostomy (EPG) has been described as an alternative to surgery for ductal decompression in symptomatic patients in whom endoscopic transpapillary access of the main pancreatic duct (MPD) is impossible. The aim of this study is to present the clinical response and follow-up of patients treated with EPG. Methods: Between 04/2000 and 07/2004, 28 patients underwent EPG for pancreatic ductal decompression in two interventional endoscopy referral centres. Technical aspects, pain relief, and follow up were retrospectively reviewed. Results: The indications for EPG were: chronic pancreatitis with complete obstruction secondary to stenosis or rupture of the MPD (n=15), anastomotic stenosis post- duodenopancreatectomy (n=12) and post-traumatic MPD rupture (n=1). The technique was unsuccessful in three patients one of which was lost to follow-up. Major complications occurred in three patients and included one hematoma and two episodes of acute pancreatitis. The median follow-up was 11 months (range 1-50 months). Pain relief was complete or partial in 20 patients (71%). Eight patients had no improvement of their symptoms but four were subsequently diagnose with cancer. Prosthesis dysfunction (migration, stenosis or fracture) occurred in ten (35%) patients. We were able to change the prosthesis in four of these cases. In the other four patients, two underwent repeat drainage procedure (one EPG and one EUS-guided pancreatobulbostomy) and two had the stents removed definitively due to lack of MPD dilation. Conclusion: EPG appears to be a safe and effective treatment for the management of pain and/or recurrent pancreatitis secondary to pancreatic ductal hypertension in patients with chronic pancreatitis or anastomotic stenosis post-duodenopancreatectomy.

Prophylactic pancreatic duct stenting: a panacea?

Prophylactic pancreatic duct stenting: a panacea?

EUS-guided pancreaticogastrostomy

Background: The pain of chronic pancreatitis can be caused by pancreatic ductal hypertension, and endoscopic drainage of the main pancreatic duct can provide relief. When transpapillary access to a dilated portion of the main duct cannot be obtained, conventional endoscopic drainage is not possible. The use of interventional EUS to perform a pancreaticogastrostomy in such cases is described. Methods: Four patients presented with pain and a dilated main pancreatic duct proximal to a complete obstruction. EUS was used to access the dilated duct and create a pancreaticogastrostomy. Patency of the latter was maintained by placement of a pancreaticogastric stent. Observations: EUS-guided pancreaticogastrostomy was performed without major complication. Three of 4 patients had satisfactory relief of pain at a median follow-up of 1 year. Conclusion: EUS-guided pancreaticogastrostomy may be a promising new technique for pancreatic drainage and pain relief when conventional transpapillary access to the pancreatic duct is not possible.

The role of endoscopic retrograde cholangiopancreatography in acute and chronic pancreatitis.

Endoscopic retrograde cholangiopancreatography (ERCP) plays a pivotal role in the management of patients with acute and chronic pancreatitis. Whereas endoscopic observation during ERCP permits recognition of abnormalities involving the major and minor duodenal papillae such as papillary tumors or choledochocele, radiographic evaluation enables the detection of structural abnormalities of pancreaticobiliary ducts like strictures or calculi. Sphincter of Oddi manometry, a technical advance of ERCP, is essential for the diagnosis of sphincter of Oddi dysfunction, which may present clinically as recurrent pancreatitis. Because structural alterations of the pancreatic duct forms the hallmark of chronic pancreatitis, ERCP is highly sensitive and specific in diagnosing chronic pancreatitis. Apart from its diagnostic role, ERCP offers a variety of possibilities for therapeutic interventions in selected problems associated with pancreatitis. Endoscopic papillectomy and mucosal resection for tumors of the papilla, unroofing of a choledochocele, and sphincterotomy for sphincter ablation in sphincter of Oddi dysfunction are some of the therapeutic interventions possible during ERCP. Pancreatic ductal hypertension, which is considered to be the major pathophysiologic mechanism for disabling abdominal pain in chronic pancreatitis, also can be managed by ERCP-directed treatments. Pancreatic sphincterotomy, dilation of strictures, lithotripsy, extraction of calculi, and deployment of endoprosthesis constitute the commonly used therapeutic techniques in this situation. Besides offering a noninvasive alternative, these treatments are associated with a favorable clinical outcome comparable with that of operative treatments. Nevertheless, complications such as acute pancreatitis, bleeding, perforation, or sepsis may occur in 5% to 10% of patients undergoing these procedures. Therefore, careful selection of patients, appropriate preoperative care, and a team approach, including surgeon, interventional radiologist, and endoscopist, are important.

Pathophysiology of gallstone pancreatitis.

Gallstone pancreatitis was first recognized as an entity by Opie in 1901 (1), and since then has generated volumes of literature which have attempted to explain its pathophysiology. Multiple animal experiments and human clinical studies in the past thirty years have led to a better understanding of both macro- and microscopic events which lead to pancreatic inflammation in the setting of a passing or impacted gallstone. Evidence suggests that pancreatic duct outflow obstruction is the initial event. Several possible sequelae of duct obstruction, including refluxed biliary-pancreatic secretions, pancreatic duct hypertension, and/or aberrant acinar cell secretion may result in pancreatic duct injury and release of pancreatic enzymes into the glandular interstitium, thus triggering a bout of acute pancreatitis. The details of many events related to gallstone pancreatitis remain unclear; this chapter attempts to present the pathophysiology of this disease as it is known today. Additionally, clinical presentation and treatment of gallstone pancreatitis will be reviewed briefly.

Acute Pancreatitis Complicating Polya Gastrectomy-Reply

We appreciate McCutcheon's interest in our article on the phenomenon of acute pancreatitis after gastrectomy. 1 We are aware of the older literature on the occasional causation of pancreatitis by the pathologic anatomy of a Polya anastomosis, which is liable to cause afferent loop obstruction by kinking or excessive bending. That mechanism is akin to, but different from, the specific strictures located at a point proximal to and separate from the anastomosis (Polya or Hofmeister) to which we called attention. We suggested that these very localized strictures may have been caused by injury from the application of bowel clamps to prevent spillage of intestinal contents during the gastrojejunal anastomoses. We agree that the pathogenesis of pancreatitis in both instances is most likely due to a closed duodenal loop that promotes both pancreatic duct hypertension and reflux of duodenal contents, including enterokinase that is the natural activator of trypsinogen.

Acute Pancreatitis: ERCPand Papillotomy

Endoscopic treatment of acute biliary pancreatitis is restricted to the treatment of bile duct stones. Three prospective randomized trials demonstrate the superiority of early ERCP/papillotomy (within 96 h) over conservative treatment of severe acute biliary pancreatitis, as well as safety and effectivity of the endoscopic procedure. The timing of the early ERCP/papillotomy (emergency vs. within 96 h) is at discussion. Although no significant benefit of immediate and early ERCP/papillotomy over the conservative approach has been shown in cases of predicted mild acute pancreatitis, the Hong Kong group advocates this procedure independent of the severity of the disease. We prefer this latter approach because potentially lethal complications are treated in time, papillotomy prevents further ampullary occlusion by stones and may early relieve pancreatic duct hypertension.

Chronic Obstructive Pancreatitis as a Delayed Complication of Pancreatic Trauma

Increasing surgical experience with the immediate consequences of pancreatic injuries has resulted from parallel growth in the volume of motor vehicle accidents and societal violence. However, few surgeons are aware that complications may be considerably delayed following pancreatic trauma, occurring in some cases months to years after apparent recovery from the original injury. In four patients with blunt pancreatic trauma initially treated by non-operative means, stricture of the main pancreatic duct developed over a period of months as a result of progressive fibrosis at the site of ductal injury. Pancreatic duct hypertension was demonstrated to be present in the obstructed duct, and secondary changes of chronic pancreatitis developed in the obstructed segment of the gland (“upstream” chronic pancreatitis). Seven similar patients with delayed onset of chronic obstructive pancreatitis after pancreatic trauma were found in the literature. Symptoms related to these acquired ductal strictures are most commonly those of abdominal pain and recurrent episodes of acute pancreatitis. Recognition of post-traumatic chronic obstructive pancreatitis principally involves awareness that injuries to the pancreatic duct can produce remote complications. Pancreatoenteric drainage, or resection of the obstructed segment of pancreas, provides prompt and effective relief.

Pancreatic duct pressure in chronic pancreatitis

The wide variety of surgical procedures available for the relief of pain in patients with chronic pancreatitis attests to a lack of understanding of the precise mechanisms responsible for the onset of pain in this condition. In the development of surgical procedures designed to “decompress” the pancreatic duct in chronic pancreatitis, it has been tacitly assumed that pancreatic duct hypertension exists and is important in the pathophysiology of the disease. In 19 patients with chronic pancreatitis and dilated pancreatic ducts, pancreatic duct pressure was significantly higher than in control patients. In view of the dramatic relief of preoperative pain after procedures for decompressing the pancreatic ducts, ductal hypertension has been confirmed as an important mechanism of pain production in this group of patients.

A study of the cholinesterases of the canine pancreatic sphincters and the relationship between reduced butyrylcholinesterase activity and pancreatic ductal hypertension.

Previous work from this laboratory revealed in increased canine pancreatic intraductal pressure following cholinesterase inhibitor intoxication. The pressure was negatively correlated with serum butyrylcholinesterase (BChE) activity, suggesting that BChE activity mediated the pressure rise. This study uses a histochemical technique to investigate the tissue cholinesterase activity of the canine pancreatic sphincters and the effect of a cholinesterase inhibitor (ChEI) on tissue cholinesterase activity. In five control dogs, serial sections of the major and minor spincters were stained for acetylcholinesterase (AChE) and BChE activity. Four treated dogs were given the ChEI, O,O-diethyl-O- (2-isopropyl-6-methyl-4-pyrimidinyl) phosphoro-thioate, 25 mg/kg, one hour prior to excising the ampullae. In the control dogs, BChE activity is present in the periampullary nerves and the pancreatic smooth muscle sphincters. AChE activity is present in nerves but not in smooth muscle. In the treated group, following a dose of ChEI known to cause ductal hypertension, BChE activity was absent in the pancreatic sphincters but AChE activity was preserved in the periampullary nerves. These data suggest that the pancreatic ductal hypertension that occurs following ChEI administration is due to a selective reduction in pancreatic smooth muscle BChE activity.

A Study of the Cholinesterases of the Canine Pancreatic Sphincters and the Relationship Between Reduced Butyrylcholinesterase Activity and Pancreatic Ductal Hypertension

A Study of the Cholinesterases of the Canine Pancreatic Sphincters and the Relationship Between Reduced Butyrylcholinesterase Activity and Pancreatic Ductal Hypertension

Use of carbonic anhydrase inhibitor in the treatment of pancreatitis.

Carbonic anhydrase inhibitors have been shown to effectively reduce the volume of pancreatic secretion. Pancreatic duct hypertension, resulting from the combination of ductal obstruction and exocrine hypersecretion, appears to play an important role in the pathogenesis of pancreatitis. With ductal hypertension, enzymes enter the interstitial tissues of the pancreas and initiate an acute inflammatory response which may vary from simple edema to necrosis.