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Endotherapy of early onset idiopathic chronic pancreatitis: Results with long-term follow-up
Endotherapy of early onset idiopathic chronic pancreatitis: results with long-term follow-up Armando Gabbrielli, MD, Massimiliano Mutignani, MD, Monica Pandolfi, MD, Vincenzo Perri, MD, Guido Costamagna, MD Rome, Italy
Background: Idiopathic chronic pancreatitis that presents at age 35 years or younger has been classified as early onset type and is often characterized by chronic severe pain. Endotherapy, with drainage of the main pancreatic duct, can lead to control of pain if ductal hypertension is an important cause. Long-term results of endotherapy in patients with early onset idiopathic chronic pancreatitis are reported herein. Methods: This retrospective study consists of 11 patients (6 men, 5 women; mean age 24.2 years, range 16-34 years) treated endoscopically in a 6.5-year period. The indication for treatment was pain in all patients and all had a dilated main pancreatic duct on pancreatography. The objectives of endoscopic treatment were to obtain good drainage of the pancreatic duct and complete clearance of ductal stones. Results: Treatment was successful in all patients with no procedure-related mortality and with mild complications. Seven patients remained free of pain relapses after a mean follow-up of 78.3 months (37-116 months). Seven relapses of pain were recorded in the remaining 4 patients. Endoscopic retreatment was successful in all cases. The difference between the number of hospitalizations during the year before treatment (mean 2.2, range 1-9) and the year after (mean 0.3, range 0-2) was statistically significant (p < 0.01). Statistical significance was maintained at 3 and 6 years’ follow-up. Conclusions: Endoscopic treatment could be regarded as the initial management of choice for patients with early onset idiopathic chronic pancreatitis. (Gastrointest Endosc 2002;55:488-93.)
Few studies have dealt specifically with idiopathic chronic pancreatitis (ICP).1-3 Amman et al.2 found several differences between ICP and alcoholinduced chronic pancreatitis (ACP). Layer et al.1 distinguished 3 forms of chronic pancreatitis: early onset ICP (onset at <35 years of age), late onset ICP (>35 years of age) and ACP. The presentation and natural histories differ among the 2 forms of ICP and ACP. Patients with early onset ICP initially have severe pain and thereafter a long course of severe pain, but the rate of development of morphologic and functional pancreatic damage is extremely slow. Patients with late onset ICP have a mild and often pain-free course. The two forms differ from ACP in that the gender distribution is equal and the rate of development of calcification is much slower. In the series of Layer et al.1 significantly more Received January 12, 2001. For revision April 11, 2001. Accepted August 8, 2001. From the Department of Digestive Diseases, Libera Università, Campus Bio Medico, and the Digestive Endoscopy Unit, Department of Surgery, Università Cattolica del Sacro Cuore, Roma, Italy. Reprint requests: Armando Gabbrielli, MD, Dipartimento Malattie Apparato Digerente, Libera Università Campus Bio Medico, Via Longoni 83, 00155, Roma, Italy. Copyright © 2002 by the American Society for Gastrointestinal Endoscopy 0016-5107/2002/$35.00 + 0 37/1/122651 doi:10.1067/mge.2002.122651 488
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patients with early onset ICP underwent surgery, intractable pain being the reason in all cases. The origin of pancreatic pain in patients with chronic pancreatitis is probably multifactorial, although increased pressure within the main pancreatic duct (MPD) must be considered an important cause.4,5 The surgical approach of choice consists of drainage of the dilated pancreatic duct. It has also been suggested that resectional surgery should be avoided to preserve, as far as possible, remaining function, especially in young patients. Therapeutic endoscopy offers several modalities for pancreatic duct drainage: endoscopic pancreatic sphincterotomy (EPS), stone removal, extracorporeal shock-wave lithotripsy (ESWL) in case of pancreatic duct stones unextractable by endoscopic techniques alone, and insertion of a pancreatic stent for strictures of the distal MPD.6-13 The results of endoscopic treatment in a highly selected subgroup of patients with early onset ICP are reported herein. PATIENTS AND METHODS Between November 1989 and April 1997 eleven patients (6 men, 5 women; mean age 24.2 years, range 1634 years) with early onset ICP were identified as being treated endoscopically. The diagnosis of chronic pancreatitis was based on medical history, presence of pancreatic calcifications, and characteristic findings on ERCP.14,15 VOLUME 55, NO. 4, 2002
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Patients in the pediatric age range (<14 years) with symptoms were excluded. Patients with hereditary pancreatitis (as determined by family history), those with preexisting disorders likely to cause chronic pancreatitis (hypertriglyceridemia, primary hyperparathyroidism, abdominal trauma, and pancreatic duct stenosis secondary to operation), and patients in whom excessive alcohol consumption could not be absolutely ruled out were also excluded. The median interval between the onset of symptoms and endoscopic treatment was 5 years (range 3 months to 10 years). The indication for treatment was pain in all cases: relapsing pain (interval between pain attacks >15 days) in 10 patients and continuous pain in 1 patient. Four patients (36.3%) also had recurrent attacks of acute pancreatitis defined as severe abdominal pain unresponsive to therapy with conventional analgesics, elevation of serum pancreatic enzymes, and the need for hospitalization. Seven patients were being treated continuously with nonsteroidal anti-inflammatory drugs (NSAIDs). All patients had been hospitalized at other institutions at least once (mean 5.7 times, range 1-27 times) before endoscopic treatment. The mean number of hospitalizations during the 12-month period before treatment was 2.2 (range 1-9). Two patients (18.1%) had undergone cholecystectomy. Weight loss (mean 5.4 kg, range 210 kg) was noted in 8 patients (72.7%). Clinically, one patient had steatorrhea and one noninsulin-dependent diabetes. Pre-ERCP evaluation included standard blood tests, US, and CT of the upper abdomen. ERCP was performed with standard duodenoscopes (TJF-100, TJF-130; Olympus Optical Co., Ltd. Tokyo, Japan) with the patient under conscious sedation with intravenously administered diazepam (10-20 mg) or midazolam (1-5 mg). Duodenal motility was inhibited with repeated intravenous injections of hyoscine N-butyl bromide (60-120 mg). In selected cases (dilation of pancreatic stricture, previous intolerance to endoscopic procedure), fentanyl (0.050.1 mg) was also given intravenously. All patients undergoing endotherapy had a dilated MPD as demonstrated by pancreatography. Dilation was defined according to reported normal parameters for MPD diameter (3 mm to 4 mm in the head, decreasing to 2 mm to 3 mm in the body and 1 mm to 2 mm in the tail).16,17 The mean MPD diameter in the study patients, measured in the body of the pancreas and corrected for magnification, was 7.4 mm (range 4-11 mm); 2 patients had a diameter of greater than 8 mm. Pancreatographic findings were classified according to Cremer et al.15: type IV pancreatitis (MPD obstruction in head with upstream dilation) was diagnosed in 10 cases (90.9%) and type V (comFigure 1. Pancreatograms obtained in a patient with Type IV idiopathic chronic pancreatitis before and after endotherapy. A, dilated main pancreatic duct containing a floating stone; B, pancreatogram after pancreatic sphincterotomy and 1 session of ESWL showing extraction of stone fragments with balloon catheter. C, Pancreatogram obtained after endotherapy showing reduction in diameter of the main duct, complete clearance of stones, and good ductal drainage. VOLUME 55, NO. 4, 2002
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Figure 2. Follow-up in 11 patients treated endoscopically for early onset idiopathic chronic pancreatitis. plete MPD obstruction in head) in 1 case. An anatomically normal pancreatic ductal arrangement was present in 10 patients, whereas 1 patient had pancreas divisum. Pancreatic stones were observed in 6 cases (54.5%). Stones were calcified in 3 patients and multiple in 3 patients. All stones were located in the head of the gland. The objectives of the endoscopic treatment were to decompress the MPD and to obtain good ductal drainage with complete duct clearance of stones (Fig. 1). Biliary sphincterotomy was performed before EPS to separate the 2 orifices and facilitate access to the pancreatic duct. EPS was performed after deep cannulation of the MPD by means of a guidewire. Section of the pancreatic sphincter was performed under direct vision by using pure cutting electrosurgical current and was extended to the duodenal wall. The same technique was used for minor papilla sphincterotomy. In case of pancreatic stones unextractable from the MPD, ESWL was performed with an electromagnetic lithotriptor (Siemens Lithostar Plus, Erlangen, Germany) with a bidimensional x-ray focusing system. The ESWL technique for pancreatic stones is described elsewhere.12,13 After EPS a nasopancreatic drainage (NPD) was inserted for a mean period of 4 days (range 2-6 days) in 10 patients (90.9%). In all patients the NPD was used to facilitate drainage of the MPD after EPS. In 5 patients an NPD was also used to improve stone targeting and to perfuse the duct with saline solution (1000 mL/day) to increase the efficacy of ESWL and induce spontaneous passage of fragments into the duodenum. Data were analyzed with the Friedman test (nonparametric analysis of variance for repeated measures), followed by Wilcoxon t test for preplanned pairwise comparisons.
RESULTS Endotherapy was technically successful in all patients. EPS was attempted 12 times (9 major papilla, 3 minor papilla), and was successful in all 490
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11 patients. Pancreatic drainage was obtained through the minor papilla in 3 patients: 1 with pancreas divisum and 2 with a dominant dorsal duct. ESWL was required in 5 of 6 patients with pancreatic stones (2 noncalcified stones) (83.3%). EPS was performed before and after ESWL, respectively, in 3 and 2 cases. The mean number of ESWL sessions was 2 (range 1-3) and the mean number of shockwaves per patient was 4470 (range 2500-7000). Only 1 of 10 sessions had to be discontinued because of bradycardia and pain. Fragmentation of stones, clearance, and decompression of the MPD were obtained in all patients treated with ESWL. Active extraction of stone fragments with Dormia baskets or balloon catheters was performed in 4 of 5 patients. In 1 patient the fragments migrated spontaneously after EPS. Complete clearance of the MPD was confirmed by pancreatography performed by means of the NPD. In 1 patient with a stricture of the distal MPD, treatment was completed with the insertion of a plastic 11.5F, 5-cm long pancreatic stent (Wilson-Cook Medical, Inc. Winston-Salem, N.C.). There was no procedure-related mortality. Amylase and lipase levels were not routinely determined after treatment. Complications developed in 4 patients (36.3%): 3 had fever with leucocytosis, twice after ESWL, and 1 developed acute cholecystitis. All complications were successfully treated with conservative measures. It was possible to discontinue therapy with NSAIDs in all patients. Steatorrhea disappeared in the only affected patient. No patient was lost to follow-up. Patients were evaluated clinically every 3 months by telephone calls and clinic visits. Routine laboratory tests and abdominal US were obtained every 6 months. ERCP, abdominal US, and CT were performed in case of a relapse of pain. Follow-up data are shown in Fig 2. Mean follow-up was 78.3 months (range 37-116). Seven patients (all with type IV chronic pancreatitis (6 with relapsing and 1 with continuous pain) were pain free at a mean follow-up of 77.7 months (range 37-116 months). One of these patients presented after 4 months with hematemesis caused by bleeding gastric fundal varices, a result of splenic vein thrombosis, and subsequently underwent splenectomy at another institution. A total of 7 episodes of pain recurrence were recorded in the remaining 4 patients over a mean follow-up of 79.5 months (range 54-106 months). ERCP was repeated in all cases within a few days. Causes of recurrent pain were (1) stenosis of the pancreatic sphincterotomy at the minor papilla in 1 case 6 months after EPS; (2) a new stricture of the distal pancreatic duct in 2 patients 2 and 7 months, respectively, after initial treatment; (3) migration of VOLUME 55, NO. 4, 2002
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pancreatic stones from secondary ducts in 1 case after 82 months; and (4) 3 instances of pancreatic stent occlusion in 2 patients. In the patient in whom a stent was inserted during the initial treatment, clogging occurred after 48 months. In the second patient, the pancreatic stent had been inserted during follow-up because of a stricture of the distal MPD; the stent occluded twice, once at 13 and again at 37 months. The mean time until clogging of pancreatic duct stents was recognized clinically was 32.6 months (range 13-48 months). The time to clogging was defined clinically and stent patency was objectively delineated only if there was a relapse of pain. Endoscopic retreatment was successful in all patients with relapsing symptoms and consisted of repeat sphincterotomy, stent insertion for strictures, exchange of occluded stents, and extraction of pancreatic stones. In 2 patients pancreatic strictures resolved, respectively, after 18 and 24 months of stent placement. A mean increase in weight of 6 kg (range 2-10 kg) was observed in the 8 patients who had lost weight before endoscopic treatment. The mean number of hospitalizations after the endoscopic treatment was 0.6 (range 0-3) and 0.3 (range 0-2) during the first year after treatment. The difference in number of hospitalizations during the year before (mean 2.2, range 1-9) and after treatment was statistically significant (p < 0.01) (Fig 3). The frequency of hospitalization pretreatment and posttreatment was also significantly different for both the 3-year and 6-year follow-up periods for which data were available, respectively, for 11 and 7 patients (3 years p < 0.001; 6 years p < 0.001). DISCUSSION According to Layer et al.,1 patients with ICP can be divided into 2 distinct groups based on age of onset: one in which onset is early, under 35 years of age, and one in which ICP presents late, after 35 years of age. Patients in the former group have pain initially and a long course characterized by severe pain, but morphologic and functional damage to the pancreas develops slowly. Those with the late onset form of ICP have a mild course, often without pain. The slow destruction of the parenchyma and late development of exocrine insufficiency and calcifications in patients with early onset ICP may explain why diagnosis is delayed and difficult. The time lapse between onset of symptoms and diagnosis averaged 5 years in the present study and ranged from 3 months to 10 years. Moreover, significantly more patients in the early onset ICP group undergo surgery compared with the late onset ICP group (60% vs. 32%), intractable pain being the indication for operation in all cases.1 VOLUME 55, NO. 4, 2002
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Figure 3. Number of hospitalizations per patient during 1year periods before and after endoscopic treatment: the difference between number of hospitalizations during the year before and that after treatment is statistically significant (Wilcoxon t test; p < 0.01).
The large percentage of patients with early onset ICP who underwent traditional surgery in the study of Layer et al.1 and the good results in terms of pain relief obtained with endoscopic treatment in patients with chronic pancreatitis 6,8,10-13 induced us to study retrospectively the efficacy of endoscopic treatment in this group of patients. To our knowledge, no data are available on endoscopic treatment of patients with early onset ICP. The results of the present study indicate that endoscopic treatment is highly effective short-, medium-, and long-term in selected patients. Endoscopic treatment should be reserved for patients with a dilated MPD. Magnetic resonance cholangiopancreatography (MRCP), now the noninvasive imaging modality of choice for the pancreas, allows selection of patients who might benefit from GASTROINTESTINAL ENDOSCOPY
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endoscopic treatment.18,19 Intravenous administration of secretin (S-MRCP), which stimulates secretion by the exocrine pancreas of fluid and bicarbonate, enhances visualization of the pancreatic ducts, including the minimally dilated secondary ducts found in the initial stages of chronic pancreatitis. Furthermore, functional studies can be performed to quantitate duodenal filling before and after secretin stimulation.20 The effectiveness of endotherapy must be correlated with the ability to achieve decompression and clearance of stones from the MPD. ESWL is a complementary technique: 83% of patients with stones in the present study required ESWL to facilitate stone extraction. Endoscopic treatment yields results that are similar to those of surgery, both for complete and partial relief of pain, with no mortality and a morbidity rate that compares favorably with surgical series. The surgical operations comparable with endotherapy are drainage procedures, such as the Partington-Rochelle (latero-lateral pancreatico-jejunostomy procedure), that are predicated on the presence of a markedly dilated MPD. In these series, short-term pain relief is achieved in about 80% of patients and operation carries low morbidity and mortality rates (0%-5%). Series with long-term follow-up show that pain commonly recurs; pain relief persists for more than 2 years in only 60% of patients.21-28 A randomized trial of endoscopy versus surgery would be of considerable interest. However it is extremely difficult to randomize patients to two treatments that have such different levels of invasiveness, as noted by Cotton.29 Furthermore Cotton believes that most of our knowledge of effectiveness does and will come from nonrandomized studies, in which precise definitions for each element are used, as suggested by the statement of the American Gastroenterological Association on treatment of patients with pain caused by chronic pancreatitis.29,30 The efficacy of endoscopic treatment was further confirmed in the present study by the statistically significant difference between rates of hospitalization during the year before and at 1, 3, and 6 years after endoscopic treatment. The number of hospitalizations appears to be an objective method of analyzing the effectiveness of endotherapy for relief of pain. Furthermore, a mean follow-up of 6 years should be adequate to confirm treatment efficacy, even in patients with relapsing pain. Moreover, recurrences of pain were successfully managed endoscopically in all cases. The possibility of repeated treatment is another advantage of endoscopic therapy for ICP. Endotherapy does not preclude subsequent surgery, should this become necessary. 492
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To our knowledge, no data are available on surgical or endoscopic treatments in patients with early onset ICP. This is the first study of the efficacy of endotherapy in this highly select subgroup of patients. More long-term studies are needed to assess the effects of this treatment on endocrine and exocrine function, especially in extremely young patients. Of interest in future prospective randomized studies will be an analysis of the efficacy of endotherapy in modifying the natural history during the initial stages of ICP. Endotherapy could be regarded as the initial treatment of choice for patients with early onset ICP. ACKNOWLEDGEMENT We thank Antonello Persico for statistical analysis. REFERENCES 1. Layer P, Yamamoto H, Kalthoff L, Clain JE, Bakken LJ, Di Magno EP. The different courses of early and late onset idiopathic and chronic pancreatitis. Gastroenterology 1994;107: 1481-7. 2. Amman RW, Buehler H, Freiburghaus AW, Siegenthaler W. Differences in the natural history of idiopathic (nonalcoholic) and alcoholic chronic pancreatitis. A comparative long-term study of 287 patients. Pancreas 1987;2:368-77. 3. Lankisch PG, Seidensticker F, Lohr-Happe A, Otto J, Oreutzfeldt W. The course of pain is the same in alcohol and nonalcohol-induced chronic pancreatitis. Pancreas 1995;10: 338-41. 4. Ebbehoj N, Borly L, Bulow J, Rasmussen SG, Madsen P. Evaluation of pancreatic tissue fluid pressure and pain in chronic pancreatitis. A longitudinal study. Scand J Gastroenterol 1990;25:462-6. 5. Okazaki K, Yamamoto Y, Ito K. Endoscopic measurement of papillary sphincter zone and pancreatic main ductal pressure in patients with chronic pancreatitis. Gastroenterology 1986;91:409-18. 6. Cremer M, Devière J, Delhaye M, Vandermeeren A, Baize M. Non surgical management of severe chronic pancreatitis. Scand J Gastroenterol 1990;25(Suppl 175):77-84. 7. Huibregtse K, Schneider B, Vrij AA, Tytgat G. Endoscopic pancreatic drainage in chronic pancreatitis. Gastrointest Endosc 1988;34:9-15. 8. Kozarek RA, Ball TJ, Patterson DJ, Brandabur JJ, Traverso LW, Raltz S. Endoscopic pancreatic duct sphincterotomy: indications, technique and results. Gastrointest Endosc 1994;40: 592-8. 9. Kozarek RA, Patterson DJ, Ball TJ. Endoscopic placement of pancreatic stent and drains in the management of pancreatitis. Ann Surg 1988;209:261-6. 10. Smits ME, Badiga SM, Rauws EAJ, Tytgat G, Huibregtse K. Long term results of pancreatic stents in chronic pancreatitis. Gastrointest Endosc 1995;42:461-7. 11. Binmoeller KF, Jue P, Seifert H, Nam WC, Izbicki J, Soehendra N. Endoscopic pancreatic stent drainage in chronic pancreatitis and a dominant stricture: long-term results Endoscopy 1995;27:638-44. 12. Delhaye M, Vandermeeren A, Baize M, Cremer M. Extracorporeal shock wave lithotripsy of pancreatic calculi. Gastroenterology 1992;102:610-20. 13. Costamagna G, Gabbrielli A, Mutignani M, Perri V, Pandolfi M, Boscaini M, et al. Extracorporeal shock wave lithotripsy of VOLUME 55, NO. 4, 2002
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pancreatic stones in chronic pancreatitis. Immediate and medium term results. Gastrointest Endosc 1997;46:231-6. Axon ATR, Classen M, Cotton PB, Cremer M, Freeny PC, Less WR. Pancreatography in chronic pancreatitis: international definition. Gut 1984;25:1107-11. Cremer M, Toussaint J, Hermanus A, Deltenre M, De Toeuf J, Engelholm L. Les pancréatites chroniques primitives. Classification sur la base de la pancréatographie endoscopique [French]. Acta Gastroenterol Belg 1976;39:522-46. Siegel HJ. Radiologic interpretation. In: Siegel HJ, editor. Endoscopic retrograde cholangiopancreatography: technique, diagnosis, and therapy. New York: Raven Press; 1992. p. 4158. Hastier P, Buckley MJM, Dumas R, Kuhdorf H, Staccini P, Demarquay P, et al. A study of the effect of age on pancreatic duct morphology. Gastrointest Endosc 1998;48:53-7. Matos C, Metens T, Devière J, Nicaise N, Braudh P, Van Yperen, et al. Pancreatic duct: morphologic and functional evaluation with dynamic MR pancreatography after secretin stimulation. Radiology 1997;203:435-41. Manfredi R, Costamagna G, Brizi MG, Maresca G, Vecchioli A, Colagrande C, et al. Severe chronic pancreatitis versus suspected pancreatic disease: dynamic MR cholangiopancreatography after secretin stimulation. Radiology 2000;214:849-55. Delhaye M, Cappeliez O, Nicaise N, Metens T, Le Moine O, Devière J, et al. Pancreatic exocrine function: evaluation with secretin-enhanced MR pancreatography [abstract]. Gut 1999;5:A68.
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21. Frey CH. The surgical treatment of chronic pancreatitis. In: Go VLW, Di Magno EP, editors. The pancreas: biology, pathobiology and disease. New York: Raven Press; 1993. p. 707-40. 22. Ebbehoj N, Boryl L, Bulow J, Rasmussen SG, Madsen P. Evaluation of pancreatic tissue fluid pressure and pain in chronic pancreatitis. Scand Gastroenterol 1990;25:462-6. 23. Prinz RA, Greenlee HB. Pancreatic duct drainage in 100 with chronic pancreatitis. Ann Surg 1981;194:313-2. 24. Holmberg JT, Isaksson G, Ihse I. Long-term results of pancreaticojejunostomy in chronic pancreatitis. Surg Gynecol Obstet 1985;160:339-46. 25. Adolff M, Schloegel M, Arnaud JP, Ollier JCL. Role of pancreaticojejunostomy in the treatment of chronic poancreatitis: study of 105 operated patients. Chirurgie 1991;117:251-7. 26. Wilson TG, Hollands MJ, Little JM. Pancreaticojejunostomy for chronic pancreatitis. Aust N Z J Surg 1992;62:111-5. 27. Bradley EL. Long-term results of pancreatojejunostomy in patients with chronic pancreatitis. Am J Surg 1987;153:207-13. 28. Warshaw AL, Banks PA, Fernandez-del Castillo C. AGA technical review: treatment of pain in chronic pancreatitis. Gastroenterology 1998;115:765-76. 29. Cotton PB. Randomization is not the (only) answer: a plea for structured objective evaluation of endoscopic therapy. Endoscopy 2000;32:402-5. 30. American Gastroenterological Association. American Gastroenterological Association Medical Position Statement: treatment of pain in chronic pancreatitis. Gastroenterology 1998; 115:763-4.
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Background: Idiopathic chronic pancreatitis that presents at age 35 years or younger has been classified as early onset type and is often characterized by chronic severe pain. Endotherapy, with drainage of the main pancreatic duct, can lead to control of pain if ductal hypertension is an important cause. Long-term results of endotherapy in patients with early onset idiopathic chronic pancreatitis are reported herein. Methods: This retrospective study consists of 11 patients (6 men, 5 women; mean age 24.2 years, range 16-34 years) treated endoscopically in a 6.5-year period. The indication for treatment was pain in all patients and all had a dilated main pancreatic duct on pancreatography. The objectives of endoscopic treatment were to obtain good drainage of the pancreatic duct and complete clearance of ductal stones. Results: Treatment was successful in all patients with no procedure-related mortality and with mild complications. Seven patients remained free of pain relapses after a mean follow-up of 78.3 months (37-116 months). Seven relapses of pain were recorded in the remaining 4 patients. Endoscopic retreatment was successful in all cases. The difference between the number of hospitalizations during the year before treatment (mean 2.2, range 1-9) and the year after (mean 0.3, range 0-2) was statistically significant (p < 0.01). Statistical significance was maintained at 3 and 6 years’ follow-up. Conclusions: Endoscopic treatment could be regarded as the initial management of choice for patients with early onset idiopathic chronic pancreatitis. (Gastrointest Endosc 2002;55:488-93.)
Few studies have dealt specifically with idiopathic chronic pancreatitis (ICP).1-3 Amman et al.2 found several differences between ICP and alcoholinduced chronic pancreatitis (ACP). Layer et al.1 distinguished 3 forms of chronic pancreatitis: early onset ICP (onset at <35 years of age), late onset ICP (>35 years of age) and ACP. The presentation and natural histories differ among the 2 forms of ICP and ACP. Patients with early onset ICP initially have severe pain and thereafter a long course of severe pain, but the rate of development of morphologic and functional pancreatic damage is extremely slow. Patients with late onset ICP have a mild and often pain-free course. The two forms differ from ACP in that the gender distribution is equal and the rate of development of calcification is much slower. In the series of Layer et al.1 significantly more Received January 12, 2001. For revision April 11, 2001. Accepted August 8, 2001. From the Department of Digestive Diseases, Libera Università, Campus Bio Medico, and the Digestive Endoscopy Unit, Department of Surgery, Università Cattolica del Sacro Cuore, Roma, Italy. Reprint requests: Armando Gabbrielli, MD, Dipartimento Malattie Apparato Digerente, Libera Università Campus Bio Medico, Via Longoni 83, 00155, Roma, Italy. Copyright © 2002 by the American Society for Gastrointestinal Endoscopy 0016-5107/2002/$35.00 + 0 37/1/122651 doi:10.1067/mge.2002.122651 488
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patients with early onset ICP underwent surgery, intractable pain being the reason in all cases. The origin of pancreatic pain in patients with chronic pancreatitis is probably multifactorial, although increased pressure within the main pancreatic duct (MPD) must be considered an important cause.4,5 The surgical approach of choice consists of drainage of the dilated pancreatic duct. It has also been suggested that resectional surgery should be avoided to preserve, as far as possible, remaining function, especially in young patients. Therapeutic endoscopy offers several modalities for pancreatic duct drainage: endoscopic pancreatic sphincterotomy (EPS), stone removal, extracorporeal shock-wave lithotripsy (ESWL) in case of pancreatic duct stones unextractable by endoscopic techniques alone, and insertion of a pancreatic stent for strictures of the distal MPD.6-13 The results of endoscopic treatment in a highly selected subgroup of patients with early onset ICP are reported herein. PATIENTS AND METHODS Between November 1989 and April 1997 eleven patients (6 men, 5 women; mean age 24.2 years, range 1634 years) with early onset ICP were identified as being treated endoscopically. The diagnosis of chronic pancreatitis was based on medical history, presence of pancreatic calcifications, and characteristic findings on ERCP.14,15 VOLUME 55, NO. 4, 2002
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Patients in the pediatric age range (<14 years) with symptoms were excluded. Patients with hereditary pancreatitis (as determined by family history), those with preexisting disorders likely to cause chronic pancreatitis (hypertriglyceridemia, primary hyperparathyroidism, abdominal trauma, and pancreatic duct stenosis secondary to operation), and patients in whom excessive alcohol consumption could not be absolutely ruled out were also excluded. The median interval between the onset of symptoms and endoscopic treatment was 5 years (range 3 months to 10 years). The indication for treatment was pain in all cases: relapsing pain (interval between pain attacks >15 days) in 10 patients and continuous pain in 1 patient. Four patients (36.3%) also had recurrent attacks of acute pancreatitis defined as severe abdominal pain unresponsive to therapy with conventional analgesics, elevation of serum pancreatic enzymes, and the need for hospitalization. Seven patients were being treated continuously with nonsteroidal anti-inflammatory drugs (NSAIDs). All patients had been hospitalized at other institutions at least once (mean 5.7 times, range 1-27 times) before endoscopic treatment. The mean number of hospitalizations during the 12-month period before treatment was 2.2 (range 1-9). Two patients (18.1%) had undergone cholecystectomy. Weight loss (mean 5.4 kg, range 210 kg) was noted in 8 patients (72.7%). Clinically, one patient had steatorrhea and one noninsulin-dependent diabetes. Pre-ERCP evaluation included standard blood tests, US, and CT of the upper abdomen. ERCP was performed with standard duodenoscopes (TJF-100, TJF-130; Olympus Optical Co., Ltd. Tokyo, Japan) with the patient under conscious sedation with intravenously administered diazepam (10-20 mg) or midazolam (1-5 mg). Duodenal motility was inhibited with repeated intravenous injections of hyoscine N-butyl bromide (60-120 mg). In selected cases (dilation of pancreatic stricture, previous intolerance to endoscopic procedure), fentanyl (0.050.1 mg) was also given intravenously. All patients undergoing endotherapy had a dilated MPD as demonstrated by pancreatography. Dilation was defined according to reported normal parameters for MPD diameter (3 mm to 4 mm in the head, decreasing to 2 mm to 3 mm in the body and 1 mm to 2 mm in the tail).16,17 The mean MPD diameter in the study patients, measured in the body of the pancreas and corrected for magnification, was 7.4 mm (range 4-11 mm); 2 patients had a diameter of greater than 8 mm. Pancreatographic findings were classified according to Cremer et al.15: type IV pancreatitis (MPD obstruction in head with upstream dilation) was diagnosed in 10 cases (90.9%) and type V (comFigure 1. Pancreatograms obtained in a patient with Type IV idiopathic chronic pancreatitis before and after endotherapy. A, dilated main pancreatic duct containing a floating stone; B, pancreatogram after pancreatic sphincterotomy and 1 session of ESWL showing extraction of stone fragments with balloon catheter. C, Pancreatogram obtained after endotherapy showing reduction in diameter of the main duct, complete clearance of stones, and good ductal drainage. VOLUME 55, NO. 4, 2002
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Figure 2. Follow-up in 11 patients treated endoscopically for early onset idiopathic chronic pancreatitis. plete MPD obstruction in head) in 1 case. An anatomically normal pancreatic ductal arrangement was present in 10 patients, whereas 1 patient had pancreas divisum. Pancreatic stones were observed in 6 cases (54.5%). Stones were calcified in 3 patients and multiple in 3 patients. All stones were located in the head of the gland. The objectives of the endoscopic treatment were to decompress the MPD and to obtain good ductal drainage with complete duct clearance of stones (Fig. 1). Biliary sphincterotomy was performed before EPS to separate the 2 orifices and facilitate access to the pancreatic duct. EPS was performed after deep cannulation of the MPD by means of a guidewire. Section of the pancreatic sphincter was performed under direct vision by using pure cutting electrosurgical current and was extended to the duodenal wall. The same technique was used for minor papilla sphincterotomy. In case of pancreatic stones unextractable from the MPD, ESWL was performed with an electromagnetic lithotriptor (Siemens Lithostar Plus, Erlangen, Germany) with a bidimensional x-ray focusing system. The ESWL technique for pancreatic stones is described elsewhere.12,13 After EPS a nasopancreatic drainage (NPD) was inserted for a mean period of 4 days (range 2-6 days) in 10 patients (90.9%). In all patients the NPD was used to facilitate drainage of the MPD after EPS. In 5 patients an NPD was also used to improve stone targeting and to perfuse the duct with saline solution (1000 mL/day) to increase the efficacy of ESWL and induce spontaneous passage of fragments into the duodenum. Data were analyzed with the Friedman test (nonparametric analysis of variance for repeated measures), followed by Wilcoxon t test for preplanned pairwise comparisons.
RESULTS Endotherapy was technically successful in all patients. EPS was attempted 12 times (9 major papilla, 3 minor papilla), and was successful in all 490
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11 patients. Pancreatic drainage was obtained through the minor papilla in 3 patients: 1 with pancreas divisum and 2 with a dominant dorsal duct. ESWL was required in 5 of 6 patients with pancreatic stones (2 noncalcified stones) (83.3%). EPS was performed before and after ESWL, respectively, in 3 and 2 cases. The mean number of ESWL sessions was 2 (range 1-3) and the mean number of shockwaves per patient was 4470 (range 2500-7000). Only 1 of 10 sessions had to be discontinued because of bradycardia and pain. Fragmentation of stones, clearance, and decompression of the MPD were obtained in all patients treated with ESWL. Active extraction of stone fragments with Dormia baskets or balloon catheters was performed in 4 of 5 patients. In 1 patient the fragments migrated spontaneously after EPS. Complete clearance of the MPD was confirmed by pancreatography performed by means of the NPD. In 1 patient with a stricture of the distal MPD, treatment was completed with the insertion of a plastic 11.5F, 5-cm long pancreatic stent (Wilson-Cook Medical, Inc. Winston-Salem, N.C.). There was no procedure-related mortality. Amylase and lipase levels were not routinely determined after treatment. Complications developed in 4 patients (36.3%): 3 had fever with leucocytosis, twice after ESWL, and 1 developed acute cholecystitis. All complications were successfully treated with conservative measures. It was possible to discontinue therapy with NSAIDs in all patients. Steatorrhea disappeared in the only affected patient. No patient was lost to follow-up. Patients were evaluated clinically every 3 months by telephone calls and clinic visits. Routine laboratory tests and abdominal US were obtained every 6 months. ERCP, abdominal US, and CT were performed in case of a relapse of pain. Follow-up data are shown in Fig 2. Mean follow-up was 78.3 months (range 37-116). Seven patients (all with type IV chronic pancreatitis (6 with relapsing and 1 with continuous pain) were pain free at a mean follow-up of 77.7 months (range 37-116 months). One of these patients presented after 4 months with hematemesis caused by bleeding gastric fundal varices, a result of splenic vein thrombosis, and subsequently underwent splenectomy at another institution. A total of 7 episodes of pain recurrence were recorded in the remaining 4 patients over a mean follow-up of 79.5 months (range 54-106 months). ERCP was repeated in all cases within a few days. Causes of recurrent pain were (1) stenosis of the pancreatic sphincterotomy at the minor papilla in 1 case 6 months after EPS; (2) a new stricture of the distal pancreatic duct in 2 patients 2 and 7 months, respectively, after initial treatment; (3) migration of VOLUME 55, NO. 4, 2002
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pancreatic stones from secondary ducts in 1 case after 82 months; and (4) 3 instances of pancreatic stent occlusion in 2 patients. In the patient in whom a stent was inserted during the initial treatment, clogging occurred after 48 months. In the second patient, the pancreatic stent had been inserted during follow-up because of a stricture of the distal MPD; the stent occluded twice, once at 13 and again at 37 months. The mean time until clogging of pancreatic duct stents was recognized clinically was 32.6 months (range 13-48 months). The time to clogging was defined clinically and stent patency was objectively delineated only if there was a relapse of pain. Endoscopic retreatment was successful in all patients with relapsing symptoms and consisted of repeat sphincterotomy, stent insertion for strictures, exchange of occluded stents, and extraction of pancreatic stones. In 2 patients pancreatic strictures resolved, respectively, after 18 and 24 months of stent placement. A mean increase in weight of 6 kg (range 2-10 kg) was observed in the 8 patients who had lost weight before endoscopic treatment. The mean number of hospitalizations after the endoscopic treatment was 0.6 (range 0-3) and 0.3 (range 0-2) during the first year after treatment. The difference in number of hospitalizations during the year before (mean 2.2, range 1-9) and after treatment was statistically significant (p < 0.01) (Fig 3). The frequency of hospitalization pretreatment and posttreatment was also significantly different for both the 3-year and 6-year follow-up periods for which data were available, respectively, for 11 and 7 patients (3 years p < 0.001; 6 years p < 0.001). DISCUSSION According to Layer et al.,1 patients with ICP can be divided into 2 distinct groups based on age of onset: one in which onset is early, under 35 years of age, and one in which ICP presents late, after 35 years of age. Patients in the former group have pain initially and a long course characterized by severe pain, but morphologic and functional damage to the pancreas develops slowly. Those with the late onset form of ICP have a mild course, often without pain. The slow destruction of the parenchyma and late development of exocrine insufficiency and calcifications in patients with early onset ICP may explain why diagnosis is delayed and difficult. The time lapse between onset of symptoms and diagnosis averaged 5 years in the present study and ranged from 3 months to 10 years. Moreover, significantly more patients in the early onset ICP group undergo surgery compared with the late onset ICP group (60% vs. 32%), intractable pain being the indication for operation in all cases.1 VOLUME 55, NO. 4, 2002
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Figure 3. Number of hospitalizations per patient during 1year periods before and after endoscopic treatment: the difference between number of hospitalizations during the year before and that after treatment is statistically significant (Wilcoxon t test; p < 0.01).
The large percentage of patients with early onset ICP who underwent traditional surgery in the study of Layer et al.1 and the good results in terms of pain relief obtained with endoscopic treatment in patients with chronic pancreatitis 6,8,10-13 induced us to study retrospectively the efficacy of endoscopic treatment in this group of patients. To our knowledge, no data are available on endoscopic treatment of patients with early onset ICP. The results of the present study indicate that endoscopic treatment is highly effective short-, medium-, and long-term in selected patients. Endoscopic treatment should be reserved for patients with a dilated MPD. Magnetic resonance cholangiopancreatography (MRCP), now the noninvasive imaging modality of choice for the pancreas, allows selection of patients who might benefit from GASTROINTESTINAL ENDOSCOPY
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Chronic pancreatitis: endotherapy of early onset with long-term follow-up
endoscopic treatment.18,19 Intravenous administration of secretin (S-MRCP), which stimulates secretion by the exocrine pancreas of fluid and bicarbonate, enhances visualization of the pancreatic ducts, including the minimally dilated secondary ducts found in the initial stages of chronic pancreatitis. Furthermore, functional studies can be performed to quantitate duodenal filling before and after secretin stimulation.20 The effectiveness of endotherapy must be correlated with the ability to achieve decompression and clearance of stones from the MPD. ESWL is a complementary technique: 83% of patients with stones in the present study required ESWL to facilitate stone extraction. Endoscopic treatment yields results that are similar to those of surgery, both for complete and partial relief of pain, with no mortality and a morbidity rate that compares favorably with surgical series. The surgical operations comparable with endotherapy are drainage procedures, such as the Partington-Rochelle (latero-lateral pancreatico-jejunostomy procedure), that are predicated on the presence of a markedly dilated MPD. In these series, short-term pain relief is achieved in about 80% of patients and operation carries low morbidity and mortality rates (0%-5%). Series with long-term follow-up show that pain commonly recurs; pain relief persists for more than 2 years in only 60% of patients.21-28 A randomized trial of endoscopy versus surgery would be of considerable interest. However it is extremely difficult to randomize patients to two treatments that have such different levels of invasiveness, as noted by Cotton.29 Furthermore Cotton believes that most of our knowledge of effectiveness does and will come from nonrandomized studies, in which precise definitions for each element are used, as suggested by the statement of the American Gastroenterological Association on treatment of patients with pain caused by chronic pancreatitis.29,30 The efficacy of endoscopic treatment was further confirmed in the present study by the statistically significant difference between rates of hospitalization during the year before and at 1, 3, and 6 years after endoscopic treatment. The number of hospitalizations appears to be an objective method of analyzing the effectiveness of endotherapy for relief of pain. Furthermore, a mean follow-up of 6 years should be adequate to confirm treatment efficacy, even in patients with relapsing pain. Moreover, recurrences of pain were successfully managed endoscopically in all cases. The possibility of repeated treatment is another advantage of endoscopic therapy for ICP. Endotherapy does not preclude subsequent surgery, should this become necessary. 492
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To our knowledge, no data are available on surgical or endoscopic treatments in patients with early onset ICP. This is the first study of the efficacy of endotherapy in this highly select subgroup of patients. More long-term studies are needed to assess the effects of this treatment on endocrine and exocrine function, especially in extremely young patients. Of interest in future prospective randomized studies will be an analysis of the efficacy of endotherapy in modifying the natural history during the initial stages of ICP. Endotherapy could be regarded as the initial treatment of choice for patients with early onset ICP. ACKNOWLEDGEMENT We thank Antonello Persico for statistical analysis. REFERENCES 1. Layer P, Yamamoto H, Kalthoff L, Clain JE, Bakken LJ, Di Magno EP. The different courses of early and late onset idiopathic and chronic pancreatitis. Gastroenterology 1994;107: 1481-7. 2. Amman RW, Buehler H, Freiburghaus AW, Siegenthaler W. Differences in the natural history of idiopathic (nonalcoholic) and alcoholic chronic pancreatitis. A comparative long-term study of 287 patients. Pancreas 1987;2:368-77. 3. Lankisch PG, Seidensticker F, Lohr-Happe A, Otto J, Oreutzfeldt W. The course of pain is the same in alcohol and nonalcohol-induced chronic pancreatitis. Pancreas 1995;10: 338-41. 4. Ebbehoj N, Borly L, Bulow J, Rasmussen SG, Madsen P. Evaluation of pancreatic tissue fluid pressure and pain in chronic pancreatitis. A longitudinal study. Scand J Gastroenterol 1990;25:462-6. 5. Okazaki K, Yamamoto Y, Ito K. Endoscopic measurement of papillary sphincter zone and pancreatic main ductal pressure in patients with chronic pancreatitis. Gastroenterology 1986;91:409-18. 6. Cremer M, Devière J, Delhaye M, Vandermeeren A, Baize M. Non surgical management of severe chronic pancreatitis. Scand J Gastroenterol 1990;25(Suppl 175):77-84. 7. Huibregtse K, Schneider B, Vrij AA, Tytgat G. Endoscopic pancreatic drainage in chronic pancreatitis. Gastrointest Endosc 1988;34:9-15. 8. Kozarek RA, Ball TJ, Patterson DJ, Brandabur JJ, Traverso LW, Raltz S. Endoscopic pancreatic duct sphincterotomy: indications, technique and results. Gastrointest Endosc 1994;40: 592-8. 9. Kozarek RA, Patterson DJ, Ball TJ. Endoscopic placement of pancreatic stent and drains in the management of pancreatitis. Ann Surg 1988;209:261-6. 10. Smits ME, Badiga SM, Rauws EAJ, Tytgat G, Huibregtse K. Long term results of pancreatic stents in chronic pancreatitis. Gastrointest Endosc 1995;42:461-7. 11. Binmoeller KF, Jue P, Seifert H, Nam WC, Izbicki J, Soehendra N. Endoscopic pancreatic stent drainage in chronic pancreatitis and a dominant stricture: long-term results Endoscopy 1995;27:638-44. 12. Delhaye M, Vandermeeren A, Baize M, Cremer M. Extracorporeal shock wave lithotripsy of pancreatic calculi. Gastroenterology 1992;102:610-20. 13. Costamagna G, Gabbrielli A, Mutignani M, Perri V, Pandolfi M, Boscaini M, et al. Extracorporeal shock wave lithotripsy of VOLUME 55, NO. 4, 2002
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21. Frey CH. The surgical treatment of chronic pancreatitis. In: Go VLW, Di Magno EP, editors. The pancreas: biology, pathobiology and disease. New York: Raven Press; 1993. p. 707-40. 22. Ebbehoj N, Boryl L, Bulow J, Rasmussen SG, Madsen P. Evaluation of pancreatic tissue fluid pressure and pain in chronic pancreatitis. Scand Gastroenterol 1990;25:462-6. 23. Prinz RA, Greenlee HB. Pancreatic duct drainage in 100 with chronic pancreatitis. Ann Surg 1981;194:313-2. 24. Holmberg JT, Isaksson G, Ihse I. Long-term results of pancreaticojejunostomy in chronic pancreatitis. Surg Gynecol Obstet 1985;160:339-46. 25. Adolff M, Schloegel M, Arnaud JP, Ollier JCL. Role of pancreaticojejunostomy in the treatment of chronic poancreatitis: study of 105 operated patients. Chirurgie 1991;117:251-7. 26. Wilson TG, Hollands MJ, Little JM. Pancreaticojejunostomy for chronic pancreatitis. Aust N Z J Surg 1992;62:111-5. 27. Bradley EL. Long-term results of pancreatojejunostomy in patients with chronic pancreatitis. Am J Surg 1987;153:207-13. 28. Warshaw AL, Banks PA, Fernandez-del Castillo C. AGA technical review: treatment of pain in chronic pancreatitis. Gastroenterology 1998;115:765-76. 29. Cotton PB. Randomization is not the (only) answer: a plea for structured objective evaluation of endoscopic therapy. Endoscopy 2000;32:402-5. 30. American Gastroenterological Association. American Gastroenterological Association Medical Position Statement: treatment of pain in chronic pancreatitis. Gastroenterology 1998; 115:763-4.
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